STZ indüklü diyabetik sıçan beyinlerinde kurkuminin IRS1, Grb2, K-Ras ve Bax ekspresyonu ve aktivasyonu üzerindeki etkisi

Yıl 2020, , 306 - 312, 01.06.2020

Gökhan Görgişen , Yılmaz Ecer Aysun Arslan Sermin Algül , Gökhan Oto , Zehra Kaya

https://doi.org/10.21601/ortadogutipdergisi.772409

Öz

Amaç: Diabetes mellitus ikincil komplikasyon olarak nöropatiye neden olmaktadır. Diyabetik nöropatinin temel mekanizması beyindeki glukoz homeostasisinin ve enerji dengesinin bozulmasıdır. Bu çalışmanın amacı anti-diyabetik bileşik olarak kurkuminin diyabetik sıçan beyinlerinde IRS1, Grb2, K-Ras ve Bax proteinlerinin ekspresyonları üzerindeki etkisinin belirlenmesidir.

Materyal-Metot: 16 adet Wistar albino sıçan rastgele 4’ erli gruplar halinde 4 gruba ayrılmıştır; kontrol grup, kurkumin grup, STZ muamele grup ve STZ+kurkumin muamele grup. STZ gruplarındaki sıçanlarda diyabet, intraperitonel STZ uygulaması ile indüklenmiştir. Ardından hayvanlar, günlük gavaj uygulamasıyla kurkumin ile muamele edilmiştir. IRS1, Grb2, K-Ras ve Bax ekspresyon ve aktivasyonu western blot yöntemi ile belirlenmiştir.

Sonuçlar: Western blot analizleri, kurkumin muamelesinin IRS1 aktivasyonunu arttırdığını ve STZ’nin IRS1 aktivasyonu üzerindeki negatif etkisini geriye çevirdiğini göstermektedir. STZ grubunda K-Ras ekspresyonu belirgin bir derecede azalırken, Bax ekspresyonu artmıştır (p<0.05). Tüm gruplarda, Grb2 ve IRS1 ekpresyonlarında herhangi bir değişiklik gözlemlenmemiştir.

Sonuç: Sonuçlar göz önüne alındığında, STZ indüklü diyabetik sıçan beyinlerinde kurkumin muamelesinin STZ’nin insülin sinyali yolağı elemanları üzerindeki negatif etkilerini geriye çevirdiği söylenebilmektedir.

Anahtar Kelimeler

kurkumin, diabetes mellitus, IRS1, insülin sinyali, STZ

Effect of curcumin on activation and expression of IRS1, Grb2, K-Ras and Bax in STZ-induced diabetic rat brains

Öz

Aim: Diabetes mellitus leads to development of neuropathy as a secondary complication. The main mechanism of diabetic neuropathy is the dysregulation of energy balance and glucose homeostasis in brain. This study aimed to examine the effects of curcumin as an antidiabetic compound on the expressions of IRS1, Grb2, K-Ras and Bax proteins in diabetic rat brains.

Material and Methods: 16 Wistar albino rats were divided randomly into four groups as: control, curcumin; STZ-treated and STZ+Curcumin treated groups. The rats in STZ group were induced to develop diabetes by intraperitoneal administration of STZ. Then, they were treated with curcumin daily by gavage. Expressions and activation of IRS1, Grb2, K-Ras and Bax were determined by western blot analyses.

Results: Western blot analyses showed that curcumin treatment increased IRS1 tyrosine phosphorylation and it reversed the negative effect of STZ on IRS1 activation. K-Ras expression significantly decreased while Bax expression increased in STZ group (p<0.05). No significant changes in the expressions of Grb2 and IRS1 were observed for all groups.

Conclusion: Based on the results, it could be suggested that curcumin treatment significantly reversed the negative effects of STZ on insulin signaling pathway members in STZ induced diabetic rat brains.

