TOCOTRIENOL-RICH FRACTION MODULATE THE PHOSPHOINOSITIDE 3-KINASES/AKT SIGNALING PATHWAY GENES AND PREVENT OXIDATIVE STRESS IN NICOTINE-INDUCED PRE-IMPLANTATION EMBRYOS
DOI:
https://doi.org/10.22159/ijap.2019.v11s5.T0055Keywords:
Tocotrienol-rich fraction, Nicotine, Preimplantation embryoAbstract
Objective: This study aimed to determine the effects of the tocotrienol-rich fraction (TRF) on the regulations of phosphoinositide 3-kinases (PI3K)/Akt
pathways related genes in preimplantation embryos induced by nicotine (Nic).
Methods: Twenty-four female BALB/c mice were divided into four groups with Nic and TRF supplementation for 7 consecutive days. Animals
were superovulated before mating with fertile males. Plasma malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase were
determined and analyzed accordingly. Embryos with two and eight blastomeres were assessed for gene expression analysis.
Results: The levels of endogenous antioxidative enzymes for the group with TRF intervention and TRF only group showed no significant changes when
compared to the control group. The level of oxidative stress (OS) biomarkers was also significantly decreased when compared to the Nic-induced group.
At 2-cell stage, Pten gene was significantly upregulated while Akt1, GSK3β, and Mapk1 were significantly downregulated almost similar to the baseline
(control) in the Nic-induced mice. Intervention with TRF resulted in a significant downregulated of Pten gene followed by a significant upregulation
of other genes. The same pattern was shown at the 8-cell stage.
Conclusion: This showed that TRF evidently has OS protection capacity and it could be through modulating the PI3K/Akt signaling pathway.
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References
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intramembrane mobility in the antioxidant properties of alphatocopherol
and alpha-tocotrienol. Free Radic Biol Med 1991;10:263-75.
2. Koba K, Abe K, Ikeda I, Sugano M. Effects of alpha-tocopherol and
tocotrienols on blood pressure and linoleic acid metabolism in the
spontaneously hypertensive rat (SHR). Biosci Biotechnol Biochem
1992;56:1420-3.
3. Rahmat A, Ngah WZ, Shamaan NA, Gapor A, Abdul Kadir K. Longterm
administration of tocotrienols and tumor-marker enzyme activities
during hepatocarcinogenesis in rats. Nutrition 1993;9:229-32.
4. Goh SH, Hew NF, Norhanom AW, Yadav M. Inhibition of
tumour promotion by various palm-oil tocotrienols. Int J Cancer
1994;57:529-31.
5. Nesaretnam K, Guthrie N, Chambers AF, Carroll KK. Effect of
tocotrienols on the growth of a human breast cancer cell line in culture.
Lipids 1995;30:1139-43.
6. Nesaretnam K, Meganathan P, Veerasenan SD, Selvaduray KR.
Tocotrienols and breast cancer: The evidence to date. Genes Nutr
2012;7:3-9.
7. Yuen KH, Wong JW, Lim AB, Ng BH, Choy WP. Effect of mixedtocotrienol
in hypercholesterolmic subjects. Funct Foods Health Dis
2011;1:106-17.
8. Patel V, Rink C, Gordillo GM, Khanna S, Gnyawali U, Roy S,
et al. Oral tocotrienols are transported to human tissues and delay the
progression of the model for end-stage liver disease score in patients.
J Nutr 2012;142:513-9.
9. Ahmad NS, Khalid BA, Luke DA, Ima Nirwana S. Tocotrienol offers
better protection than tocopherol from free radical-induced damage of
rat bone. Clin Exp Pharmacol Physiol 2005;32:761-70.
10. Hermizi H, Faizah O, Ima-Nirwana S, Ahmad Nazrun S,
Norazlina M. Beneficial effects of tocotrienol and tocopherol on bone
histomorphometric parameters in sprague-dawley male rats after
nicotine cessation. Calcif Tissue Int 2009;84:65-74.
11. Mokhtar N, Rajikin MH, Zakaria Z. Role of tocotrienol-rich palm
Vitamin E on pregnancy and preimplantation embryos in nicotine
treated rats. Biomed Res 2008;19:181-4.
12. Nasibah A, Rajikin MH, Nor-Ashikin MN, Nuraliza AS. Tocotrienol
Improves the Quality of Impaired Mouse Embryos Induced by
Corticosterone. Kota Kinabalu: CHUSER 2012-2012 IEEE Colloquium
on Humanities, Science and Engineering Research; 2012. p. 135-8.
