Bahetibieke Tuohetaerbaike1, Yan Zhang2, Yali Tian3, Nan Nan Zhang3, Jinsen Kang3, Xinmin Mao3, Yanzhi Zhang4, Xuejun Li5. 1. State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, Xinjiang, PR China. 2. Department of Pediatrics, Military General Hospital, Urumqi, PR China. 3. Department of Pharmacology, College of Pharmacy, Xinjiang Medical University, Urumqi, 830011, PR China. 4. Department of Pharmacology, College of Pharmacy, Xinjiang Medical University, Urumqi, 830011, PR China. Electronic address: 1533465971@qq.com. 5. Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, PR China. Electronic address: xjli@bjmu.edu.cn.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Urolithin A (UroA), the main intestinal microflora metabolite of ellagic acid of berries, pomegranate,and some other traditional chinese herbals such as emblica officinalis,etc,has been reported to exhibit anti-inflammatory, anti-oxidative, anti-tumor and pro-autophagy effects. AIM OF THE STUDY: This study evaluated the anti-diabetic and pancreas-protective effects of UroA using a mice model of type 2 diabetes and preliminarily explored its effect on autophagy as well as the mechanism involved. MATERIALS AND METHODS: Type 2 diabetes model was induced by high-fat diet (HFD; 60% energy as fat) and low-dose streptozotocin (85 mg/kg) injection. Mice were administered with UroA (50 mg/kg/d) alone or UroA-chloroquine (autophagy inhibitor) combination for 8 weeks. RESULTS: UroA improved symptoms of diabetic mice such as high water intake volume, high urine volume, significantly decreased fasting blood glucose (FBG), after-glucose-loading glucose, glycated hemoglobin (GHb) levels, plasma C-peptide, malondialdehyde (MDA) and interleukin-1 β level, increased reduced glutathione (GSH), interleukin-10 content, and glucose tolerance. UroA also improved pancreatic function indexes such as HOMA-β as evidenced by improved pathological and ultrastructural features of the pancreas assessed by light microscopy and transmission electron microscopy (TEM). Accordingly, UroA decreased mitochondrial swelling and myelin-like cytoplasmic inclusions. UroA significantly upregulated the protein levels of microtubule-associated protein 1 light chain 3-II (LC3II) and beclin1, downregulated sequestosome 1 (p62) accompanied by decreased expression of apoptotic protein cleaved caspase3 in pancreas of diabetic mice. In addition, it increased the phosphorylation level of protein kinase B (p-Akt) and mammalian target of rapamycin (p-mTOR). Most of these effects of UroA were reversed by treatment with autophagy inhibitor chloroquine. CONCLUSIONS: Our findings reveal that the pancreas protective effects of UroA against diabetes were partially mediated by its regulation of autophagy and AKT/mTOR signal pathway.
ETHNOPHARMACOLOGICAL RELEVANCE: Urolithin A (UroA), the main intestinal microflora metabolite of ellagic acid of berries, pomegranate,and some other traditional chinese herbals such as emblica officinalis,etc,has been reported to exhibit anti-inflammatory, anti-oxidative, anti-tumor and pro-autophagy effects. AIM OF THE STUDY: This study evaluated the anti-diabetic and pancreas-protective effects of UroA using a mice model of type 2 diabetes and preliminarily explored its effect on autophagy as well as the mechanism involved. MATERIALS AND METHODS: Type 2 diabetes model was induced by high-fat diet (HFD; 60% energy as fat) and low-dose streptozotocin (85 mg/kg) injection. Mice were administered with UroA (50 mg/kg/d) alone or UroA-chloroquine (autophagy inhibitor) combination for 8 weeks. RESULTS:UroA improved symptoms of diabeticmice such as high water intake volume, high urine volume, significantly decreased fasting blood glucose (FBG), after-glucose-loading glucose, glycated hemoglobin (GHb) levels, plasma C-peptide, malondialdehyde (MDA) and interleukin-1 β level, increased reduced glutathione (GSH), interleukin-10 content, and glucose tolerance. UroA also improved pancreatic function indexes such as HOMA-β as evidenced by improved pathological and ultrastructural features of the pancreas assessed by light microscopy and transmission electron microscopy (TEM). Accordingly, UroA decreased mitochondrial swelling and myelin-like cytoplasmic inclusions. UroA significantly upregulated the protein levels of microtubule-associated protein 1 light chain 3-II (LC3II) and beclin1, downregulated sequestosome 1 (p62) accompanied by decreased expression of apoptotic protein cleaved caspase3 in pancreas of diabeticmice. In addition, it increased the phosphorylation level of protein kinase B (p-Akt) and mammalian target of rapamycin (p-mTOR). Most of these effects of UroA were reversed by treatment with autophagy inhibitor chloroquine. CONCLUSIONS: Our findings reveal that the pancreas protective effects of UroA against diabetes were partially mediated by its regulation of autophagy and AKT/mTOR signal pathway.
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