Chuan Tian

Shanghai Institutes for Biological Sciences, Shanghai, Shanghai Shi, China

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Publications (6)25.97 Total impact

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    ABSTRACT: Chemerin is a novel adipokine associated with obesity and metabolic syndrome. Previous studies indicate that chemerin may also function as a stimulator of angiogenesis. However, the underlying mechanism of its regulatory role in angiogenesis remains largely unknown. In this study, we determined the role of autophagy in chemerin-induced angiogenesis. Treatment of human aorta endothelial cells (HAEC) with chemerin increased the generation of mitochondrial reactive oxygen species (ROS) concurrent with the induced, time-dependent expression of LC3-II and upregulation of the autophagy-related genes beclin-1, Atg 7 and Atg12-Atg5. Knockdown of chemerin receptor 23 (ChemR23) by shRNA or treatment with the mitochondria-targeted antioxidant, Mito-TEMPO, decreased the chemerin-associated ROS generation and abolished the upregulation of autophagy-related genes. Furthermore, chemerin treatment of HAECs augmented the AMP-activated protein kinase-alpha (AMPKα) activity, acetyl-CoA carboxylase (ACC) phosphorylation and reduced phosphorylation of the mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase-1 (p70S6K1) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), which were blocked by co-administration of Mito-TEMPO or shRNA-mediated knockdown of AMPKα. Analysis of the HAECs revealed that inhibition of autophagy by Mito-TEMPO or shRNA against ChemR23, AMPKα, and beclin-1 impaired the chemerin-induced tube formation and cell proliferation. These studies show that mitochondrial ROS are important for autophagy in chemerin-induced angiogenesis and that targeting autophagy may provide an important new tool for treating cardiovascular disease.
    Free Radical Biology and Medicine 11/2012; · 5.27 Impact Factor
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    ABSTRACT: Metabolic dysfunction due to loss of mitochondria plays an important role in diabetes, and stimulation of mitochondrial biogenesis by anti-diabetic drugs improves mitochondrial function. In a search for potent stimulators of mitochondrial biogenesis, we examined the effects and mechanisms of lipoamide and α-lipoic acid (LA) in adipocytes. Differentiated 3T3-L1 adipocytes were treated with lipoamide or LA. Mitochondrial biogenesis and possible signalling pathways were examined. Exposure of 3T3-L1 cells to lipoamide or LA for 24 h increased the number and mitochondrial mass per cell. Such treatment also increased mitochondrial DNA copy number, protein levels and expression of transcription factors involved in mitochondrial biogenesis, including PGC-1α, mitochondrial transcription factor A and nuclear respiratory factor 1. Lipoamide produced these effects at concentrations of 1 and 10 µmol·L⁻¹, whereas LA was most effective at 100 µmol·L⁻¹. At 10 µmol·L⁻¹, lipoamide, but not LA, stimulated mRNA expressions of PPAR-γ, PPAR-α and CPT-1α. The potency of lipoamide was 10-100-fold greater than that of LA. Lipoamide dose-dependently stimulated expression of endothelial nitric oxide synthase (eNOS) and formation of cGMP. Knockdown of eNOS (with small interfering RNA) prevented lipoamide-induced mitochondrial biogenesis, which was also blocked by the soluble guanylate cyclase inhibitor, ODQ and the protein kinase G (PKG) inhibitor, KT5823. Thus, stimulation of mitochondrial biogenesis by lipoamide involved signalling via the eNOS-cGMP-PKG pathway. Our data suggest that lipoamide is a potent stimulator of mitochondrial biogenesis in adipocyte, and may have potential therapeutic application in obesity and diabetes.
    British Journal of Pharmacology 03/2011; 162(5):1213-24. · 5.07 Impact Factor
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    ABSTRACT: Vitamin E has long been identified as a major lipid-soluble chain-breaking antioxidant in mammals. α-Tocopherol is a vitamin E component and the major form in the human body. We propose that, besides its direct chain-breaking antioxidant activity, α-tocopherol may exert an indirect antioxidant activity by enhancing the cell's antioxidant system as a Phase II enzyme inducer. We investigated α-tocopherol's inducing effect on Phase II enzymes and its protective effect on acrolein-induced toxicity in a human retinal pigment epithelial (RPE) cell line, ARPE-19. Acrolein, a major component of cigarette smoke and also a product of lipid peroxidation, at 75 μmol/L over 24 h, caused significant loss of ARPE-19 cell viability, increased oxidative damage, decreased antioxidant defense, inactivation of the Keap1/Nrf2 pathway, and mitochondrial dysfunction. ARPE-19 cells have been used as a model of smoking- and age-related macular degeneration. Pretreatment with α-tocopherol activated the Keap1/Nrf2 pathway by increasing Nrf2 expression and inducing its translocation to the nucleus. Consequently, the expression and/or activity of the following Phase II enzymes increased: glutamate cysteine ligase, NAD(P)H:quinone oxidoreductase 1, heme-oxygenase 1, glutathione S-transferase and superoxide dismutase; total antioxidant capacity and glutathione also increased. This antioxidant defense enhancement protected ARPE-19 cells from an acrolein-induced decrease in cell viability, lowered reactive oxygen species and protein oxidation levels, and improved mitochondrial function. These results suggest that α-tocopherol protects ARPE-19 cells from acrolein-induced cellular toxicity, not only as a chain-breaking antioxidant, but also as a Phase II enzyme inducer.
