UNIVERSITI TEKNOLOGI MARA
HISTOLOGICAL ANALYSIS ON UTERUS FOLLOWING TREATMENT WITH NICOTINE AND ALPHA-TOCOTRIENOL IN MICE
AZIZUL HAKIM BIN MOHD TOBRONI
Dissertation submitted in partial fulfilment of the requirements for the Bachelor of Pharmacy (Hons.)
Faculty of pharmacy
June 2018
APPROVAL SHEET
I hereby recommend that the dissertation prepared under my supervision by Azizul Hakim bin Mohd Tobroni entitled Histological Analysis on Uterus Following Treatment with Nicotine and Alpha-Tocotrienol in Mice to be accepted in partial requirement for the degree of Bachelor of Pharmacy (Hons.) from the Faculty of Pharmacy, UiTM.

……………………. ………………………………….
(Date) (Madam Siti Syairah Mohd Mutalip)
……………………. …………………………………… (Date) (Prof Dr Aishah Adam)
ABSTRACT
The objective of the study was to examine the effect of nicotine on the structures of the uterus as well as to identify the effect of ?-tocotrienol on the structural changes in the uterus of nicotine-treated mice. 24 female mice were divided into 4 groups which were A, B, C and D consist of 6 mice per group. They are treated with corn oil, nicotine, nicotine and ?-tocotrienol, and ?-tocotrienol respectively. Those treatment were given for 7 days before they are sacrificed with cervical dislocation on the 8th day. The uterus of the mice were collected immediately and were processed until the slides of the sample were prepared for microscopic observation. The results showed that ?-tocotrienol reversed the adverse effect of the nicotine-treated mice. It increased the thickness of uterus wall.
acknowledgement
Special appreciation to my supervisor Madam Siti Syairah binti Mohd Mutalip, my teammate Muhammad Adib bin Ramli and all staff as well as Postgraduate students of Brain Research Laboratory and Laboratory Animal Facility and Management (LAFAM), Faculty of Pharmacy, UiTM Puncak Alam for their help and support in completing this project.

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TABLE OF CONTENTS
TITLE PAGE………………………………………………………….. iAPPROVAL SHEET………………………………………………….. iiABSTRACT…………………………………..……………………… iii
ACKNOWLEDGEMENT…………………………………………… ivTABLE OF CONTENT………………………………………………. v
LIST OF FIGURES …………………………………………………. vii
LIST OF TABLES ………………………………………………….. viiLIST OF ABBREVIATION AND SYMBOLS …………………….. vii TOC o “1-3” h z u CHAPTER ONE PAGEREF _Toc517181608 h 11.1BACKGROUND OF STUDY………………………………… PAGEREF _Toc517181610 h 11.2RESEARCH OBJECTIVE…………………………………… PAGEREF _Toc517181611 h 21.3PROBLEM STATEMENTS…………………………………. PAGEREF _Toc517181612 h 21.4SIGNIFICANCE OF STUDY ……………………………….. PAGEREF _Toc517181613 h 31.5HYPOTHESIS ……………………………………………….. PAGEREF _Toc517181614 h 3CHAPTER TWO PAGEREF _Toc517181615 h 42.1VITAMIN E …………………………………………………. PAGEREF _Toc517181617 h 42.1.1Overview ………………………………………………… PAGEREF _Toc517181618 h 42.1.2Tocotrienols ……………………………………………… PAGEREF _Toc517181619 h 52.1.3Alpha-tocotrienol ………………………………………… PAGEREF _Toc517181620 h 82.2NICOTINE …………………………………………………… PAGEREF _Toc517181621 h 92.2.1Overview …………………………………………………. PAGEREF _Toc517181622 h 92.2.2Harmful effects of nicotine ………………………………. PAGEREF _Toc517181623 h 9CHAPTER THREE PAGEREF _Toc517181624 h 123.1TREATMENTS …………………………………………….. PAGEREF _Toc517181626 h 123.2HISTOLOGICAL ANALYSIS …………………………….. PAGEREF _Toc517181627 h 133.2.1Histological Sample Collection …………………………. PAGEREF _Toc517181628 h 133.2.2Fixation …………………………………………………. PAGEREF _Toc517181629 h 133.2.3Dehydration ……………………………………………… PAGEREF _Toc517181630 h 143.2.4Clearing …………………………………………………. PAGEREF _Toc517181631 h 143.2.5Embedding ………………………………………………. PAGEREF _Toc517181632 h 143.2.6Sectioning ……………………………………………….. PAGEREF _Toc517181633 h 153.2.7Staining ………………………………………………….. PAGEREF _Toc517181634 h 153.2.8Mounting ……………………………………………….. PAGEREF _Toc517181635 h 17CHAPTER FOUR PAGEREF _Toc517181636 h 18CHAPTER FIVE PAGEREF _Toc517181639 h 22REFERENCES ……………………………………………………… 23

LIST OF FIGURES
Figure 2.1: The structures of tocopherols and tocotrienols. PAGEREF _Toc517177938 h 5Figure 4.1: Microphotograph of uteruses in the experimental groups.. PAGEREF _Toc517177939 h 18LIST OF TABLES
TOC h z c “Table” Table 3.1: Steps involving in H & E staining PAGEREF _Toc517178241 h 16Table 4.1: Effect of the treatment on histometric changes of uterus in mice. PAGEREF _Toc517178242 h 19
LIST OF ABBREVIATION AND SYMBOLS
? – Alpha
? – Beta
? – Gamma
? – Delta
L – Liter
Kg – Kilogram
mg – Milligram
mm – Millimeter
?m – Micrometer
°C – Degree Celsius
% – Percent
pH – Potential of hydrogen
pKa- Acid dissociation constant
U – Uterus
NADPH – Nicotinamide adenine nucleotide phosphate
UDP – UDP-Glucuronosyltransferase
FMO – Flavin-containing monooxygenase
GERD – Gastrointestinal reflux disorder
PUD – Peptic ulcer disease
H&E – Hematoxylene – Eosin

introductionBACKGROUND OF STUDYVitamin E is known to have antioxidant property ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1007/BF02522884″,”ISBN”:”10.1007/BF02522884″,”ISSN”:”0024-4201″,”PMID”:”8827691″,”abstract”:”This article is a review of the fundamental chemistry of the tocopherols and tocotrienols relevant to their antioxidant action. Despite the general agreement that alpha-tocopherol is the most efficient antioxidant and vitamin E homologue in vivo, there was always a considerable discrepancy in its “absolute” and “relative” antioxidant effectiveness in vitro, especially when compared to gamma-tocopherol. Many chemical, physical, biochemical, physicochemical, and other factors seem responsible for the observed discrepancy between the relative antioxidant potencies of the tocopherols in vivo and in vitro. This paper aims at highlighting some possible reasons for the observed differences between the tocopherols (alpha-, beta-, gamma-, and delta-) in relation to their interactions with the important chemical species involved in lipid peroxidation, specifically trace metal ions, singlet oxygen, nitrogen oxides, and antioxidant synergists. Although literature reports related to the chemistry of the tocotrienols are quite meager, they also were included in the discussion in virtue of their structural and functional resemblance to the tocopherols.”,”author”:{“dropping-particle”:””,”family”:”Kamal-Eldin”,”given”:”Afaf”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Appelqvist”,”given”:”Lars-Åke”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Lipids”,”id”:”ITEM-1″,”issue”:”7″,”issued”:{“date-parts”:”1996″},”page”:”671-701″,”title”:”The chemistry and antioxidant properties of tocopherols and tocotrienols”,”type”:”article-journal”,”volume”:”31″},”uris”:”http://www.mendeley.com/documents/?uuid=fc9da027-4132-48bd-87d5-326782903763″,”http://www.mendeley.com/documents/?uuid=dd4be371-1f2a-471e-b53e-c013a21c4671″},”mendeley”:{“formattedCitation”:”(Kamal-Eldin & Appelqvist, 1996)”,”plainTextFormattedCitation”:”(Kamal-Eldin & Appelqvist, 1996)”,”previouslyFormattedCitation”:”(Kamal-Eldin & Appelqvist, 1996)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Kamal-Eldin & Appelqvist, 1996) that depends primarily on the phenolic group in the chromanol ring, rather than the side chain ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“ISBN”:”0021-9258 (Print)\r0021-9258 (Linking)”,”ISSN”:”00219258″,”PMID”:”3972787″,”abstract”:”Inhibition of the oxidation of methyl linoleate and soybean phosphatidylcholine in homogeneous solution and in aqueous dispersion by four chain-breaking antioxidants, vitamin E (alpha-tocopherol), 2,2,5,7,8-pentamethyl-6-chromanol, 2,6-di-tert-butyl-4-methylphenol, and stearyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, was studied to examine the effect of the phytyl side chain of vitamin E on its antioxidant activity. These four antioxidants exerted similar antioxidative activities. They were also effective as antioxidants in protecting the oxidation of soybean phosphatidylcholine liposomes in water dispersion. However, when they were incorporated into dimyristoyl phosphatidylcholine liposomes, only 2,2,5,7,8-pentamethyl-6-chromanol and 2,6-di-tert-butyl-4-methylphenol could suppress the oxidation of soybean phosphatidylcholine liposomes dispersed in the same aqueous system. It was concluded that the antioxidative properties of vitamin E and its model without the phytyl side chain are quite similar within micelles and liposomes as well as in homogeneous solution but that the phytyl side chain enhances the retainment of vitamin E in liposomes and suppresses the transfer of vitamin E between liposomal membranes.”,”author”:{“dropping-particle”:””,”family”:”Niki”,”given”:”E.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Kawakami”,”given”:”A.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Saito”,”given”:”M.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Yamamoto”,”given”:”Y.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Tsuchiya”,”given”:”J.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Kamiya”,”given”:”Y.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Journal of Biological Chemistry”,”id”:”ITEM-1″,”issue”:”4″,”issued”:{“date-parts”:”1985″},”page”:”2191-2196″,”title”:”Effect of phytyl side chain of vitamin E on its antioxidant activity”,”type”:”article-journal”,”volume”:”260″},”uris”:”http://www.mendeley.com/documents/?uuid=d3fb3ab9-68ce-41a1-91c7-bb161b33ac91″,”http://www.mendeley.com/documents/?uuid=9f40061f-5d94-43f5-a850-bbe925a6260a”},”mendeley”:{“formattedCitation”:”(Niki et al., 1985)”,”manualFormatting”:”(Niki, Kawakami, Saito, Yamamoto, Tsuchiya, Kamiya, 1985)”,”plainTextFormattedCitation”:”(Niki et al., 1985)”,”previouslyFormattedCitation”:”(Niki et al., 1985)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Niki, Kawakami, Saito, Yamamoto, Tsuchiya, Kamiya, 1985). Peroxidation of membrane lipids functions to modify and inactivate cellular components that can be the factors leading to disease. Tocotrienols possess the same capabilities as tocopherols in scavenging and quenching the reactive oxygen species. Peroxyl and alkoxyl radicals are generated during lipid peroxidation and neutralized by tocotrienols antioxidant activity, resides mainly with its “chain-breaking” property ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1007/BF02522884″,”ISBN”:”10.1007/BF02522884″,”ISSN”:”0024-4201″,”PMID”:”8827691″,”abstract”:”This article is a review of the fundamental chemistry of the tocopherols and tocotrienols relevant to their antioxidant action. Despite the general agreement that alpha-tocopherol is the most efficient antioxidant and vitamin E homologue in vivo, there was always a considerable discrepancy in its “absolute” and “relative” antioxidant effectiveness in vitro, especially when compared to gamma-tocopherol. Many chemical, physical, biochemical, physicochemical, and other factors seem responsible for the observed discrepancy between the relative antioxidant potencies of the tocopherols in vivo and in vitro. This paper aims at highlighting some possible reasons for the observed differences between the tocopherols (alpha-, beta-, gamma-, and delta-) in relation to their interactions with the important chemical species involved in lipid peroxidation, specifically trace metal ions, singlet oxygen, nitrogen oxides, and antioxidant synergists. Although literature reports related to the chemistry of the tocotrienols are quite meager, they also were included in the discussion in virtue of their structural and functional resemblance to the tocopherols.”,”author”:{“dropping-particle”:””,”family”:”Kamal-Eldin”,”given”:”Afaf”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Appelqvist”,”given”:”Lars-Åke”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Lipids”,”id”:”ITEM-1″,”issue”:”7″,”issued”:{“date-parts”:”1996″},”page”:”671-701″,”title”:”The chemistry and antioxidant properties of tocopherols and tocotrienols”,”type”:”article-journal”,”volume”:”31″},”uris”:”http://www.mendeley.com/documents/?uuid=dd4be371-1f2a-471e-b53e-c013a21c4671″,”http://www.mendeley.com/documents/?uuid=fc9da027-4132-48bd-87d5-326782903763″},”mendeley”:{“formattedCitation”:”(Kamal-Eldin & Appelqvist, 1996)”,”plainTextFormattedCitation”:”(Kamal-Eldin & Appelqvist, 1996)”,”previouslyFormattedCitation”:”(Kamal-Eldin & Appelqvist, 1996)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Kamal-Eldin & Appelqvist, 1996).

Alpha-tocopherol is considered as the most potent antioxidant against lipid peroxidation in the vitamin E group for a long time. In 1991, ?-tocotrienol was found to be a better antioxidant than ?- tocopherol ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1016/0891-5849(91)90033-Y”,”ISBN”:”0891-5849 (Print)\r0891-5849″,”ISSN”:”08915849″,”PMID”:”1649783″,”abstract”:”d-Alpha-tocopherol (2R, 4?R,8?R-Alpha-tocopherol) and d-alpha-tocotrienol are two main vitamin E constituents having the same aromatic chromanol “head” but differing in their hydrocarbon “tail”: tocopherol with a saturated and toctrienol with an unsaturated isoprenoid chain. d-Alpha-tocopherol has the highest vitamin E activity, while d-alpha-tocotrienol manifests only about 30% of this activity. Since vitamin E is considered to be physiologically the most important lipid-soluble chain-breaking antioxidant of membranes, we studied alpha-tocotrienol as compared to alpha-tocopherol under conditions which are important for their antioxidant function. d-Alpha-tocotrienol possesses 40-60 times higher antioxidant activity against (Fe2+ + ascorbate)- and (Fe2+ + NADPH)-induced lipid peroxidation in rat liver microsomal membranes and 6.5 times better protection of cytochrome P-450 against oxidative damage than d-alpha-tocopherol. To clarify the mechanisms responsible for the much higher antioxidant potency of d-alpha-tocotrienol compared to d-alpha-tocopherol, ESR studies were performed of recycling efficiency of the chromanols from their chromanoxyl radicals, 1H-NMR measurements of lipid molecular mobility in liposomes containing chromanols, and fluorescence measurements which reveal the uniformity of distribution (clusterizations) of chromanols in the lipid bilayer. From the results, we concluded that this higher antioxidant potency of d-alpha-tocotrienol is due to the combined effects of three properties exhibited by d-alpha-tocotrienol as compared to d-alpha-tocopherol: (i) its higher recycling efficiency from chromanoxyl radicals, (ii) its more uniform distribution in membraned bilayer, and (iii) its stronger disordering of membrane lipids which makes interaction of chromanols with lipid radicals more efficient. The data presented show that there is a considerable discrepancy between the relative in vitro antioxidant activity of d-alpha-tocotrienol with the conventional bioassays of their vitamin activity. © 1991.”,”author”:{“dropping-particle”:””,”family”:”Serbinova”,”given”:”Elena”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Kagan”,”given”:”Valerian”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Han”,”given”:”Derick”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Packer”,”given”:”Lester”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Free Radical Biology and Medicine”,”id”:”ITEM-1″,”issue”:”5″,”issued”:{“date-parts”:”1991″},”page”:”263-275″,”title”:”Free radical recycling and intramembrane mobility in the antioxidant properties of alpha-tocopherol and alpha-tocotrienol”,”type”:”article-journal”,”volume”:”10″},”uris”:”http://www.mendeley.com/documents/?uuid=0bbeb224-d552-4ee9-a0c0-be88d6fe5984″,”http://www.mendeley.com/documents/?uuid=dfda199a-9691-4f26-9ca2-2baa60e5cacd”},”mendeley”:{“formattedCitation”:”(E. Serbinova, Kagan, Han, & Packer, 1991)”,”manualFormatting”:”(Serbinova, Kagan, Han, & Packer, 1991)”,”plainTextFormattedCitation”:”(E. Serbinova, Kagan, Han, & Packer, 1991)”,”previouslyFormattedCitation”:”(E. Serbinova, Kagan, Han, & Packer, 1991)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Serbinova, Kagan, Han, & Packer, 1991). In 1993, a study demonstrates that ?-tocotrienol is more potent in scavenging peroxyl radicals in membranes ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1021/bi00091a020″,”ISSN”:”15204995″,”author”:{“dropping-particle”:””,”family”:”Suzuki”,”given”:”Yuichiro J.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Tsuchiya”,”given”:”Masahiko”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Choo”,”given”:”Yuen M.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Kagan”,”given”:”Valerian E.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Packer”,”given”:”Lester”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Wassall”,”given”:”Stephen R.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Govil”,”given”:”Girjesh”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Kagan”,”given”:”Valerian E.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Biochemistry”,”id”:”ITEM-1″,”issue”:”40″,”issued”:{“date-parts”:”1993″},”page”:”10692-10699″,”title”:”Structural and Dynamic Membrane Properties of ?-Tocopherol and ?-Tocotrienol: Implication to the Molecular Mechanism of Their Antioxidant Potency”,”type”:”article-journal”,”volume”:”32″},”uris”:”http://www.mendeley.com/documents/?uuid=42263b22-0e53-41ca-93d4-8317e938ea14″,”http://www.mendeley.com/documents/?uuid=8733183d-270f-4e3a-9535-92132d80a7e9″},”mendeley”:{“formattedCitation”:”(Suzuki et al., 1993)”,”manualFormatting”:”(Suzuki,.Tsuchiya, Choo, Kagan, Packer, Wassall, Govil, Kagan, 1993)”,”plainTextFormattedCitation”:”(Suzuki et al., 1993)”,”previouslyFormattedCitation”:”(Suzuki et al., 1993)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Suzuki,.Tsuchiya, Choo, Kagan, Packer, Wassall, Govil, Kagan, 1993).
Nicotine is an alkaloid that can be found primarily in the members of the solanaceous plant family. It has an active centre and occurs as stereoisomers ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1111/j.1476-5381.1965.tb01773.x”,”ISSN”:”14765381″,”author”:{“dropping-particle”:””,”family”:”BARLOW”,”given”:”R. B.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”HAMILTON”,”given”:”J. T.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”British Journal of Pharmacology and Chemotherapy”,”id”:”ITEM-1″,”issue”:”1″,”issued”:{“date-parts”:”1965″},”page”:”206-212″,”title”:”THE STEREOSPECIFICITY OF NICOTINE”,”type”:”article-journal”,”volume”:”25″},”uris”:”http://www.mendeley.com/documents/?uuid=0ad8656c-ad41-4934-9ab1-c919ebd097ff”,”http://www.mendeley.com/documents/?uuid=c5ad1abe-7b70-4319-9117-615b519e43a1″},”mendeley”:{“formattedCitation”:”(BARLOW & HAMILTON, 1965)”,”manualFormatting”:”(Barlow & Hamilton, 1965)”,”plainTextFormattedCitation”:”(BARLOW & HAMILTON, 1965)”,”previouslyFormattedCitation”:”(BARLOW & HAMILTON, 1965)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Barlow & Hamilton, 1965). Nicotine acts on nicotinic cholinergic receptors that will produce rewarding psychoactive effects results from the release of neurotransmitters ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1016/j.tips.2004.04.006″,”ISBN”:”0165-6147 (Print)\r0165-6147 (Linking)”,”ISSN”:”0165-6147 (Print)”,”PMID”:”15165747″,”abstract”:”Neuronal nicotinic acetylcholine (nACh) receptors in the brain are more commonly associated with modulatory events than mediation of synaptic transmission. nACh receptors have a high permeability for Ca(2+), and Ca(2+) signals are pivotal in shaping nACh receptor-mediated neuromodulatory effects. In this review, we consider the mechanisms through which nACh receptors convert rapid ionic signals into sustained, wide-ranging phenomena. The complex Ca(2+) responses that are generated after activation of nACh receptors can transmit information beyond the initial domain and facilitate the interface with many intracellular processes. These mechanisms underlie the diverse repertoire of neuronal activities of nicotine in the brain, from the enhancement of learning and memory, to addiction and neuroprotection.”,”author”:{“dropping-particle”:””,”family”:”Dajas-Bailador”,”given”:”F”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Wonnacott”,”given”:”S”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Trends Pharmacol Sci”,”id”:”ITEM-1″,”issue”:”6″,”issued”:{“date-parts”:”2004″},”page”:”317-324″,”title”:”Nicotinic acetylcholine receptors and the regulation of neuronal signalling”,”type”:”article-journal”,”volume”:”25″},”uris”:”http://www.mendeley.com/documents/?uuid=c120a58e-4da8-4cbf-b593-9720c2a2e934″,”http://www.mendeley.com/documents/?uuid=a6d91457-3fcf-43e1-9a23-95ff030d483c”},”mendeley”:{“formattedCitation”:”(Dajas-Bailador & Wonnacott, 2004)”,”plainTextFormattedCitation”:”(Dajas-Bailador & Wonnacott, 2004)”,”previouslyFormattedCitation”:”(Dajas-Bailador & Wonnacott, 2004)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Dajas-Bailador & Wonnacott, 2004).
In female reproductive system, nicotine can cause the inappropriate cytokine production and irregular bleeding in the endometrium ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“ISBN”:”1122-9497″,”ISSN”:”11229497″,”abstract”:”The composition of the uterine fluid is of importance for the development of the embryo. The ionic composition of the uterine fluid is determined by transport processes in the uterine epithelium. The aim of the present study was to investigate whether nicotine can affect the ion transport processes and ultrastructure of the uterine epithelium in mouse and rat. The effects of nicotine on the uterine epithelium were compared with those on kidney and liver. Nicotine was administered to mice as an intraperitoneal injection of a 1 microgram/l nicotine solution twice daily for 8 days, or in the drinking water (108 microM nicotine) for 15 days, whereas rats received nicotine in their drinking water for 10 days (54 or 108 microM nicotine). In addition, primary cultures of endometrial cells were exposed to nicotine in vitro. Changes in morphology were examined by transmission electron microscopy and changes in elemental content by X-ray microanalysis. Nicotine caused a significant decrease in the concentrations of Na, K, and Cl in the uterine fluid and in the endometrial cells in situ. Similar changes in elemental concentrations were observed in endometrial cells in vitro. Ultrastructural changes in endometrial cells included swollen and damaged mitochondria. In liver and kidney much smaller effects of nicotine on the elemental composition of the cells were observed. However, marked ultrastructural effects were seen in the kidney: a reduction in mitochondrial size and an increase in lysosomal volume. It is concluded that nicotine directly interferes with fluid transport across the uterine epithelium.”,”author”:{“dropping-particle”:””,”family”:”Jin”,”given”:”Z”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Roomans”,”given”:”G M”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Journal of Submicroscopic Cytology & Pathology”,”id”:”ITEM-1″,”issue”:”2″,”issued”:{“date-parts”:”1997″},”page”:”179-186″,”title”:”Effects of nicotine on the uterine epithelium studied by X-ray microanalysis”,”type”:”article-journal”,”volume”:”29″},”uris”:”http://www.mendeley.com/documents/?uuid=ef438643-a0f1-45fb-8826-58bcd29654c6″,”http://www.mendeley.com/documents/?uuid=e0e597f8-acca-4501-a25c-c523111b358f”},”mendeley”:{“formattedCitation”:”(Jin & Roomans, 1997)”,”plainTextFormattedCitation”:”(Jin & Roomans, 1997)”,”previouslyFormattedCitation”:”(Jin & Roomans, 1997)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Jin & Roomans, 1997). Histological observations in uterus showed a decrease in the thickness of myometrium, endometrium and its epithelial cells. ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“ISSN”:”00195499″,”PMID”:”10874351″,”abstract”:”Nicotine at the dose level of 0.3 mg/100 g body weight was administered to normal cycling mice for 15 days through oral and intraperitoneal routes. At autopsy on 16th day significant reduction in the ovarian and uterine weight was observed. Histological observations showed decrease in the number and size of Graafian follicles, corpora lutea and increase in the atretic follicles in the ovary. The uterus showed absence of endometrial glands, decrease in the height of myometrium, endometrium and its epithelial cells. The total cholesterol content of the ovary and uterus is increased whereas the protein content is decreased. This antagonistic action of nicotine to gonadotrophins is discussed.”,”author”:{“dropping-particle”:””,”family”:”Patil”,”given”:”Somnath Reddy”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Ravindra”,”given”:””,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Patil”,”given”:”Srinivas Reddy”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Londonkar”,”given”:”Ramesh”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Patil”,”given”:”Saraswati B.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Indian Journal of Physiology and Pharmacology”,”id”:”ITEM-1″,”issued”:{“date-parts”:”1998″},”title”:”Nicotine induced ovarian and uterine changes in albino mice”,”type”:”article-journal”},”uris”:”http://www.mendeley.com/documents/?uuid=ec3cd087-d20a-41da-ab66-aa8da21ee5ff”},”mendeley”:{“formattedCitation”:”(Patil, Ravindra, Patil, Londonkar, & Patil, 1998)”,”plainTextFormattedCitation”:”(Patil, Ravindra, Patil, Londonkar, & Patil, 1998)”,”previouslyFormattedCitation”:”(Patil, Ravindra, Patil, Londonkar, & Patil, 1998)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Patil, Ravindra, Patil, Londonkar, & Patil, 1998)
RESEARCH OBJECTIVE
The objective of this study is to study on the changes in histological structures of uterus following treatment with nicotine and ?-tocotrienol in mice.

