Yaşa bağlı gelişen bozukluklarda polifenoller ve hedefleri; mTOR sinyal ileti yolu

Abstract

Dünya çapında, yaşa bağlı hastalıkların insidansının artmasıyla birlikte mortalite ve morbiditenin de yüksek olması yaşlanmayı yavaşlatan veya geciktiren müdahalelerin geliştirilmesine neden olmaktadır. Son yıllarda yaşa bağlı gelişebilecek bozukluklarla ilgili yapılan araştırmalar mTOR sinyal ileti yolu üzerinde yoğunlaşmıştır. mTOR ve yapısına dahil olduğu kompleksler yaşlanma ile ilişkilendirilen en önemli hücresel sinyal ileti yolu molekülleri olarak kabul edilmektedir. Ayrıca, mTOR inhibitörleri ile ilgili yaşlanma sürecini yavaşlatabildiklerine dair bulguların ortaya çıkması bu konu üzerindeki ilgiyi giderek arttırmaktadır. Bu derlemede, yaşa bağlı gelişebilecek bozukluklarda mTOR sinyal ileti yolunu hedefleyen diyet türevi doğal polifenolik bileşiklerle ilgili güncel bilgiler derlenmiştir. Ayrıca, polifenollerin yaşa bağlı bozukluklarının moleküler patojenezi üzerindeki etkilerinden de bahsedilmiştir.

Keywords

• Yaşlanma,yaşa bağlı bozukluklar,polifenoller,mTOR

Polyphenols and targets in age-related disorders; mTOR signalling pathway

Abstract

With the increase in the incidence of age-related diseases worldwide, the high mortality and morbidity cause the development of interventions that slow down or delay aging. In recent years, studies related to age-related disorders have been focused on the mTOR signalling pathway. mTOR and the complexes that mTOR involved in its structure are considered the most important cellular signalling pathway molecules associated with aging. In addition, the emergence of evidence that mTOR inhibitors can slow down the aging process is gradually increasing interest in this issue. In this review, current knowledge about diet-derived natural polyphenolic compounds targeting mTOR signal transduction pathways has been reviewed. Also, the effects of polyphenols on the molecular pathogenesis of age-related disorders have also been discussed.

Keywords

• Aging,age-related disorders,polyphenols,mTOR

References

1. 1. Minino AM, Murphy SL. Death in the United States, 2010. NCHS Data Brief 2012;99:1-8.
2. 2. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 2011;12(1):21-35.
3. 3. Kyriakakis E, Princz A, Tavernarakis N. Stress responses during ageing: molecular pathways regulating protein homeostasis. Stress Responses Methods Protoc 2015;1292:215-234.
4. 4. Mondal SC, Singh P, Kumar B, Singh SK, Gupta SK, Verma A. Ageing and potential anti-aging phytochemicals: an overview. World J Pharm Pharm Sci 2014;4:426-454.
5. 5. Zhang Y. Ageing and cancer: breaking the don’t put all eggs in one basket and natural self-organisation, and their potential reprogramming via modulation of mi-2/NuRD, mTOR kinase and metabolism. Enz Eng 2012;2:109.
6. 6. McCormick MA, Tsai SY, Kennedy BK. TOR and ageing: a complex pathway for a complex process. Philos Trans R Soc Lond B Biol Sci 2011;366(1561):17-27.
7. 7. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature 2013;493(7432):338-345.
8. 8. Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, Partridge L. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab 2010;11:35-46.

