Quercetin and quercitrin protect against cytokine‑induced injuries in RINm5F β-cells via the mitochondrial pathway and NF-κB signaling

Dai,Xiaoqian; Ding,Ye; Zhang,Zhaofeng; Cai,Xiaxia; Li,Yong

doi:10.3892/ijmm.2012.1177

Quercetin and quercitrin protect against cytokine‑induced injuries in RINm5F β-cells via the mitochondrial pathway and NF-κB signaling

Authors:
- Xiaoqian Dai
- Ye Ding
- Zhaofeng Zhang
- Xiaxia Cai
- Yong Li
View Affiliations

Affiliations: Department of Nutrition and Food Hygiene, School of Public Health, Peking University Health Science Center, Haidian, Beijing 100191, P.R. China
Published online on: November 8, 2012 https://doi.org/10.3892/ijmm.2012.1177
Pages: 265-271

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Quercetin, existing mostly in its glycoside form quercitrin, is the most widely distributed flavonoid in nature. It possesses various potential effects as an antioxidant, anti-inflammatory for cell damage of β-cells, however, studies on this topic are limited and controversial. In order to examine the effects of quercetin on type I diabetes mellitus, we investigated the role of quercetin/quercitrin in cytokine-induced β-cell injuries in RINm5F rat insulinoma cells. Cell viability, glucose-stimulated insulin secretion (GSIS), intracellular reactive oxygen species (ROS), nitric oxide (NO) and inflammation or apoptosis-associated protein expression were measured with or without quercetin/quercitrin treatment. We also compared the differences between the aglycone and the glycoside forms of quercetin, with the aim to shed some light on their structures and transportation into cells. The results showed that quercetin/quercitrin protected against cytokine-induced cell death, improved GSIS, and inhibited ROS as well as NO accumulation. These effects were associated with reduced expression of inducible nitric oxide synthases (iNOS) and inhibited translocation of nuclear factor-κB (NF-κB). Also, quercetin/quercitrin suppressed cytochrome c release from mitochondria and the following alteration of downstream proteins, suggesting that mitochondrial apoptosis was attenuated by quercetin treatment. In summary, quercetin and quercitrin are potential candidates to prevent β-cell death via the mitochondrial pathway and NF-κB signaling, and quercetin may be more efficacious than quercitrin as an anti-diabetic agent.

