Metformin is a widely used antidiabetic drug that exerts cardiovascular protective effects in patients with diabetes. How metformin protects against diabetes-related cardiovascular diseases remains poorly understood. Here, we show that metformin abated the progression of diabetes-accelerated atherosclerosis by inhibiting mitochondrial fission in endothelial cells. Metformin treatments markedly reduced mitochondrial fragmentation, mitigated mitochondrial-derived superoxide release, improved endothelial-dependent vasodilation, inhibited vascular inflammation, and suppressed atherosclerotic lesions in streptozotocin (STZ)-induced diabetic ApoE−/− mice. In high glucose–exposed endothelial cells, metformin treatment and adenoviral overexpression of constitutively active AMPK downregulated mitochondrial superoxide, lowered levels of dynamin-related protein (Drp1) and its translocation into mitochondria, and prevented mitochondrial fragmentation. In contrast, AMPK-α2 deficiency abolished the effects of metformin on Drp1 expression, oxidative stress, and atherosclerosis in diabetic ApoE−/−/AMPK-α2−/− mice, indicating that metformin exerts an antiatherosclerotic action in vivo via the AMPK-mediated blockage of Drp1-mediated mitochondrial fission. Consistently, mitochondrial division inhibitor 1, a potent and selective Drp1 inhibitor, reduced mitochondrial fragmentation, attenuated oxidative stress, ameliorated endothelial dysfunction, inhibited inflammation, and suppressed atherosclerosis in diabetic mice. These findings show that metformin attenuated the development of atherosclerosis by reducing Drp1-mediated mitochondrial fission in an AMPK-dependent manner. Suppression of mitochondrial fission may be a therapeutic approach for treating macrovascular complications in patients with diabetes.

No abstract

Cigarette smoking promotes body weight reduction in humans while paradoxically also promoting insulin resistance (IR) and hyperinsulinemia. The mechanisms behind these effects of smoking are unclear. Here, we show that nicotine, a major constitute of cigarette smoke, selectively activates AMP-activated protein kinase α2 (AMPKα2) in adipocytes, which, in turn, phosphorylates MAP kinase phosphatase-1 (MKP1) at serine 334, initiating a proteasome-dependent degradation of this latter protein. The nicotine-dependent reduction in MKP1 induces the aberrant activation of p38 mitogen-activated protein kinase and c-Jun amino-terminal kinase leading to increased phosphorylation of insulin receptor substrate 1 (IRS1) at serine 307. This phosphorylation of IRS1 leads to its degradation, Akt inhibition, and the loss of insulin-mediated inhibition of lipolysis. Consequently, nicotine increases lipolysis, which results in body weight reduction, but this increase also elevates the levels of circulating free fatty acids and thus causes IR in insulin-sensitive tissues. These results newly place AMPKα2 as an essential mediator of nicotine-induced whole-body IR in spite of reductions in adiposity.

No abstract

Authorship note: KW and YG share first authorship. RRJ and KW share senior authorship. Conflict of interest: RRJ is a consultant of Boston Scientific and received a research grant from the company. He also serves on the board of directors of Ascletis Pharma. RRJ and KW also filed a patent, Methods and kits for treating pain (16/612,909), in association with Duke University.

No abstract

No abstract

The effects of increasing NaCl concentrations on biomass, superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and phenylalanine ammonia-lyase (PAL) in Jatropha curcas L. seedlings were investigated. The fresh weights of cotyledons and radicles with increasing NaCl concentrations decreased progressively, and the fresh weight of hypocotyls reached the lowest level at NaCl concentration of 150 mmol and then increased. SOD activity in the cotyledons, hypocotyls and radicles increased gradually up to NaCl concentrations of 150, 200 and 150 mmol, respectively. The highest POD activities in the cotyledons, hypocotyls and radicles were observed at NaCl concentrations of 150, 200 and 150 mmol, respectively. CAT activity in the cotyledons, hypocotyls and radicles enhanced gradually up to 100, 200 and 150 mmol NaCl concentrations, respectively. Increased PAL activity in the hypocotyls and radicles was linearly and positively correlated with increasing NaCl concentrations, but the peak activity in the cotyledons was observed at NaCl concentration of 150 mmol. Electrophoresis analysis suggested that different patterns in SOD and POD isoenzymes depend on NaCl concentrations and organ type, and the staining intensities of these isoforms are consistent with the changes of enzyme activity assayed in solutions.