Abderrazak Amna, El Hadri Khadija, Bosc Elodie, Blondeau Bertrand, Slimane Mohamed-Naceur, Büchele Berthold, Simmet Thomas, Couchie Dominique, Rouis Mustapha
Biological Adaptation and Ageing, Institute of Biology Paris-Seine, UMR-8256/INSERM ERL-U1164 (A.A., K.E.H., E.B., D.C., M.R.), and Cordeliers Research Center, INSERM, UMR 872 (N.B.), University Pierre & Marie Curie, Paris, France; Biochemistry Laboratory, Faculty of Medicine, Monastir, Tunisia (M.-N.S.); Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany (B.B., T.S.).
Biological Adaptation and Ageing, Institute of Biology Paris-Seine, UMR-8256/INSERM ERL-U1164 (A.A., K.E.H., E.B., D.C., M.R.), and Cordeliers Research Center, INSERM, UMR 872 (N.B.), University Pierre & Marie Curie, Paris, France; Biochemistry Laboratory, Faculty of Medicine, Monastir, Tunisia (M.-N.S.); Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany (B.B., T.S.)
J Pharmacol Exp Ther. 2016 Jun;357(3):487-94. doi: 10.1124/jpet.116.232934. Epub 2016 Apr 4.
Intraperitoneal injection of arglabin (2.5 ng/g of body weight, twice daily, 13 weeks) into female human apolipoprotein E2 gene knock-in (ApoE2Ki) mice fed a high-fat Western-type diet (HFD) reduced plasma levels of glucose and insulin by ∼20.0% ± 3.5% and by 50.0% ± 2.0%, respectively, in comparison with vehicle-treated mice. Immunohistochemical analysis revealed the absence of active caspase-3 in islet sections from ApoE2Ki mice fed a HFD and treated with arglabin. In addition, arglabin reduced interleukin-1β (IL-1β) production in a concentration-dependent manner in Langerhans islets isolated from ApoE2Ki mice treated with lipopolysaccharide (LPS) and with cholesterol crystals. This inhibitory effect is specific for the inflammasome NOD-like receptor family, pyrin domain-containing 3 (NLRP3) because IL-1β production was abolished in Langerhans islets isolated from Nlrp3(-/-) mice. In the insulin-secreting INS-1 cells, arglabin inhibited, in a concentration-dependent manner, the maturation of pro-IL-1β into biologically active IL-1β probably through the inhibition of the maturation of procaspase-1 into active capsase-1. Moreover, arglabin reduced the susceptibility of INS-1 cells to apoptosis by increasing Bcl-2 levels. Similarly, autophagy activation by rapamycin decreased apoptosis susceptibility while autophagy inhibition by 3-methyladenin treatment promoted apoptosis. Arglabin further increased the expression of the autophagic markers Bcl2-interacting protein (Beclin-1) and microtubule-associated protein 1 light chain 3 II (LC3-II) in a concentration-dependent manner. Thus, arglabin reduces NLRP3-dependent inflammation as well as apoptosis in pancreatic β-cells in vivo and in the INS-1 cell line in vitro, whereas it increases autophagy in cultured INS-1 cells, indicating survival-promoting properties of the compound in these cells. Hence, arglabin may represent a new promising compound to treat inflammation and type 2 diabetes mellitus development.
给喂食高脂西式饮食（HFD）的雌性人载脂蛋白E2基因敲入（ApoE2Ki）小鼠腹腔注射阿格拉宾（2.5纳克/克体重，每日两次，共13周），与注射赋形剂的小鼠相比，血浆葡萄糖和胰岛素水平分别降低了约20.0%±3.5%和50.0%±2.0%。免疫组织化学分析显示，喂食HFD并接受阿格拉宾治疗的ApoE2Ki小鼠胰岛切片中不存在活性半胱天冬酶-3。此外，阿格拉宾以浓度依赖的方式降低了从用脂多糖（LPS）和胆固醇晶体处理的ApoE2Ki小鼠分离的胰岛中白细胞介素-1β（IL-1β）的产生。这种抑制作用对含吡咯结构域的NOD样受体家族炎性小体3（NLRP3）具有特异性，因为从Nlrp3(-/-)小鼠分离的胰岛中IL-1β的产生被消除。在胰岛素分泌型INS-1细胞中，阿格拉宾可能通过抑制前半胱天冬酶-1成熟为活性半胱天冬酶-1，以浓度依赖的方式抑制前IL-1β成熟为具有生物活性的IL-1β。此外，阿格拉宾通过提高Bcl-2水平降低了INS-1细胞对凋亡的敏感性。同样，雷帕霉素激活自噬降低了凋亡敏感性，而3-甲基腺嘌呤处理抑制自噬则促进了凋亡。阿格拉宾还以浓度依赖的方式进一步增加了自噬标志物Beclin-1和微管相关蛋白1轻链3 II（LC3-II）的表达。因此，阿格拉宾在体内和体外的INS-1细胞系中均可降低胰腺β细胞中NLRP3依赖性炎症以及凋亡，而在培养的INS-1细胞中增加自噬，表明该化合物在这些细胞中具有促进存活的特性。因此，阿格拉宾可能是一种治疗炎症和2型糖尿病发展的有前景的新型化合物。