View Figures

View References

1	Wagner C, Vargas AP, Roos DH, et al: Comparative study of quercetin and its two glycoside derivatives quercitrin and rutin against methylmercury (MeHg)-induced ROS production in rat brain slices. Arch Toxicol. 84:89–97. 2010. View Article : Google Scholar : PubMed/NCBI
2	Hertog MG, Feskens EJ, Hollman PC, Katan MB and Kromhout D: Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet. 342:1007–1011. 1993. View Article : Google Scholar : PubMed/NCBI
3	Babujanarthanam R, Kavitha P, Mahadeva Rao US and Pandian MR: Quercitrin a bioflavonoid improves the antioxidant status in streptozotocin: induced diabetic rat tissues. Mol Cell Biochem. 358:121–129. 2011. View Article : Google Scholar : PubMed/NCBI
4	Coskun O, Kanter M, Korkmaz A and Oter S: Quercetin, a flavonoid antioxidant, prevents and protects streptozotocin-induced oxidative stress and beta-cell damage in rat pancreas. Pharmacol Res. 51:117–123. 2005. View Article : Google Scholar : PubMed/NCBI
5	Mathis D, Vence L and Benoist C: beta-Cell death during progression to diabetes. Nature. 414:792–798. 2001. View Article : Google Scholar : PubMed/NCBI
6	Mandrup-Poulsen T: Apoptotic signal transduction pathways in diabetes. Biochem Pharmacol. 66:1433–1440. 2003. View Article : Google Scholar : PubMed/NCBI
7	Saldeen J: Cytokines induce both necrosis and apoptosis via a common Bcl-2-inhibitable pathway in rat insulin-producing cells. Endocrinology. 141:2003–2010. 2000.PubMed/NCBI
8	Cnop M, Welsh N, Jonas JC, Jorns A, Lenzen S and Eizirik DL: Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes. 54(Suppl 2): S97–S107. 2005. View Article : Google Scholar : PubMed/NCBI
9	Tsujimoto Y: Cell death regulation by the Bcl-2 protein family in the mitochondria. J Cell Physiol. 195:158–167. 2003. View Article : Google Scholar : PubMed/NCBI
10	Menegazzi M, Novelli M, Beffy P, et al: Protective effects of St. John’s wort extract and its component hyperforin against cytokine-induced cytotoxicity in a pancreatic beta-cell line. Int J Biochem Cell Biol. 40:1509–1521. 2008.
11	Adewole SO, Caxton-Martins EA and Ojewole JA: Protective effect of quercetin on the morphology of pancreatic beta-cells of streptozotocin-treated diabetic rats. Afr J Tradit Complement Altern Med. 4:64–74. 2006.PubMed/NCBI
12	Youl E, Bardy G, Magous R, et al: Quercetin potentiates insulin secretion and protects INS-1 pancreatic beta-cells against oxidative damage via the ERK1/2 pathway. Br J Pharmacol. 161:799–814. 2010. View Article : Google Scholar : PubMed/NCBI
13	Cho JM, Chang SY, Kim DB, Needs PW, Jo YH and Kim MJ: Effects of physiological quercetin metabolites on interleukin-1beta-induced inducible NOS expression. J Nutr Biochem. Jan 3–2012.(Epub ahead of print).
14	Babujanarthanam R, Kavitha P and Pandian MR: Quercitrin, a bioflavonoid improves glucose homeostasis in streptozotocin-induced diabetic tissues by altering glycolytic and gluconeogenic enzymes. Fundam Clin Pharmacol. 24:357–364. 2010. View Article : Google Scholar
15	Hollman PC, de Vries JH, van Leeuwen SD, Mengelers MJ and Katan MB: Absorption of dietary quercetin glycosides and quercetin in healthy ileostomy volunteers. Am J Clin Nutr. 62:1276–1282. 1995.PubMed/NCBI
16	Rattanajarasroj S and Unchern S: Comparable attenuation of Abeta(25–35)-induced neurotoxicity by quercitrin and 17beta-estradiol in cultured rat hippocampal neurons. Neurochem Res. 35:1196–1205. 2010.PubMed/NCBI
17	Chow JM, Shen SC, Huan SK, Lin HY and Chen YC: Quercetin, but not rutin and quercitrin, prevention of H₂O₂-induced apoptosis via anti-oxidant activity and heme oxygenase 1 gene expression in macrophages. Biochem Pharmacol. 69:1839–1851. 2005.PubMed/NCBI
18	Cai L, Li W, Wang G, Guo L, Jiang Y and Kang YJ: Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes. 51:1938–1948. 2002. View Article : Google Scholar : PubMed/NCBI
