کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8299288 | 1537129 | 2018 | 50 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Apoptosis signal regulating kinase-1 and NADPH oxidase mediate human amylin evoked redox stress and apoptosis in pancreatic beta-cells
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کلمات کلیدی
JnkLACASK1GSHNACBMEhIAPPN-acetyl-l-cysteineHFIPc-Jun N-terminal kinase - C-Jun N-terminal kinaseMitogen activated protein kinases - Mitogen فعال پروتئین کینازNOx - NOXROS - ROSβ-mercaptoethanol - β-merkaptoethanolhuman amylin - انسان آمیلینNADPH oxidase - اکسیداز NADPH Oxidative stress - تنش اکسیداتیوHuman islets - جزایر انسانیtype-2 diabetes mellitus - دیابت نوع 2Superoxide - سوپر اکسیدPlasma membrane - غشای پلاسماLactacystin - لاکتاسیستینmap - نقشهhuman islet amyloid polypeptide - پلی اتیل آمیلوئید جزیره انسانGlutathione - گلوتاتیونReactive oxygen species - گونههای فعال اکسیژن
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
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چکیده انگلیسی
Misfolded toxic human islet amyloid polypeptide or amylin (hA) and plasma membrane-associated redox complex, NADPH oxidase (NOX), have been implicated in the islet β-cell demise associated with type-2 diabetes mellitus (T2DM). Studies show that hA accumulation is stressful to β-cells and that misfolding of human amylin evokes redox stress and activates mitogen activated protein (MAP) kinases, p38 MAPK and c-Jun N-terminal (JNK) kinase. However, the molecular link and causality between hA-evoked redox stress, NOX activity and MAP kinases signaling in pancreatic β-cells is incompletely understood. Here, we show that in the process of activating JNK, aggregation prone hA also activates an upstream apoptosis signal regulating kinase-1 (ASK1) with concomitant decrease in intracellular levels of reduced glutathione. Inhibition of ASK1 kinase activity, either by specific ASK1 inhibitor, NQDI1 or by thiol antioxidants reduces human amylin-evoked ASK1 and JNK activation and consequently human amylin toxicity in rat insulinoma Rin-m5F cells and human islets. β-cell specific overexpression of human amylin in mouse islets elicited ASK1 phosphorylation and activation in β-cells but not in other rodent's islet or exocrine cells. This ASK1 activation strongly correlated with islet amyloidosis and diabetes progression. Cytotoxic human amylin additionally stimulated pro-oxidative activity and expressions of plasma membrane bound NADPH oxidase (NOX) and its regulatory subunits. siRNA mediated NOX1 knockdown and selective NOX inhibitors, ML171 and apocynin, significantly reduced hA-induced mitochondrial stress in insulinoma beta-cells. However, NOX inhibitors were largely ineffective against hA-evoked redox stress and activation of cytotoxic ASK1/JNK signaling complex. Thus, our studies suggest that NOX1 and ASK1 autonomously mediate human amylin-evoked redox and mitochondrial stress in pancreatic β-cells.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimica et Biophysica Acta (BBA) - Biomembranes - Volume 1860, Issue 9, September 2018, Pages 1721-1733
Journal: Biochimica et Biophysica Acta (BBA) - Biomembranes - Volume 1860, Issue 9, September 2018, Pages 1721-1733
نویسندگان
Sanghamitra Singh, Diti Chatterjee Bhowmick, Satyabrata Pany, Myungkuk Joe, Noor Zaghlula, Aleksandar M. Jeremic,