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      Hypoglycemic and hypolipidemic effects of total saponins from Stauntonia chinensis in diabetic db/db mice

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          Abstract

          Stauntonia chinensis DC. has been utilised as a traditional herbal medicine for its anti‐hyperglycemic characteristic, which has been associated with triterpene saponins. The goal of the current evaluation was to examine hypoglycemic activity and affiliated mechanism of total saponins from S. chinensis. The chemical composition was analysed by HPLCESIMS/ MS. The fasting blood glucose, oral glucose tolerance test, insulin tolerance test, insulin and glycogen levels of type 2 diabetic db/db mice administered total saponins were quantified to determine the hypoglycemic effects. The serum lipid profiles were assessed to determine the hypolipidemic effects. Western blotting was used to quantify the protein levels of insulin receptor substrates ( IRS)‐1/ PI3K/ AKT, AMPK/ ACC and GLUT4. Twenty triterpene saponins were identified from the total saponins, which exhibited hypoglycemic activities and modulated hyperlipidemia that was associated with type 2 diabetes. The hypoglycemic effects were partly due to the activation of GLUT4, which is regulated by IRS‐1/ PI3K/ AKT. The activation of the AMPK/ ACC signalling pathway may be responsible for the hypolipidemic activity. This study revealed that total saponins from S. chinensis have significant hypoglycemic and hypolipidemic activity in diabetic db/db mice, indicating that these may be utilised in the development of saponins based on S. chinensis for the treatment of type 2 diabetes.

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          Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2.

          Malonyl-coenzyme A (malonyl-CoA), generated by acetyl-CoA carboxylases ACC1 and ACC2, is a key metabolite in the regulation of energy homeostasis. Here, we show that Acc2-/- mutant mice have a normal life span, a higher fatty acid oxidation rate, and lower amounts of fat. In comparison to the wild type, Acc2-deficient mice had 10- and 30-fold lower levels of malonyl-CoA in heart and muscle, respectively. The fatty acid oxidation rate in the soleus muscle of the Acc2-/- mice was 30% higher than that of wild-type mice and was not affected by addition of insulin; however, addition of insulin to the wild-type muscle reduced fatty acid oxidation by 45%. The mutant mice accumulated 50% less fat in their adipose tissue than did wild-type mice. These results raise the possibility that pharmacological manipulation of ACC2 may lead to loss of body fat in the context of normal caloric intake.
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            alpha-Amylase inhibitory activity of some Malaysian plants used to treat diabetes; with particular reference to Phyllanthus amarus.

            Extracts of six selected Malaysian plants with a reputation of usefulness in treating diabetes were examined for alpha-amylase inhibition using an in vitro model. Inhibitory activity studied by two different protocols (with and without pre-incubation) showed that Phyllanthus amarus hexane extract had alpha-amylase inhibitory properties. Hexane and dichloromethane extracts of Anacardium occidentale, Lagerstroemia speciosa, Averrhoa bilimbiPithecellobium jiringa and Parkia speciosa were not active when tested without pre-incubation. Extraction and fractionation of Phyllanthus amarus hexane extract led to the isolation of dotriacontanyl docosanoate, triacontanol and a mixture of oleanolic acid and ursolic acid. Dotriacontanyl docosanoate and the mixture of oleanolic acid and ursolic acid are reported from this plant species for the first time. All compounds were tested in the alpha-amylase inhibition assay and the results revealed that the oleanolic acid and ursolic acid (2:1) mixture was a potent alpha-amylase inhibitor with IC(50)=2.01 microg/ml (4.41 microM) and that it contributes significantly to the alpha-amylase inhibition activity of the extract. Three pure pentacyclic triterpenoids, oleanolic acid, ursolic acid and lupeol were shown to inhibit alpha-amylase.
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              AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells.

              The antidiabetic drug metformin stimulates AMP-activated protein kinase (AMPK) activity in the liver and in skeletal muscle. To better understand the role of AMPK in the regulation of hepatic lipids, we studied the effect of metformin on AMPK and its downstream effector, acetyl-CoA carboxylase (ACC), as well as on lipid content in cultured human hepatoma HepG2 cells. Metformin increased Thr-172 phosphorylation of the alpha subunit of AMPK in a dose- and time-dependent manner. In parallel, phosphorylation of ACC at Ser-79 was increased, which was consistent with decreasing ACC activity. Intracellular triacylglycerol and cholesterol contents were also decreased. These effects of metformin were mimicked or completely abrogated by adenoviral-mediated expression of a constitutively active AMPKalpha or a kinase-inactive AMPKalpha, respectively. An insulin-resistant state was induced by exposing cells to 30 mm glucose as indicated by decreased phosphorylation of Akt and its downstream effector, glycogen synthase kinase 3alpha/beta. Under these conditions, the phosphorylation of AMPK and ACC was also decreased, and the level of hepatocellular triacylglycerols increased. The inhibition of AMPK and the accumulation of lipids caused by high glucose concentrations were prevented either by metformin or by expressing the constitutively active AMPKalpha. The kinase-inactive AMPKalpha increased lipid content and blocked the ability of metformin to decrease lipid accumulation caused by high glucose concentrations. Taken together, these results indicate that AMPKalpha negatively regulates ACC activity and hepatic lipid content. Inhibition of AMPK may contribute to lipid accumulation induced by high concentrations of glucose associated with insulin resistance. Metformin lowers hepatic lipid content by activating AMPK, thereby mediating beneficial effects in hyperglycemia and insulin resistance.
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                Author and article information

                Contributors
                chenyuwh888@126.com
                yanggz888@126.com , 1411057263@qq.com
                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                16 October 2018
                December 2018
                : 22
                : 12 ( doiID: 10.1111/jcmm.2018.22.issue-12 )
                : 6026-6038
                Affiliations
                [ 1 ] School of Pharmaceutical Sciences South‐Central University for Nationalities Wuhan China
                [ 2 ] College of Chemistry and Material Sciences South‐Central University for Nationalities Wuhan China
                [ 3 ] National Demonstration Center for Experimental Ethnopharmacology Education South‐Central University for Nationalities Wuhan China
                Author notes
                [*] [* ] Correspondence

                Yu Chen, College of Chemistry and Material Sciences, South‐Central University for Nationalities, Wuhan, China.

                Email: chenyuwh888@ 123456126.com

                Guangzhong Yang, School of Pharmaceutical Sciences, South‐Central University for Nationalities, Wuhan, China.

                Email: yanggz888@ 123456126.com or 1411057263@ 123456qq.com

                Author information
                http://orcid.org/0000-0001-9853-5078
                Article
                JCMM13876
                10.1111/jcmm.13876
                6237556
                30324705
                0032458f-6ddc-47e6-aa46-6db961b1f92c
                © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 22 May 2018
                : 31 July 2018
                : 06 August 2018
                Page count
                Figures: 9, Tables: 2, Pages: 13, Words: 6807
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 31370379
                Funded by: Special Fund for Basic Scientific Research of Central Colleges
                Award ID: CZP18004
                Award ID: CZY18038
                Funded by: National Major New Drugs Innovation and Development program
                Award ID: 2017ZX09301060006
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                jcmm13876
                December 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.1 mode:remove_FC converted:15.11.2018

                Molecular medicine
                ampk/acc signalling pathway,hypoglycemic effect,hypolipidemic effect,irs‐1/pi3k/akt signalling pathway,stauntonia chinensis,triterpene saponins

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