19	Veluthakal R, Jangati GR and Kowluru A: IL-1beta-induced iNOS expression, NO release and loss in metabolic cell viability are resistant to inhibitors of ceramide synthase and sphingomyelinase in INS 832/13 cells. JOP. 7:593–601. 2006.PubMed/NCBI
20	Denis MC, Mahmood U, Benoist C, Mathis D and Weissleder R: Imaging inflammation of the pancreatic islets in type 1 diabetes. Proc Natl Acad Sci USA. 101:12634–12639. 2004. View Article : Google Scholar : PubMed/NCBI
21	Michalska M, Wolf G, Walther R and Newsholme P: Effects of pharmacological inhibition of NADPH oxidase or iNOS on pro-inflammatory cytokine, palmitic acid or H₂O₂-induced mouse islet or clonal pancreatic beta-cell dysfunction. Biosci Rep. 30:445–453. 2010. View Article : Google Scholar : PubMed/NCBI
22	Pi J, Bai Y, Zhang Q, et al: Reactive oxygen species as a signal in glucose-stimulated insulin secretion. Diabetes. 56:1783–1791. 2007. View Article : Google Scholar : PubMed/NCBI
23	Cumaoglu A, Ari N, Kartal M and Karasu C: Polyphenolic extracts from Olea europea L. protect against cytokine-induced beta-cell damage through maintenance of redox homeostasis. Rejuvenation Res. 14:325–334. 2011.
24	Burkle A: Physiology and pathophysiology of poly(ADP-ribosyl)ation. Bioessays. 23:795–806. 2001. View Article : Google Scholar : PubMed/NCBI
25	Allagnat F, Cunha D, Moore F, Vanderwinden JM, Eizirik DL and Cardozo AK: Mcl-1 downregulation by pro-inflammatory cytokines and palmitate is an early event contributing to beta-cell apoptosis. Cell Death Differ. 18:328–337. 2011. View Article : Google Scholar : PubMed/NCBI
26	Barbu A, Welsh N and Saldeen J: Cytokine-induced apoptosis and necrosis are preceded by disruption of the mitochondrial membrane potential (Deltapsi(m)) in pancreatic RINm5F cells: prevention by Bcl-2. Mol Cell Endocrinol. 190:75–82. 2002. View Article : Google Scholar
27	Mehmeti I, Lenzen S and Lortz S: Modulation of Bcl-2-related protein expression in pancreatic beta cells by pro-inflammatory cytokines and its dependence on the antioxidative defense status. Mol Cell Endocrinol. 332:88–96. 2011. View Article : Google Scholar : PubMed/NCBI
28	Lakhani SA, Masud A, Kuida K, et al: Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science. 311:847–851. 2006. View Article : Google Scholar : PubMed/NCBI
29	Muranyi M, Fujioka M, He Q, et al: Diabetes activates cell death pathway after transient focal cerebral ischemia. Diabetes. 52:481–486. 2003. View Article : Google Scholar : PubMed/NCBI
30	Virag L, Marmer DJ and Szabo C: Crucial role of apopain in the peroxynitrite-induced apoptotic DNA fragmentation. Free Radic Biol Med. 25:1075–1082. 1998. View Article : Google Scholar : PubMed/NCBI
31	Roeske-Nielsen A, Dalgaard LT, Mansson JE and Buschard K: The glycolipid sulfatide protects insulin-producing cells against cytokine-induced apoptosis, a possible role in diabetes. Diabetes Metab Res Rev. 26:631–638. 2010. View Article : Google Scholar : PubMed/NCBI
32	Zhang ZJ, Cheang LC, Wang MW and Lee SM: Quercetin exerts a neuroprotective effect through inhibition of the iNOS/NO system and pro-inflammation gene expression in PC12 cells and in zebrafish. Int J Mol Med. 27:195–203. 2011.PubMed/NCBI
33	Hirst DG and Robson T: Nitrosative stress as a mediator of apoptosis: implications for cancer therapy. Curr Pharm Des. 16:45–55. 2010. View Article : Google Scholar : PubMed/NCBI
34	Melloul D: Role of NF-kappaB in beta-cell death. Biochem Soc Trans. 36:334–339. 2008. View Article : Google Scholar : PubMed/NCBI
35	Ghosh S and Karin M: Missing pieces in the NF-kappaB puzzle. Cell. 109(Suppl): S81–S96. 2002. View Article : Google Scholar : PubMed/NCBI
36	Yamaguchi M and Weitzmann MN: Quercetin, a potent suppressor of NF-κB and Smad activation in osteoblasts. Int J Mol Med. 28:521–525. 2011.PubMed/NCBI
37	Morand C, Manach C, Crespy V and Remesy C: Quercetin 3-O-beta-glucoside is better absorbed than other quercetin forms and is not present in rat plasma. Free Radic Res. 33:667–676. 2000. View Article : Google Scholar : PubMed/NCBI