A small molecule UPR modulator for diabetes identified by high throughput screening
| العنوان: | A small molecule UPR modulator for diabetes identified by high throughput screening |
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| المؤلفون: | Siying Zhu, Matthew S. Tremblay, Sean B. Joseph, Seung Hyuk Choi, Mitch Hull, Weijun Shen, Valeria Marrocco, Sijia Li, Marta Diez Cunado, Ana M. Gamo, Tuan Tran, Jason Roland, Arnab K. Chatterjee, Qiangwei Fu, Van Nguyen-Tran, Nikki Rogers |
| المصدر: | Acta Pharmaceutica Sinica. B Acta Pharmaceutica Sinica B, Vol 11, Iss 12, Pp 3983-3993 (2021) |
| بيانات النشر: | Elsevier, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | TG, thapsigargin, Cell signaling, ATF4, activating transcription factor 4, IKKβ, inhibitor of nuclear factor kappa-B kinase subunit beta, PERK, PKR-like ER kinase, XBP1, X-box-binding protein 1, OGTT, oral glucose tolerance test, GAPDH, glyceraldehyde 3-phosphate dehydrogenase, Unfolded protein response, 0302 clinical medicine, UPR, unfolded protein response, GLuc, Gaussia luciferase, Chaperones, Protein biosynthesis, IL1β, interleukin 1β, General Pharmacology, Toxicology and Pharmaceutics, uHTS, ultra-high throughput screening, IRE1, inositol requiring enzyme 1α/β, 0303 health sciences, ASGR, asialoglycoprotein receptor 1, biology, Chemistry, Small molecules, Diabetes, NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells, ATF6, activating transcription factor 6α/β, β cells, i.p., intraperitoneal, Cell biology, Liver, 030220 oncology & carcinogenesis, T1/2D, type1/2 diabetes, Tm, tunicamycin, Protein folding, Original Article, ER stress, NASH, nonalcoholic steatohepatitis, INFγ, interferon gamma, TNFα, tumor necrosis factor alpha, RM1-950, GRPRP94, glucose-regulated protein 94, ER, endoplasmic reticulum, 03 medical and health sciences, SP1/2, serine protease1/2, GRP78, 78-kDa glucose-regulated protein, BID, twice a day, Pancreas, 030304 developmental biology, Reporter gene, Nod, non-obese diabetic, Activator (genetics), Endoplasmic reticulum, Metabolic diseases, Chaperone (protein), EGFP-VSVG, enhanced green fluorescence protein-vesicular stomatitis virus ts045 G protein, GSIS, glucose stimulated insulin secretion, biology.protein, Asialoglycoprotein receptor, Therapeutics. Pharmacology, CLuc, Cypridina luciferase, ERP72, endoplasmic reticulum proteins 72 |
| الوصف: | Unfolded protein response (UPR) is a stress response that is specific to the endoplasmic reticulum (ER). UPR is activated upon accumulation of unfolded (or misfolded) proteins in the ER's lumen to restore protein folding capacity by increasing the synthesis of chaperones. In addition, UPR also enhances degradation of unfolded proteins and reduces global protein synthesis to alleviate additional accumulation of unfolded proteins in the ER. Herein, we describe a cell-based ultra-high throughput screening (uHTS) campaign that identifies a small molecule that can modulate UPR and ER stress in cellular and in vivo disease models. Using asialoglycoprotein receptor 1 (ASGR) fused with Cypridina luciferase (CLuc) as reporter assay for folding capacity, we have screened a million small molecule library and identified APC655 as a potent activator of protein folding, that appears to act by promoting chaperone expression. Furthermore, APC655 improved pancreatic β cell viability and insulin secretion under ER stress conditions induced by thapsigargin or cytokines. APC655 was also effective in preserving β cell function and decreasing lipid accumulation in the liver of the leptin-deficient (ob/ob) mouse model. These results demonstrate a successful uHTS campaign that identified a modulator of UPR, which can provide a novel candidate for potential therapeutic development for a host of metabolic diseases. Graphical abstract A cell-based high throughput screening identified a small molecule that improves pancreatic beta cell viability and function through increased UPR chaperones and ER folding capacity.Image 1 |
| اللغة: | English |
| تدمد: | 2211-3843 2211-3835 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c176a631b2a5bf8251732009aad27d09 http://europepmc.org/articles/PMC8727761 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....c176a631b2a5bf8251732009aad27d09 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22113843 22113835 |
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