Polyaniline (PANI) is one of the most widely investigated conducting polymers and is considered to be of practical use for many future applications. Here, we first demonstrate that the anisotropic growth of PANI at the nanometer scale can be kinetically controlled by employing a polymeric stabilizer, poly(N-vinylpyrrolidone). The polymerization rate became slower in the presence of the stabilizer (the rate constants calculated at the initial stage decreased with increasing concentration of the stabilizer), yielding PANI nanostructures with lower aspect ratios. Therefore, it is believed that the stabilizer sterically restricts the directional fiber growth mechanism governing PANI chain growth in aqueous solution. Three PANI nanostructures, specifically nanospheres, nanorods, and nanofibers, were fabricated and their oxidation/protonation levels were investigated systematically. It was found that the nanofibers had the most outstanding oxidation/protonation level accompanied by structural ordering (note that the only difference between the polymerization conditions in each case was the concentration of the stabilizer). We also examine the electrochemical properties of PANI nanostructure electrodes in three-electrode and two-electrode (actual capacitor cell) configurations. The intrinsic charge-transport ability of individual nanostructures strongly affected the electrochemical properties of the electrodes. Briefly, the nanofiber electrode had faster electrode kinetics and better capacitance than the nanorods and nanospheres. Lastly, an extrinsic factor, the interparticle contact resistance, also turned out to noticeably influence the capacitances of the electrodes.

Aims: Increased oxidative stress and mitochondrial dysfunction in obese adipocytes contribute to adipokine dysregulation, inflammation, and insulin resistance. Results: Through an advanced proteomic analysis, we found that peroxiredoxin 3 (Prx3), a thioredoxin-dependent mitochondrial peroxidase, is highly expressed in 3T3-L1 adipocytes compared to preadipocytes. Interestingly, in obese db/db mice and human subjects, adipose Prx3 levels were significantly decreased, indicating its association with obesity. We therefore employed Prx3 knockout (KO) mice and transfected 3T3-L1 cells to examine the role of endogenous Prx3 in adipocyte metabolism. Prx3 KO mice had increased fat mass compared to wild-type due to adipocyte hypertrophy. Increased adipogenic transcription factors and lipogenic gene expression during differentiation of adipose tissue-derived stem cells from Prx3-deficient mice confirmed that these adipocytes are likely to accumulate fat. Mitochondrial protein carbonylation in Prx3 KO adipose tissue and mitochondrial superoxide level in Prx3 knockdown 3T3-L1 cells were increased showing aberrant regulation of oxidative stress. Proteomic analysis and gene expression analysis of Prx3 KO mice adipocytes also showed defect in mitochondria biogenesis along with enzymes involved in glucose/lipid metabolism and oxidative phosphorylation. In addition, expression level of adiponectin was downregulated and plasminogen activator inhibitor-1 was upregulated in Prx3 KO adipocytes. Impaired glucose tolerance and insulin resistance further implied metabolic dysregulation in Prx3 KO mice. Innovation and Conclusion: These data suggest that endogenous Prx3 may play an essential role in maintaining normal characteristics of adipocytes and that defect in Prx3 alters mitochondrial redox state and function, and adipokine expression in adipocytes leading to metabolic alteration. Antioxid. Redox Signal. 16,[229][230][231][232][233][234][235][236][237][238][239][240][241][242][243]