9. 9. Schreiber KH, Ortiz D, Academia EC, Anies AC, Liao CY, Kennedy BK. Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins. Aging cell 2015;14(2):265-273.
10. 10 Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci 2009;122(20): 3589-3594.
11. 11. Alessi DR, Pearce LR, Garcia-Martinez JM. New insights into mTOR signaling: mTORC2 and beyond. Sci Signal 2009;2(67):27.
12. 12. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 2002;110(2):177-189.
13. 13. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004;14(14):1296-1302.
14. 14. Dibble CC, Cantley LC. Regulation of mTORC1 by PI3K signaling. Trends Cell Biol 2015;25(9):545-555.
15. 15. Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, Gray NS, Sabatini DM. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 2009;137(5):873-886.
16. 16. Carr TD, Feehan RP, Hall MN, Rüegg MA, Shantz LM. Conditional disruption of rictor demonstrates a direct requirement for mTORC2 in skin tumor development and continued growth of established tumors. Carcinogenesis 2015;36(4):487-497.
17. 17. Beevers CS, Chen L, Liu L, Luo Y, Webster NJ, Huang S. Curcumin disrupts the Mammalian target of rapamycin-raptor complex. Cancer Res 2009;69:1000-1008.
18. 18. Jiang H, Shang X, Wu H, Gautam SC, Al-Holou S, Li C, Kuo J, Zhang L, Chopp M. Resveratrol downregulates PI3K/Akt/mTOR signaling pathways in human U251 glioma cells. J Exp Ther Oncol 2009;8:25-33.
19. 19. Zhang Q, Kelly AP, Wang L, French SW, Tang X, Duong HS, Messadi DV, Le AD. Green tea extract and (-)-epigallocatechin-3-gallate inhibit mast cell-stimulated type I collagen expression in keloid fibroblasts via blocking PI3K/AkT signaling pathways. J Invest Dermatol 2006;126:2607-2613.
20. 20. Anastasius N, Boston S, Lacey M, Storing N, Whitehead SA. Evidence that low-dose, long-term genistein treatment inhibits oestradiol-stimulated growth in MCF-7 cells by down-regulation of the PI3-kinase/Akt signalling pathway. J Steroid Biochem Mol Biol 2009;116:50-55.
21. 21. Nakamura Y, Yogosawa S, Izutani Y, Watanabe H, Otsuji E, Sakai T. A combination of indol-3-carbinol and genistein synergistically induces apoptosis in human colon cancer HT-29 cells by inhibiting Akt phosphorylation and progression of autophagy. Mol Cancer 2009;8:100.
22. 22. Kong D, Banerjee S, Huang W, Li Y, Wang Z, Kim HR, Sarkar FH. Mammalian target of rapamycin repression by 3,3′-diindolylmethane inhibits invasion and angiogenesis in platelet-derived growth factor-D-overexpressing PC3 cells. Cancer Res 2008;68:1927-1934.
23. 23. Lu W, Kelly AL, Miao S. Emulsion-based encapsulation and delivery systems for polyphenols. Trends Food Sci Technol. 2016;47:1-9.
24. 24. Sharma RA, Gescher AJ, Steward WP. Curcumin: the story so far. Eur J Cancer, 2005;41:1955-1968.
25. 25. Alanon M, Castro-Vazquez L, Diaz-Maroto M, Gordon M, Perez-Coello M. A study of the antioxidant capacity of oak wood used in wine ageing and the correlation with polyphenol composition. Food Chem 2011;128(4):997-1002.
26. 26. Schaffer S, Asseburg H, Kuntz S, Muller WE, Eckert GP. Effects of polyphenols on brain ageing and Alzheimer’s disease: focus on mitochondria. Mol Neurobiol 2012;46(1):161-178.
27. 27. Shen Y, Zhang H, Cheng L, Wang L, Qian H, Qi X. In vitro and in vivo antioxidant activity of polyphenols extracted from black highland barley. Food Chem 2016;194:1003-1012.
28. 28. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1. Cell 2006;127(6):1109-1122.
29. 29. Charles AL, Meyer A, Dal-Ros S, Auger C, Keller N, Ramamoorthy TG, Zoll J, Metzger D, Schini-Kerth V, Geny B. Polyphenols prevent ageing-related impairment in skeletal muscle mitochondrial function through decreased reactive oxygen species production. Exp Physiol 2013;98(2):536-545.
30. 30. Khurana S, Venkataraman K, Hollingsworth A, Piche M, Tai T. Polyphenols: benefits to the cardiovascular system in health and in aging. Nutrients 2013;5(10):3779-3827.
31. 31. Zhang L, Shamaladevi N, Jayaprakasha G, Patil B, Lokeshwar B. Polyphenol-rich extract of Pimenta dioica berries (Allspice) kills breast cancer cells by autophagy and delays growth of triple negative breast cancer in athymic mice. Oncotarget 2015;6(18):16379–16395.
32. 32. Yeh PS, Wang W, Chang YA, Lin CJ, Wang JJ, Chen RM. Honokiol induces autophagy of neuroblastoma cells through activating thePI3K/Akt/mTOR and endoplasmic reticular stress/ERK1/2 signaling pathways and suppressing cell migration. Cancer Lett 2016;370(1):66–77.
33. 33. Chung JH, Manganiello V, Dyck JR. Resveratrol as a calorie restriction mimetic: therapeutic implications. Trends Cell Biol 2012;22:546-554.
34. 34. Park SJ, Ahmad F, Philp A, Baar K, Williams T, Luo H, Ke H, Rehmann H, Taussig R, Brown AL, Kim MK, Beaven MA, Burgin AB, Manganiello V, Chung JH. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 2012;148(3):421-433.