    The Journal of nutritional biochemistry 02/2010; 21(12):1222-31. · 4.29 Impact Factor
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    ABSTRACT: The development of type 2 diabetes is accompanied by decreased immune function and the mechanisms are unclear. We hypothesize that oxidative damage and mitochondrial dysfunction may play an important role in the immune dysfunction in diabetes. In the present study, we investigated this hypothesis in diabetic Goto-Kakizaki rats by treatment with a combination of four mitochondrial-targeting nutrients, namely, R-α-lipoic acid, acetyl-L-carnitine, nicotinamide and biotin. We first studied the effects of the combination of these four nutrients on immune function by examining cell proliferation in immune organs (spleen and thymus) and immunomodulating factors in the plasma. We then examined, in the plasma and thymus, oxidative damage biomarkers, including lipid peroxidation, protein oxidation, reactive oxygen species, calcium and antioxidant defence systems, mitochondrial potential and apoptosis-inducing factors (caspase 3, p53 and p21). We found that immune dysfunction in these animals is associated with increased oxidative damage and mitochondrial dysfunction and that the nutrient treatment effectively elevated immune function, decreased oxidative damage, enhanced mitochondrial function and inhibited the elevation of apoptosis factors. These effects are comparable to, or greater than, those of the anti-diabetic drug pioglitazone. These data suggest that a rational combination of mitochondrial-targeting nutrients may be effective in improving immune function in type 2 diabetes through enhancement of mitochondrial function, decreased oxidative damage, and delayed cell death in the immune organs and blood.
    Journal of Cellular and Molecular Medicine 03/2009; 13(4):701 - 711. · 4.75 Impact Factor
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    ABSTRACT: Mitochondrial dysfunction due to oxidative stress and concomitant impaired beta-cell function may play a key role in type 2 diabetes. Preventing and/or ameliorating oxidative mitochondrial dysfunction with mitochondria-specific nutrients may have preventive or therapeutic potential. In the present study, the oxidative mechanism of mitochondrial dysfunction in pancreatic beta-cells exposed to sublethal levels of oleic acid (OA) and the protective effects of mitochondrial nutrients [R-alpha-lipoic acid (LA) and acetyl-L-carnitine (ALC)] were investigated. Chronic exposure (72 h) of insulinoma MIN6 cells to OA (0.2-0.8 mM) increased intracellular oxidant formation, decreased mitochondrial membrane potential (MMP), enhanced uncoupling protein-2 (UCP-2) mRNA and protein expression, and consequently, decreased glucose-induced ATP production and suppressed glucose-stimulated insulin secretion. Pretreatment with LA and/or ALC reduced oxidant formation, increased MMP, regulated UCP-2 mRNA and protein expression, increased glucose-induced ATP production, and restored glucose-stimulated insulin secretion. The key findings on ATP production and insulin secretion were verified with isolated rat islets. These results suggest that mitochondrial dysfunction is involved in OA-induced pancreatic beta-cell dysfunction and that pretreatment with mitochondrial protective nutrients could be an effective strategy to prevent beta-cell dysfunction.
    Journal of Cellular Biochemistry 08/2008; 104(4):1232-43. · 3.06 Impact Factor
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    ABSTRACT: Recent evidence indicates that insulin resistance in skeletal muscle may be related to reduce mitochondrial number and oxidation capacity. However, it is not known whether increasing mitochondrial number and function improves insulin resistance. In the present study, we investigated the effects of a combination of nutrients on insulin resistance and mitochondrial biogenesis/function in skeletal muscle of type 2 diabetic Goto-Kakizaki rats. We demonstrated that defect of glucose and lipid metabolism is associated with low mitochondrial content and reduced mitochondrial enzyme activity in skeletal muscle of the diabetic Goto-Kakizaki rats. The treatment of combination of R-alpha-lipoic acid, acetyl-L-carnitine, nicotinamide, and biotin effectively improved glucose tolerance, decreased the basal insulin secretion and the level of circulating free fatty acid (FFA), and prevented the reduction of mitochondrial biogenesis in skeletal muscle. The nutrients treatment also significantly increased mRNA levels of genes involved in lipid metabolism, including peroxisome proliferator-activated receptor-alpha (Ppar alpha), peroxisome proliferator-activated receptor-delta (Ppar delta), and carnitine palmitoyl transferase-1 (Mcpt-1) and activity of mitochondrial complex I and II in skeletal muscle. All of these effects of mitochondrial nutrients are comparable to that of the antidiabetic drug, pioglitazone. In addition, the treatment with nutrients, unlike pioglitazone, did not cause body weight gain. These data suggest that a combination of mitochondrial targeting nutrients may improve skeletal mitochondrial dysfunction and exert hypoglycemic effects, without causing weight gain.
    PLoS ONE 01/2008; 3(6):e2328. · 3.53 Impact Factor

Publication Stats

143 Citations
25.97 Total Impact Points

Institutions

  • 2011–2012
    • Shanghai Institutes for Biological Sciences
      Shanghai, Shanghai Shi, China
    • Ruijin Hospital North
      Shanghai, Shanghai Shi, China
  • 2008–2010
    • Northeast Institute of Geography and Agroecology
      • • Institute for Nutritional Sciences
      • • Graduate School
      Beijing, Beijing Shi, China