PROBLEM STATEMENTSNicotine uses in smoking is a serious health problem because it reduced fertility. Alpha-tocotrienol is known as an antioxidant, however its effect on reproductive health is understudied particularly in its effects on the structures of reproductive organs such as uterus. ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1016/j.lfs.2005.12.001″,”ISBN”:”0024-3205″,”ISSN”:”00243205″,”PMID”:”16458936″,”abstract”:”In nature, eight substances have been found to have vitamin E activity: ?-, ?-, ?- and ?-tocopherol; and ?-, ?-, ?- and ?-tocotrienol. Yet, of all papers on vitamin E listed in PubMed less than 1% relate to tocotrienols. The abundance of ?-tocopherol in the human body and the comparable efficiency of all vitamin E molecules as antioxidants, led biologists to neglect the non-tocopherol vitamin E molecules as topics for basic and clinical research. Recent developments warrant a serious reconsideration of this conventional wisdom. Tocotrienols possess powerful neuroprotective, anti-cancer and cholesterol lowering properties that are often not exhibited by tocopherols. Current developments in vitamin E research clearly indicate that members of the vitamin E family are not redundant with respect to their biological functions. ?-Tocotrienol, ?-tocopherol, and ?-tocotrienol have emerged as vitamin E molecules with functions in health and disease that are clearly distinct from that of ?-tocopherol. At nanomolar concentration, ?-tocotrienol, not ?-tocopherol, prevents neurodegeneration. On a concentration basis, this finding represents the most potent of all biological functions exhibited by any natural vitamin E molecule. An expanding body of evidence support that members of the vitamin E family are functionally unique. In recognition of this fact, title claims in manuscripts should be limited to the specific form of vitamin E studied. For example, evidence for toxicity of a specific form of tocopherol in excess may not be used to conclude that high-dosage “vitamin E” supplementation may increase all-cause mortality. Such conclusion incorrectly implies that tocotrienols are toxic as well under conditions where tocotrienols were not even considered. The current state of knowledge warrants strategic investment into the lesser known forms of vitamin E. This will enable prudent selection of the appropriate vitamin E molecule for studies addressing a specific need.”,”author”:{“dropping-particle”:””,”family”:”Sen”,”given”:”Chandan K.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Khanna”,”given”:”Savita”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Roy”,”given”:”Sashwati”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Life Sciences”,”id”:”ITEM-1″,”issue”:”18″,”issued”:{“date-parts”:”2006″},”page”:”2088-2098″,”title”:”Tocotrienols: Vitamin E beyond tocopherols”,”type”:”paper-conference”,”volume”:”78″},”uris”:”http://www.mendeley.com/documents/?uuid=9481d64c-8e3a-47d6-b9f9-4fe3c2cf85cd”,”http://www.mendeley.com/documents/?uuid=d61ef9df-b5df-4cf5-bd64-39db9274b5ed”},”mendeley”:{“formattedCitation”:”(Sen, Khanna, & Roy, 2006)”,”plainTextFormattedCitation”:”(Sen, Khanna, & Roy, 2006)”,”previouslyFormattedCitation”:”(Sen, Khanna, & Roy, 2006)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Sen, Khanna, & Roy, 2006).

SIGNIFICANCE OF STUDYAlpha-tocotrienol was found to have better antioxidant properties than ?-tocopherol. But, the studies on ?-tocotrienol effects on female reproductive system are considerably lesser compared to that of ?-tocopherol. This study may provide the fundamental information on the effect of ?-tocotrienol on female reproductive system particularly on the histological structure of uterus.

HYPOTHESIS
Alpha-tocotrienol will reduce the nicotine-induced adverse effect on the structure of uterus.

LITERATURE REVIEWVITAMIN EOverview
Vitamin E refers to a group of compounds that include both tocopherols and tocotrienols. There are 8 fat-soluble compounds present which are ?????????????-tocopherol, and ??????????????tocotrienol. They are synthesized by photosynthetic plants. Tocopherols can be found in plant tissues, exclusively in plant leaves and seeds of most dicots. Tocotrienol can be found as primary form of vitamin E in the seed endosperm of most monocots, including agronomically important cereal grains such as wheat, rice and barley. Tocotrienols are rarely found in vegetative tissues of plants. Crude palm oil extracted from the fruits of Elaeis guineensis particularly contains a high amount of tocotrienols especially the ??tocotrienol and ??tocotrienol. Tocopherols consist of a chromanol ring derived from homogentisate (HGA) and a 15-carbon tail derived from phytyl diphosphate. In contrast, tocotrienols differ structurally by the presence of the three trans-double bonds in the hydrocarbon tail. ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1007/s12263-011-0234-x”,”ISBN”:”1555-8932 (Print)\r1555-8932 (Linking)”,”ISSN”:”15558932″,”PMID”:”21590364″,”author”:{“dropping-particle”:””,”family”:”Aggarwal”,”given”:”Bharat”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Nesaretnam”,”given”:”Kalanithi”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Genes and Nutrition”,”id”:”ITEM-1″,”issue”:”1″,”issued”:{“date-parts”:”2012″},”page”:”1″,”title”:”Vitamin E tocotrienols: Life beyond tocopherols”,”type”:”article-magazine”,”volume”:”7″},”uris”:”http://www.mendeley.com/documents/?uuid=10d475c9-de43-49ad-9bbc-9a4e08d77c8c”,”http://www.mendeley.com/documents/?uuid=3eb2d9f6-974f-438a-a0f2-cdeea0a07631″},”mendeley”:{“formattedCitation”:”(B. Aggarwal & Nesaretnam, 2012)”,”manualFormatting”:”(Aggarwal & Nesaretnam, 2012)”,”plainTextFormattedCitation”:”(B. Aggarwal & Nesaretnam, 2012)”,”previouslyFormattedCitation”:”(B. Aggarwal & Nesaretnam, 2012)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Aggarwal & Nesaretnam, 2012). The figure is shown in Figure 2.1
120653048000
Figure 2. SEQ Figure * ARABIC s 1 1: The structures of tocopherols and tocotrienols. Tocopherol possesses saturated hydrocarbon tail while tocotrienol possesses three trans-double bonds in the hydrocarbon tail. ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”S0304394002012934 pii”,”ISBN”:”0304-3940 (Print)\r0304-3940 (Linking)”,”ISSN”:”0304-3940″,”PMID”:”12524170″,”abstract”:”Alpha-tocopherol and its derivatives have been shown to be effective in reducing cerebral ischemia-induced brain damage. However, the effects of other vitamin E isoforms have not been characterized. In the present study, we investigated the effects of six different isoforms of vitamin E on the ischemic brain damage in the mice middle cerebral artery (MCA) occlusion model. All vitamin E isoforms were injected i.v., twice, immediately before and 3 h after the occlusion. Alpha-tocopherol (2 mM), alpha-tocotrienol (0.2 and 2 mM) and gamma-tocopherol (0.2 and 2 mM) significantly decreased the size of the cerebral infarcts 1 day after the MCA occlusion, while gamma-tocotrienol, delta-tocopherol and delta-tocotrienol showed no effect on the cerebral infarcts. These results suggest that alpha-tocotrienol and gamma-tocopherol are potent and effective agents for preventing cerebral infarction induced by MCA occlusion.”,”author”:{“dropping-particle”:””,”family”:”Mishima”,”given”:”Kenichi”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Tanaka”,”given”:”Takamitsu”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Pu”,”given”:”Fengling”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Egashira”,”given”:”Nobuaki”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Iwasaki”,”given”:”Katsunori”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Hidaka”,”given”:”Ryoji”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Matsunaga”,”given”:”Kazuhisa”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Takata”,”given”:”Jiro”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Karube”,”given”:”Yoshiharu”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Fujiwara”,”given”:”Michihiro”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Neuroscience letters”,”id”:”ITEM-1″,”issue”:”1″,”issued”:{“date-parts”:”2003″},”page”:”56-60″,”title”:”Vitamin E isoforms alpha-tocotrienol and gamma-tocopherol prevent cerebral infarction in mice.”,”type”:”article-journal”,”volume”:”337″},”uris”:”http://www.mendeley.com/documents/?uuid=4e2c91fc-57c6-4e1b-bdf4-b41b4f8ece7d”,”http://www.mendeley.com/documents/?uuid=7c01eeb9-df13-4b6d-8eb0-c15ded0746c0″},”mendeley”:{“formattedCitation”:”(Mishima et al., 2003)”,”manualFormatting”:”(Mishima, Tanaka, Pu, Egashira, Iwasaki, Hidaka, Matsunaga, Takata, Karube, Fujiwara, 2003)”,”plainTextFormattedCitation”:”(Mishima et al., 2003)”,”previouslyFormattedCitation”:”(Mishima et al., 2003)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Mishima, Tanaka, Pu, Egashira, Iwasaki, Hidaka, Matsunaga, Takata, Karube, Fujiwara, 2003)
Vitamin E is an essential fat-soluble nutrient that functions as antioxidant in the human body. However, it can’t be produced by human body and have to take from foods or supplement. Vitamin E possesses many important roles in human body. It functions as dietary factor essential to prevent fetal reabsorption in rats ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1126/science.56.1458.650″,”ISBN”:”0036-8075″,”ISSN”:”0036-8075″,”PMID”:”17838496″,”abstract”:”The vitamin E family consists of eight isomers known as alpha-?, beta-?, gamma-?, and delta-?tocopherols and alpha-?, beta-?, gamma-?, and delta-?tocotrienols. Numerous studies focused on the health benefits of these isomers have been performed since the discovery of vitamin E in 1922. Recent discoveries on the potential therapeutic applications of tocotrienols have revolutionized vitamin E research. Nevertheless, despite the abundance of literature, only 1?% of vitamin E research has been conducted on tocotrienols. Many new advances suggest that the use of tocotrienols for health improvement or therapeutic purposes is promising. Although the mechanisms of action of tocotrienols in certain disease conditions have been explored, more detailed investigations into the fundamentals of the health-?promoting effects of these molecules must be elucidated before they can be recommended for health improvement or for the treatment or prevention of disease. Furthermore, many of the studies on the effects of tocotrienols have been carried out using cell lines and animal models. The effects in humans must be well established before tocotrienols are used as therapeutic agents in various disease conditions, hence the need for more evidence-?based human clinical trials.”,”author”:{“dropping-particle”:””,”family”:”Evans”,”given”:”H. M.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Bishop”,”given”:”K. S.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Science”,”id”:”ITEM-1″,”issue”:”1458″,”issued”:{“date-parts”:”1922″},”page”:”650-651″,”title”:”ON THE EXISTENCE OF A HITHERTO UNRECOGNIZED DIETARY FACTOR ESSENTIAL FOR REPRODUCTION”,”type”:”article-journal”,”volume”:”56″},”uris”:”http://www.mendeley.com/documents/?uuid=778e2f1e-d3fe-4ea3-86c8-e778a4a973df”,”http://www.mendeley.com/documents/?uuid=2c8ce678-7142-4401-b0fe-9800d330577f”},”mendeley”:{“formattedCitation”:”(Evans & Bishop, 1922)”,”plainTextFormattedCitation”:”(Evans & Bishop, 1922)”,”previouslyFormattedCitation”:”(Evans & Bishop, 1922)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Evans ; Bishop, 1922). Later, it was identified to be an antioxidant of polyunsaturated lipids ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1128/?CMR.18.3.446-464.2005″,”ISBN”:”0022-3166 (Print)\r0022-3166 (Linking)”,”ISSN”:”0022-3166″,”PMID”:”15735064″,”abstract”:”To evaluate any association between obesity in middle age, measured by body mass index and skinfold thickness, and risk of dementia later in life.”,”author”:{“dropping-particle”:””,”family”:”Wolf”,”given”:”George”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”The Journal of nutrition”,”id”:”ITEM-1″,”issue”:”3″,”issued”:{“date-parts”:”2005″},”page”:”363-6″,”title”:”The discovery of the antioxidant function of vitamin E: the contribution of Henry A. Mattill.”,”type”:”article-journal”,”volume”:”135″},”uris”:”http://www.mendeley.com/documents/?uuid=1204cd10-2b92-40e3-9029-e3e5096bf413″,”http://www.mendeley.com/documents/?uuid=c09e052f-7e69-43d8-a5a6-648335fbd869″},”mendeley”:{“formattedCitation”:”(Wolf, 2005)”,”plainTextFormattedCitation”:”(Wolf, 2005)”,”previouslyFormattedCitation”:”(Wolf, 2005)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Wolf, 2005). Different forms of vitamin E act as signalling and gene regulation molecules independent from their antioxidant function ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1002/biof.75″,”ISBN”:”1617556327″,”ISSN”:”09516433″,”PMID”:”20108329″,”abstract”:”Nearly after one century of research and thousands of publications, the physiological function(s) of vitamin E remain unclear. Available evidence suggests a role in cell homeostasis that occurs through the modulation of specific signaling pathways and genes involved in proliferative, metabolic, inflammatory, and antioxidant pathways. Vitamin E presence in the human body is under close metabolic control so that only alpha-tocopherol and, to a lower extent, gamma-tocopherol are retained and delivered to tissues. Other vitamin E forms that are not retained in the body in significant amounts, exhibit responses in vitro that are different form those of alpha-tocopherol and may include tumor cell specific toxicity and apoptosis. These responses provide a therapeutic potential for these minor forms, either as such or metabolically modified, to produce bioactive metabolites. These cellular effects go beyond the properties of lipophilic antioxidant attributed to alpha-tocopherol particularly investigated for its alleged protective role in atherosclerosis or other oxidative stress conditions. Understanding signaling and gene expression effects of vitamin E could help assign a physiological role to this vitamin, which will be discussed in this review. Besides vitamin E signaling, attention will be given to tocotrienols as one of the emerging topics in vitamin E research and a critical re-examination of the most recent clinical trials will be provided together with the potential use of vitamin E in disease prevention and therapy.”,”author”:{“dropping-particle”:””,”family”:”Galli”,”given”:”Francesco”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Azzi”,”given”:”Angelo”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”BioFactors”,”id”:”ITEM-1″,”issue”:”1″,”issued”:{“date-parts”:”2010″},”page”:”33-42″,”title”:”Present trends in vitamin E research”,”type”:”article”,”volume”:”36″},”uris”:”http://www.mendeley.com/documents/?uuid=57167d06-870d-4954-9070-3145ed1affc9″,”http://www.mendeley.com/documents/?uuid=0276cab7-9767-4a69-8ff9-04f2983102f7″},{“id”:”ITEM-2″,”itemData”:{“DOI”:”10.1016/j.freeradbiomed.2007.03.013″,”ISBN”:”0891-5849 (Print)\n0891-5849 (Linking)”,”ISSN”:”0891-5849″,”PMID”:”17561089″,”abstract”:”The inability of other antioxidants to substitute for alpha-tocopherol in a number of cellular reactions, the lack of a compensatory antioxidant response in the gene expression under conditions of alpha-tocopherol deficiency, the unique uptake of alpha-tocopherol relative to the other tocopherols and its slower catabolism, and the striking differences in the molecular function of the different tocopherols and tocotrienols, observed in vitro, unrelated to their antioxidant properties, are all data in support of a nonantioxidant molecular function of alpha-tocopherol. Furthermore, in vivo studies have also shown that alpha-tocopherol is not able, at physiological concentrations, to protect against oxidant-induced damage or prevent disease allegedly caused by oxidative damage. Alpha-tocopherol appears to act as a ligand of not yet identified specific proteins (receptors, transcription factors) capable of regulating signal transduction and gene expression.”,”author”:{“dropping-particle”:””,”family”:”Azzi”,”given”:”Angelo”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Free radical biology & medicine”,”id”:”ITEM-2″,”issue”:”1″,”issued”:{“date-parts”:”2007″},”page”:”16-21″,”title”:”Molecular mechanism of alpha-tocopherol action.”,”type”:”article-journal”,”volume”:”43″},”uris”:”http://www.mendeley.com/documents/?uuid=4d2773cd-2b93-4bd0-a520-558e3829f2d0″,”http://www.mendeley.com/documents/?uuid=e902736d-00b0-4e20-ae98-29f6d29b12fd”},”mendeley”:{“formattedCitation”:”(Azzi, 2007; Galli & Azzi, 2010)”,”plainTextFormattedCitation”:”(Azzi, 2007; Galli & Azzi, 2010)”,”previouslyFormattedCitation”:”(Azzi, 2007; Galli & Azzi, 2010)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Azzi, 2007; Galli ; Azzi, 2010).
TocotrienolsThe only difference between tocotrienols and tocopherols is by their side chain at the C-2 position. Tocotrienols contain an unsaturated isoprenoid side chain while tocopherols has a saturated phytyl tail ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1016/S0009-9120(99)00027-2″,”ISBN”:”0009-9120″,”ISSN”:”00099120″,”PMID”:”10480444″,”abstract”:”Objectives: To summarize new knowledge surrounding the physiological activity of tocotrienol, a natural analogue of tocopherol. Results: The biological activity of vitamin E has generally been associated with its well-defined antioxidant property, specifically against lipid peroxidation in biological membranes. In the vitamin E group, ?-tocopherol is considered to be the most active form. However, recent research has suggested tocotrienol to be a better antioxidant. Moreover, tocotrienol has been shown to possess novel hypocholesterolemic effects together with an ability to reduce the atherogenic apolipoprotein B and lipoprotein(a) plasma levels. In addition, tocotrienol has been suggested to have an anti-thrombotic and anti-tumor effect indicating that tocotrienol may serve as an effective agent in the prevention and/or treatment of cardiovascular disease and cancer. Conclusion: The physiological activities of tocotrienol suggest it to be superior than ?-tocopherol in many situations. Hence, the role of tocotrienol in the prevention of cardiovascular disease and cancer may have significant clinical implications. Additional studies on its mechanism of action, as well as, long-term intervention studies, are needed to clarify its function. From the pharmacological point-of-view, the current formulation of vitamin E supplements, which is comprised mainly of ?-tocopherol, may be questionable.”,”author”:{“dropping-particle”:””,”family”:”Theriault”,”given”:”Andre”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Chao”,”given”:”Jun-Tzu”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Wang”,”given”:”Qi”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Gapor”,”given”:”Abdul”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Adeli”,”given”:”Khosrow”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Clinical Biochemistry”,”id”:”ITEM-1″,”issue”:”5″,”issued”:{“date-parts”:”1999″},”page”:”309-319″,”title”:”Tocotrienol: a review of its therapeutic potential”,”type”:”article-journal”,”volume”:”32″},”uris”:”http://www.mendeley.com/documents/?uuid=defa1c0e-5b9d-4c4b-8901-61278b8c3e54″,”http://www.mendeley.com/documents/?uuid=9c47acc4-fb61-4b23-93c4-f7ccb2799034″},”mendeley”:{“formattedCitation”:”(Theriault, Chao, Wang, Gapor, & Adeli, 1999)”,”plainTextFormattedCitation”:”(Theriault, Chao, Wang, Gapor, & Adeli, 1999)”,”previouslyFormattedCitation”:”(Theriault, Chao, Wang, Gapor, & Adeli, 1999)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Theriault, Chao, Wang, Gapor, ; Adeli, 1999). Both tocopherols and tocotrienols act as antioxidant by scavenging the chain-propagating peroxyl radical ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1016/j.lfs.2005.12.001″,”ISBN”:”0024-3205″,”ISSN”:”00243205″,”PMID”:”16458936″,”abstract”:”In nature, eight substances have been found to have vitamin E activity: ?-, ?-, ?- and ?-tocopherol; and ?-, ?-, ?- and ?-tocotrienol. Yet, of all papers on vitamin E listed in PubMed less than 1% relate to tocotrienols. The abundance of ?-tocopherol in the human body and the comparable efficiency of all vitamin E molecules as antioxidants, led biologists to neglect the non-tocopherol vitamin E molecules as topics for basic and clinical research. Recent developments warrant a serious reconsideration of this conventional wisdom. Tocotrienols possess powerful neuroprotective, anti-cancer and cholesterol lowering properties that are often not exhibited by tocopherols. Current developments in vitamin E research clearly indicate that members of the vitamin E family are not redundant with respect to their biological functions. ?-Tocotrienol, ?-tocopherol, and ?-tocotrienol have emerged as vitamin E molecules with functions in health and disease that are clearly distinct from that of ?-tocopherol. At nanomolar concentration, ?-tocotrienol, not ?-tocopherol, prevents neurodegeneration. On a concentration basis, this finding represents the most potent of all biological functions exhibited by any natural vitamin E molecule. An expanding body of evidence support that members of the vitamin E family are functionally unique. In recognition of this fact, title claims in manuscripts should be limited to the specific form of vitamin E studied. For example, evidence for toxicity of a specific form of tocopherol in excess may not be used to conclude that high-dosage “vitamin E” supplementation may increase all-cause mortality. Such conclusion incorrectly implies that tocotrienols are toxic as well under conditions where tocotrienols were not even considered. The current state of knowledge warrants strategic investment into the lesser known forms of vitamin E. This will enable prudent selection of the appropriate vitamin E molecule for studies addressing a specific need.”,”author”:{“dropping-particle”:””,”family”:”Sen”,”given”:”Chandan K.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Khanna”,”given”:”Savita”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Roy”,”given”:”Sashwati”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Life Sciences”,”id”:”ITEM-1″,”issue”:”18″,”issued”:{“date-parts”:”2006″},”page”:”2088-2098″,”title”:”Tocotrienols: Vitamin E beyond tocopherols”,”type”:”paper-conference”,”volume”:”78″},”uris”:”http://www.mendeley.com/documents/?uuid=d61ef9df-b5df-4cf5-bd64-39db9274b5ed”,”http://www.mendeley.com/documents/?uuid=9481d64c-8e3a-47d6-b9f9-4fe3c2cf85cd”},”mendeley”:{“formattedCitation”:”(Sen et al., 2006)”,”plainTextFormattedCitation”:”(Sen et al., 2006)”,”previouslyFormattedCitation”:”(Sen et al., 2006)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Sen et al., 2006).

