Role of pterostilbene in attenuating immune mediated devastation of pancreatic beta cells via Nrf2 signaling cascade.
Nrf2 (nuclear factor erythroid 2-related factor-2) is a transcription factor that regulates oxidative/xenobiotic stress response and also suppress inflammation. Nrf2 signaling is associated with an increased susceptibility to various kinds of stress. Nrf2 has been shown as a promising therapeutic target in various human diseases including diabetes. Our earlier studies showed Pterostilbene (PTS) as a potent Nrf2 activator, and it protects the pancreatic β-cells against oxidative stress. In this study, we investigated PTS confer protection against cytokine-induced β-cell apoptosis and its role on insulin secretion in streptozotocin (STZ)-induced diabetic mice. The Nrf2 activation potential of PTS was assessed by dissociation of the Nrf2-Keap1 complex and by expression of ARE-driven downstream target genes in MIN6 cells. Further, the nuclear Nrf2 translocation and blockage of apoptotic signaling as demonstrated by the reduction of BAX/Bcl-2 ratio, Annexin-V positive cells and caspase-3 activity conferred the cyto-protection of PTS against cytokine-induced cellular damage. In addition, PTS treatment markedly improved glucose homeostasis and abated inflammatory response evidenced by the reduction of proinflammatory cytokines in diabetic mice. The inhibition of β-cell apoptosis by PTS as assessed by BAX/Bcl-2 ratio and caspase-3 activity in the pancreas was associated with the activation of Nrf2 and the expression of its downstream target genes. PTS also inhibited the activation of iNOS and decreased nitric oxide (NO) formation in the pancreas of diabetic animals. The results obtained from both in vitro and in vivo experiments showed that PTS improves β-cell function and survival against cytokine stress and also prevents STZ-induced diabetes.
SRM Research Institute, SRM University, Kattankulathur-603 203, Tamilnadu, India.
Dornadula
D
Sireesh
Interdisciplinary Institute of Indian System of Medicine, SRM University, Kattankulathur 603 203, Tamilnadu, India.
Munuswamy-Ramanujam
MR
Ganesh
SRM Research Institute, SRM University, Kattankulathur-603 203, Tamilnadu, India.
Umapathy
U
Dhamodharan
King Institute of Preventive Medicine and Research, Guindy, Chennai-600032, Tamilnadu, India.
Murugesan
M
Sakthivadivel
King Institute of Preventive Medicine and Research, Guindy, Chennai-600032, Tamilnadu, India.
Srinivasan
S
Sivasubramanian
King Institute of Preventive Medicine and Research, Guindy, Chennai-600032, Tamilnadu, India.
Palani
P
Gunasekaran
SRM Research Institute, SRM University, Kattankulathur-603 203, Tamilnadu, India. Electronic address: ramkumar.km@res.srmuniv.ac.in.
Kunka Mohanram
KM
Ramkumar
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D000975:Antioxidants; C494827:Bax protein, mouse; D001786:Blood Glucose; D016207:Cytokines; D007328:Insulin; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D013267:Stilbenes; D051028:bcl-2-Associated X Protein; C107773:pterostilbene; C505409:Casp3 protein, mouse; D053148:Caspase 3
Cytokine cocktail; Diabetes; MIN6; Nrf2; Streptozotocin