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Astragalus polysaccharides alleviates glucose toxicity and restores glucose homeostasis in diabetic states via activation of AMPK.

ABSTRACT: AIM: To establish the mechanism underlying the improvement of glucose toxicity by Astragalus polysaccharide (APS), which occurred via an AMP activated protein kinase (AMPK)-dependent pathway. METHODS: In vivo and in vitro effects of APS on glucose homeostasis were examined in a type 2 diabetes mellitus (T2DM) rat model. The T2DM rat model was duplicated by a high-fat diet (58% fat, 25.6% carbohydrate, and 16.4% protein) and a small dose of streptozotocin (STZ, 25 mg/kg, ip). After APS therapy (700 mg.kg(-1).d(-1), ig) for 8 weeks, blood glucose, glycosylated hemoglobin, and serum insulin were measured. Insulin sensitivity was evaluated by the comprehensive analysis of oral glucose tolerance tests (OGTT) and HOMA IR index. Hepatic glycogen was observed by the PAS staining method. The expression and activity of skeletal muscle AMPKalpha and acetyl-CoA carboxylase (ACC), and the phosphorylation of hepatic glycogen synthase (GS), the glycogen synthase (GS),were measured by Western blotting. Glucose uptake was measured with the 2-deoxy-[(3)H]-D-glucose method in C2C12 cells. RESULTS: The hyperglycemia status, insulin sensitivity, glucose uptake, and activation level of AMPK in diabetic rats were improved in response to APS administration. APS could also alleviate glucose toxicity in cultured mouse cells by the activation of AMPK. CONCLUSION: APS can alleviate glucose toxicity by increasing liver glycogen synthesis and skeletal muscle glucose translocation in the T2DM rat model, via activation of AMPK.

SUBMITTER: Zou F

PROVIDER: S-EPMC4007496 | biostudies-other | 2009 Dec

REPOSITORIES: biostudies-other

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Astragalus polysaccharides inhibit oxidation in high glucose-challenged or SOD2-silenced H9C2 cells.

Project description:Introduction:Oxidative stress plays an important role in the development of diabetic cardio-myopathy (DCM). Previously, we reported that Astragalus polysaccharides (APS) improved DCM by inhibition of cardiac oxidative stress. In this study, we evaluated the beneficial effect of APS on high glucose-induced oxidative stress in cardiomyocytes in vitro. Materials and methods:H9C2 cells were cultured in the presence of high concentration of glucose or transfected with siRNASOD2, followed by APS treatment. The cellular mitochondrial ultrastructure was observed using a transmission electron microscope. Cell apoptosis was detected using hairpin oligonucleotide probes and quantified by flow cytometry analysis. Superoxide production was determined by immunohistochemistry using the fluorescent dye dihydroethidium (DHE). Nitrotyrosine and 8-OH-dG antibodies were employed to detect oxidative damage to cytoplasmic proteins and oxidative stress in the nuclei, respectively. Superoxide dismutase (SOD) activity was measured utilizing the SOD Assay Kit, and SOD protein levels were analyzed by Western blotting. Results:APS treatment protected cellular mitochondrial ultrastructure, reduced cell apoptosis (hairpin-1), inhibited cellular superoxide production (DHE), and reduced oxidative damage to cytoplasmic proteins (nitrotyrosine) and oxidative stress in the nuclei (8-OH-dG) in high glucose-induced and/or SOD2-silenced H9C2 cells, together with induction of SOD2 enzyme activity and increase of protein levels. Conclusion:Our findings indicated the beneficial effect of APS on high glucose-challenged H9C2 cells, which was associated with inhibition of oxidative stress in vitro.

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The hepatic AMPK-TET1-SIRT1 axis regulates glucose homeostasis.

Project description:Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) is involved in multiple biological functions in cell development, differentiation, and transcriptional regulation. Tet1 deficient mice display the defects of murine glucose metabolism. However, the role of TET1 in metabolic homeostasis keeps unknown. Here, our finding demonstrates that hepatic TET1 physically interacts with silent information regulator T1 (SIRT1) via its C-terminal and activates its deacetylase activity, further regulating the acetylation-dependent cellular translocalization of transcriptional factors PGC-1α and FOXO1, resulting in the activation of hepatic gluconeogenic gene expression that includes PPARGC1A, G6PC, and SLC2A4. Importantly, the hepatic gluconeogenic gene activation program induced by fasting is inhibited in Tet1 heterozygous mice livers. The adenosine 5'-monophosphate-activated protein kinase (AMPK) activators metformin or AICAR-two compounds that mimic fasting-elevate hepatic gluconeogenic gene expression dependent on in turn activation of the AMPK-TET1-SIRT1 axis. Collectively, our study identifies TET1 as a SIRT1 coactivator and demonstrates that the AMPK-TET1-SIRT1 axis represents a potential mechanism or therapeutic target for glucose metabolism or metabolic diseases.

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Astragalus polysaccharide stimulates glucose uptake in L6 myotubes through AMPK activation and AS160/TBC1D4 phosphorylation.