13. Nasibah A, Rajikin MH, Nor-Ashikin MN, Nuraliza AS. Effects of
tocotrienol supplementation on pregnancy outcome in mice subjected to
maternal corticosterone administration. J Oil Palm Res 2012;24:1550-8.
14. Kamsani YS, Rajikin MH, Mohamed Nor Khan NA, Abdul Satar N,
Chatterjee A. Nicotine-induced cessation of embryonic development
is reversed by ?-tocotrienol in mice. Med Sci Monit Basic Res
2013;19:87-92.
15. Snyder JM. Department of Anatomy and Cell Biology, University
of Iowa. Lecture Medical Cell Biology. Iowa: Fertilization and
Implantation; 2001.
16. Benkhalifa M, Menezo Y. Geneva Foundation for Medical Research
and Education. Gamete and Embryo Quality, Role in Fertilization
Failures and Reproductive Pathology: The Contribution of Fluorescent
in Situ Hybridization (FISH). Geneva: GFMER; 2003.
17. Ertzeid G, Storeng R. Adverse effects of gonadotrophin treatment
on pre- and postimplantation development in mice. J Reprod Fertil
1992;96:649-55.
18. Hemachandra LM, Chandrasekaran A, Melendez JA, Hempel N.
Regulation of the Cellular Redox Environment by Superoxide
Dismutases, Catalase, and Glutathione Peroxidases During Tumor
Metastasis. Redox Active Therapeutics. Switzerland: Springer; 2016.
p. 51-79.
19. Lei XG, Zhu JH, Cheng WH, Bao Y, Ho YS, Reddi AR, et al.
Paradoxical roles of antioxidant enzymes: Basic mechanisms and
health implications. Physiol Rev 2016;96:307-64.
20. Grimm MO, Regner L, Mett J, Stahlmann CP, Schorr P, Nelke C, et al.
Tocotrienol affects oxidative stress, cholesterol homeostasis and the
amyloidogenic pathway in neuroblastoma cells: Consequences for
Alzheimer’s disease. Int J Mol Sci 2016;17:E1809.
21. Tan JK, Then SM, Mazlan M, Jamal R, Ngah WZ. Vitamin E,
?-tocotrienol, protects against buthionine sulfoximine-induced cell
death by scavenging free radicals in SH-SY5Y neuroblastoma cells.
Nutr Cancer 2016;68:507-17.
22. Yao Y, Lacroix D, Mak AF. Effects of oxidative stress-induced
changes in the actin cytoskeletal structure on myoblast damage
under compressive stress: Confocal-based cell-specific finite element
analysis. Biomech Model Mechanobiol 2016;15:1495-508.
23. Huang X, Chen L, Liu W, Qiao Q, Wu K, Wen J, et al. Involvement
of oxidative stress and cytoskeletal disruption in microcystin-induced
apoptosis in CIK cells. Aquat Toxicol 2015;165:41-50.
24. Zhang Y, Qian D, Li Z, Huang Y, Wu Q, Ru G, et al. Oxidative stressinduced
DNA damage of mouse zygotes triggers G2/M checkpoint
and phosphorylates cdc25 and cdc2. Cell Stress Chaperones
2016;21:687-96.
25. Jadhav JT, Kengar S. Influence of hydrogen peroxide induced oxidative
stress on survival rate of early chick embryo development. Int J
Bioassays 2016;5:4603-6.
26. Niu Z, Xie C, Wen X, Tian F, Yuan S, Jia D, et al. Potential pathways by
which maternal second-hand smoke exposure during pregnancy causes
full-term low birth weight. Sci Rep 2016;6:24987.
27. Rajikin MH, Latif ES, Mar MR, Top AG, Mokhtar NM. Deleterious
effects of nicotine on the ultrastructure of oocytes: Role of gammatocotrienol.
Med Sci Monit 2009;15:BR378-83.
28. Knopik VS, Maccani MA, Francazio S, McGeary JE. The epigenetics
of maternal cigarette smoking during pregnancy and effects on child
development. Dev Psychopathol 2012;24:1377-90.
29. Gu YH, Li Y, Huang XF, Zheng JF, Yang J, Diao H, et al. Reproductive
effects of two neonicotinoid insecticides on mouse sperm function and
early embryonic development in vitro. PLoS One 2013;8:e70112.
30. Hirata N, Yamada S, Asanagi M, Sekino Y, Kanda Y. Nicotine
induces mitochondrial fission through mitofusin degradation in
human multipotent embryonic carcinoma cells. Biochem Biophys Res
Commun 2016;470:300-5.