Tocotrienols and the antioxidant activityTocotrienols exhibit antioxidant function like tocopherols, and it was found that tocotrienols exhibit more antioxidant activity. It was several-fold more effective than tocopherols in inhibiting the proliferation of mouse mammary tumour epithelial cells and in inducing apoptosis ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1046/j.1525-1373.2000.22434.x”,”ISBN”:”0037-9727″,”ISSN”:”0037-9727″,”PMID”:”10964265″,”abstract”:”Studies were conducted to determine the comparative effects of tocopherols and tocotrienols on preneoplastic (CL-S1), neoplastic (-SA), and highly malignant (+SA) mouse mammary epithelial cell growth and viability in vitro. Over a 5-day culture period, treatment with 0-120 microM alpha- and gamma-tocopherol had no effect on cell proliferation, whereas growth was inhibited 50% (IC50) as compared with controls by treatment with the following: 13, 7, and 6 microM tocotrienol-rich-fraction of palm oil (TRF); 55, 47, and 23 microM delta-tocopherol; 12, 7, and 5 microM alpha-tocotrienol; 8, 5, and 4 microM gamma-tocotrienol; or 7, 4, and 3 microM delta-tocotrienol in CL-S1, -SA and +SA cells, respectively. Acute 24-hr exposure to 0-250 microM alpha- or gamma-tocopherol (CL-S1, -SA, and +SA) or 0-250 microM delta-tocopherol (CL-S1) had no effect on cell viability, whereas cell viability was reduced 50% (LD50) as compared with controls by treatment with 166 or 125 microM delta-tocopherol in -SA and +SA cells, respectively. Additional LD50 doses were determined as the following: 50, 43, and 38 microM TRF; 27, 28, and 23 microM alpha-tocotrienol; 19, 17, and 14 microM gamma-tocotrienol; or 16, 15, or 12 microM delta-tocotrienol in CL-S1, -SA, and +SA cells, respectively. Treatment-induced cell death resulted from activation of apoptosis, as indicated by DNA fragmentation. Results also showed that CL-S1, -SA, and +SA cells preferentially accumulate tocotrienols as compared with tocopherols, and this may partially explain why tocotrienols display greater biopotency than tocopherols. These data also showed that highly malignant +SA cells were the most sensitive, whereas the preneoplastic CL-S1 cells were the least sensitive to the antiproliferative and apoptotic effects of tocotrienols, and suggest that tocotrienols may have potential health benefits in preventing and/or reducing the risk of breast cancer in women.”,”author”:{“dropping-particle”:””,”family”:”McIntyre”,”given”:”B S”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Briski”,”given”:”K P”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Gapor”,”given”:”A”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Sylvester”,”given”:”P W”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)”,”id”:”ITEM-1″,”issue”:”4″,”issued”:{“date-parts”:”2000″},”page”:”292-301″,”title”:”Antiproliferative and apoptotic effects of tocopherols and tocotrienols on preneoplastic and neoplastic mouse mammary epithelial cells.”,”type”:”article-journal”,”volume”:”224″},”uris”:”http://www.mendeley.com/documents/?uuid=ed8e0786-e3a9-4a62-b330-e3fad9bb7ca2″,”http://www.mendeley.com/documents/?uuid=6be8d2ae-b04f-42de-abb1-afd5e6b167d2″},”mendeley”:{“formattedCitation”:”(McIntyre, Briski, Gapor, & Sylvester, 2000)”,”plainTextFormattedCitation”:”(McIntyre, Briski, Gapor, & Sylvester, 2000)”,”previouslyFormattedCitation”:”(McIntyre, Briski, Gapor, & Sylvester, 2000)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(McIntyre, Briski, Gapor, ; Sylvester, 2000). The preferential accumulation of tocotrienols as compared to tocopherols could be the reason why there are differences in their effectiveness ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1016/S0014-5793(97)00499-7″,”ISBN”:”0014-5793 (Print)\r0014-5793 (Linking)”,”ISSN”:”00145793″,”PMID”:”9199513″,”abstract”:”?-Tocopherol transfer protein (?TTP), a product of the gene which causes familial isolated vitamin E deficiency, plays an important role in determining the plasma vitamin E level. We examined the structural characteristics of vitamin E analogs required for recognition by ?TTP. Ligand specificity was assessed by evaluating the competition of non-labeled vitamin E analogs and ?-3Htocopherol for transfer between membranes in vitro. Relative affinities (RRR-?-tocopherol=100%) calculated from the degree of competition were as follows: ?-tocopherol, 38%; ?-tocopherol, 9%; ?-tocopherol, 2%; ?-tocopherol acetate, 2%; ?-tocopherol quinone, 2%; SRR-?-tocopherol, 11%; ?:-tocotrienol, 12%; trolox, 9%. Interestingly, there was a linear relationship between the relative affinity and the known biological activity obtained from the rat resorption-gestation assay. From these observations, we conclude that the affinity of vitamin E analogs for ?TTP is one of the critical determinants of their biological activity.”,”author”:{“dropping-particle”:””,”family”:”Hosomi”,”given”:”Akihiro”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Arita”,”given”:”Makoto”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Sato”,”given”:”Yuji”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Kiyose”,”given”:”Chikako”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Ueda”,”given”:”Tadahiko”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Igarashi”,”given”:”Osamu”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Arai”,”given”:”Hiroyuki”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Inoue”,”given”:”Keizo”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”FEBS Letters”,”id”:”ITEM-1″,”issue”:”1″,”issued”:{“date-parts”:”1997″},”page”:”105-108″,”title”:”Affinity for ?-tocopherol transfer protein as a determinant of the biological activities of vitamin E analogs”,”type”:”article-journal”,”volume”:”409″},”uris”:”http://www.mendeley.com/documents/?uuid=f32dca4e-57dd-4d3a-b12e-ea8d416eaf55″,”http://www.mendeley.com/documents/?uuid=0a0b0c12-3e07-461e-99a5-a4bb28b1e5a7″},”mendeley”:{“formattedCitation”:”(Hosomi et al., 1997)”,”manualFormatting”:”( Hosomi, Arita, Sato, Kiyose, Ueda, Igarashi, Arai, Inoue, 1997)”,”plainTextFormattedCitation”:”(Hosomi et al., 1997)”,”previouslyFormattedCitation”:”(Hosomi et al., 1997)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}( Hosomi, Arita, Sato, Kiyose, Ueda, Igarashi, Arai, Inoue, 1997).