Obesity is one of the most prevalent chronic diseases worldwide, and dysregulated adipocyte function plays an important role in obesity-associated metabolic disorder. The level of plasma plasminogen activator inhibitor-1 (PAI-1) is increased in obese subjects, and PAI-1 null mice show improved insulin sensitivity when subjected to high-fat and high-sucrose diet-induced metabolic stress, suggesting that a best-in-class PAI-1 inhibitor may become a novel therapeutic agent for obesity-associated metabolic syndrome. TM5441 is a novel orally active PAI-1 inhibitor that does not cause bleeding episodes. Hence, in the present study we examined the preventive effect of TM5441 on high-fat diet (HFD)-induced adipocyte dysfunction. EXPERIMENTAL APPROACHTen-week-old C57BL/6J mice were fed a normal diet (18% of total calories from fat) or HFD (60% of total calories from fat) for 10 weeks, and TM5441 (20 mg·kg À1 oral gavage) was administered daily with the initiation of HFD. KEY RESULTSTM5441 prevented HFD-induced body weight gain and systemic insulin resistance. TM5441 normalized HFD-induced dysregulated JNK and Akt phosphorylation, suggesting that it prevents the insulin resistance of adipocytes. TM5441 also attenuated the macrophage infiltration and increased expression of pro-inflammatory cytokines, such as inducible nitric oxide synthase, induced by the HFD. In addition, TM5441 prevented the HFD-induced down-regulation of genes involved in mitochondrial biogenesis and function, suggesting that it may prevent adipocyte inflammation and dysregulation by maintaining mitochondrial fitness. CONCLUSION AND IMPLICATIONSOur data suggest that TM5441 may become a novel therapeutic agent for obesity and obesity-related metabolic disorders.Abbreviations ATGL, adipose triglyceride lipase; Cox, cytochrome c oxidase; FAS, fatty acid synthase; FFA, free fatty acid; GTT, glucose tolerance test; H&E, haematoxylin and eosin; HFD, high-fat diet; HSL, hormone-sensitive lipase; iNOS, inducible nitric oxide synthase; ITT, insulin tolerance test; KO, knockout; MCP-1, monocyte chemotactic protein-1; mtDNA, mitochondrial DNA; ND, normal diet; PAI-1, plasminogen activator inhibitor-1; PGC1α, PPARγ coactivator-1α; Tfam, mitochondrial transcription factor A; TG, triglyceride; TM5275, 5-chloro-2- [({2-[4-(diphenylmethyl)piperazin-1-yl]-2-oxoethoxy}acetyl) amino]benzoate; TM5441, 5-chloro-2 {[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy) acethyl]amino} benzoic acid; UCP, uncoupling protein; WAT, white adipose tissue

8-Hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative stress, has been recently rediscovered to inhibit Rac1 in neutrophils and macrophages, thereby inhibiting Rac1-linked functions of these cells, including reactive oxygen species production through NADPH oxidase activation, phagocytosis, chemotaxis, and cytokine release. In vascular smooth muscle cells (VSMCs), reactive oxygen species also induce abnormal proliferation and migration leading to progression of atherosclerosis. Based upon the involvement of reactive oxygen species in phagocytic cells and VSMCs during the atherosclerotic process, we hypothesized that 8-OHdG could have antiatherosclerotic action and tested this hypothesis in an experimentally induced atherosclerosis in mice. Partially ligated ApoE knockout mice, a more physiologically relevant model of low and oscillatory flow, developed an advanced lesion in 2 weeks, and orally administered 8-OHdG significantly reduced plaque formation along with reduced superoxide formation, monocyte/macrophage infiltration, and extracellular matrix (ECM) accumulation. The effects of 8-OHdG observed in primary VSMCs were consistent with the in vivo effects of 8-OHdG and were inhibitory to angiotensin II or platelet-derived growth factor-induced production of reactive oxygen species, proliferation, migration, and ECM production. Also, angiotensin II-induced Rac1 activity in VSMCs was significantly inhibited by 8-OHdG, and transfection of constitutively active Rac1 reversed the inhibitory effect of 8-OHdG on VSMC activation. Molecular docking study showed that 8-OHdG stabilizes Rac1–GEF complex, indicating the physical contact of 8-OHdG with Rac1. These findings highly suggest that the antiatherosclerotic effect of 8-OHdG is mediated by inhibition of Rac1 activity. In conclusion, our results show a novel action of orally active 8-OHdG in suppressing atherosclerotic plaque formation in vivo and VSMC activation in vitro through inhibition of Rac1, which emphasizes a new therapeutic avenue to benefit atherosclerosis.

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