31. Bellomo G, Mirabelli F. Oxidative stress and cytoskeletal alterations.
Ann N Y Acad Sci 1992;663:97-109.
32. Wang X, Falcone T, Attaran M, Goldberg JM, Agarwal A, Sharma RK,
et al. Vitamin C and Vitamin E supplementation reduce oxidative stressinduced
embryo toxicity and improve the blastocyst development rate.
Fertil Steril 2002;78:1272-7.
33. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol
3-kinases as regulators of growth and metabolism. Nat Rev Genet
2006;7:606-19.
34. García Z, Kumar A, Marqués M, Cortés I, Carrera AC. Phosphoinositide
3-kinase controls early and late events in mammalian cell division.
EMBO J 2006;25:655-61.
35. Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls
tumour cell growth. Nature 2006;441:424-30.
36. Zhao JJ, Roberts TM. PI3 kinases in cancer: From oncogene artifact to
leading cancer target. Sci STKE 2006;2006:pe52.
37. Thompson JE, Thompson CB. Putting the rap on akt. J Clin Oncol
2004;22:4217-26.
38. Datta SR, Brunet A, Greenberg ME. Cellular survival: A play in three
akts. Genes Dev 1999;13:2905-27.
39. Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C. PI3K/Akt
and apoptosis: Size matters. Oncogene 2003;22:8983-98.
40. Syairah SM, Rajikin MH, Sharaniza AR. Chromosomal status in murine
preimplantation 2-cell embryos following annatto (Bixa orellana)-
derived pure delta-tocotrienol supplementation in normal and nicotinetreated
mice. World Appl Sci J 2016;34:1855-9.
41. Hamirah NK, Kamsani YS, Mohamed Nor Khan NA,
Ab Rahim supplementation on cytoskeletal structures of murine
pre-implantation embryos. Med Sci Monit Basic Res 2017;23:373-9.
42. Kirkham PA, Barnes PJ. Oxidative stress in COPD. Chest
2013;144:266-73.
43. Uchida T, Abe C, Nomura S, Ichikawa T, Ikeda S. Tissue distribution of
?- and ?-tocotrienol and ?-tocopherol in rats and interference with their
accumulation by ?-tocopherol. Lipids 2012;47:129-39.
44. Atkinson J, Epand RF, Epand RM. Tocopherols and tocotrienols in
membranes: A critical review. Free Radic Biol Med 2008;44:739-64.
45. Lee SP, Mar GY, Ng LT. Effects of tocotrienol-rich fraction on exercise
endurance capacity and oxidative stress in forced swimming rats. Eur J
Appl Physiol 2009;107:587-95.
46. Li L, Zheng P, Dean J. Maternal control of early mouse development.
Development 2010;137:859-70.
intramembrane mobility in the antioxidant properties of alphatocopherol
and alpha-tocotrienol. Free Radic Biol Med 1991;10:263-75.
2. Koba K, Abe K, Ikeda I, Sugano M. Effects of alpha-tocopherol and
tocotrienols on blood pressure and linoleic acid metabolism in the
spontaneously hypertensive rat (SHR). Biosci Biotechnol Biochem
1992;56:1420-3.
3. Rahmat A, Ngah WZ, Shamaan NA, Gapor A, Abdul Kadir K. Longterm
administration of tocotrienols and tumor-marker enzyme activities
during hepatocarcinogenesis in rats. Nutrition 1993;9:229-32.
4. Goh SH, Hew NF, Norhanom AW, Yadav M. Inhibition of
tumour promotion by various palm-oil tocotrienols. Int J Cancer
1994;57:529-31.
5. Nesaretnam K, Guthrie N, Chambers AF, Carroll KK. Effect of
tocotrienols on the growth of a human breast cancer cell line in culture.
Lipids 1995;30:1139-43.
6. Nesaretnam K, Meganathan P, Veerasenan SD, Selvaduray KR.
Tocotrienols and breast cancer: The evidence to date. Genes Nutr
2012;7:3-9.
7. Yuen KH, Wong JW, Lim AB, Ng BH, Choy WP. Effect of mixedtocotrienol
in hypercholesterolmic subjects. Funct Foods Health Dis
2011;1:106-17.
8. Patel V, Rink C, Gordillo GM, Khanna S, Gnyawali U, Roy S,
et al. Oral tocotrienols are transported to human tissues and delay the
progression of the model for end-stage liver disease score in patients.
J Nutr 2012;142:513-9.