Factor affecting the potential of tocotrienols and tocopherolsThere are many mechanisms that cause the difference in the potential of tocotrienols and tocopherols. Firstly, it is because tocotrienols may be more uniformly distributed in the lipid bilayer compared to tocopherols in term of their structural differences ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1016/0891-5849(91)90033-Y”,”ISBN”:”0891-5849 (Print)\r0891-5849″,”ISSN”:”08915849″,”PMID”:”1649783″,”abstract”:”d-Alpha-tocopherol (2R, 4?R,8?R-Alpha-tocopherol) and d-alpha-tocotrienol are two main vitamin E constituents having the same aromatic chromanol “head” but differing in their hydrocarbon “tail”: tocopherol with a saturated and toctrienol with an unsaturated isoprenoid chain. d-Alpha-tocopherol has the highest vitamin E activity, while d-alpha-tocotrienol manifests only about 30% of this activity. Since vitamin E is considered to be physiologically the most important lipid-soluble chain-breaking antioxidant of membranes, we studied alpha-tocotrienol as compared to alpha-tocopherol under conditions which are important for their antioxidant function. d-Alpha-tocotrienol possesses 40-60 times higher antioxidant activity against (Fe2+ + ascorbate)- and (Fe2+ + NADPH)-induced lipid peroxidation in rat liver microsomal membranes and 6.5 times better protection of cytochrome P-450 against oxidative damage than d-alpha-tocopherol. To clarify the mechanisms responsible for the much higher antioxidant potency of d-alpha-tocotrienol compared to d-alpha-tocopherol, ESR studies were performed of recycling efficiency of the chromanols from their chromanoxyl radicals, 1H-NMR measurements of lipid molecular mobility in liposomes containing chromanols, and fluorescence measurements which reveal the uniformity of distribution (clusterizations) of chromanols in the lipid bilayer. From the results, we concluded that this higher antioxidant potency of d-alpha-tocotrienol is due to the combined effects of three properties exhibited by d-alpha-tocotrienol as compared to d-alpha-tocopherol: (i) its higher recycling efficiency from chromanoxyl radicals, (ii) its more uniform distribution in membraned bilayer, and (iii) its stronger disordering of membrane lipids which makes interaction of chromanols with lipid radicals more efficient. The data presented show that there is a considerable discrepancy between the relative in vitro antioxidant activity of d-alpha-tocotrienol with the conventional bioassays of their vitamin activity. © 1991.”,”author”:{“dropping-particle”:””,”family”:”Serbinova”,”given”:”Elena”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Kagan”,”given”:”Valerian”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Han”,”given”:”Derick”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Packer”,”given”:”Lester”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Free Radical Biology and Medicine”,”id”:”ITEM-1″,”issue”:”5″,”issued”:{“date-parts”:”1991″},”page”:”263-275″,”title”:”Free radical recycling and intramembrane mobility in the antioxidant properties of alpha-tocopherol and alpha-tocotrienol”,”type”:”article-journal”,”volume”:”10″},”uris”:”http://www.mendeley.com/documents/?uuid=dfda199a-9691-4f26-9ca2-2baa60e5cacd”,”http://www.mendeley.com/documents/?uuid=0bbeb224-d552-4ee9-a0c0-be88d6fe5984″},”mendeley”:{“formattedCitation”:”(E. Serbinova et al., 1991)”,”manualFormatting”:”(Serbinova et al., 1991)”,”plainTextFormattedCitation”:”(E. Serbinova et al., 1991)”,”previouslyFormattedCitation”:”(E. Serbinova et al., 1991)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Serbinova et al., 1991). Secondly, the chromanol ring of tocotrienols may be interact more efficiently with the lipid bilayer than tocopherols ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1016/0891-5849(91)90033-Y”,”ISBN”:”0891-5849 (Print)\r0891-5849″,”ISSN”:”08915849″,”PMID”:”1649783″,”abstract”:”d-Alpha-tocopherol (2R, 4?R,8?R-Alpha-tocopherol) and d-alpha-tocotrienol are two main vitamin E constituents having the same aromatic chromanol “head” but differing in their hydrocarbon “tail”: tocopherol with a saturated and toctrienol with an unsaturated isoprenoid chain. d-Alpha-tocopherol has the highest vitamin E activity, while d-alpha-tocotrienol manifests only about 30% of this activity. Since vitamin E is considered to be physiologically the most important lipid-soluble chain-breaking antioxidant of membranes, we studied alpha-tocotrienol as compared to alpha-tocopherol under conditions which are important for their antioxidant function. d-Alpha-tocotrienol possesses 40-60 times higher antioxidant activity against (Fe2+ + ascorbate)- and (Fe2+ + NADPH)-induced lipid peroxidation in rat liver microsomal membranes and 6.5 times better protection of cytochrome P-450 against oxidative damage than d-alpha-tocopherol. To clarify the mechanisms responsible for the much higher antioxidant potency of d-alpha-tocotrienol compared to d-alpha-tocopherol, ESR studies were performed of recycling efficiency of the chromanols from their chromanoxyl radicals, 1H-NMR measurements of lipid molecular mobility in liposomes containing chromanols, and fluorescence measurements which reveal the uniformity of distribution (clusterizations) of chromanols in the lipid bilayer. From the results, we concluded that this higher antioxidant potency of d-alpha-tocotrienol is due to the combined effects of three properties exhibited by d-alpha-tocotrienol as compared to d-alpha-tocopherol: (i) its higher recycling efficiency from chromanoxyl radicals, (ii) its more uniform distribution in membraned bilayer, and (iii) its stronger disordering of membrane lipids which makes interaction of chromanols with lipid radicals more efficient. The data presented show that there is a considerable discrepancy between the relative in vitro antioxidant activity of d-alpha-tocotrienol with the conventional bioassays of their vitamin activity. © 1991.”,”author”:{“dropping-particle”:””,”family”:”Serbinova”,”given”:”Elena”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Kagan”,”given”:”Valerian”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Han”,”given”:”Derick”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Packer”,”given”:”Lester”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Free Radical Biology and Medicine”,”id”:”ITEM-1″,”issue”:”5″,”issued”:{“date-parts”:”1991″},”page”:”263-275″,”title”:”Free radical recycling and intramembrane mobility in the antioxidant properties of alpha-tocopherol and alpha-tocotrienol”,”type”:”article-journal”,”volume”:”10″},”uris”:”http://www.mendeley.com/documents/?uuid=dfda199a-9691-4f26-9ca2-2baa60e5cacd”,”http://www.mendeley.com/documents/?uuid=0bbeb224-d552-4ee9-a0c0-be88d6fe5984″},”mendeley”:{“formattedCitation”:”(E. Serbinova et al., 1991)”,”manualFormatting”:”(Serbinova et al., 1991)”,”plainTextFormattedCitation”:”(E. Serbinova et al., 1991)”,”previouslyFormattedCitation”:”(E. Serbinova et al., 1991)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Serbinova et al., 1991). Thirdly, tocotrienols may have higher recycling efficiency ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1016/0076-6879(94)34105-2″,”ISBN”:”0076-6879″,”ISSN”:”15577988″,”abstract”:”This chapter describes the antioxidant properties of ?-tocopherol and ?-tocotrienol. Tocopherols and tocotrienols are present in various components of the human diet. Tocopherols are found in polyunsaturated vegetable oils and in the germ of cereal seeds, whereas tocotrienols are found in the aleurone and subaleurone layers of cereal seeds and in palm oil. Although the tocopherols and tocotrienols are closely related chemically, they have widely varying degrees of biological effectiveness. The potency of ?-tocotrienol evaluated by gestation-resorption assays are 32% of the potency of ?-tocopherol. The chapter discusses the relative and the absolute antioxidant effectiveness in vitro of the individual tocopherols that make up vitamin E. It is recognized that differences in vivo in the antioxidant activity of tocopherols and tocotrienols may depend greatly on their pharmacokinetics. However, ?-tocotrienol may have higher antioxidant activity in vivo under conditions of oxidative stress because of its more effective antioxidant potency in membranes. © 1994, Elsevier Inc. All rights reserved.”,”author”:{“dropping-particle”:””,”family”:”Serbinova”,”given”:”Elena A.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Packer”,”given”:”Lester”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Methods in Enzymology”,”id”:”ITEM-1″,”issue”:”C”,”issued”:{“date-parts”:”1994″},”page”:”354-366″,”title”:”Antioxidant properties of ?-tocopherol and ?-tocotrienol”,”type”:”article-journal”,”volume”:”234″},”uris”:”http://www.mendeley.com/documents/?uuid=91912a76-e6fb-41a4-9a75-080519e731fa”,”http://www.mendeley.com/documents/?uuid=b6364100-6380-469b-a0d0-4d68c8fb328d”},”mendeley”:{“formattedCitation”:”(E. A. Serbinova & Packer, 1994)”,”manualFormatting”:”(Serbinova & Packer, 1994)”,”plainTextFormattedCitation”:”(E. A. Serbinova & Packer, 1994)”,”previouslyFormattedCitation”:”(E. A. Serbinova & Packer, 1994)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Serbinova ; Packer, 1994). And finally, in term of cellular uptake, tocotrienols have 70 times higher than tocopherols ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1196/annals.1331.047″,”ISSN”:”00778923″,”PMID”:”15753172″,”abstract”:”We previously reported that tocotrienols acted as more potent inhibitors against selenium deficiency-induced cell death than the corresponding tocopherol isoforms (J. Biol. Chem. 2003;278:39428-39434). In the present study, we first compared the differences in the cellular uptake between alpha-tocopherol (alpha-Toc) and alpha-tocotrienol (alpha-Toc-3). The initial rate of cellular uptake of alpha-Toc-3 was 70-fold higher than that of alpha-Toc. Subcellular fractionation analysis of alpha-Toc-3 and alpha-Toc-fortified cells showed similar cellular distribution of these antioxidants, which was directly proportional to the lipid distribution. The cells containing similar amounts of alpha-Toc-3 and alpha-Toc showed similar resistance against the oxidative stress caused by peroxides. These results suggest that the apparent higher cytoprotective effect of alpha-Toc-3 than alpha-Toc is primarily ascribed to its higher cellular uptake.”,”author”:{“dropping-particle”:””,”family”:”Saito”,”given”:”Yoshiro”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Yoshida”,”given”:”Yasukazu”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Nishio”,”given”:”Keiko”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Hayakawa”,”given”:”Mieko”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Niki”,”given”:”Etsuo”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Annals of the New York Academy of Sciences”,”id”:”ITEM-1″,”issued”:{“date-parts”:”2004″},”page”:”368-375″,”title”:”Characterization of cellular uptake and distribution of vitamin E”,”type”:”paper-conference”,”volume”:”1031″},”uris”:”http://www.mendeley.com/documents/?uuid=ebd0fbe3-36e8-4a15-aca5-84a68a258be5″,”http://www.mendeley.com/documents/?uuid=90482098-b133-48bc-bd20-333ab6c924c6″},”mendeley”:{“formattedCitation”:”(Saito, Yoshida, Nishio, Hayakawa, & Niki, 2004)”,”plainTextFormattedCitation”:”(Saito, Yoshida, Nishio, Hayakawa, & Niki, 2004)”,”previouslyFormattedCitation”:”(Saito, Yoshida, Nishio, Hayakawa, & Niki, 2004)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Saito, Yoshida, Nishio, Hayakawa, ; Niki, 2004). All of these factors may contribute to tocotrienols greater efficacy than tocopherols. It also has been shown that tocotrienols isomers are accumulated and secreted at greater rates in Caco2 cells than tocopherols isomers ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1016/j.bcp.2010.07.043″,”ISBN”:”0006-2952″,”ISSN”:”00062952″,”PMID”:”20696139″,”abstract”:”Initially discovered in 1938 as a ” fertility factor,” vitamin E now refers to eight different isoforms that belong to two categories, four saturated analogues (?, ?, ?, and ?) called tocopherols and four unsaturated analogues referred to as tocotrienols. While the tocopherols have been investigated extensively, little is known about the tocotrienols. Very limited studies suggest that both the molecular and therapeutic targets of the tocotrienols are distinct from those of the tocopherols. For instance, suppression of inflammatory transcription factor NF-?B, which is closely linked to tumorigenesis and inhibition of HMG-CoA reductase, mammalian DNA polymerases and certain protein tyrosine kinases, is unique to the tocotrienols. This review examines in detail the molecular targets of the tocotrienols and their roles in cancer, bone resorption, diabetes, and cardiovascular and neurological diseases at both preclinical and clinical levels. As disappointment with the therapeutic value of the tocopherols grows, the potential of these novel vitamin E analogues awaits further investigation. © 2010 Elsevier Inc.”,”author”:{“dropping-particle”:””,”family”:”Aggarwal”,”given”:”Bharat B.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Sundaram”,”given”:”Chitra”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Prasad”,”given”:”Seema”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Kannappan”,”given”:”Ramaswamy”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Biochemical Pharmacology”,”id”:”ITEM-1″,”issue”:”11″,”issued”:{“date-parts”:”2010″},”page”:”1613-1631″,”title”:”Tocotrienols, the vitamin E of the 21st century: Its potential against cancer and other chronic diseases”,”type”:”article”,”volume”:”80″},”uris”:”http://www.mendeley.com/documents/?uuid=1b0c7f4b-1543-451e-8c8f-2918227cb58e”,”http://www.mendeley.com/documents/?uuid=df05c14a-81f9-4f9b-9cd8-a1672dbd8bd9″},”mendeley”:{“formattedCitation”:”(B. B. Aggarwal, Sundaram, Prasad, & Kannappan, 2010)”,”manualFormatting”:”(Aggarwal, Sundaram, Prasad, & Kannappan, 2010)”,”plainTextFormattedCitation”:”(B. B. Aggarwal, Sundaram, Prasad, & Kannappan, 2010)”,”previouslyFormattedCitation”:”(B. B. Aggarwal, Sundaram, Prasad, & Kannappan, 2010)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Aggarwal, Sundaram, Prasad, ; Kannappan, 2010).
Biological activities of tocotrienolsVarious isoforms of tocotrienols that differ in their number of methyl groups, also differ in their biological activities. Alpha-tocotrienol have been shown to be neuroprotective ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1074/jbc.275.17.13049″,”ISBN”:”0021-9258 (Print)\n0021-9258 (Linking)”,”ISSN”:”00219258″,”PMID”:”10777609″,”abstract”:”HT4 hippocampal neuronal cells were studied to compare the efficacy of tocopherols and tocotrienol to protect against glutamate-induced death. Tocotrienols were more effective than alpha-tocopherol in preventing glutamate-induced death. Uptake of tocotrienols from the culture medium was more efficient compared with that of alpha-tocopherol. Vitamin E molecules have potent antioxidant properties. Results show that at low concentrations, tocotrienols may have protected cells by an antioxidant-independent mechanism. Examination of signal transduction pathways revealed that protein tyrosine phosphorylation processes played a central role in the execution of death. Activation of pp60(c-Src) kinase and phosphorylation of ERK were observed in response to glutamate treatment. Nanomolar amounts of alpha-tocotrienol, but not alpha-tocopherol, blocked glutamate-induced death by suppressing glutamate-induced early activation of c-Src kinase. Overexpression of kinase-active c-Src sensitized cells to glutamate-induced death. Tocotrienol treatment prevented death of Src-overexpressing cells treated with glutamate. alpha-Tocotrienol did not influence activity of recombinant c-Src kinase suggesting that its mechanism of action may include regulation of SH domains. This study provides first evidence describing the molecular basis of tocotrienol action. At a concentration 4-10-fold lower than levels detected in plasma of supplemented humans, tocotrienol regulated unique signal transduction processes that were not sensitive to comparable concentrations of tocopherol.”,”author”:{“dropping-particle”:””,”family”:”Sen”,”given”:”Chandan K.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Khanna”,”given”:”Savita”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Roy”,”given”:”Sashwati”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Packer”,”given”:”Lester”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Journal of Biological Chemistry”,”id”:”ITEM-1″,”issue”:”17″,”issued”:{“date-parts”:”2000″},”page”:”13049-13055″,”title”:”Molecular basis of vitamin E action. Tocotrienol potently inhibits glutamate-induced pp(60c-Src) kinase activation and death of HT4 neuronal cells”,”type”:”article-journal”,”volume”:”275″},”uris”:”http://www.mendeley.com/documents/?uuid=b1a8929a-96fc-40bc-9444-5c503b1e926e”,”http://www.mendeley.com/documents/?uuid=7df26f48-63d0-4f4c-a03d-3114a6a6c8dd”},{“id”:”ITEM-2″,”itemData”:{“DOI”:”10.1161/01.STR.0000181082.70763.22″,”ISBN”:”1524-4628 (Electronic)\r0039-2499 (Linking)”,”ISSN”:”1524-4628″,”PMID”:”16166580″,”abstract”:”The current work is based on our previous finding that in neuronal cells, nmol/L concentrations of alpha-tocotrienol (TCT), but not alpha-tocopherol (TCP), blocked glutamate-induced death by suppressing early activation of c-Src kinase and 12-lipoxygenase.”,”author”:{“dropping-particle”:””,”family”:”Khanna”,”given”:”Savita”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Roy”,”given”:”Sashwati”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Slivka”,”given”:”Andrew”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Craft”,”given”:”Tara K S”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Chaki”,”given”:”Soma”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Rink”,”given”:”Cameron”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Notestine”,”given”:”Margaret a”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”DeVries”,”given”:”A Courtney”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Parinandi”,”given”:”Narasimham L”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Sen”,”given”:”Chandan K”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Stroke; a journal of cerebral circulation”,”id”:”ITEM-2″,”issue”:”10″,”issued”:{“date-parts”:”2005″},”page”:”2258-2264″,”title”:”Neuroprotective properties of the natural vitamin E alpha-tocotrienol.”,”type”:”article-journal”,”volume”:”36″},”uris”:”http://www.mendeley.com/documents/?uuid=563022a6-056c-417e-adc3-5d79dcf820e7″,”http://www.mendeley.com/documents/?uuid=f7eedcdd-a7c8-4906-b546-49514b251ea9″},”mendeley”:{“formattedCitation”:”(Khanna et al., 2005; Sen, Khanna, Roy, & Packer, 2000)”,”manualFormatting”:”( Khanna, Roy, Sashwati, Slivka, Craft, Chaki, Rink, Notestine, DeVries, Sen, 2005; Sen, Khanna, Roy, & Packer, 2000)”,”plainTextFormattedCitation”:”(Khanna et al., 2005; Sen, Khanna, Roy, & Packer, 2000)”,”previouslyFormattedCitation”:”(Khanna et al., 2005; Sen, Khanna, Roy, & Packer, 2000)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}( Khanna, Roy, Sashwati, Slivka, Craft, Chaki, Rink, Notestine, DeVries, Sen, 2005; Sen, Khanna, Roy, ; Packer, 2000), while ? and ?-tocotrienol exhibit the greatest anticancer effects. Alpha???? and ? isomers of tocotrienol have 30 fold-difference in the ability to inhibit cholesterols biosynthesis ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1021/jm00098a002″,”ISBN”:”1054410550″,”ISSN”:”15204804″,”PMID”:”1433170″,”abstract”:”Tocotrienols are farnesylated benzopyran natural products that exhibit hypocholesterolemic activity in vitro and in vivo. The mechanism of their hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase by a process distinct from other known inhibitors of cholesterol biosynthesis. An efficient synthetic route to tocotrienols and their isolation from palm oil distillate using an improved procedure is presented. gamma-Tocotrienol exhibits a 30-fold greater activity toward cholesterol biosynthesis inhibition compared to alpha-tocotrienol in HepG2 cells in vitro. The synthetic (racemic) and natural (chiral) tocotrienols exhibit nearly identical cholesterol biosynthesis inhibition and HMG-CoA reductase suppression properties as demonstrated in vitro and in vivo.”,”author”:{“dropping-particle”:””,”family”:”Pearce”,”given”:”Bradley C.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Parker”,”given”:”Rex A.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Deason”,”given”:”Michael E.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Qureshi”,”given”:”Asaf A.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Wright”,”given”:”J. J.Kim”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Journal of Medicinal Chemistry”,”id”:”ITEM-1″,”issue”:”20″,”issued”:{“date-parts”:”1992″},”page”:”3595-3606″,”title”:”Hypocholesterolemic Activity of Synthetic and Natural Tocotrienols”,”type”:”article-journal”,”volume”:”35″},”uris”:”http://www.mendeley.com/documents/?uuid=2c7fe9f7-75b4-4bf4-80e0-81399dfbd405″,”http://www.mendeley.com/documents/?uuid=1c4cfbf9-e23a-4208-886a-1dfe20dc61af”},”mendeley”:{“formattedCitation”:”(Pearce, Parker, Deason, Qureshi, & Wright, 1992)”,”plainTextFormattedCitation”:”(Pearce, Parker, Deason, Qureshi, & Wright, 1992)”,”previouslyFormattedCitation”:”(Pearce, Parker, Deason, Qureshi, & Wright, 1992)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Pearce, Parker, Deason, Qureshi, ; Wright, 1992). The antioxidant capacity of these three isomers is ??tocotrienol ; ?-tocotrienol ; ?-tocotrienol ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1007/BF02522884″,”ISBN”:”10.1007/BF02522884″,”ISSN”:”0024-4201″,”PMID”:”8827691″,”abstract”:”This article is a review of the fundamental chemistry of the tocopherols and tocotrienols relevant to their antioxidant action. Despite the general agreement that alpha-tocopherol is the most efficient antioxidant and vitamin E homologue in vivo, there was always a considerable discrepancy in its “absolute” and “relative” antioxidant effectiveness in vitro, especially when compared to gamma-tocopherol. Many chemical, physical, biochemical, physicochemical, and other factors seem responsible for the observed discrepancy between the relative antioxidant potencies of the tocopherols in vivo and in vitro. This paper aims at highlighting some possible reasons for the observed differences between the tocopherols (alpha-, beta-, gamma-, and delta-) in relation to their interactions with the important chemical species involved in lipid peroxidation, specifically trace metal ions, singlet oxygen, nitrogen oxides, and antioxidant synergists. Although literature reports related to the chemistry of the tocotrienols are quite meager, they also were included in the discussion in virtue of their structural and functional resemblance to the tocopherols.”,”author”:{“dropping-particle”:””,”family”:”Kamal-Eldin”,”given”:”Afaf”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Appelqvist”,”given”:”Lars-Åke”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Lipids”,”id”:”ITEM-1″,”issue”:”7″,”issued”:{“date-parts”:”1996″},”page”:”671-701″,”title”:”The chemistry and antioxidant properties of tocopherols and tocotrienols”,”type”:”article-journal”,”volume”:”31″},”uris”:”http://www.mendeley.com/documents/?uuid=dd4be371-1f2a-471e-b53e-c013a21c4671″,”http://www.mendeley.com/documents/?uuid=fc9da027-4132-48bd-87d5-326782903763″},”mendeley”:{“formattedCitation”:”(Kamal-Eldin & Appelqvist, 1996)”,”plainTextFormattedCitation”:”(Kamal-Eldin & Appelqvist, 1996)”,”previouslyFormattedCitation”:”(Kamal-Eldin & Appelqvist, 1996)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Kamal-Eldin ; Appelqvist, 1996). Alpha-tocotrienol and ?-tocopherol have similar antioxidant activity ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1016/0005-2760(93)90092-N”,”ISBN”:”0006-3002 (Print)\r0006-3002 (Linking)”,”ISSN”:”00052760″,”PMID”:”8443232″,”abstract”:”The antioxidant activity of tocotrienols toward peroxyl radicals was compared with that of other natural lipid-soluble antioxidants in three different systems by measuring the temporal disappearance of antioxidants and the formation of lipid hydroperoxides. In homogeneous solution, the initial rates of consumption of the various antioxidants, assessed by competition experiments between pairs of antioxidants for radicals, decreased in the order: ubiquinol-10 ? ubiquinol-9 ? ?-tocopherol ? ?-tocotrienol ? ? lycopene ? ?-tocopherol ? ?-tocotrienol. Following in vitro incubation of human plasma with ?-tocotrienol, this form of vitamin E was present in all classes of lipoproteins isolated from the supplemented plasma. Dietary supplementation of rats and humans with a tocotrienol-rich preparation resulted in a dose-dependent appearance of ?- and ?-tocotrienols in plasma and all circulating lipoproteins, respectively. Exposure of such enriched rat plasma to aqueous peroxyl radicals resulted in simultaneous consumption of the ?- and then ?-isomers of vitamin E. The sequence of radical-induced consumption of antioxidants in freshly isolated, in vitro and in vivo tocotrienol-enriched low density lipoprotein (LDL) was again ubiquinol-10 ? ?-tocotrienol ? ?-tocopherol ? carotenoids ? ?-tocopherol ? ?-tocotrienol. Under conditions where radicals were generated at constant rates, the rate of lipid hydroperoxide formation in LDL was not constant. It proceeded in at least three stages separated by the phase of ubiquinol-10 consumption and, subsequently, that of ?-tocopherol/ ?-tocotrienol. Our results show that dietary tocotrienols become incorporated into circulating human lipoproteins where they react with peroxyl radicals as efficiently as the corresponding tocopherol isomers. © 1993.”,”author”:{“dropping-particle”:””,”family”:”Suarna”,”given”:”Cacang”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Hood”,”given”:”Ross L.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Dean”,”given”:”Roger T.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Stocker”,”given”:”Roland”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Biochimica et Biophysica Acta (BBA)/Lipids and Lipid Metabolism”,”id”:”ITEM-1″,”issue”:”2-3″,”issued”:{“date-parts”:”1993″},”page”:”163-170″,”title”:”Comparative antioxidant activity of tocotrienols and other natural lipid-soluble antioxidants in a homogeneous system, and in rat and human lipoproteins”,”type”:”article-journal”,”volume”:”1166″},”uris”:”http://www.mendeley.com/documents/?uuid=02888566-af7f-4713-bf05-9f28a08d8706″,”http://www.mendeley.com/documents/?uuid=30631016-8542-4772-bd7d-9bcb0dde1d26″},”mendeley”:{“formattedCitation”:”(Suarna, Hood, Dean, & Stocker, 1993)”,”plainTextFormattedCitation”:”(Suarna, Hood, Dean, & Stocker, 1993)”,”previouslyFormattedCitation”:”(Suarna, Hood, Dean, & Stocker, 1993)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Suarna, Hood, Dean, ; Stocker, 1993). Various tocotrienols differ in their potential in the proliferation of mouse mammary tumour epithelial cells inhibition and in apoptosis induction ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1046/j.1525-1373.2000.22434.x”,”ISBN”:”0037-9727″,”ISSN”:”0037-9727″,”PMID”:”10964265″,”abstract”:”Studies were conducted to determine the comparative effects of tocopherols and tocotrienols on preneoplastic (CL-S1), neoplastic (-SA), and highly malignant (+SA) mouse mammary epithelial cell growth and viability in vitro. Over a 5-day culture period, treatment with 0-120 microM alpha- and gamma-tocopherol had no effect on cell proliferation, whereas growth was inhibited 50% (IC50) as compared with controls by treatment with the following: 13, 7, and 6 microM tocotrienol-rich-fraction of palm oil (TRF); 55, 47, and 23 microM delta-tocopherol; 12, 7, and 5 microM alpha-tocotrienol; 8, 5, and 4 microM gamma-tocotrienol; or 7, 4, and 3 microM delta-tocotrienol in CL-S1, -SA and +SA cells, respectively. Acute 24-hr exposure to 0-250 microM alpha- or gamma-tocopherol (CL-S1, -SA, and +SA) or 0-250 microM delta-tocopherol (CL-S1) had no effect on cell viability, whereas cell viability was reduced 50% (LD50) as compared with controls by treatment with 166 or 125 microM delta-tocopherol in -SA and +SA cells, respectively. Additional LD50 doses were determined as the following: 50, 43, and 38 microM TRF; 27, 28, and 23 microM alpha-tocotrienol; 19, 17, and 14 microM gamma-tocotrienol; or 16, 15, or 12 microM delta-tocotrienol in CL-S1, -SA, and +SA cells, respectively. Treatment-induced cell death resulted from activation of apoptosis, as indicated by DNA fragmentation. Results also showed that CL-S1, -SA, and +SA cells preferentially accumulate tocotrienols as compared with tocopherols, and this may partially explain why tocotrienols display greater biopotency than tocopherols. These data also showed that highly malignant +SA cells were the most sensitive, whereas the preneoplastic CL-S1 cells were the least sensitive to the antiproliferative and apoptotic effects of tocotrienols, and suggest that tocotrienols may have potential health benefits in preventing and/or reducing the risk of breast cancer in women.”,”author”:{“dropping-particle”:””,”family”:”McIntyre”,”given”:”B S”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Briski”,”given”:”K P”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Gapor”,”given”:”A”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Sylvester”,”given”:”P W”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)”,”id”:”ITEM-1″,”issue”:”4″,”issued”:{“date-parts”:”2000″},”page”:”292-301″,”title”:”Antiproliferative and apoptotic effects of tocopherols and tocotrienols on preneoplastic and neoplastic mouse mammary epithelial cells.”,”type”:”article-journal”,”volume”:”224″},”uris”:”http://www.mendeley.com/documents/?uuid=6be8d2ae-b04f-42de-abb1-afd5e6b167d2″,”http://www.mendeley.com/documents/?uuid=ed8e0786-e3a9-4a62-b330-e3fad9bb7ca2″},”mendeley”:{“formattedCitation”:”(McIntyre et al., 2000)”,”manualFormatting”:”(McIntyre, Briski, Gapor, Sylvester, 2000)”,”plainTextFormattedCitation”:”(McIntyre et al., 2000)”,”previouslyFormattedCitation”:”(McIntyre et al., 2000)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(McIntyre, Briski, Gapor, Sylvester, 2000). They identified the relative potentials of these three isomers as ??tocotrienol ; ??tocotrienol ; ??tocotrienol. In addition, the relative potentials for the proliferation suppression of bovine, human endothelial cells, and tube formation were ??tocotrienol ; ??tocotrienol ; ??tocotrienol = ??tocotrienol ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1271/bbb.67.1623″,”ISSN”:”0916-8451″,”PMID”:”12913317″,”abstract”:”The anti-angiogenic property of vitamin E compounds, with particular emphasis on tocotrienol, has been investigated in vitro. Tocotrienol, but not tocopherol, inhibited both the proliferation and tube formation of bovine aortic endothelial cells, with delta-tocotrienol appearing the highest activity. Also, delta-tocotrienol reduced the vascular endothelial growth factor-stimulated tube formation by human umbilical vein endothelial cells. Our findings suggest that tocotrienol has potential use as a therapeutic dietary supplement for minimizing tumor angiogenesis.”,”author”:{“dropping-particle”:””,”family”:”Inokuchi”,”given”:”Hitoshi”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Hirokane”,”given”:”Hisako”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Tsuzuki”,”given”:”Tsuyoshi”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Nakagawa”,”given”:”Kiyotaka”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Igarashi”,”given”:”Miki”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Miyazawa”,”given”:”Teruo”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Bioscience, biotechnology, and biochemistry”,”id”:”ITEM-1″,”issue”:”7″,”issued”:{“date-parts”:”2003″},”page”:”1623-7″,”title”:”Anti-angiogenic activity of tocotrienol.”,”type”:”article-journal”,”volume”:”67″},”uris”:”http://www.mendeley.com/documents/?uuid=7ab698bd-8e99-49d8-bdf6-43973d4f6db2″,”http://www.mendeley.com/documents/?uuid=d197b092-74af-4771-857f-78ff452aae7f”},{“id”:”ITEM-2″,”itemData”:{“DOI”:”10.1196/annals.1331.057″,”ISSN”:”00778923″,”PMID”:”15753181″,”abstract”:”We investigated the antiangiogenic property and mechanism of vitamin E compounds, with particular emphasis on tocotrienol (T3), a natural analogue of tocopherol (Toc). T3 inhibited both the proliferation and tube formation of bovine aortic endothelial cells, with delta-T3 appearing to have the highest activity. delta-T3 also reduced the vascular endothelial growth factor (VEGF)-stimulated tube formation by human umbilical vein endothelial cells. Moreover, delta-T3 inhibited the new blood vessel formation on the growing chick embryo chorioallantoic membrane (assay for in vivo angiogenesis). Orally administered T3 suppressed the tumor cell-induced angiogenesis in the mouse dorsal air sac assay. In contrast with T3, Toc showed very weak inhibition. Based on DNA microarray analysis, antiangiogenic effect of T3 was attributable in part to regulation of intracellular VEGF signaling (phospholipase C-gamma and protein kinase C). Our findings suggest that T3 has potential as a therapeutic dietary supplement for preventing angiogenic disorders.”,”author”:{“dropping-particle”:””,”family”:”Miyazawa”,”given”:”Teruo”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Tsuzuki”,”given”:”Tsuyoshi”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Nakagawa”,”given”:”Kiyotaka”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Igarashi”,”given”:”Miki”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Annals of the New York Academy of Sciences”,”id”:”ITEM-2″,”issued”:{“date-parts”:”2004″},”page”:”401-404″,”title”:”Antiangiogenic potency of vitamin E”,”type”:”paper-conference”,”volume”:”1031″},”uris”:”http://www.mendeley.com/documents/?uuid=05a40a07-6b05-4e05-8819-0b39412fb9ae”,”http://www.mendeley.com/documents/?uuid=42dfe6c7-fdc7-40e0-859e-b3cc2e948ade”},{“id”:”ITEM-3″,”itemData”:{“DOI”:”10.1023/B:BIRY.0000016353.18007.39″,”ISSN”:”00062979″,”PMID”:”14972020″,”abstract”:”Modulation of angiogenesis is now a recognized strategy for the prevention of various angiogenesis-mediated disorders. We investigated, using well-characterized in vitro systems, the anti-angiogenic property of vitamin E compounds, with particular emphasis on tocotrienol, a natural analog of tocopherol. Tocotrienol, but not tocopherol, inhibited the proliferation of bovine aortic endothelial cells in dose dependent manner at half-maximal concentrations in the low micromolar range. Tocotrienol also significantly inhibited the formation of networks of elongated endothelial cells within 3D collagen gels. From these results, we suggest that tocotrienol is a potential candidate for the development of useful therapeutic agents or preventive food factors for tumor angiogenesis.”,”author”:{“dropping-particle”:””,”family”:”Miyazawa”,”given”:”T.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Inokuchi”,”given”:”H.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Hirokane”,”given”:”H.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Tsuzuki”,”given”:”T.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Nakagawa”,”given”:”K.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Igarashi”,”given”:”M.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Biochemistry (Moscow)”,”id”:”ITEM-3″,”issue”:”1″,”issued”:{“date-parts”:”2004″},”page”:”67-69″,”title”:”Anti-angiogenic potential of tocotrienol in vitro”,”type”:”paper-conference”,”volume”:”69″},”uris”:”http://www.mendeley.com/documents/?uuid=c70a59d4-4a99-4480-82eb-ba6d7f12ebe8″,”http://www.mendeley.com/documents/?uuid=c463f30f-92ac-43e2-9423-a4e73b2f1bec”},”mendeley”:{“formattedCitation”:”(Inokuchi et al., 2003; T. Miyazawa et al., 2004; Teruo Miyazawa, Tsuzuki, Nakagawa, & Igarashi, 2004)”,”manualFormatting”:”( Inokuchi, Hirokane, Tsuzuki, Nakagawa, Igarashi, Miyazawa, 2003; Miyazawa, Inokuchi, Hirokane, Tsuzuki, Nakagawa, Igarashi, 2004; Teruo Miyazawa, Tsuzuki, Nakagawa, & Igarashi, 2004)”,”plainTextFormattedCitation”:”(Inokuchi et al., 2003; T. Miyazawa et al., 2004; Teruo Miyazawa, Tsuzuki, Nakagawa, & Igarashi, 2004)”,”previouslyFormattedCitation”:”(Inokuchi et al., 2003; T. Miyazawa et al., 2004; Teruo Miyazawa, Tsuzuki, Nakagawa, & Igarashi, 2004)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}( Inokuchi, Hirokane, Tsuzuki, Nakagawa, Igarashi, Miyazawa, 2003; Miyazawa, Inokuchi, Hirokane, Tsuzuki, Nakagawa, Igarashi, 2004; Teruo Miyazawa, Tsuzuki, Nakagawa, ; Igarashi, 2004). All of these reports point to differences in the mechanisms of action of the tocotrienol isomers.
Alpha-tocotrienolComparing alpha-tocotrienol and ?-tocopherol in their antioxidant activityAlpha-tocotrienol possesses numerous functions that are not shared by ?-tocopherol. For example, nanomolar concentrations of ?-tocotrienol uniquely prevents inducible neurodegeneration by regulating specific mediators of cell death ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1074/jbc.M307075200″,”ISBN”:”4350843515″,”ISSN”:”00219258″,”PMID”:”12917400″,”abstract”:”Vitamin E is a generic term for tocopherols and tocotrienols. This work is based on our striking evidence that, in neuronal cells, nanomolar concentrations of alpha-tocotrienol, but not alpha-tocopherol, block glutamate-induced death by suppressing early activation of c-Src kinase (Sen, C. K., Khanna, S., Roy, S., and Packer, L. (2000) J. Biol. Chem. 275, 13049-13055). This study on HT4 and immature primary cortical neurons suggests a central role of 12-lipoxygenase (12-LOX) in executing glutamate-induced neurodegeneration. BL15, an inhibitor of 12-LOX, prevented glutamate-induced neurotoxicity. Moreover, neurons isolated from 12-LOX-deficient mice were observed to be resistant to glutamate-induced death. In the presence of nanomolar alpha-tocotrienol, neurons were resistant to glutamate-, homocysteine-, and l-buthionine sulfoximine-induced toxicity. Long-term time-lapse imaging studies revealed that neurons and their axo-dendritic network are fairly motile under standard culture conditions. Such motility was arrested in response to glutamate challenge. Tocotrienol-treated primary neurons maintained healthy growth and motility even in the presence of excess glutamate. The study of 12-LOX activity and metabolism revealed that this key mediator of glutamate-induced neurodegeneration is subject to control by the nutrient alpha-tocotrienol. In silico docking studies indicated that alpha-tocotrienol may hinder the access of arachidonic acid to the catalytic site of 12-LOX by binding to the opening of a solvent cavity close to the active site. These findings lend further support to alpha-tocotrienol as a potent neuroprotective form of vitamin E.”,”author”:{“dropping-particle”:””,”family”:”Khanna”,”given”:”Savita”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Roy”,”given”:”Sashwati”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Ryu”,”given”:”Hoon”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Bahadduri”,”given”:”Praveen”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Swaan”,”given”:”Peter W.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Ratan”,”given”:”Rajiv R.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Sent”,”given”:”Chandan K.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Journal of Biological Chemistry”,”id”:”ITEM-1″,”issued”:{“date-parts”:”2003″},”title”:”Molecular Basis of Vitamin E Action: Tocotrienol modulates 12-lipoxygenase, a key mediator of glutamate-induced neurodegeneration”,”type”:”article-journal”},”uris”:”http://www.mendeley.com/documents/?uuid=9ed1a86a-fce6-4748-8d31-8cd0da0d6dfc”},{“id”:”ITEM-2″,”itemData”:{“DOI”:”10.1074/jbc.275.17.13049″,”ISBN”:”0021-9258 (Print)\n0021-9258 (Linking)”,”ISSN”:”00219258″,”PMID”:”10777609″,”abstract”:”HT4 hippocampal neuronal cells were studied to compare the efficacy of tocopherols and tocotrienol to protect against glutamate-induced death. Tocotrienols were more effective than alpha-tocopherol in preventing glutamate-induced death. Uptake of tocotrienols from the culture medium was more efficient compared with that of alpha-tocopherol. Vitamin E molecules have potent antioxidant properties. Results show that at low concentrations, tocotrienols may have protected cells by an antioxidant-independent mechanism. Examination of signal transduction pathways revealed that protein tyrosine phosphorylation processes played a central role in the execution of death. Activation of pp60(c-Src) kinase and phosphorylation of ERK were observed in response to glutamate treatment. Nanomolar amounts of alpha-tocotrienol, but not alpha-tocopherol, blocked glutamate-induced death by suppressing glutamate-induced early activation of c-Src kinase. Overexpression of kinase-active c-Src sensitized cells to glutamate-induced death. Tocotrienol treatment prevented death of Src-overexpressing cells treated with glutamate. alpha-Tocotrienol did not influence activity of recombinant c-Src kinase suggesting that its mechanism of action may include regulation of SH domains. This study provides first evidence describing the molecular basis of tocotrienol action. At a concentration 4-10-fold lower than levels detected in plasma of supplemented humans, tocotrienol regulated unique signal transduction processes that were not sensitive to comparable concentrations of tocopherol.”,”author”:{“dropping-particle”:””,”family”:”Sen”,”given”:”Chandan K.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Khanna”,”given”:”Savita”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Roy”,”given”:”Sashwati”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Packer”,”given”:”Lester”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Journal of Biological Chemistry”,”id”:”ITEM-2″,”issue”:”17″,”issued”:{“date-parts”:”2000″},”page”:”13049-13055″,”title”:”Molecular basis of vitamin E action. Tocotrienol potently inhibits glutamate-induced pp(60c-Src) kinase activation and death of HT4 neuronal cells”,”type”:”article-journal”,”volume”:”275″},”uris”:”http://www.mendeley.com/documents/?uuid=7df26f48-63d0-4f4c-a03d-3114a6a6c8dd”},”mendeley”:{“formattedCitation”:”(Khanna et al., 2003; Sen et al., 2000)”,”plainTextFormattedCitation”:”(Khanna et al., 2003; Sen et al., 2000)”,”previouslyFormattedCitation”:”(Khanna et al., 2003; Sen et al., 2000)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Khanna et al., 2003; Sen et al., 2000). In addition, tocopherols do not seem to share the cholesterol-lowering properties of tocotrienol ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“ISBN”:”1054410550″,”ISSN”:”00219258″,”PMID”:”3733719″,”abstract”:”Purification of the oily, nonpolar fraction of high protein barley (Hordeum vulgare L.) flour by high pressure liquid chromatography yielded 10 major components, two (I, II) of which were potent inhibitors of cholesterogenesis in vivo and in vitro. The addition of purified inhibitor I (2.5-20 ppm) to chick diets significantly decreased hepatic cholesterogenesis and serum total and low density lipoprotein cholesterol and concomitantly increased lipogenic activity. The high resolution mass spectrometric analysis and measurement of different peaks of inhibitor I gave a molecular ion at m/e 424 (C29H44O2) and main peaks at m/e 205, 203, and 165 corresponding to C13H17O2, C13H15O2, and C10H13O2 moieties, respectively. which are characteristic of d-alpha-tocotrienol. This identification was confirmed against synthetic samples. The tocotrienols are widely distributed in the plant kingdom and differ from tocopherols (vitamin E) only in three double bonds in the isoprenoid chain which appear to be essential for the inhibition of cholesterogenesis.”,”author”:{“dropping-particle”:””,”family”:”Qureshi”,”given”:”A. A.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Burger”,”given”:”W. C.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Peterson”,”given”:”D. M.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Elson”,”given”:”C. E.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Journal of Biological Chemistry”,”id”:”ITEM-1″,”issued”:{“date-parts”:”1986″},”title”:”The structure of an inhibitor of cholesterol biosysnthesis isolated from barley”,”type”:”article-journal”},”uris”:”http://www.mendeley.com/documents/?uuid=3c397ae3-bf29-461c-9303-c078f87a1117″},{“id”:”ITEM-2″,”itemData”:{“DOI”:”10.1016/S0021-9150(01)00619-0″,”ISBN”:”0021-9150 (Print)\n0021-9150 (Linking)”,”ISSN”:”00219150″,”PMID”:”11882333″,”abstract”:”Tocotrienols are effective in lowering serum total and LDL-cholesterol levels by inhibiting the hepatic enzymic activity of ?-hydroxy-?-methylglutaryl coenzymeA (HMG-CoA) reductase through the post-transcriptional mechanism. ?-Tocopherol, however, has an opposite effect (induces) on this enzyme activity. Since tocotrienols are also converted to tocopherols in vivo, it is necessary not to exceed a certain dose, as this would be counter-productive. The present study demonstrates the effects of various doses of a tocotrienol-rich fraction (TRF25) of stabilized and heated rice bran in hypercholesterolemic human subjects on serum lipid parameters. Ninety (18/group) hypercholesterolemic human subjects participated in this study, which comprised three phases of 35 days each. The subjects were initially placed on the American Heart Association (AHA) Step-1 diet and the effects noted. They were then administered 25, 50, 100, and 200 mg/day of TRF25while on the restricted (AHA) diet. The results show that a dose of 100 mg/day of TRF25produce maximum decreases of 20, 25, 14 (P<0.05) and 12%, respectively, in serum total cholesterol, LDL-cholesterol, apolipoprotein B and triglycerides compared with the baseline values, suggesting that a dose of 100 mg/day TRF25plus AHA Step-1 diet may be the optimal dose for controlling the risk of coronary heart disease in hypercholesterolemic human subjects. © 2002 Elsevier Science Ireland Ltd. All rights reserved.”,”author”:{“dropping-particle”:””,”family”:”Qureshi”,”given”:”Asaf A.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Sami”,”given”:”Saeed A.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Salser”,”given”:”Winston A.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Khan”,”given”:”Farooq A.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Atherosclerosis”,”id”:”ITEM-2″,”issued”:{“date-parts”:”2002″},”title”:”Dose-dependent suppression of serum cholesterol by tocotrienol-rich fraction (TRF25) of rice bran in hypercholesterolemic humans”,”type”:”article-journal”},”uris”:”http://www.mendeley.com/documents/?uuid=67a888cd-9b6b-49ad-80a6-d042025a03e3″},”mendeley”:{“formattedCitation”:”(A. A. Qureshi, Burger, Peterson, & Elson, 1986; Asaf A. Qureshi, Sami, Salser, & Khan, 2002)”,”manualFormatting”:”(Qureshi, Burger, Peterson, & Elson, 1986; Qureshi, Sami, Salser, & Khan, 2002)”,”plainTextFormattedCitation”:”(A. A. Qureshi, Burger, Peterson, & Elson, 1986; Asaf A. Qureshi, Sami, Salser, & Khan, 2002)”,”previouslyFormattedCitation”:”(A. A. Qureshi, Burger, Peterson, & Elson, 1986; Asaf A. Qureshi, Sami, Salser, & Khan, 2002)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Qureshi, Burger, Peterson, ; Elson, 1986; Qureshi, Sami, Salser, ; Khan, 2002). Tocotrienol, not tocopherol, administration reduces oxidative protein damage and extends the mean lifespan of C. elegans. ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1093/gerona/55.6.B280″,”ISBN”:”1079-5006 (Print)”,”ISSN”:”1079-5006″,”PMID”:”10843344″,”abstract”:”To assess the efficiency of tocotrienols against oxidative damage, we have demonstrated in a model-system nematode, Caenorhabditis elegans, that tocotrienol administration reduced the accumulation of protein carbonyl (a good indicator of oxidative damage during aging) and consequently extended the mean life span (LS), but not the maximum LS. Conversely, alpha-tocopherol acetate did not affect these parameters. As a way to evaluate the protective ability of tocotrienols against oxidative stress, the life spans of animals administrated tocotrienols before or after exposure to ultraviolet B-induced oxidative stress were measured. Ultraviolet B irradiation shortened the mean LS of animals, whereas preadministration of tocotrienols recovered the mean LS to that of unirradiated animals. Interestingly, postadministration also extended the mean LS more than that of unirradiated animals, and administration through the LS conferred greater protection. Thus, the administration of tocotrienols to animals results in a reduction of oxidative stress risks. These data indicated that tocotrienols merit further investigation as possible agents for antiaging and oxidative stress prevention. In addition, they suggest that C. elegans will continue to provide provocative clues into the mechanisms of aging.”,”author”:{“dropping-particle”:””,”family”:”Adachi”,”given”:”H”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Ishii”,”given”:”N”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”The journals of gerontology. Series A, Biological sciences and medical sciences”,”id”:”ITEM-1″,”issued”:{“date-parts”:”2000″},”title”:”Effects of tocotrienols on life span and protein carbonylation in Caenorhabditis elegans.”,”type”:”article-journal”},”uris”:”http://www.mendeley.com/documents/?uuid=f2202702-c9ee-4567-a5ad-23da55daf1f8″},”mendeley”:{“formattedCitation”:”(Adachi & Ishii, 2000)”,”plainTextFormattedCitation”:”(Adachi & Ishii, 2000)”,”previouslyFormattedCitation”:”(Adachi & Ishii, 2000)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Adachi ; Ishii, 2000). Furthermore, tocotrienol but not tocopherol, suppresses growth of human breast cancer cells ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1007/BF02536615″,”ISSN”:”0024-4201″,”PMID”:”8614304″,”abstract”:”The tocotrienol-rich fraction (TRF) of palm oil consists of tocotrienols and some alpha-tocopherol (alpha-T). Tocotrienols are a form of vitamin E having an unsaturated side-chain, rather than the saturated side-chain of the more common tocopherols. Because palm oil has been shown not to promote chemically-induced mammary carcinogenesis, we tested effects of TRF and alpha-T on the proliferation, growth, and plating efficiency (PE) of the MDA-MB-435 estrogen-receptor-negative human breast cancer cells. TRF inhibited the proliferation of these cells with a concentration required to inhibit cell proliferation by 50% of 180 microgram/mL whereas alpha-T had no effect at concentrations up to 1000 microgram/mL as measured by incorporation of 3Hthymidine. The effects of TRF and alpha-T also were tested in longer-term growth experiments, using concentrations of 180 and 500 microgram/mL. We found that TRF inhibited the growth of these cells by 50%, whereas alpha-T did not. Their effect on the ability of these cells to form colonies also was studied, and it was found that TRF inhibited PE, whereas alpha T had no effect. These results suggest that the inhibition is due to the presence of tocotrienols in TRF rather than alpha T.”,”author”:{“dropping-particle”:””,”family”:”Nesaretnam”,”given”:”K”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Guthrie”,”given”:”N”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Chambers”,”given”:”A F”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Carroll”,”given”:”K K”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Lipids”,”id”:”ITEM-1″,”issued”:{“date-parts”:”1995″},”title”:”Effect of tocotrienols on the growth of a human breast cancer cell line in culture.”,”type”:”article-journal”},”uris”:”http://www.mendeley.com/documents/?uuid=3e393532-5ba6-4a3e-8b1b-27afea833a1c”},”mendeley”:{“formattedCitation”:”(Nesaretnam, Guthrie, Chambers, & Carroll, 1995)”,”plainTextFormattedCitation”:”(Nesaretnam, Guthrie, Chambers, & Carroll, 1995)”,”previouslyFormattedCitation”:”(Nesaretnam, Guthrie, Chambers, & Carroll, 1995)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Nesaretnam, Guthrie, Chambers, ; Carroll, 1995).