35. 35. Morselli E, Maiuri MC, Markaki M, Megalou E, Pasparaki A, Palikaras K, Criollo A, Galluzzi L, Malik SA, Vitale I. The life span-prolonging effect of sirtuin-1 is mediated by autophagy. Autophagy 2010;6(1):186-188.
36. 36. Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA, Wang Y, Raederstorff D, Morrow JD, Leeuwenburgh C. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One 2008;3(6):2264.
37. 37. Huang S. Inhibition of PI3K/Akt/mTOR signaling by natural products. 2013. Anticancer Agents Med Chem 2013;13(7):967-970.
38. 38. Liu M, Wilk SA, Wang A, Zhou L, Wang RH, Ogawa W, Deng C, Dong LQ, Liu F. Resveratrol inhibits mTOR signaling by promoting the interaction between mTOR and DEPTOR. J Biol Chem 2010;285:36387-36394.
39. 39. Tong X, Pelling J. Targeting the PI3K/Akt/mTOR axis by apigenin for cancer prevention. Anticancer Agents Med Chem 2013;13(7):971-978.
40. 40. George VC. Promising tumor inhibiting potentials of fisetin throughPI3K/AKT/mTOR pathway. Am J Transl Res 2016;8(2):1293-1294.
41. 41. Syed DN, Adhami VM, Khan MI, Mukhtar H. Inhibition of Akt/mTOR signaling by the dietary flavonoid fisetin. Anticancer Agents Med Chem 2013;13(7):995-1001.
42. 42. Haddad AQ, Fleshner N, Nelson C, Saour B, Musquera M, Venkateswaran V, Klotz L. Antiproliferative mechanisms of the flavonoids2,2’-Dihydroxychalcone and fisetin in human prostate cancer cells. Nutr Cancer 2010;62(5):668-681.
43. 43. Ahmad A, Biersack B, Li Y, Bao B, Kong D, Schobert R, Padhye SB, Sarkar FH. Deregulation of PI3K/Akt/mTOR signaling by isoflavones and its implication in cancer research. Anticancer Agents Med Chem 2013;13(7):1014-1024.
44. 44. Anand P, Sundaram C, Jhurani S, Kunnumakkara AB, Aggarwal BB. Curcumin and cancer: An ‘‘old-age” disease with an ‘‘age-old” solution. Cancer Letters 2008;267:133-164.
45. 45. Beevers CS, Huang S. Hitting the Golden TORget: Curcumin's Effects on mTOR Signaling. Anticancer Agents Med Chem 2013;13(7):988-994.
46. 46. Brown D. Antibiotic resistance breakers: can repurposed drugs fill the antibiotic discovery void? Nature Rev Drug Discovery 2015;14(12):821-832.
47. 47. Wee LH, Morad NA, Aan GJ, Makpol S, Ngah WZW, Yusof YAM. Mechanism of chemoprevention against colon cancer cells using combinedgelam honey and ginger extract via mTOR and Wnt/β-catenin pathways. Asian Pacific J Cancer Prev 2015;16(15):6549-6456.
48. 48. Cerella C, Gaigneaux A, Dicato M, Diederich M, Antagonistic role of natural compounds in mTOR-mediated metabolic reprogramming. Cancer Lett 2015;356(2):251-262.
49. 49. Hoek-van den Hil EF, van Schothorst EM, van der Stelt I, Swarts HJ, van Vliet M, Amolo T, Vervoort JJ, Venema D, Hollman PC, Rietjens IM, Keijer J. Direct comparison of metabolic health effects of the flavonoids quercetin, hesperetin, epicatechin, apigenin and anthocyanins inhigh-fat-diet-fed mice. Genes Nutr 2015;4:469.
50. 50. Kobylinska A, Janas KM. Health-promoting effect of quercetin in human diet. Postepy Hig Med Dosw 2015;69:51-62.
51. 51. Chen X, Dong XS, Gao HY, Jiang YF, Jin YL, Chang YY, Chen LY, Wang JH. Suppression of HSP27 increases the anti-tumor effects of quercetin in human leukemia U937 cells. Mol Med Rep 2016;13(1):689-696.
52. 52. Hadrich F, Garcia M, Maalej A, Moldes M, Isoda H, Feve B, Sayadi S. Oleuropein activated AMPK and induced insulin sensitivity in C2C12 muscle cells. Life Sci 2016;151:167-173.
53. 53. Rigacci S, Miceli C, Nediani C, Berti A, Cascella R, Pantano D, Nardiello P, Luccarini I, Casamenti F, Stefani M. Oleuropein aglycone induces autophagy via the AMPK/mTOR signalling pathway: a mechanistic insight. Oncotarget 2015;6(34):35344-35357.
54. 54. Ahmad A, Biersack B, Li Y, Kong D, Bao B, Schobert R, Padhye SB, Sarkar FH. Targeted regulation of PI3K/Akt/mTOR/NF-κB signaling by indole compounds and their derivatives: Mechanistic details and biological implications for cancer therapy. Anticancer Agents Med Chem 2013;13(7):1002-1013.
55. 55. Singh BN, Shankar S, Srivastava RK. Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications. Biochem Pharmacol 2011;82:1807-1821.
56. 56. Zhang Q, Kelly AP, Wang L, French SW, Tang X, Duong HS, Messadi DV, Le AD. Green tea extract and (-)-epigallocatechin-3-gallate inhibit mast cell-stimulated type I collagen expression in keloid fibroblasts via blocking PI3K/Akt signaling pathways. J Invest Dermatol 2006;126:2607-2613.
57. 57. Huang CH, Tsai SJ, Wang YJ, Pan MH, Kao JY, Way TD. EGCG inhibits protein synthesis, lipogenesis, and cell cycle progression through activation of AMPK in p53 positive and negative human hepatoma cells. Mol Nutr Food Res 2009;53:1156-1165.
58. 58. Zaveri NT. Grean tea and its Polyphenolic catechins: medicinal uses in cancer and noncancer applications. Life Sci 2006;78:2073-2080.