9. Ahmad NS, Khalid BA, Luke DA, Ima Nirwana S. Tocotrienol offers
better protection than tocopherol from free radical-induced damage of
rat bone. Clin Exp Pharmacol Physiol 2005;32:761-70.
10. Hermizi H, Faizah O, Ima-Nirwana S, Ahmad Nazrun S,
Norazlina M. Beneficial effects of tocotrienol and tocopherol on bone
histomorphometric parameters in sprague-dawley male rats after
nicotine cessation. Calcif Tissue Int 2009;84:65-74.
11. Mokhtar N, Rajikin MH, Zakaria Z. Role of tocotrienol-rich palm
Vitamin E on pregnancy and preimplantation embryos in nicotine
treated rats. Biomed Res 2008;19:181-4.
12. Nasibah A, Rajikin MH, Nor-Ashikin MN, Nuraliza AS. Tocotrienol
Improves the Quality of Impaired Mouse Embryos Induced by
Corticosterone. Kota Kinabalu: CHUSER 2012-2012 IEEE Colloquium
on Humanities, Science and Engineering Research; 2012. p. 135-8.
13. Nasibah A, Rajikin MH, Nor-Ashikin MN, Nuraliza AS. Effects of
tocotrienol supplementation on pregnancy outcome in mice subjected to
maternal corticosterone administration. J Oil Palm Res 2012;24:1550-8.
14. Kamsani YS, Rajikin MH, Mohamed Nor Khan NA, Abdul Satar N,
Chatterjee A. Nicotine-induced cessation of embryonic development
is reversed by ?-tocotrienol in mice. Med Sci Monit Basic Res
2013;19:87-92.
15. Snyder JM. Department of Anatomy and Cell Biology, University
of Iowa. Lecture Medical Cell Biology. Iowa: Fertilization and
Implantation; 2001.
16. Benkhalifa M, Menezo Y. Geneva Foundation for Medical Research
and Education. Gamete and Embryo Quality, Role in Fertilization
Failures and Reproductive Pathology: The Contribution of Fluorescent
in Situ Hybridization (FISH). Geneva: GFMER; 2003.
17. Ertzeid G, Storeng R. Adverse effects of gonadotrophin treatment
on pre- and postimplantation development in mice. J Reprod Fertil
1992;96:649-55.
18. Hemachandra LM, Chandrasekaran A, Melendez JA, Hempel N.
Regulation of the Cellular Redox Environment by Superoxide
Dismutases, Catalase, and Glutathione Peroxidases During Tumor
Metastasis. Redox Active Therapeutics. Switzerland: Springer; 2016.
p. 51-79.
19. Lei XG, Zhu JH, Cheng WH, Bao Y, Ho YS, Reddi AR, et al.
Paradoxical roles of antioxidant enzymes: Basic mechanisms and
health implications. Physiol Rev 2016;96:307-64.
20. Grimm MO, Regner L, Mett J, Stahlmann CP, Schorr P, Nelke C, et al.
Tocotrienol affects oxidative stress, cholesterol homeostasis and the
amyloidogenic pathway in neuroblastoma cells: Consequences for
Alzheimer’s disease. Int J Mol Sci 2016;17:E1809.
21. Tan JK, Then SM, Mazlan M, Jamal R, Ngah WZ. Vitamin E,
?-tocotrienol, protects against buthionine sulfoximine-induced cell
death by scavenging free radicals in SH-SY5Y neuroblastoma cells.
Nutr Cancer 2016;68:507-17.
22. Yao Y, Lacroix D, Mak AF. Effects of oxidative stress-induced
changes in the actin cytoskeletal structure on myoblast damage
under compressive stress: Confocal-based cell-specific finite element
analysis. Biomech Model Mechanobiol 2016;15:1495-508.
23. Huang X, Chen L, Liu W, Qiao Q, Wu K, Wen J, et al. Involvement
of oxidative stress and cytoskeletal disruption in microcystin-induced
apoptosis in CIK cells. Aquat Toxicol 2015;165:41-50.
24. Zhang Y, Qian D, Li Z, Huang Y, Wu Q, Ru G, et al. Oxidative stressinduced
DNA damage of mouse zygotes triggers G2/M checkpoint
and phosphorylates cdc25 and cdc2. Cell Stress Chaperones
2016;21:687-96.
25. Jadhav JT, Kengar S. Influence of hydrogen peroxide induced oxidative
stress on survival rate of early chick embryo development. Int J
Bioassays 2016;5:4603-6.