There are two factors that must be considered to compare the difference between vitamin E homologues. The factors are constituents on the chromanol nucleus and the properties of the side chain. The activity of ?-tocotrienol in scavenging peroxyl radicals is 1.5-fold higher in liposomes compared with a-tocopherol ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1016/0891-5849(91)90033-Y”,”ISBN”:”0891-5849 (Print)\r0891-5849″,”ISSN”:”08915849″,”PMID”:”1649783″,”abstract”:”d-Alpha-tocopherol (2R, 4?R,8?R-Alpha-tocopherol) and d-alpha-tocotrienol are two main vitamin E constituents having the same aromatic chromanol “head” but differing in their hydrocarbon “tail”: tocopherol with a saturated and toctrienol with an unsaturated isoprenoid chain. d-Alpha-tocopherol has the highest vitamin E activity, while d-alpha-tocotrienol manifests only about 30% of this activity. Since vitamin E is considered to be physiologically the most important lipid-soluble chain-breaking antioxidant of membranes, we studied alpha-tocotrienol as compared to alpha-tocopherol under conditions which are important for their antioxidant function. d-Alpha-tocotrienol possesses 40-60 times higher antioxidant activity against (Fe2+ + ascorbate)- and (Fe2+ + NADPH)-induced lipid peroxidation in rat liver microsomal membranes and 6.5 times better protection of cytochrome P-450 against oxidative damage than d-alpha-tocopherol. To clarify the mechanisms responsible for the much higher antioxidant potency of d-alpha-tocotrienol compared to d-alpha-tocopherol, ESR studies were performed of recycling efficiency of the chromanols from their chromanoxyl radicals, 1H-NMR measurements of lipid molecular mobility in liposomes containing chromanols, and fluorescence measurements which reveal the uniformity of distribution (clusterizations) of chromanols in the lipid bilayer. From the results, we concluded that this higher antioxidant potency of d-alpha-tocotrienol is due to the combined effects of three properties exhibited by d-alpha-tocotrienol as compared to d-alpha-tocopherol: (i) its higher recycling efficiency from chromanoxyl radicals, (ii) its more uniform distribution in membraned bilayer, and (iii) its stronger disordering of membrane lipids which makes interaction of chromanols with lipid radicals more efficient. The data presented show that there is a considerable discrepancy between the relative in vitro antioxidant activity of d-alpha-tocotrienol with the conventional bioassays of their vitamin activity. © 1991.”,”author”:{“dropping-particle”:””,”family”:”Serbinova”,”given”:”Elena”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Kagan”,”given”:”Valerian”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Han”,”given”:”Derick”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Packer”,”given”:”Lester”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Free Radical Biology and Medicine”,”id”:”ITEM-1″,”issue”:”5″,”issued”:{“date-parts”:”1991″},”page”:”263-275″,”title”:”Free radical recycling and intramembrane mobility in the antioxidant properties of alpha-tocopherol and alpha-tocotrienol”,”type”:”article-journal”,”volume”:”10″},”uris”:”http://www.mendeley.com/documents/?uuid=dfda199a-9691-4f26-9ca2-2baa60e5cacd”,”http://www.mendeley.com/documents/?uuid=0bbeb224-d552-4ee9-a0c0-be88d6fe5984″},”mendeley”:{“formattedCitation”:”(E. Serbinova et al., 1991)”,”manualFormatting”:”(Serbinova et al., 1991)”,”plainTextFormattedCitation”:”(E. Serbinova et al., 1991)”,”previouslyFormattedCitation”:”(E. Serbinova et al., 1991)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Serbinova et al., 1991). The efficacy of ?-tocotrienol to protect against Fe (II) + NADPH-induced lipid peroxidation was 40 times higher than a-tocopherol in rat liver microsomes ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1016/0891-5849(91)90033-Y”,”ISBN”:”0891-5849 (Print)\r0891-5849″,”ISSN”:”08915849″,”PMID”:”1649783″,”abstract”:”d-Alpha-tocopherol (2R, 4?R,8?R-Alpha-tocopherol) and d-alpha-tocotrienol are two main vitamin E constituents having the same aromatic chromanol “head” but differing in their hydrocarbon “tail”: tocopherol with a saturated and toctrienol with an unsaturated isoprenoid chain. d-Alpha-tocopherol has the highest vitamin E activity, while d-alpha-tocotrienol manifests only about 30% of this activity. Since vitamin E is considered to be physiologically the most important lipid-soluble chain-breaking antioxidant of membranes, we studied alpha-tocotrienol as compared to alpha-tocopherol under conditions which are important for their antioxidant function. d-Alpha-tocotrienol possesses 40-60 times higher antioxidant activity against (Fe2+ + ascorbate)- and (Fe2+ + NADPH)-induced lipid peroxidation in rat liver microsomal membranes and 6.5 times better protection of cytochrome P-450 against oxidative damage than d-alpha-tocopherol. To clarify the mechanisms responsible for the much higher antioxidant potency of d-alpha-tocotrienol compared to d-alpha-tocopherol, ESR studies were performed of recycling efficiency of the chromanols from their chromanoxyl radicals, 1H-NMR measurements of lipid molecular mobility in liposomes containing chromanols, and fluorescence measurements which reveal the uniformity of distribution (clusterizations) of chromanols in the lipid bilayer. From the results, we concluded that this higher antioxidant potency of d-alpha-tocotrienol is due to the combined effects of three properties exhibited by d-alpha-tocotrienol as compared to d-alpha-tocopherol: (i) its higher recycling efficiency from chromanoxyl radicals, (ii) its more uniform distribution in membraned bilayer, and (iii) its stronger disordering of membrane lipids which makes interaction of chromanols with lipid radicals more efficient. The data presented show that there is a considerable discrepancy between the relative in vitro antioxidant activity of d-alpha-tocotrienol with the conventional bioassays of their vitamin activity. © 1991.”,”author”:{“dropping-particle”:””,”family”:”Serbinova”,”given”:”Elena”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Kagan”,”given”:”Valerian”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Han”,”given”:”Derick”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Packer”,”given”:”Lester”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Free Radical Biology and Medicine”,”id”:”ITEM-1″,”issue”:”5″,”issued”:{“date-parts”:”1991″},”page”:”263-275″,”title”:”Free radical recycling and intramembrane mobility in the antioxidant properties of alpha-tocopherol and alpha-tocotrienol”,”type”:”article-journal”,”volume”:”10″},”uris”:”http://www.mendeley.com/documents/?uuid=dfda199a-9691-4f26-9ca2-2baa60e5cacd”,”http://www.mendeley.com/documents/?uuid=0bbeb224-d552-4ee9-a0c0-be88d6fe5984″},”mendeley”:{“formattedCitation”:”(E. Serbinova et al., 1991)”,”manualFormatting”:”(Serbinova et al., 1991)”,”plainTextFormattedCitation”:”(E. Serbinova et al., 1991)”,”previouslyFormattedCitation”:”(E. Serbinova et al., 1991)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Serbinova et al., 1991). Alpha-tocotrienol was 6.5 times more effective in protection of cytochrome P-450 against oxidative damage ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1016/0891-5849(91)90033-Y”,”ISBN”:”0891-5849 (Print)\r0891-5849″,”ISSN”:”08915849″,”PMID”:”1649783″,”abstract”:”d-Alpha-tocopherol (2R, 4?R,8?R-Alpha-tocopherol) and d-alpha-tocotrienol are two main vitamin E constituents having the same aromatic chromanol “head” but differing in their hydrocarbon “tail”: tocopherol with a saturated and toctrienol with an unsaturated isoprenoid chain. d-Alpha-tocopherol has the highest vitamin E activity, while d-alpha-tocotrienol manifests only about 30% of this activity. Since vitamin E is considered to be physiologically the most important lipid-soluble chain-breaking antioxidant of membranes, we studied alpha-tocotrienol as compared to alpha-tocopherol under conditions which are important for their antioxidant function. d-Alpha-tocotrienol possesses 40-60 times higher antioxidant activity against (Fe2+ + ascorbate)- and (Fe2+ + NADPH)-induced lipid peroxidation in rat liver microsomal membranes and 6.5 times better protection of cytochrome P-450 against oxidative damage than d-alpha-tocopherol. To clarify the mechanisms responsible for the much higher antioxidant potency of d-alpha-tocotrienol compared to d-alpha-tocopherol, ESR studies were performed of recycling efficiency of the chromanols from their chromanoxyl radicals, 1H-NMR measurements of lipid molecular mobility in liposomes containing chromanols, and fluorescence measurements which reveal the uniformity of distribution (clusterizations) of chromanols in the lipid bilayer. From the results, we concluded that this higher antioxidant potency of d-alpha-tocotrienol is due to the combined effects of three properties exhibited by d-alpha-tocotrienol as compared to d-alpha-tocopherol: (i) its higher recycling efficiency from chromanoxyl radicals, (ii) its more uniform distribution in membraned bilayer, and (iii) its stronger disordering of membrane lipids which makes interaction of chromanols with lipid radicals more efficient. The data presented show that there is a considerable discrepancy between the relative in vitro antioxidant activity of d-alpha-tocotrienol with the conventional bioassays of their vitamin activity. © 1991.”,”author”:{“dropping-particle”:””,”family”:”Serbinova”,”given”:”Elena”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Kagan”,”given”:”Valerian”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Han”,”given”:”Derick”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Packer”,”given”:”Lester”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Free Radical Biology and Medicine”,”id”:”ITEM-1″,”issue”:”5″,”issued”:{“date-parts”:”1991″},”page”:”263-275″,”title”:”Free radical recycling and intramembrane mobility in the antioxidant properties of alpha-tocopherol and alpha-tocotrienol”,”type”:”article-journal”,”volume”:”10″},”uris”:”http://www.mendeley.com/documents/?uuid=dfda199a-9691-4f26-9ca2-2baa60e5cacd”,”http://www.mendeley.com/documents/?uuid=0bbeb224-d552-4ee9-a0c0-be88d6fe5984″},”mendeley”:{“formattedCitation”:”(E. Serbinova et al., 1991)”,”manualFormatting”:”(Serbinova et al., 1991)”,”plainTextFormattedCitation”:”(E. Serbinova et al., 1991)”,”previouslyFormattedCitation”:”(E. Serbinova et al., 1991)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Serbinova et al., 1991).

NICOTINEOverview
Nicotine is used in tobacco. It also used as a pharmacological aid in smoking cessation. Nicotine is metabolized primarily by the liver enzymes CYP2A6, UDP-glucuronosyltransferase (UGT), and Flavin-containing monooxygenase (FMO). In addition to genetic factors, nicotine metabolism is influenced by diet and meals, age, sex, use of estrogen-containing hormone preparations, pregnancy and kidney disease, other medications and smoking itself. Cotinine is the most widely used biomarker of nicotine intake which may be measured in blood, urine, saliva, hair, or nails ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1007/978-3-540-69248-5_18″,”ISBN”:”9783540692461″,”ISSN”:”01712004″,”PMID”:”19184655″,”abstract”:”The fact that tobacco ingestion can affect how people feel and think has been known for millennia, placing the plant among those used spiritually, honori?cally, and habitually (Corti 1931; Wilbert 1987). However, the conclusion that nicotine – counted for many of these psychopharmacological effects did not emerge until the nineteenth century (Langley 1905). This was elegantly described by Lewin in 1931 as follows: “The decisive factor in the effects of tobacco, desired or undesired, is nicotine. . . “(Lewin 1998). The use of nicotine as a pharmacological probe to und- stand physiological functioning at the dawn of the twentieth century was a landmark in the birth of modern neuropharmacology (Limbird 2004; Halliwell 2007), and led the pioneering researcher John Langley to conclude that there must exist some “- ceptive substance” to explain the diverse actions of various substances, including nicotine, when applied to muscle tissue (Langley 1905). Research on tobacco and nicotine progressed throughout the twentieth century, but much of this was from a general pharmacological and toxicological rather than a psychopharmacological perspective (Larson et al. 1961). There was some attention to the effects related to addiction, such as euphoria (Johnston 1941), tolerance (Lewin 1931), and withdrawal (Finnegan et al. 1945), but outside of research supported by the tobacco industry, addiction and psychopharmacology were not major foci for research (Slade et al. 1995; Hurt and Robertson 1998; Henning?eld et al. 2006; Henning?eld and Hartel 1999; Larson et al. 1961).”,”author”:{“dropping-particle”:””,”family”:”Henningfield”,”given”:”Jack E.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Zeller”,”given”:”Mitch”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Handbook of Experimental Pharmacology”,”id”:”ITEM-1″,”issued”:{“date-parts”:”2009″},”page”:”511-534″,”title”:”Nicotine psychopharmacology: Policy and regulatory”,”type”:”article”,”volume”:”192″},”uris”:”http://www.mendeley.com/documents/?uuid=8a37f026-21c8-4ba0-84fb-406598ff74cf”,”http://www.mendeley.com/documents/?uuid=86bd1674-c7ac-4f66-b7ef-db749d486106″},”mendeley”:{“formattedCitation”:”(Henningfield & Zeller, 2009)”,”plainTextFormattedCitation”:”(Henningfield & Zeller, 2009)”,”previouslyFormattedCitation”:”(Henningfield & Zeller, 2009)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Henningfield ; Zeller, 2009).