Anahtar Kelimeler

curcumin, diabetes mellitus, IRS1, insulin signaling, STZ

Kaynakça

• Harding JL, Pavkov ME, Magliano DJ, Shaw JE, Gregg EW. Global trends in diabetes complications: a review of current evidence. Diabetologia 2019; 62: 3-16. (doi: 10.1007/s00125-018-4711-2).
• Wang P, Su C, Feng H et al. Curcumin regulates insulin pathways and glucose metabolism in the brains of APPswe/PS1dE9 mice. International Journal of Immunopathology and Pharmacology 2017; 30(1): 25-43. (doi: 10.1177/0394632016688025).
• Gorgisen G, Gulacar IM, Ozes N. The role of insulin receptor substrate (IRS) proteins in oncogenic transformation. Cell Mol Biol (Noisy-le-grand) 2017; 63(1): 1-5. (doi: 10.14715/cmb/2017.63.1.1).
• Gorgisen G, Balci MK, Celik FC, et al. Differential activation and expression of Insulin Receptor Substrate 1 (IRS1) in mononuclear cells of Type 2 Diabetes patients after insulin stimulation. Cell Mol Biol (Noisy-le-grand) 2016; 62(2): 25-30. (doi: 10.14715/cmb/2017.63.1.1).
• Gupta SC, Prasad S, Kim JH, et al. Multitargeting by curcumin as revealed by molecular interaction studies. Nat Prod Rep. 2011; 28(12): 1937-55. (doi: 10.1039/c1np00051a).
• Gupta SC, Kismali G, Aggarwal BB. Curcumin, a component of turmeric:from farm to pharmacy. Biofactors 2013; 39(1): 2-13. (doi: 10.1002/biof.1079).
• Ye M, Qiu H, Cao Y, et al. Curcumin Improves Palmitate-Induced Insulin Resistance in Human Umbilical Vein Endothelial Cells by Maintaining Proteostasis in Endoplasmic Reticulum. Front Pharmacol 2017; 8: 148. (doi: 10.3389/fphar.2017.00148).
• Seymen CM, Kaplanoglu I, Kaplanoglu GT, Yazici GN, Erdogan D. The possible protective effects of curcumin in the case of benzo(a)pyrene administration on rat sperm motility and morphology. Ortadogu Tıp Derg 2020; 12(2): 241-50. (doi: 10.21601/ortadogutipdergisi.723357).
• Den Hartogh DJ, Gabriel A, Tsiani E. Antidiabetic Properties of Curcumin II: Evidence from In Vivo Studies. Nutrients 2020; 12: 58. (doi: 10.3390/nu12010058).
• Peeyush KT, Gireesh G, Jobin M, Paulose CS. Neuroprotective role of curcumin in the cerebellum of streptozotocin-induced dia¬betic rats. Life sciences 2009; 85(19-20): 704-10. (doi: 10.1016/j.lfs.2009.09.012).
• El-Moselhy MA, Taye A, Sharkawi SS, El-Sisi SF, Ahmed AF. The antihyperglycemic effect of curcumin in high fat diet fed rats. Role of TNF-alpha and free fatty acids. Food Chem Toxicol. 2011; 49(5): 1129-40. (doi: 10.1016/j.fct.2011.02.004).
• Seo KI, Choi MS, Jung UJ, Kim HJ, Yeo J, Jeon SM, et al. Effect of cur¬cumin supplementation on blood glucose, plasma insulin, and glucose homeostasis related enzyme activities in diabetic db/db mice. Mol Nutr Food Res. 2008; 52(9): 995-1004. (doi: 10.1002/mnfr.200700184).
• Isik AT, Celik T, Ulusoy G, et al. Curcumin ameliorates impaired insulin/IGF signaling and memory deficit in a streptozotocin-treated rat model. Age 2009; 31: 39-49. (doi: 10.1007/s11357-008-9078-8).
• Lavin DP, White MF, Bazil DP. IRS proteins and diabetic complications. Diabetologia 2016; 59: 2280-91. (doi: 10.1007/s00125-016-4072-7).
• Zhang DW, Fu M, Gao SH, Liu JL. Curcumin and Diabetes: A Systematic Review. Evid Based Complement Alternat Med. 2013; 2013: 636053. (doi: 10.1155/2013/636053).
• Tanti JF, Jager J. Cellular mechanisms of insulin resistance: role of stress regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation. Current Opinion in Pharmacology 2009, 9: 753-62. (doi: 10.1016/j.coph.2009.07.004).
• Song Z, Wang H, Lin Zhu L, et al. Curcumin improves high glucose-induced INS-1 cell insulin resistance via activation of insulin signaling. Food Funct. 2015; 6(2): 461-9. (doi: 10.1039/C4FO00608A).
• Gorgisen G, Yaren Z. Insulin receptor substrate 1 overexpression promotes survival of glioblastoma cells through AKT1 activation. Folia Neuropathol 2020; 58(1): 38-44. (doi: 10.5114/fn.2020.94005).
• Sathe G, Pinto SM, Syed N, et al. Phosphotyrosine profiling of curcumin-induced signaling. 2016; 13: 13. (doi: 10.1186/s12014-016-9114-0).
• Perrone D, Ardito F, Giannatempo G, et al. Biological and therapeutic activities, and anticancer properties of curcumin. Exp Ther Med. 2015; 10: 1615-23. (doi: 10.3892/etm.2015.2749).
• Cao AL, Tang QF, Zhou WC, Qiu YY, Hu SJ, Yin PH. Ras/ERK signaling pathway is involved in curcumin-induced cell cycle arrest and apoptosis in human gastric carcinoma AGS cells. J Asian Nat Prod Res. 2015; 17(1): 56-63. (doi: 10.1080/10286020.2014.951923).
• Ono M, Higuchi T, Takeshima M, Chen C, Nakano S. Differential anti-tumor activities of curcumin against Ras- and Src-activated human adenocarcinoma cells. Biochem Biophys Res Commun. 2013; 436(2): 186-91. (doi: 10.1016/j.bbrc.2013.05.071).
• Bathina S, Das UN. Dysregulation of PI3K-Akt-mTOR pathway in brain of streptozotocin-induced type 2 diabetes mellitus in Wistar rats. Lipids Health Dis. 2018; 17(1): 168. (doi: 10.1186/s12944-018-0809-2).
• Zhao L, Gu Q, Xiang L, et al. Curcumin inhibits apoptosis by modulating Bax/Bcl-2 expression and alleviates oxidative stress in testes of streptozotocin-induced diabetic rats. Ther Clin Risk Manag. 2017; 13: 1099-105. (doi: 10.2147/TCRM.S141738).