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J Pharmacol Exp Ther. 2016 Jun;357(3):487-94. doi: 10.1124/jpet.116.232934. Epub 2016 Apr 4.

Inhibition of the Inflammasome NLRP3 by Arglabin Attenuates Inflammation, Protects Pancreatic β-Cells from Apoptosis, and Prevents Type 2 Diabetes Mellitus Development in ApoE2Ki Mice on a Chronic High-Fat Diet.

Author information

1
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.).
2
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.) mustapha.rouis@upmc.fr.

Abstract

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.

PMID:
27044804
DOI:
10.1124/jpet.116.232934
[Indexed for MEDLINE]
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