Harmful effects of nicotineNicotine increased the risk of cardiovascular ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1172/JCI113227″,”ISSN”:”00219738″,”PMID”:”3680508″,”abstract”:”Persons exposed to nicotine develop tolerance to many of its effects. When heart rate and forearm venous blood concentration are plotted against time after intravenous administration of nicotine, a greater increase in heart rate is seen for a given nicotine concentration during the rising phase of nicotine concentrations than during the decreasing phase. This could be due to acute tolerance or to more rapid distribution of drug to effect site (brain) than to venous blood. To distinguish between these possibilities, six rabbits were given nicotine intravenously. Blood samples were taken from the internal jugular vein (reflecting brain concentration), and the femoral vein and artery. Brain concentrations peaked before femoral venous concentrations. Seven men received intravenous infusions of nicotine. Peripheral venous blood concentrations and cardiovascular responses were measured. Heart rate peaked before venous concentrations. A physiological kinetic model, fit to the rabbit data, was scaled to humans and used to predict “brain” concentrations in them. Heart rate and predicted brain concentrations peaked simultaneously. We conclude that the rapid development of tolerance to the cardioaccelerating effect of nicotine can be attributed, at least in part, to its distribution kinetics.”,”author”:{“dropping-particle”:””,”family”:”Porchet”,”given”:”H. C.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Benowitz”,”given”:”N. L.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Sheiner”,”given”:”L. B.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Copeland”,”given”:”J. R.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Journal of Clinical Investigation”,”id”:”ITEM-1″,”issue”:”5″,”issued”:{“date-parts”:”1987″},”page”:”1466-1471″,”title”:”Apparent tolerance to the acute effect of nicotine results in part from distribution kinetics”,”type”:”article-journal”,”volume”:”80″},”uris”:”http://www.mendeley.com/documents/?uuid=5ff1475a-f568-47e6-a5b9-cbcfa53cc1f1″,”http://www.mendeley.com/documents/?uuid=dc87b324-8887-45ec-b2db-a2c1b1fce88a”},”mendeley”:{“formattedCitation”:”(Porchet, Benowitz, Sheiner, & Copeland, 1987)”,”plainTextFormattedCitation”:”(Porchet, Benowitz, Sheiner, & Copeland, 1987)”,”previouslyFormattedCitation”:”(Porchet, Benowitz, Sheiner, & Copeland, 1987)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Porchet, Benowitz, Sheiner, ; Copeland, 1987), respiratory ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1523/JNEUROSCI.3711-12.2013″,”ISBN”:”1529-2401 (Electronic) 0270-6474 (Linking)”,”ISSN”:”0270-6474″,”PMID”:”23392689″,”abstract”:”Developmental nicotine exposure (DNE) impacts central respiratory control in neonates born to smoking mothers. We previously showed that DNE enhances the respiratory motor response to bath application of AMPA to the brainstem, although it was unclear which brainstem respiratory neurons mediated these effects (Pilarski and Fregosi, 2009). Here we examine how DNE influences AMPA-type glutamatergic neurotransmission in the pre-Bötzinger complex (pre-BötC) and the hypoglossal motor nucleus (XIIMN), which are neuronal populations located in the medulla that are necessary for normal breathing. Using rhythmic brainstem slices from neonatal rats, we microinjected AMPA into the pre-BötC or the XIIMN while recording from XII nerve rootlets (XIIn) as an index of respiratory motor output. DNE increased the duration of tonic activity and reduced rhythmic burst amplitude after AMPA microinjection into the XIIMN. Also, DNE led to an increase in respiratory burst frequency after AMPA injection into the pre-BötC. Whole-cell patch-clamp recordings of XII motoneurons showed that DNE increased motoneuron excitability but did not change inward currents. Immunohistochemical studies indicate that DNE reduced the expression of glutamate receptor subunits 2 and 3 (GluR2/3) in the XIIMN and the pre-BötC. Our data show that DNE alters AMPAergic synaptic transmission in both the XIIMN and pre-BötC, although the mechanism by which this occurs is unclear. We suggest that the DNE-induced reduction in GluR2/3 may represent an attempt to compensate for increased cell excitability, consistent with mechanisms underlying homeostatic plasticity.”,”author”:{“dropping-particle”:””,”family”:”Jaiswal”,”given”:”S. J.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Pilarski”,”given”:”J. Q.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Harrison”,”given”:”C. M.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Fregosi”,”given”:”R. F.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Journal of Neuroscience”,”id”:”ITEM-1″,”issue”:”6″,”issued”:{“date-parts”:”2013″},”page”:”2616-2625″,”title”:”Developmental Nicotine Exposure Alters AMPA Neurotransmission in the Hypoglossal Motor Nucleus and Pre-Botzinger Complex of Neonatal Rats”,”type”:”article-journal”,”volume”:”33″},”uris”:”http://www.mendeley.com/documents/?uuid=85fa15d6-5916-459b-9cdd-ceecd822d36e”,”http://www.mendeley.com/documents/?uuid=5a386dae-7105-4b35-9565-a4f75836e525″},”mendeley”:{“formattedCitation”:”(Jaiswal, Pilarski, Harrison, & Fregosi, 2013)”,”plainTextFormattedCitation”:”(Jaiswal, Pilarski, Harrison, & Fregosi, 2013)”,”previouslyFormattedCitation”:”(Jaiswal, Pilarski, Harrison, & Fregosi, 2013)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Jaiswal, Pilarski, Harrison, ; Fregosi, 2013), and gastrointestinal disorders ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“ISSN”:”0928-4257 (Print)”,”PMID”:”8292987″,”abstract”:”Chronic nicotine treatment worsens stomach mucosal damage by cold (4 degrees C) and restraint (stress): it dose- and time-dependently intensifies stress-evoked gastric glandular ulceration, mast cell degranulation and motility. Nicotine 50 micrograms/ml drinking water, given ad libitum to female Sprague-Dawley rats for 10 days, increases the sensitivity of the isolated stomach strip to acetylcholine-induced contractions; atropine abolishes this action. The isolated anococcygeus muscle from nicotine-treated male rats shows increased sensitivity to noradrenaline-induced contractions, but not to those by acetylcholine. Hexamethonium or atropine pretreatment antagonises stress-induced gastric effects in nicotine-drinking rats. Muscarinic M1- and M2-, but not M3-, receptor block (by pirenzepine, AF-DX 116BS and HHSiD, respectively) inhibits stress ulcer formation in female rats. Although tobacco smoking has been reported to increase free radical formation, mucosal xanthine oxidase which initiates free radical formation is uninfluenced by nicotine; antagonising this enzyme (by allopurinol) or hydroxyl free radical scavenging (by dimethylsulfoxide) does not lessen the effect of nicotine on stress-evoked ulceration. The findings suggest that chronic nicotine treatment produces partial ganglionic blockade of the vagal nerve which leads to muscarinic receptor supersensitivity. This phenomenon contributes significantly to the ulcer-worsening mechanism; muscarinic M1- and M2-receptors appear to be involved. The gastric ulcer-aggravating effect of nicotine in stressed rats appears not to be due to increased free radical formation.”,”author”:{“dropping-particle”:””,”family”:”Ogle”,”given”:”C W”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Qiu”,”given”:”B S”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Cho”,”given”:”C H”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Journal of physiology, Paris”,”id”:”ITEM-1″,”issue”:”6″,”issued”:{“date-parts”:”1993″},”page”:”359-365″,”title”:”Nicotine and gastric ulcers in stress.”,”type”:”article-journal”,”volume”:”87″},”uris”:”http://www.mendeley.com/documents/?uuid=08721ebe-f4bc-49ca-a625-6cb16631375c”,”http://www.mendeley.com/documents/?uuid=0cf8325e-f804-466e-ae69-1b8857c380c2″},”mendeley”:{“formattedCitation”:”(Ogle, Qiu, & Cho, 1993)”,”plainTextFormattedCitation”:”(Ogle, Qiu, & Cho, 1993)”,”previouslyFormattedCitation”:”(Ogle, Qiu, & Cho, 1993)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Ogle, Qiu, ; Cho, 1993). It also decrease the immune response ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1016/S0306-4530(97)00076-0″,”ISBN”:”0306-4530 (Print)”,”ISSN”:”03064530″,”PMID”:”9621398″,”abstract”:”Nicotine (NT) treatment impairs T-cell receptor (TCR)-mediated signaling, leading to the arrest of T cells in the G1 phase of the cell cycle and inhibition of the antibody plaque-forming cell (AFC) response to sheep red blood cells (SRBC). This paper summarizes some of the previous findings related to cigarette smoke/NT and the immune response, and presents preliminary evidence suggesting that mice chronically treated with NT (0.5 mg/day/kg body weight) have a depressed inflammatory response in the turpentine-induced abscess model of inflammation. This ability of nicotine to attenuate an inflammatory response may also be the cause of reduced mortality of chronically nicotine-treated mice from acute influenza A pneumonitis. Moreover, in LEW rats, decreased anti-SRBC AFC responses were also observed after intracerebroventricular (ICV) administration of relatively small concentrations of NT (28 ??g/day/kg body weight) which, when given peripherally, did not affect the AFC response. In vitro the addition of NT to T cells increased protein tyrosine kinase (PTK) activity and intracellular Ca2+ concentration Ca2+(i). These results support the hypothesis that NT alters immune responses by directly interacting with T cells, as well as indirectly through brain-immune interactions.”,”author”:{“dropping-particle”:””,”family”:”Sopori”,”given”:”Mohan L.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Kozak”,”given”:”Wieslaw”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Savage”,”given”:”Susan M.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Geng”,”given”:”Yuemei”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Soszynski”,”given”:”Dariusz”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Kluger”,”given”:”Matthew J.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Perryman”,”given”:”Elizabeth K.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Snow”,”given”:”George E.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Psychoneuroendocrinology”,”id”:”ITEM-1″,”issue”:”2″,”issued”:{“date-parts”:”1998″},”page”:”189-204″,”title”:”Effect of nicotine on the immune system: Possible regulation of immune responses by central and peripheral mechanisms”,”type”:”paper-conference”,”volume”:”23″},”uris”:”http://www.mendeley.com/documents/?uuid=856e8947-c5a3-4a18-b3b4-4b3a754f80b4″,”http://www.mendeley.com/documents/?uuid=04404722-1354-40fb-b262-806643ca0142″},”mendeley”:{“formattedCitation”:”(Sopori et al., 1998)”,”manualFormatting”:”( Sopori, Kozak, Savage, Geng, Soszynski, Kluger, Perryman, Snow, 1998)”,”plainTextFormattedCitation”:”(Sopori et al., 1998)”,”previouslyFormattedCitation”:”(Sopori et al., 1998)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}( Sopori, Kozak, Savage, Geng, Soszynski, Kluger, Perryman, Snow, 1998) and also poses ill impacts on the reproductive health ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1093/toxsci/kfq149″,”ISBN”:”9133235538″,”ISSN”:”10960929″,”PMID”:”20498001″,”abstract”:”The present study was done to evaluate the pituitary-testicular activities of rats subjected to chronic nicotine treatment. The testicular key androgenic enzymes activities, plasma and intratesticular testosterone (ITT) concentrations, and plasma concentration of gonadotropin were significantly reduced by nicotine treatment along with the decreased sperm counts and the disruption of spermatogenesis indicated by significant reduction in the number of different generations of germ cells at stage VII of the spermatogenesis cycle with increased sperm head abnormalities. The Western blot and the reverse transcriptase-PCR analysis revealed that the nicotine induced a marked decrease in the expression of testicular steroidogenic acute regulatory (StAR) protein, which helps in the transfer of cholesterol in mitochondria for the testosterone biosynthesis. The increased testicular lipid peroxidation, plasma concentration of corticosterone, with enhanced hydrogen peroxide and hydroxyl radical generations, as well as decreased glutathione level, reduced antioxidant enzymes activities, and mitochondrial membrane potential (Deltapsi(m)) of testis, were noted after nicotine treatment in rats. Human chorionic gonadotropin or taurine supplementation with nicotine prevented the degeneration of germ cells to some extent, restored spermatogenesis moderately with decreased sperm head abnormalities, and enhanced sperm counts, accompanied with increase in plasma and ITT concentrations, testicular StAR gene expression, and key androgenic enzymes activities. Moreover, taurine supplementation to nicotine-treated animals resulted in the diminution of testicular lipid peroxidation, hydrogen peroxide and hydroxyl radical generations, with the elevation in glutathione level as well as different antioxidant enzymes activities and Deltapsi(m) in testis. The results indicated that nicotine caused testicular toxicity by germ cell degeneration, inhibition of StAR gene expression along with androgen production in adult male rats probably by affecting pituitary gonadotropin, and/or modulating the extent of testicular antioxidant status.”,”author”:{“dropping-particle”:””,”family”:”Jana”,”given”:”Kuladip”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Samanta”,”given”:”Prabhat Kumar”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Kumar De”,”given”:”Dipak”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Toxicological Sciences”,”id”:”ITEM-1″,”issue”:”2″,”issued”:{“date-parts”:”2010″},”page”:”647-659″,”title”:”Nicotine diminishes testicular gametogenesis, steroidogenesis, and steroidogenic acute regulatory protein expression in adult albino rats: Possible influence on pituitary gonadotropins and alteration of testicular antioxidant status”,”type”:”article-journal”,”volume”:”116″},”uris”:”http://www.mendeley.com/documents/?uuid=d5c5a144-fba1-4c64-935e-f0173a55ba60″,”http://www.mendeley.com/documents/?uuid=6da779f4-174d-4cc7-84fa-0f3186f3f617″},”mendeley”:{“formattedCitation”:”(Jana, Samanta, & Kumar De, 2010)”,”plainTextFormattedCitation”:”(Jana, Samanta, & Kumar De, 2010)”,”previouslyFormattedCitation”:”(Jana, Samanta, & Kumar De, 2010)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Jana, Samanta, ; Kumar De, 2010).
Female reproductive system
In female reproductive system, nicotine can cause inappropriate cytokine production and irregular bleeding in the endometrium ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“ISBN”:”1122-9497″,”ISSN”:”11229497″,”abstract”:”The composition of the uterine fluid is of importance for the development of the embryo. The ionic composition of the uterine fluid is determined by transport processes in the uterine epithelium. The aim of the present study was to investigate whether nicotine can affect the ion transport processes and ultrastructure of the uterine epithelium in mouse and rat. The effects of nicotine on the uterine epithelium were compared with those on kidney and liver. Nicotine was administered to mice as an intraperitoneal injection of a 1 microgram/l nicotine solution twice daily for 8 days, or in the drinking water (108 microM nicotine) for 15 days, whereas rats received nicotine in their drinking water for 10 days (54 or 108 microM nicotine). In addition, primary cultures of endometrial cells were exposed to nicotine in vitro. Changes in morphology were examined by transmission electron microscopy and changes in elemental content by X-ray microanalysis. Nicotine caused a significant decrease in the concentrations of Na, K, and Cl in the uterine fluid and in the endometrial cells in situ. Similar changes in elemental concentrations were observed in endometrial cells in vitro. Ultrastructural changes in endometrial cells included swollen and damaged mitochondria. In liver and kidney much smaller effects of nicotine on the elemental composition of the cells were observed. However, marked ultrastructural effects were seen in the kidney: a reduction in mitochondrial size and an increase in lysosomal volume. It is concluded that nicotine directly interferes with fluid transport across the uterine epithelium.”,”author”:{“dropping-particle”:””,”family”:”Jin”,”given”:”Z”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Roomans”,”given”:”G M”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Journal of Submicroscopic Cytology & Pathology”,”id”:”ITEM-1″,”issue”:”2″,”issued”:{“date-parts”:”1997″},”page”:”179-186″,”title”:”Effects of nicotine on the uterine epithelium studied by X-ray microanalysis”,”type”:”article-journal”,”volume”:”29″},”uris”:”http://www.mendeley.com/documents/?uuid=ef438643-a0f1-45fb-8826-58bcd29654c6″,”http://www.mendeley.com/documents/?uuid=e0e597f8-acca-4501-a25c-c523111b358f”},”mendeley”:{“formattedCitation”:”(Jin & Roomans, 1997)”,”plainTextFormattedCitation”:”(Jin & Roomans, 1997)”,”previouslyFormattedCitation”:”(Jin & Roomans, 1997)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Jin ; Roomans, 1997). Histological observations in uterus showed decrease in the thickness of myometrium, endometrium and its epithelial cells. ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“ISSN”:”00195499″,”PMID”:”10874351″,”abstract”:”Nicotine at the dose level of 0.3 mg/100 g body weight was administered to normal cycling mice for 15 days through oral and intraperitoneal routes. At autopsy on 16th day significant reduction in the ovarian and uterine weight was observed. Histological observations showed decrease in the number and size of Graafian follicles, corpora lutea and increase in the atretic follicles in the ovary. The uterus showed absence of endometrial glands, decrease in the height of myometrium, endometrium and its epithelial cells. The total cholesterol content of the ovary and uterus is increased whereas the protein content is decreased. This antagonistic action of nicotine to gonadotrophins is discussed.”,”author”:{“dropping-particle”:””,”family”:”Patil”,”given”:”Somnath Reddy”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Ravindra”,”given”:””,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Patil”,”given”:”Srinivas Reddy”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Londonkar”,”given”:”Ramesh”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Patil”,”given”:”Saraswati B.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Indian Journal of Physiology and Pharmacology”,”id”:”ITEM-1″,”issued”:{“date-parts”:”1998″},”title”:”Nicotine induced ovarian and uterine changes in albino mice”,”type”:”article-journal”},”uris”:”http://www.mendeley.com/documents/?uuid=ec3cd087-d20a-41da-ab66-aa8da21ee5ff”},”mendeley”:{“formattedCitation”:”(Patil et al., 1998)”,”plainTextFormattedCitation”:”(Patil et al., 1998)”,”previouslyFormattedCitation”:”(Patil et al., 1998)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Patil et al., 1998)
Nicotine affects the ovaries and alters the production of oocytes in various animal studies. Nicotine-treated oocytes appeared non-spherical with rough surface and torn and irregular zona-pellucida. Nicotine also caused disturbed oocyte maturation. There is a decreased blood flow to the oviducts and thus impaired fertilization ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1530/JRF.0.0630163″,”ISSN”:”0022-4251″,”PMID”:”7277314″,”abstract”:”Subcutaneous injection of nicotine (0.5 or 5 mg/kg body wt) resulted in a marked and prolonged reduction in uterine blood flow and intrauterine oxygen tension in pseudopregnant rats. By 10 min after nicotine administration (5 mg/kg) uterine perfusion was reduced by 40%, remained suppressed for 90 min and returned to the pre-treatment level by 120 min. Rats receiving the 0.5 mg nicotine/kg also showed a marked reduction in uterine blood flow, although the response was slower in onset and longer in duration. Nicotine (5 mg/kg) also resulted in a sustained decrease in intrauterine oxygen tension from a control value of 48.9 +/- 3.6 to 22.2 +/- 2.6 mmHg at 45–60 min and 21.7 +/- 1.5 mmHg at 60–90 min. The frequency and amplitude of fluctuations in intrauterine oxygen tension were still reduced by 90 min after treatment.”,”author”:{“dropping-particle”:””,”family”:”Hammer”,”given”:”R E”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Goldman”,”given”:”H”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Mitchell”,”given”:”J a”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Journal of reproduction and fertility”,”id”:”ITEM-1″,”issued”:{“date-parts”:”1981″},”title”:”Effects of nicotine on uterine blood flow and intrauterine oxygen tension in the rat.”,”type”:”article-journal”},”uris”:”http://www.mendeley.com/documents/?uuid=766f46a9-afb0-468c-8076-c054a981f4fa”},”mendeley”:{“formattedCitation”:”(Hammer, Goldman, & Mitchell, 1981)”,”plainTextFormattedCitation”:”(Hammer, Goldman, & Mitchell, 1981)”,”previouslyFormattedCitation”:”(Hammer, Goldman, & Mitchell, 1981)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Hammer, Goldman, ; Mitchell, 1981).