26. Niu Z, Xie C, Wen X, Tian F, Yuan S, Jia D, et al. Potential pathways by
which maternal second-hand smoke exposure during pregnancy causes
full-term low birth weight. Sci Rep 2016;6:24987.
27. Rajikin MH, Latif ES, Mar MR, Top AG, Mokhtar NM. Deleterious
effects of nicotine on the ultrastructure of oocytes: Role of gammatocotrienol.
Med Sci Monit 2009;15:BR378-83.
28. Knopik VS, Maccani MA, Francazio S, McGeary JE. The epigenetics
of maternal cigarette smoking during pregnancy and effects on child
development. Dev Psychopathol 2012;24:1377-90.
29. Gu YH, Li Y, Huang XF, Zheng JF, Yang J, Diao H, et al. Reproductive
effects of two neonicotinoid insecticides on mouse sperm function and
early embryonic development in vitro. PLoS One 2013;8:e70112.
30. Hirata N, Yamada S, Asanagi M, Sekino Y, Kanda Y. Nicotine
induces mitochondrial fission through mitofusin degradation in
human multipotent embryonic carcinoma cells. Biochem Biophys Res
Commun 2016;470:300-5.
31. Bellomo G, Mirabelli F. Oxidative stress and cytoskeletal alterations.
Ann N Y Acad Sci 1992;663:97-109.
32. Wang X, Falcone T, Attaran M, Goldberg JM, Agarwal A, Sharma RK,
et al. Vitamin C and Vitamin E supplementation reduce oxidative stressinduced
embryo toxicity and improve the blastocyst development rate.
Fertil Steril 2002;78:1272-7.
33. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol
3-kinases as regulators of growth and metabolism. Nat Rev Genet
2006;7:606-19.
34. García Z, Kumar A, Marqués M, Cortés I, Carrera AC. Phosphoinositide
3-kinase controls early and late events in mammalian cell division.
EMBO J 2006;25:655-61.
35. Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls
tumour cell growth. Nature 2006;441:424-30.
36. Zhao JJ, Roberts TM. PI3 kinases in cancer: From oncogene artifact to
leading cancer target. Sci STKE 2006;2006:pe52.
37. Thompson JE, Thompson CB. Putting the rap on akt. J Clin Oncol
2004;22:4217-26.
38. Datta SR, Brunet A, Greenberg ME. Cellular survival: A play in three
akts. Genes Dev 1999;13:2905-27.
39. Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C. PI3K/Akt
and apoptosis: Size matters. Oncogene 2003;22:8983-98.
40. Syairah SM, Rajikin MH, Sharaniza AR. Chromosomal status in murine
preimplantation 2-cell embryos following annatto (Bixa orellana)-
derived pure delta-tocotrienol supplementation in normal and nicotinetreated
mice. World Appl Sci J 2016;34:1855-9.
41. Hamirah NK, Kamsani YS, Mohamed Nor Khan NA,
Ab Rahim supplementation on cytoskeletal structures of murine
pre-implantation embryos. Med Sci Monit Basic Res 2017;23:373-9.
42. Kirkham PA, Barnes PJ. Oxidative stress in COPD. Chest
2013;144:266-73.
43. Uchida T, Abe C, Nomura S, Ichikawa T, Ikeda S. Tissue distribution of
?- and ?-tocotrienol and ?-tocopherol in rats and interference with their
accumulation by ?-tocopherol. Lipids 2012;47:129-39.
44. Atkinson J, Epand RF, Epand RM. Tocopherols and tocotrienols in
membranes: A critical review. Free Radic Biol Med 2008;44:739-64.
45. Lee SP, Mar GY, Ng LT. Effects of tocotrienol-rich fraction on exercise
endurance capacity and oxidative stress in forced swimming rats. Eur J
Appl Physiol 2009;107:587-95.
46. Li L, Zheng P, Dean J. Maternal control of early mouse development.
Development 2010;137:859-70.
Published
15-09-2019
How to Cite
KAMSANI, N. H., AB-RAHIM, S., KAMSANI, Y. S., NOOR KHAN, N. A. M., & RAJIKIN, M. H. (2019). TOCOTRIENOL-RICH FRACTION MODULATE THE PHOSPHOINOSITIDE 3-KINASES/AKT SIGNALING PATHWAY GENES AND PREVENT OXIDATIVE STRESS IN NICOTINE-INDUCED PRE-IMPLANTATION EMBRYOS. International Journal of Applied Pharmaceutics, 11(5), 80–85. https://doi.org/10.22159/ijap.2019.v11s5.T0055
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