Project description:AimTo establish the mechanism responsible for the stimulation of glucose uptake by Astragalus polysaccharide (APS), extracted from Astragalus membranaceus Bunge, in L6 myotubes in vitro.MethodsAPS-stimulated glucose uptake in L6 myotubes was measured using the 2-deoxy-[(3)H]-D-glucose method. The adenine nucleotide contents in the cells were measured by HPLC. The phosphorylation of AMP-activated protein kinase (AMPK) and Akt substrate of 160 kDa (AS160) was examined using Western blot analysis. The cells transfected with 4P mutant AS160 (AS160-4P) were constructed using gene transfer approach.ResultsTreatment of L6 myotubes with APS (100-1600 μg/mL) significantly increased glucose uptake in time- and concentration-dependent manners. The maximal glucose uptake was reached in the cells treated with APS (400 μg/mL) for 36 h. The APS-stimulated glucose uptake was significantly attenuated by pretreatment with Compound C, a selective AMPK inhibitor or in the cells overexpressing AS160-4P. Treatment of L6 myotubes with APS strongly promoted the activation of AMPK. We further demonstrated that either Ca(2+)/calmodulin-dependent protein kinase kinase β (CaMKKβ) or liver kinase B1 (LKB1) mediated APS-induced activation of AMPK in L6 myotubes, and the increased cellular AMP: ATP ratio was also involved. Treatment of L6 myotubes with APS robustly enhanced the phosphorylation of AS160, which was significantly attenuated by pretreatment with Compound C.ConclusionOur results demonstrate that APS stimulates glucose uptake in L6 myotubes through the AMP-AMPK-AS160 pathway, which may contribute to its hypoglycemic effect.

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Expression data from PC3 cells treated with astragalus polysaccharides

Project description:Astragalus polysaccharides (APS), as one of the main effective components of astragalus, have been reported to regulate the processes of inflammation, metabolism, and carcinogenes. We used microarrays to detect the different expression of mRNA in PC3 cells upon APS treatment.

2019-09-17 | GSE137486 | GEO

Astragalus polysaccharide promotes autophagy and alleviates diabetic nephropathy by targeting the lncRNA Gm41268/PRLR pathway.

Project description:BackgroundAstragalus polysaccharide (APS) is a major bioactive component of the Chinese herb astragalus, with well-established protective effects on the kidney. However, the effect of APS on diabetic nephropathy (DN) is unclear.MethodsLong non-coding RNA (lncRNA) expression profiles in kidney samples from control, db/db, and APS-treated db/db mice were evaluated using RNA high-throughput sequencing techniques. Additionally, rat renal tubular epithelial (NRK-52E) cells were cultured in high glucose (HG) media. We inhibited the expression of Gm41268 and prolactin receptor (PRLR) by transfecting NRK-52E cells with Gm41268-targeting antisense oligonucleotides and PRLR siRNA.ResultsWe found that APS treatment reduced 24-h urinary protein levels and fasting blood glucose and improved glucose intolerance and pathological renal damage in db/db mice. Furthermore, APS treatment enhanced autophagy and alleviated fibrosis in the db/db mice. We identified a novel lncRNA, Gm41268, which was differentially expressed in the three groups, and the cis-regulatory target gene PRLR. APS treatment induced autophagy by reducing p62 and p-mammalian target of rapamycin (mTOR) protein levels and increasing the LC3 II/I ratio. Furthermore, APS alleviated fibrosis by downregulating fibronectin (FN), transforming growth factor-β (TGF-β), and collagen IV levels. In addition, APS reversed the HG-induced overexpression of Gm41268 and PRLR. Reduction of Gm41268 decreased PRLR expression, restored autophagy, and ameliorated renal fibrosis in vitro. Inhibition of PRLR could enhance the protective effect of APS.ConclusionsIn summary, we demonstrated that the therapeutic effect of APS on DN is mediated via the Gm41268/PRLR pathway. This information contributes to the exploration of bioactive constituents in Chinese herbs as potential treatments for DN.

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Immunosuppressive Effects of Thallium Toxicity in Nile Tilapia Fingerlings: Elucidating the Rescue Role of <i>Astragalus membranaceus</i> Polysaccharides.

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Adropin treatment restores cardiac glucose oxidation in pre-diabetic obese mice.

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The critical role of Astragalus polysaccharides for the improvement of PPARα [ correction of PPRAα]-mediated lipotoxicity in diabetic cardiomyopathy.

Project description:BackgroundObesity-related diabetes mellitus leads to increased myocardial uptake and oxidation of fatty acids, resulting in a form of cardiac dysfunction referred to as lipotoxic cardiomyopathy. We have shown previously that Astragalus polysaccharides (APS) administration was sufficient to improve the systemic metabolic disorder and cardiac dysfunction in diabetic models.Methodology/principal findingsTo investigate the precise role of APS therapy in the pathogenesis of myocardial lipotoxity in diabetes, db/db diabetic mice and myosin heavy chain (MHC)- peroxisome proliferator-activated receptor (PPAR) α mice were characterized and administrated with or without APS with C57 wide- type mice as normal control. APS treatment strikingly improved the myocyte triacylglyceride accumulation and cardiac dysfunction in both db/db mice and MHC-PPARα mice, with the normalization of energy metabolic derangements in both db/db diabetic hearts and MHC-PPARα hearts. Consistently, the activation of PPARα target genes involved in myocardial fatty acid uptake and oxidation in both db/db diabetic hearts and MHC-PPARα hearts was reciprocally repressed by APS administration, while PPARα-mediated suppression of genes involved in glucose utilization of both diabetic hearts and MHC-PPARα hearts was reversed by treatment with APS.ConclusionsWe conclude that APS therapy could prevent the development of diabetic cardiomyopathy through a mechanism mainly dependent on the cardiac PPARα-mediated regulatory pathways.

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| S-EPMC10759471 | biostudies-literature

High glucose alters tendon homeostasis through downregulation of the AMPK/Egr1 pathway.

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