Maternal smoking has always been known to have deleterious effects on the fetal outcome. There is an increased incidence of intrauterine growth restriction, stillbirth, miscarriages and mental retardation ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1016/j.etp.2007.05.007″,”ISSN”:”09402993″,”PMID”:”17881205″,”abstract”:”Overexposure to glucocorticoid during fetal development can result in intrauterine growth retardation (IUGR) as well as other diseases after birth. The purpose of this study is to investigate the possibility of glucocorticoid disturbance-mediated nicotine-induced IUGR after chronic prenatal exposure. Nicotine at 1.0 mg/kg twice a day was administered subcutaneously to pregnant rats from gestational day (GD) 8 to GD 15 (mid-gestation) or GD 21 (late-gestation). Placental weights and fetal developmental parameters were recorded. Corticosterone levels were determined by radioimmunoassay. The mRNA expressions of adrenal steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side chain cleavage (P450scc) and placental 11?-hydroxysteroid dehydrogenase type 2 (11?-HSD-2) were determined using real-time quantitative RT-PCR. The results showed that prenatal chronic nicotine exposure causes IUGR in rats (P<0.01); in response to nicotine exposure, maternal serum corticosterone levels were elevated at mid- and late-gestations (P<0.05); mRNA expressions of StAR and P450scc increased in maternal adrenals (P<0.05 or 0.01) but decreased in fetal adrenals (P=0.16 or 0.11). Furthermore, the mRNA levels of placental 11?-HSD-2 were reduced at mid- and late-gestations (P<0.05). These results suggest that nicotine-induced IUGR is associated with the disturbances of glucocorticoid homeostasis in maternal and fetal rats. A possible underlying mechanism is that long term nicotine administration leads to fetal overexposure to maternal glucocorticoid by the combined effect of increased maternal glucocorticoid level and impaired placental barrier to it, all of which eventually leads to the fetal adrenocortical dysfunction and IUGR. © 2007 Elsevier GmbH. All rights reserved.”,”author”:{“dropping-particle”:””,”family”:”Chen”,”given”:”Man”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Wang”,”given”:”Ting”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Liao”,”given”:”Zhang xiu”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Pan”,”given”:”Xiao liang”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Feng”,”given”:”Ying Hong”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Wang”,”given”:”Hui”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Experimental and Toxicologic Pathology”,”id”:”ITEM-1″,”issued”:{“date-parts”:”2007″},”title”:”Nicotine-induced prenatal overexposure to maternal glucocorticoid and intrauterine growth retardation in rat”,”type”:”article-journal”},”uris”:”http://www.mendeley.com/documents/?uuid=295e10b6-bc20-49ec-9a94-152a650bbf8b”},”mendeley”:{“formattedCitation”:”(Chen et al., 2007)”,”manualFormatting”:”( Chen, Wang, Liao, Pan, Feng, Wang, 2007)”,”plainTextFormattedCitation”:”(Chen et al., 2007)”,”previouslyFormattedCitation”:”(Chen et al., 2007)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}( Chen, Wang, Liao, Pan, Feng, Wang, 2007). Various animal studies show retarded fetal growth and lower birth weight when treated prenatally with nicotine. The lower levels of ACTH and cortisol due to nicotine are probable reasons for the incidence of lower birth weight in the newborns ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1016/j.toxlet.2012.09.001″,”ISBN”:”1879-3169 (Electronic)\r0378-4274 (Linking)”,”ISSN”:”03784274″,”PMID”:”22975262″,”abstract”:”Prenatal nicotine exposure inhibits the functional development of the hypothalamic-pituitary-adrenal (HPA) axis and alters glucose and lipid metabolism in intrauterine growth retardation (IUGR) fetal rats, but the postnatal consequence is unknown. We aimed to verify a neuroendocrine metabolic programmed alteration in IUGR offspring whose mothers were subcutaneously treated with 2. mg/kg. d of nicotine from gestational day 11 to 20. In the nicotine group, blood adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels were higher before postnatal day 35 and then returned to lower than the respective control. The adult offspring showed unchanged blood glucose but increased blood total cholesterol (TCH) and triglyceride (TG) levels. However, after chronic stress, the mRNA expression levels of hippocampal glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) were lower, but gain rates of ACTH and CORT levels were greater compared to the control. Additionally, the level of blood glucose was increased, while the elevated levels of blood TCH and TG before stress were close to the control levels. These results suggested that prenatal nicotine exposure induced an HPA axis-associated neuroendocrine metabolic programmed alteration in adult offspring, which might be attributed to hippocampal functional injury in utero. © 2012 Elsevier Ireland Ltd.”,”author”:{“dropping-particle”:””,”family”:”Liu”,”given”:”L.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Liu”,”given”:”F.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Kou”,”given”:”H.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Zhang”,”given”:”B. J.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Xu”,”given”:”D.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Chen”,”given”:”B.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Chen”,”given”:”L. B.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Magdalou”,”given”:”J.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Wang”,”given”:”H.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Toxicology Letters”,”id”:”ITEM-1″,”issued”:{“date-parts”:”2012″},”title”:”Prenatal nicotine exposure induced a hypothalamic-pituitary-adrenal axis-associated neuroendocrine metabolic programmed alteration in intrauterine growth retardation offspring rats”,”type”:”article-journal”},”uris”:”http://www.mendeley.com/documents/?uuid=fb451845-4e9c-4c40-af9b-c16dfa20d660″},”mendeley”:{“formattedCitation”:”(Liu et al., 2012)”,”manualFormatting”:”( Liu, L. Liu, F. Kou, Zhang,Xu,Chen, Chen, Magdalou, Wang, 2012)”,”plainTextFormattedCitation”:”(Liu et al., 2012)”,”previouslyFormattedCitation”:”(Liu et al., 2012)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}( Liu, L. Liu, F. Kou, Zhang, Xu, Chen, Chen, Magdalou, Wang, 2012).
Other body systemsNicotine increases atherosclerotic plaque formation in cardiovascular system. It alters the structural and functional characteristics of vascular smooth muscle and endothelial cells ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1067/mcp.2000.105153″,”ISBN”:”0009-9236 (Print)\r0009-9236 (Linking)”,”ISSN”:”00099236″,”PMID”:”10801248″,”abstract”:”BACKGROUND: Cigarette smoking is associated with impaired endothelium-dependent dilatation in human veins and arteries. An in vivo study in animals suggests that nicotine may contribute to this abnormality. We tested the hypothesis that local administration of nicotine at a dose reproducing the plasma concentration observed during smoking would impair endothelium-dependent vasodilatation in human veins in vivo.\n\nMETHODS: We studied 11 healthy nonsmokers with the dorsal hand vein compliance technique. After 70% to 80% preconstriction with phenylephrine, endothelium-dependent venous relaxation was assessed by infusion of bradykinin (1 to 278 ng/min), a potent vasodilator acting primarily in this model through endothelial release of nitric oxide and prostanoids. Sodium nitroprusside (0.0001 to 3166 ng/min) was used to test endothelium-independent relaxation. Dose-response curves were constructed before and during nicotine coinfusion at a rate of 40 ng/min, reproducing a plasma concentration of 15 ng/mL.\n\nRESULTS: After a 10-minute preinfusion, nicotine administration was associated with a loss in sensitivity to bradykinin (P < .001). After 30 and 60 minutes of preinfusion with nicotine, the venorelaxant effect of bradykinin was further reduced (P < .001). A similar inhibition of the response to bradykinin by nicotine persisted in the presence of indomethacin (INN, indomethacin). Coinfusion of nicotine did not attenuate sodium nitroprusside-induced venodiiation.\n\nCONCLUSION: The results show that acute local exposure to nicotine in vivo is associated with an impaired response to endothelium-derived nitric oxide in human veins. This finding may provide further insight into the pathophysiology of smoking-induced endothelial dysfunction.”,”author”:{“dropping-particle”:””,”family”:”Chalon”,”given”:”S”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Clinical Pharmacology & Therapeutics”,”id”:”ITEM-1″,”issue”:”4″,”issued”:{“date-parts”:”2000″},”page”:”391-397″,”title”:”Nicotine impairs endothelium-dependent dilatation in human veins in vivo”,”type”:”article-journal”,”volume”:”67″},”uris”:”http://www.mendeley.com/documents/?uuid=5861d6c8-7f42-48a1-ace1-09c77dc6497a”,”http://www.mendeley.com/documents/?uuid=7c2ed2db-1ffe-4d16-8638-b95f8b7d650f”},”mendeley”:{“formattedCitation”:”(Chalon, 2000)”,”plainTextFormattedCitation”:”(Chalon, 2000)”,”previouslyFormattedCitation”:”(Chalon, 2000)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Chalon, 2000).
Nicotine increased gastric acid secretion, pepsinogen secretion and stimulatory effects on vasopressin. This lead to Gastro Esophageal Reflux Disorder (GERD) and peptic ulcer disease (PUD) in gastrointestinal tract ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1158/1541-7786.MCR-05-0106″,”ISBN”:”1541-7786 (Print)”,”ISSN”:”1541-7786″,”PMID”:”16317086″,”abstract”:”Blockade of angiogenesis is a promising strategy to suppress tumor growth, invasion, and metastasis. Vascular endothelial growth factor (VEGF), which binds to tyrosine kinase receptors VEGF receptors (VEGFR) 1 and 2, is the mediator of angiogenesis and mitogen for endothelial cells. Cyclooxygenase-2 (COX-2) plays an important role in the promoting action of nicotine on gastric cancer growth. However, the action of nicotine and the relationship between COX-2 and VEGF/VEGFR system in tumorigenesis remain undefined. In this study, the effects of nicotine in tumor angiogenesis, invasiveness, and metastasis were studied with sponge implantation and Matrigel membrane models. Nicotine (200 microg/mL) stimulated gastric cancer cell proliferation, which was blocked by SC-236 (a highly selective COX-2 inhibitor) and CBO-P11 (a VEGFR inhibitor). This was associated with decreased VEGF levels as well as VEGFR-2 but not VEGFR-1 expression. Topical injection of nicotine enhanced tumor-associated vascularization, with a concomitant increase in VEGF levels in sponge implants. Again, application of SC-236 (2 mg/kg) and CBO-P11 (0.4 mg/kg) partially attenuated vascularization by approximately 30%. Furthermore, nicotine enhanced tumor cell invasion through the Matrigel membrane by 4-fold and promoted migration of human umbilical vein endothelial cells in a cocultured system with gastric cancer cells. The activity of matrix metalloproteinases 2 and 9 and protein expressions of plasminogen activators (urokinase-type plasminogen activator and its receptor), which are the indicators of invasion and migration processes, were increased by nicotine but blocked by COX-2 and VEGFR inhibitors. Taken together, our results reveal that the promoting action of nicotine on angiogenesis, tumor invasion, and metastasis is COX-2/VEGF/VEGFR dependent.”,”author”:{“dropping-particle”:””,”family”:”Shin”,”given”:”V. Y.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Molecular Cancer Research”,”id”:”ITEM-1″,”issue”:”11″,”issued”:{“date-parts”:”2005″},”page”:”607-615″,”title”:”Nicotine Induces Cyclooxygenase-2 and Vascular Endothelial Growth Factor Receptor-2 in Association with Tumor-Associated Invasion and Angiogenesis in Gastric Cancer”,”type”:”article-journal”,”volume”:”3″},”uris”:”http://www.mendeley.com/documents/?uuid=65ae2238-9e00-42ee-97a9-668f4269f3bf”,”http://www.mendeley.com/documents/?uuid=edd827e7-2eff-40c2-8dee-fce137b99ad3″},{“id”:”ITEM-2″,”itemData”:{“ISBN”:”1873-4286 (Electronic)\r1381-6128 (Linking)”,”ISSN”:”1873-4286″,”PMID”:”22950507″,”abstract”:”Cigarette smoke has always been the single most preventive cause of death in the world. In 2011, over 460,000 died from cigarette smoke-related diseases in US. The detrimental effects of cigarette smoke on human beings are due to the presence of many carcinogens and other components (e.g. nicotine and tar). Nicotine is now accepted as one of the major components responsible for gastrointestinal disorders. Cigarette smoking, nicotine and a nicotine-derived nitrosamine, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are considered as risk factors for gastrointestinal cancer, however, the underlying mechanism remains largely unknown. Previous studies reported that cigarette smoke and nicotine aggravated inflammation not only in the stomach, but also in the colon. The carcinogenic actions of cigarette smoke, nicotine and NNK on gastrointestinal cancers development have been widely studied. The strong association of cyclooxygenase-2 (COX-2) with gastrointestinal diseases has been extensively studied, however, due to the unresolved cardiovascular risk, it is of great importance to develop other new anti-cancer drugs for the treatment of cancers. This current review aims to provide an overview of the effects of cigarette smoke, nicotine and NNK on gastrointestinal inflammation, and also the carcinogenic properties in cancer development (tumor growth, angiogenesis and epithelial-mesenchymal transition). In addition, current studies on nicotinic acetylcholine receptors, adrenergic receptors and miRNAs in nicotine-related cancer pathogenesis are also highlighted.”,”author”:{“dropping-particle”:””,”family”:”Chu”,”given”:”Kent-Man”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Cho”,”given”:”Chi H”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Shin”,”given”:”Vivian Y”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Current pharmaceutical design”,”id”:”ITEM-2″,”issue”:”1″,”issued”:{“date-parts”:”2013″},”page”:”5-10″,”title”:”Nicotine and gastrointestinal disorders: its role in ulceration and cancer development.”,”type”:”article-journal”,”volume”:”19″},”uris”:”http://www.mendeley.com/documents/?uuid=816b618b-ffa9-4caa-891b-546be2b5a701″,”http://www.mendeley.com/documents/?uuid=c6e7965c-7bdf-4651-9fa7-ac632dbd4596″},”mendeley”:{“formattedCitation”:”(Chu, Cho, & Shin, 2013; Shin, 2005)”,”plainTextFormattedCitation”:”(Chu, Cho, & Shin, 2013; Shin, 2005)”,”previouslyFormattedCitation”:”(Chu, Cho, & Shin, 2013; Shin, 2005)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Chu, Cho, ; Shin, 2013; Shin, 2005). The action on the cyclooxygenase pathway also increases the risk of GERD and PUD ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“ISSN”:”0928-4257 (Print)”,”PMID”:”8292987″,”abstract”:”Chronic nicotine treatment worsens stomach mucosal damage by cold (4 degrees C) and restraint (stress): it dose- and time-dependently intensifies stress-evoked gastric glandular ulceration, mast cell degranulation and motility. Nicotine 50 micrograms/ml drinking water, given ad libitum to female Sprague-Dawley rats for 10 days, increases the sensitivity of the isolated stomach strip to acetylcholine-induced contractions; atropine abolishes this action. The isolated anococcygeus muscle from nicotine-treated male rats shows increased sensitivity to noradrenaline-induced contractions, but not to those by acetylcholine. Hexamethonium or atropine pretreatment antagonises stress-induced gastric effects in nicotine-drinking rats. Muscarinic M1- and M2-, but not M3-, receptor block (by pirenzepine, AF-DX 116BS and HHSiD, respectively) inhibits stress ulcer formation in female rats. Although tobacco smoking has been reported to increase free radical formation, mucosal xanthine oxidase which initiates free radical formation is uninfluenced by nicotine; antagonising this enzyme (by allopurinol) or hydroxyl free radical scavenging (by dimethylsulfoxide) does not lessen the effect of nicotine on stress-evoked ulceration. The findings suggest that chronic nicotine treatment produces partial ganglionic blockade of the vagal nerve which leads to muscarinic receptor supersensitivity. This phenomenon contributes significantly to the ulcer-worsening mechanism; muscarinic M1- and M2-receptors appear to be involved. The gastric ulcer-aggravating effect of nicotine in stressed rats appears not to be due to increased free radical formation.”,”author”:{“dropping-particle”:””,”family”:”Ogle”,”given”:”C W”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Qiu”,”given”:”B S”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Cho”,”given”:”C H”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Journal of physiology, Paris”,”id”:”ITEM-1″,”issue”:”6″,”issued”:{“date-parts”:”1993″},”page”:”359-365″,”title”:”Nicotine and gastric ulcers in stress.”,”type”:”article-journal”,”volume”:”87″},”uris”:”http://www.mendeley.com/documents/?uuid=0cf8325e-f804-466e-ae69-1b8857c380c2″,”http://www.mendeley.com/documents/?uuid=08721ebe-f4bc-49ca-a625-6cb16631375c”},”mendeley”:{“formattedCitation”:”(Ogle et al., 1993)”,”manualFormatting”:”( Ogle, Qiu, Cho, 1993)”,”plainTextFormattedCitation”:”(Ogle et al., 1993)”,”previouslyFormattedCitation”:”(Ogle et al., 1993)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}( Ogle, Qiu, Cho, 1993). Nicotine act as a non-adrenergic and non-cholinergic neurotransmitter causes smooth muscle relaxation by action of endogenous nitric oxide ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1016/0014-2999(91)90307-C”,”ISSN”:”00142999″,”abstract”:”We studied the effects of L-NG-nitro-arginine (L-NOARG), which inhibits nitric oxide (NO) biosynthesis from L-arginine, on the non-adrenergic, non-cholinergic (NANC)-mediated relaxation induced by nicotine in isolated rat duodenum. L-NOARG reduced nicotine-induced relaxation, and L-arginine prevented the inhibitory effect of L-NOARG. However, L-NOARG did not inhibit the tetrodotoxin-insensitive relaxation induced by adenosine 5???-triphosphate, ??,??-methyleneadenosine 5???-triphosphate, thyrotropin-releasing hormone or the calcitonin gene-related peptide. Endogenous NO thus could possibly be involved in the NANC-mediated relaxation of rat duodenum induced by nicotine. ?? 1991.”,”author”:{“dropping-particle”:””,”family”:”Kaoru”,”given”:”Irie”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Takamura”,”given”:”Muraki”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Kyoko”,”given”:”Furukawa”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Teruko”,”given”:”Nomoto”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”European Journal of Pharmacology”,”id”:”ITEM-1″,”issue”:”2″,”issued”:{“date-parts”:”1991″},”page”:”285-288″,”title”:”L-NG-nitro-arginine inhibits nicotine-induced relaxation of isolated rat duodenum”,”type”:”article-journal”,”volume”:”202″},”uris”:”http://www.mendeley.com/documents/?uuid=2595c66f-359d-477e-8918-c3548bfdb4ad”,”http://www.mendeley.com/documents/?uuid=86eeb100-5bbc-4b08-a340-c0d83af17d83″},”mendeley”:{“formattedCitation”:”(Kaoru, Takamura, Kyoko, & Teruko, 1991)”,”plainTextFormattedCitation”:”(Kaoru, Takamura, Kyoko, & Teruko, 1991)”,”previouslyFormattedCitation”:”(Kaoru, Takamura, Kyoko, & Teruko, 1991)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Kaoru, Takamura, Kyoko, ; Teruko, 1991). Increased incidence of GERD happen due to decrease in tone of the colon and gastric motility and reduced lower esophagal sphincter pressure ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“ISSN”:”0163-2116″,”PMID”:”8943963″,”abstract”:”Cigarette smoking has been shown to decrease lower esophageal sphincter pressure (LESP) by 19-42%. This decrease in LESP may be due to nicotine in the cigarette smoke or substances other than nicotine. The aim of this study was to evaluate the effects of a nicotine patch on esophageal motility since nicotine patches are devoid of all toxins present in the cigarette smoke except the nicotine. Ten healthy nonsmoking volunteers underwent baseline esophageal manometry. Esophageal manometry was repeated after placing a nicotine transdermal patch (Nicotrol) designed to deliver 15 mg of nicotine per day. The parameters that were compared included LESP by rapid pull-through (LESP-RPT) and station pull-through (LESP-SPT), LES relaxation, and velocity, amplitude, and duration of esophageal contractions. Plasma nicotine and cotinine levels were measured prior to baseline manometry and after 12 hr of placing the nicotine patch, the LESP-RPT decreased by 31% from 17.4 +/- 6.1 to 12.1 +/- 3.3 (P = 0.013) and the LESP-SPT by 27% from 13.4 +/- 5.4 to 9.8 +/- 4.8 (P = 0.029) after the nicotine patch. LES relaxation was present in 100% before and after nicotine patch. There were no significant differences in velocity, duration, and amplitude of esophageal contractions after the nicotine patch. Plasma nicotine and cotinine was absent in all subjects at baseline but was significantly elevated after 12 hr of nicotine patch. Transdermal delivery of nicotine results in a significant reduction in LESP in healthy subjects without effecting LES relaxation or esophageal body motility.”,”author”:{“dropping-particle”:””,”family”:”Kadakia”,”given”:”S C”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”La Baume”,”given”:”H R”,”non-dropping-particle”:”De”,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Shaffer”,”given”:”R T”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Digestive diseases and sciences”,”id”:”ITEM-1″,”issue”:”11″,”issued”:{“date-parts”:”1996″},”page”:”2130-4″,”title”:”Effects of transdermal nicotine on lower esophageal sphincter and esophageal motility.”,”type”:”article-journal”,”volume”:”41″},”uris”:”http://www.mendeley.com/documents/?uuid=44f7a091-e687-4ba4-afb6-2c82e1a86885″,”http://www.mendeley.com/documents/?uuid=37cc55ed-24c1-4c60-8a3f-9725c790332b”},”mendeley”:{“formattedCitation”:”(Kadakia, De La Baume, & Shaffer, 1996)”,”plainTextFormattedCitation”:”(Kadakia, De La Baume, & Shaffer, 1996)”,”previouslyFormattedCitation”:”(Kadakia, De La Baume, & Shaffer, 1996)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Kadakia, De La Baume, ; Shaffer, 1996).

Nicotine is also known to be immunosuppressive through the central and peripheral mechanisms in immune system. It decreases immunological response by impairing antigen and receptor-mediated signal transduction in the lymphoid system. Arrest of cell cycle reduced the T-cell population. In addition, nicotine increase the incidences of tuberculosis because the macrophage which acts as the first line defence against tuberculosis becomes dysfunctional ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”S0041008X85712331 pii”,”ISBN”:”0041-008X (Print)\r0041-008X (Linking)”,”ISSN”:”0041-008X”,”PMID”:”8545837″,”abstract”:”Previous work has demonstrated that chronic exposure of rats to cigarette smoke causes inhibition of the antibody-forming cell (AFC) response and that the particulate phase of cigarette smoke, containing most of the nicotine in cigarette smoke, is essential for immunosuppression. Using intradermally implanted miniosmotic pumps, LEW rats were exposed to nicotine or its principal metabolite, cotinine, at the rate of about 14 micrograms/hr for 3-4 weeks. Serum cotinine levels in nicotine-treated (NT) animals of 219 +/- 40 ng/ml (on Day 10) were comparable to average human smokers. No significant differences between control (CON) and NT animals were observed in the distribution of lymphocyte subsets. However, nicotine, but not cotinine, treatment for 3 to 4 weeks inhibited both the T-dependent and T-independent AFC responses and proliferation to anti-CD3. Con A response was observed in 4-week but not in 3-week NT animals. Cell cycle analysis revealed that upon stimulation with Con A or anti-CD3, in spite of comparable surface expression of IL-2 receptors and class II MHC molecules, significantly fewer NT T cells entered the S and G2/M phases than CON T cells, indicating an arrest in the G0/G1 phase. Furthermore, B and T cells from NT animals were unable to elevate the intracellular calcium levels normally in response to ligation of antigen receptors, although Ca2+ responses of salivary gland cells to acetylcholine were normal. Thus, nicotine may significantly contribute to the immunosuppressive effects of chronic smoking by inducing a state of anergy in lymphocytes and may be related to their impaired response to antigen-induced signaling.”,”author”:{“dropping-particle”:””,”family”:”Geng”,”given”:”Y”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Savage”,”given”:”S M”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Johnson”,”given”:”L J”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Seagrave”,”given”:”J”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Sopori”,”given”:”M L”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Toxicol Appl Pharmacol”,”id”:”ITEM-1″,”issue”:”2″,”issued”:{“date-parts”:”1995″},”page”:”268-278″,”title”:”Effects of nicotine on the immune response. I. Chronic exposure to nicotine impairs antigen receptor-mediated signal transduction in lymphocytes”,”type”:”article-journal”,”volume”:”135″},”uris”:”http://www.mendeley.com/documents/?uuid=267939a1-0981-4608-b5bd-b1820f9e1887″,”http://www.mendeley.com/documents/?uuid=46029a7a-abe2-4f9a-a0d1-7474be2c8a04″},”mendeley”:{“formattedCitation”:”(Geng, Savage, Johnson, Seagrave, & Sopori, 1995)”,”plainTextFormattedCitation”:”(Geng, Savage, Johnson, Seagrave, & Sopori, 1995)”,”previouslyFormattedCitation”:”(Geng, Savage, Johnson, Seagrave, & Sopori, 1995)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Geng, Savage, Johnson, Seagrave, ; Sopori, 1995).
MATERIAL AND METHODTREATMENTSTwenty four female mice are used in this experiment. The mice are divided into 4 groups which are A, B, C and D. Each of this group consists of 6 mice. Group A are treated with 0.1 ml of corn oil by oral administration. This group is the control group in this experiment. Group B are treated 3mg/kg/day of nicotine by subcutaneous injection. Group C are treated with 3mg/kg/day of nicotine and 60mg/kg/day of??-tocotrienol by subcutaneous injection and oral administration respectively. Group D are treated with 60mg/kg/day of ?-tocotrienol by oral administration. The mice are given the treatment for 7 days. On the 8th day, all mice are sacrificed with cervical dislocation.
HISTOLOGICAL ANALYSISHistological Sample CollectionFemale mice are sacrificed by using cervical dislocation and their uterus are collected immediately after death. All organs that are used in this study are washed by 0.9% normal saline solution to clean any blood clotting on the surface of the organs. Then, several processes including fixation, dehydration, clearing, embedding, sectioning, staining and mounting are done on the samples.

FixationNormally organs begin to undergo progressive changes due to autolysis, self-digestion or postmortem degeneration. Thus, those process is prevented by fixation. In this research, the organs are fixed in Bouin solution. It contain picric acid, acetic acid and formaldehyde in an aqueous solution. The picric acid will penetrates the tissues slowly, coagulating proteins and causing some shrinkage. It also will make the tissue yellow in colour. Acetic acid coagulates nuclear chromatin and opposes the shrinkage caused by picric acid. The formaldehyde fixes protein by forming cross-linking methylene bridges that will stabilize the structure of the protein molecules. The volume of bouin solution that is needed is 10 times greater than the volume of organ. The entire organ should be in this solution for overnight.
DehydrationAfter the fixation process, the part of organ that is used for study is cut into small pieces. In order to remove all the water content from the organs, hydration process is used. All organs are placed successively in solutions of alcohol of increasing strength, from alcohol 70%, 80%, 95% and ending with a couple of passage through absolute alcohol. The volume of each alcohol concentration that is used is 10 times greater than the volume in of the respective organs. In every alcohol solution, the organ is immersed for an hour.

ClearingAfter the dehydration process, the samples are then placed in a clearing agent, toluene to clean the organs from any alcohol effect and also because toluene can easily mix with paraffin. This is important in the next step in this study. The volume of the toluene being used is 10 times greater than the volume of the respective organ. In toluene solution, the organ was immersed for overnight.

EmbeddingAfter immersing in the toluene solution overnight, all of the sample organs are embedded in paraffin. In this process, the sample organs are dipped by using hot forceps into a small beaker containing paraffin at 60 °C in the oven. These steps are being repeated three times, one hour each. Paraffin are melted in an oven at 60 °C overnight. The volume of the paraffin wax used are three times the volume of organ sample. The melting point for paraffin used is 58 °C. This step is to ensure that all paraffin can penetrate through to the entire sample. Next, the paraffin waxes were poured into a cast block sized 70mm long x 30mm length x 30mm width by using tissue embedding until the paraffin on the bottom melt cube solidifies. Then the sample organ was taken out from the small beaker by using hot forceps and place it on the mould to make the sectioning process easier later on. Sample organ in the cast block is left to solidify at room temperature for a week. The embedding step is to ensure the sample organs are in the shape for easy sectioning later.

SectioningThe ease with which thin shavings can be cut from a candle suggests the reasons for embedding tissue in paraffin. Tissue embedded in, and so impregnated with paraffin may be sliced very thinly. To cut such thin slices necessitates special equipment called a microtome blade. Sections are cut by the steel blade of the microtome to a thickness between 4?m and 5?m. each section is transferred to a clean glass microscope slide on which a drop of water has been smeared. Then, the slides are placed on heater for water evaporation to occur.

StainingThe purpose of staining is to enhance natural contrast and to make cells look more evident, so that it can be easily observed under microscope. Staining process is done with the using Hematoxylene-Eosin (H ; E) procedure. All steps in this procedure are shown in Table 3.1.
Table 3. SEQ Table * ARABIC s 1 1: Steps involving in H ; E stainingStep Solution Time (min)
1 Xylene 1 10
2 Xylene 2 5
3 Pure Alcohol : Xylene (1:1) 5
4 Pure Alcohol 3
5 95% Alcohol 3
6 80% Alcohol 3
7 70% Alcohol 3
8 Distilled Water 5
9 Hematoxylene5
10 Tapping water 5
11 Eosin 4
12 95% Alcohol 2 times immerse
13 95% Alcohol 1 times immerse
14 Pure Alcohol 3
15 Pure Alcohol : Xylene (1:1) 5
16 Xylene 3 10
17 Xylene 4 15
After the 17th step, slides are prepared for mounting with DPX medium.

MountingExcess dye is removed by washing with water-alcohol after staining and the section is dehydrated through ascending grades of alcohol. Following absolute alcohol, the section is transferred to a solution of clearing agent. Then, the slides is covered with a coverslip and allowed to dry. After one week, the specimen is available for a microscopic examination by using microscope and storage.

RESULT AND DISCUSSIONHISTOLOGICAL AND HISTOMETRIC CHANGES IN UTERUS95255342255Figure 4. SEQ Figure * ARABIC s 1 1: Microphotograph of uteruses in the experimental groups. Group A treated with corn oil (A), Group B injected with nicotine (B), Group C treated with nicotine and a-tocotrienol (C), and group D with a-tocotrienol.Figure 4. SEQ Figure * ARABIC s 1 1: Microphotograph of uteruses in the experimental groups. Group A treated with corn oil (A), Group B injected with nicotine (B), Group C treated with nicotine and a-tocotrienol (C), and group D with a-tocotrienol.9525157162500After undergoing the histological process, the slides that have been prepared were observed using a microscope. The figure of 4x magnification is shown in Figure 4.1
Table 4. SEQ Table * ARABIC s 1 1: Effect of the treatment on histometric changes of uterus in mice.Overall thickness
(?m) Thickness of endometrium
(?m) Thickness of myometrium
(?m) Thickness of perimetrium (?m)
Group A 504.38 ± 64.91 250.73 ± 66.02 99.42 ± 14.27 154.21 ± 31.90
Group B 405.71 ± 89.86 213.45 ± 81.70 82.93 ± 21.34 109.28 ± 28.85
Group C 589.85 ± 59.00 321.67 ± 72.49 134.26 ± 27.00 133.98 ± 43.65
Group D 876.48 ± 232.43 485.61 ± 162.73 210.12 ± 80.74 180.74 ± 33.80
Mean ± Standard deviation

The mean of the overall uterus wall thickness, endometrium thickness and myometrium thickness are D ; C ; A ; B meanwhile the mean of perimetrium thickness is D ; A ; C ; B.

Upon microscopic observation, the uterus structure of nicotine-treated mice group (Group B) was having more damages comparing with the control group. Besides, the thickness of the endometrium, myometrium and perimetrium of this group are not evenly distributed compared to the control group. Their lumen also showed that it was more loosen comparing with the control group. As shown in Table 4.1, the thickness of overall uterus wall, endometrium, myometrium and perimetrium were decreased compared to the control group.
For the group that was treated with both nicotine and ?-tocotrienol (Group C), their microscopic observation shows that the uterus structures were similar with the control group. The overall thickness of uterus, endometrium and myometrium were increased compared with control group while the perimetrium thickness was decreased compared to the control group. This may be due to the anti-oxidative effect of a-tocotrienol that reversed the adverse effect of the nicotine.

When the mice were treated with ?-tocotrienol only (Group D), the structure of the uteruses was solid and rigid compared to the control group. The thickness of the layer of the uterus wall was evenly distributed. They also have the well-shaped lumen. This observation shows that ?-tocotrienol also improved the structure of normal mice. The thickness of overall uterus wall, endometrium, myometrium and perimetrium show increase in thickness.

The hypothalamus regulates the rhythmic release of pituitary gonadotrophins such as FSH, LH and prolactin through neural stimulus to GnRH ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“ISBN”:”0022-3565″,”ISSN”:”0022-3565 (Print)”,”PMID”:”3016239″,”abstract”:”The dose of nicotine and the frequency of its administration appear to be essential determinants of its action on multiple systems including the neuroendocrine regulation of the adrenocorticotropin (ACTH)-corticosterone and prolactin (PRL) axes in the rat. Because desensitization to the acute depressive effects of nicotine has been observed after both acute and chronic administration, these investigations assessed whether desensitization to the stimulative effects of nicotine on ACTH and PRL secretion occurs with repetitive dosing. Extensive dose and time course experiments showed that nicotine rapidly elevates rat plasma ACTH and PRL levels with a threshold dose between 0.1 to 0.25 mg/kg b.wt. i.p. After the stimulation of PRL, levels became significantly depressed. Desensitization to the acute stimulatory effects of nicotine on both hormones was induced by a single dose of nicotine (0.5 mg/kg). One hour later nicotine (1.0 mg/kg) failed to significantly stimulate PRL levels and resulted in a modest increase of ACTH. Desensitization was maximal by 1 hr after the first dose and persisted for at least 6 hr. Adrenalectomy, performed to eliminate corticosterone-induced negative feedback, did not enhance PRL responsiveness to a second dose of nicotine but it partially restored the ACTH response. Pretreatment with corticosterone also failed to modify the PRL response to a single dose of nicotine whereas it partially suppressed the ACTH response. Rapid desensitization to the acute stimulatory effects of nicotine on plasma PRL is independent of glucocorticoid negative-feedback whereas desensitization of the ACTH response is modestly dependent.”,”author”:{“dropping-particle”:””,”family”:”Sharp”,”given”:”B M”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Beyer”,”given”:”H S”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”J Pharmacol Exp Ther.”,”id”:”ITEM-1″,”issued”:{“date-parts”:”1986″},”title”:”Rapid Desensitization of the Acute Stimulatory Effects of Nicotine on Rat Plasma Adrenocorticotropin and Prolactin”,”type”:”article-journal”},”uris”:”http://www.mendeley.com/documents/?uuid=deeb974a-752c-497c-9979-4727137da594″},”mendeley”:{“formattedCitation”:”(Sharp & Beyer, 1986)”,”plainTextFormattedCitation”:”(Sharp & Beyer, 1986)”,”previouslyFormattedCitation”:”(Sharp & Beyer, 1986)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Sharp ; Beyer, 1986). The orderly event of follicular growth and ovulation depends upon the pituitary FSH, LH and prolactin.
The gonadotropin secretion is controlled by central nervous system. The secretion is stoped after the vascular connection between the anterior pituitary gland and the hypothalamus is interrupted ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1016/B978-0-12-373975-9.00013-6″,”ISBN”:”9780123739759″,”abstract”:”The ovaries serve the dual function of producing eggs and the hormones that support reproductive functions in females. This chapter describes the ovarian hormones, control of ovarian functions, physiological actions of ovarian hormones, and mechanism and regulation of female reproductive cycle. The functional unit of ovary is ovarian follicle, and the principal ovarian hormones are the steroids estradiol and progesterone and the peptide inhibin, which orchestrates the cyclic series of events that unfold in the ovary, pituitary, and the reproductive tract. Ovarian function is driven by the two pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the secretion of which depends on stimulatory input from the hypothalamus through the gonadotropin-releasing hormone (GnRH), and complex inhibitory and stimulatory input from ovarian steroid and peptide hormones. At puberty estrogens promote growth and development of the oviducts, uterus, vagina, and external genitalia. Ovulation, the hallmark of ovarian activity, occurs episodically at 28-day intervals. It is the central and signature event of each ovarian cycle. It follows selection and maturation of the dominant follicle and is triggered by a massive increase in blood LH concentration. If fertilization does not occur, a new follicle must be prepared. Coordination of these events requires two-way communication between the pituitary and the ovaries, and between the ovaries and the reproductive tract.”,”author”:{“dropping-particle”:””,”family”:”Goodman”,”given”:”H. Maurice”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Goodman”,”given”:”H. Maurice”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Basic Medical Endocrinology”,”id”:”ITEM-1″,”issued”:{“date-parts”:”2009″},”title”:”Chapter 13 – Hormonal Control of Reproduction in the Female: The Menstrual Cycle”,”type”:”chapter”},”uris”:”http://www.mendeley.com/documents/?uuid=6ef854a7-05fa-4fc5-9ae1-de6ad5f89aae”},”mendeley”:{“formattedCitation”:”(Goodman & Goodman, 2009)”,”manualFormatting”:”(Maurice Goodman, 2009)”,”plainTextFormattedCitation”:”(Goodman & Goodman, 2009)”,”previouslyFormattedCitation”:”(Goodman & Goodman, 2009)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Maurice Goodman, 2009). Investigations on nicotine indicate that nicotine being a central nervous system influencing drug inhibits the release of gonadotropins from the pituitary ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1210/endo-95-4-999″,”ISBN”:”0013-7227 (Print) 0013-7227 (Linking)”,”ISSN”:”19457170″,”PMID”:”4606769″,”author”:{“dropping-particle”:””,”family”:”Blake”,”given”:”Charles A.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Endocrinology”,”id”:”ITEM-1″,”issued”:{“date-parts”:”1974″},”title”:”Localization of the inhibitory actions of ovulation-blocking drugs on release of luteinizing hormone in ovariectomized rats”,”type”:”article-journal”},”uris”:”http://www.mendeley.com/documents/?uuid=16e65958-f25d-4958-af41-bde255dacf27″},{“id”:”ITEM-2″,”itemData”:{“DOI”:”10.1677/joe.0.0790319″,”ISSN”:”00220795″,”author”:{“dropping-particle”:””,”family”:”Blake”,”given”:”C. A.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Journal of Endocrinology”,”id”:”ITEM-2″,”issued”:{“date-parts”:”1978″},”title”:”Paradoxical effects of drugs acting on the central nervous system on the preovulatory release of pituitary luteinizing hormone in pro-oestrous rats”,”type”:”article-journal”},”uris”:”http://www.mendeley.com/documents/?uuid=750d2b26-8fbe-45bf-9458-418fd31c7dfb”},{“id”:”ITEM-3″,”itemData”:{“DOI”:”10.1111/j.1748-1716.1982.tb10597.x”,”ISSN”:”1365201X”,”abstract”:”The effects of high repeated subcutaneous doses (4×2 mg/kg) of nicotine have been evaluated on dopamine (DA) and noradrenaline (NA) levels and turnover in the long?term castrated male rat using catecholamine (CA) fluorescence histochemistry in combination with quantitative microfluorometry. The CA turnover was evaluated by studying the decline of the CA stores following tyrosine hydroxylase inhibition using ??methyltyrosine methyl ester (H 44/68). In the same experiments trunk blood was collected for the determination of serum prolactin, LH, FSH and TSH levels using standard radioimmun?oassay procedures. The nicotine treatment produced a significant depletion of CA stores and an increase of CA turnover in DA and NA nerve terminals of the median eminence and in peri? and paraventricular NA systems. These effects were significantly counteracted by pretreatment with mecamylamine. Nicotine significantly reduced serum prolactin and TSH levels, and after H 44/68 it also reduced LH and FSH serum levels. These actions were counteracted by mecamylamine pretreatment, except the effects on serum TSH levels after H 44/68, which were even enhanced by pretreatment with mecamylamine. Overall intraindividual correlations showed a significant correlation between reduced CA turnover in several hypothalamic areas and increased serum LH and FSH levels, increased NA turnover in the paraventricular hypothalamic nucleus and increased serum TSH levels, and reduced DA turnover in the median eminence and increased serum LH levels. It is suggested that in the castrated male rat nicotine can activate cholinergic nicotine?like receptors facilitating DA and NA turnover and release in various hypothalamic CA nerve terminal systems including those inhibiting the secretion of prolactin and LH (DA terminals in medial and lateral palisade zone, respectively) and facilitating secretion of TSH (NA terminals in the parvocellular part of the paraventricular hypothalamic nucleus). © 1982 Scandinavian Physiological Society”,”author”:{“dropping-particle”:””,”family”:”ANDERSSON”,”given”:”KURT”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”FUXE”,”given”:”KJELL”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”ENEROTH”,”given”:”PETER”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”AGNATI”,”given”:”LUIGI F.”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Acta Physiologica Scandinavica”,”id”:”ITEM-3″,”issued”:{“date-parts”:”1982″},”title”:”Involvement of cholinergic nicotine???like receptors as modulators of amine turnover in various types of hypothalamic dopamine and noradrenaline nerve terminal systems and of prolactin, LH, FSH and TSH secretion in the castrated male rat”,”type”:”article-journal”},”uris”:”http://www.mendeley.com/documents/?uuid=6c786806-b68d-4111-8a09-0b2fb6a76660″},”mendeley”:{“formattedCitation”:”(ANDERSSON, FUXE, ENEROTH, & AGNATI, 1982; C. A. Blake, 1978; Charles A. Blake, 1974)”,”manualFormatting”:”(Anderson, Fuxe, Eneroth, & Agnati, 1982; C. A. Blake, 1978; Charles A. Blake, 1974)”,”plainTextFormattedCitation”:”(ANDERSSON, FUXE, ENEROTH, & AGNATI, 1982; C. A. Blake, 1978; Charles A. Blake, 1974)”,”previouslyFormattedCitation”:”(ANDERSSON, FUXE, ENEROTH, & AGNATI, 1982; C. A. Blake, 1978; Charles A. Blake, 1974)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Anderson, Fuxe, Eneroth, ; Agnati, 1982; C. A. Blake, 1978; Charles A. Blake, 1974). As reported by Patil in 1998, the destructive effect of nicotine which it reduces the thickness of uterus wall, endometrium and myometrium compared to the control group.
When the mice are treated with ?-tocotrienol in group C and group D, the thickness of uterus wall is increased in size compared to the control group treated with corn oil. Tocotrienols exhibit antioxidant function like tocopherols, and it was discovered that tocotrienols exhibit more antioxidant activity. It was several-fold more effective than tocopherols in inhibiting the proliferation of mouse mammary tumour epithelial cells and in inducing apoptosis ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1046/j.1525-1373.2000.22434.x”,”ISBN”:”0037-9727″,”ISSN”:”0037-9727″,”PMID”:”10964265″,”abstract”:”Studies were conducted to determine the comparative effects of tocopherols and tocotrienols on preneoplastic (CL-S1), neoplastic (-SA), and highly malignant (+SA) mouse mammary epithelial cell growth and viability in vitro. Over a 5-day culture period, treatment with 0-120 microM alpha- and gamma-tocopherol had no effect on cell proliferation, whereas growth was inhibited 50% (IC50) as compared with controls by treatment with the following: 13, 7, and 6 microM tocotrienol-rich-fraction of palm oil (TRF); 55, 47, and 23 microM delta-tocopherol; 12, 7, and 5 microM alpha-tocotrienol; 8, 5, and 4 microM gamma-tocotrienol; or 7, 4, and 3 microM delta-tocotrienol in CL-S1, -SA and +SA cells, respectively. Acute 24-hr exposure to 0-250 microM alpha- or gamma-tocopherol (CL-S1, -SA, and +SA) or 0-250 microM delta-tocopherol (CL-S1) had no effect on cell viability, whereas cell viability was reduced 50% (LD50) as compared with controls by treatment with 166 or 125 microM delta-tocopherol in -SA and +SA cells, respectively. Additional LD50 doses were determined as the following: 50, 43, and 38 microM TRF; 27, 28, and 23 microM alpha-tocotrienol; 19, 17, and 14 microM gamma-tocotrienol; or 16, 15, or 12 microM delta-tocotrienol in CL-S1, -SA, and +SA cells, respectively. Treatment-induced cell death resulted from activation of apoptosis, as indicated by DNA fragmentation. Results also showed that CL-S1, -SA, and +SA cells preferentially accumulate tocotrienols as compared with tocopherols, and this may partially explain why tocotrienols display greater biopotency than tocopherols. These data also showed that highly malignant +SA cells were the most sensitive, whereas the preneoplastic CL-S1 cells were the least sensitive to the antiproliferative and apoptotic effects of tocotrienols, and suggest that tocotrienols may have potential health benefits in preventing and/or reducing the risk of breast cancer in women.”,”author”:{“dropping-particle”:””,”family”:”McIntyre”,”given”:”B S”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Briski”,”given”:”K P”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Gapor”,”given”:”A”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Sylvester”,”given”:”P W”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)”,”id”:”ITEM-1″,”issue”:”4″,”issued”:{“date-parts”:”2000″},”page”:”292-301″,”title”:”Antiproliferative and apoptotic effects of tocopherols and tocotrienols on preneoplastic and neoplastic mouse mammary epithelial cells.”,”type”:”article-journal”,”volume”:”224″},”uris”:”http://www.mendeley.com/documents/?uuid=ed8e0786-e3a9-4a62-b330-e3fad9bb7ca2″,”http://www.mendeley.com/documents/?uuid=6be8d2ae-b04f-42de-abb1-afd5e6b167d2″},”mendeley”:{“formattedCitation”:”(McIntyre et al., 2000)”,”plainTextFormattedCitation”:”(McIntyre et al., 2000)”,”previouslyFormattedCitation”:”(McIntyre et al., 2000)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(McIntyre et al., 2000). On the other hand, tocotrienol administration reduces oxidative protein damage and extends the mean lifespan of C. elegans. compared to tocopherol ADDIN CSL_CITATION {“citationItems”:{“id”:”ITEM-1″,”itemData”:{“DOI”:”10.1093/gerona/55.6.B280″,”ISBN”:”1079-5006 (Print)”,”ISSN”:”1079-5006″,”PMID”:”10843344″,”abstract”:”To assess the efficiency of tocotrienols against oxidative damage, we have demonstrated in a model-system nematode, Caenorhabditis elegans, that tocotrienol administration reduced the accumulation of protein carbonyl (a good indicator of oxidative damage during aging) and consequently extended the mean life span (LS), but not the maximum LS. Conversely, alpha-tocopherol acetate did not affect these parameters. As a way to evaluate the protective ability of tocotrienols against oxidative stress, the life spans of animals administrated tocotrienols before or after exposure to ultraviolet B-induced oxidative stress were measured. Ultraviolet B irradiation shortened the mean LS of animals, whereas preadministration of tocotrienols recovered the mean LS to that of unirradiated animals. Interestingly, postadministration also extended the mean LS more than that of unirradiated animals, and administration through the LS conferred greater protection. Thus, the administration of tocotrienols to animals results in a reduction of oxidative stress risks. These data indicated that tocotrienols merit further investigation as possible agents for antiaging and oxidative stress prevention. In addition, they suggest that C. elegans will continue to provide provocative clues into the mechanisms of aging.”,”author”:{“dropping-particle”:””,”family”:”Adachi”,”given”:”H”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},{“dropping-particle”:””,”family”:”Ishii”,”given”:”N”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””},”container-title”:”The journals of gerontology. Series A, Biological sciences and medical sciences”,”id”:”ITEM-1″,”issued”:{“date-parts”:”2000″},”title”:”Effects of tocotrienols on life span and protein carbonylation in Caenorhabditis elegans.”,”type”:”article-journal”},”uris”:”http://www.mendeley.com/documents/?uuid=f2202702-c9ee-4567-a5ad-23da55daf1f8″},”mendeley”:{“formattedCitation”:”(Adachi & Ishii, 2000)”,”plainTextFormattedCitation”:”(Adachi & Ishii, 2000)”,”previouslyFormattedCitation”:”(Adachi & Ishii, 2000)”},”properties”:{“noteIndex”:0},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”}(Adachi ; Ishii, 2000).

CONCLUSION
Nicotine gives the adverse effect to the uterus while ?-tocotrienol reversed the adverse effect of the nicotine on the uterus. However, this finding is still in experimental level to verify the effectiveness of ?-tocotrienol. It is a stepping point for further experimentation in the future regarding the usage of ?-tocotrienol in various health application.

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