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The dried, immature fruit of Citrus aurantium L., 'Zhiqiao' in Chinese, has been used to treat cardiovascular diseases in traditional Chinese medicine for centuries. Naringenin and hesperetin and their glycosides present in considerable amounts (about 10 approximately 15%) in the herb. The aim of this study is to test whether naringenin and hesperetin influence adiponectin expression, which plays an important role in glucose and lipid metabolism with antiatherogenic and anti-inflammatory properties. Treatment with naringenin and hesperetin enhanced adiponectin transcription in differentiated 3T3-L1 cells. Both naringenin and hesperetin induced peroxisome proliferator-activated receptor (PPAR)gamma-controlled luciferase expression in a dose-dependent manner (20-160 microM), whereas only naringenin possessed significant activity to activate PPARalpha. These results suggested the two flavonoids might exert antiatherogenic effects partly through activating PPAR and up-regulating adiponectin expression in adipocytes. Our findings give new insight for the molecular explanations for the therapeutic effects of Zhiqiao.

Tubular injury is one of the crucial determinants of progressive renal failure in diabetic nephropathy (DN), while epithelial-to-mesenchymal transition (EMT) of tubular cells contributes to the accumulation of matrix protein in the diabetic kidney. Activation of the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome leads to the maturation of interleukin (IL)-1B and is involved in the pathogenic mechanisms of diabetes. In this study, we explored the role of NLRP3 inflammasome on high glucose (HG) or transforming growth factor-B1 (TGFB1)-induced EMT in HK-2 cells. We evaluated EMT through the expression of α-smooth muscle actin (α-SMA) and E-cadherin as well as the induction of a myofibroblastic phenotype. Reactive oxygen species (ROS) was observed using the confocal microscopy. HG was shown to induce EMT at 48 h, which was blocked by NLRP3 silencing or antioxidant N-acetyl-L-cysteine (NAC). We found that NLRP3 interference could inhibit HG-induced ROS. Knockdown of NLRP3 could prevent HG-induced EMT by inhibiting the phosphorylation of SMAD3, P38 MAPK and ERK1/2. In addition, P38 MAPK and ERK1/2 might be involved in HG-induced NLRP3 inflammasome activation. Besides, TGFB1 induced the activation of NLRP3 inflammasome and the generation of ROS, which were blocked by NLRP3 interference or NAC. Tubular cells exposed to TGFB1 also underwent EMT, and this could be inhibited by NLRP3 shRNA or NAC. These results indicated that knockdown of NLRP3 antagonized HG-induced EMT by inhibiting ROS production, phosphorylation of SMAD3, P38MAPK and ERK1/2, highlighting NLRP3 as a potential therapy target for diabetic nephropathy.

P EROXISOME PROLIFERATOR-activated receptor (PPAR)-␥ belongs to the nuclear receptor family that serves as a ligand-regulated transcription factor. PPAR␥ forms a heterodimer with the retinoid X receptor (RXR) and regulates gene expression by either binding to specific DNA sequences termed peroxisome proliferator response elements (PPREs) or interacting with other transcription factors in a DNA binding-independent manner (1). The role of PPAR␥ in regulation of glucose and lipid metabolism has been well established, as illustrated by the applications of the thiazolidinedione (TZD) type of PPAR␥ agonists (2). TZDs such as rosiglitazone and pioglitazone improve insulin sensitivity and relieve type 2 diabetes primarily by up-regulating genes involved in glucose and lipid metabolism in adipose tissue, liver, and skeleton muscle (3). PPAR␥ agonists are also shown to reduce triglyceride (TG) content in liver and/or skeleton muscle in both animal models (4, 5) and type 2 diabetes patients (6 -8).Hormone-sensitive lipase (HSL) is an intracellular neutral lipase with a broad specificity for lipid substrates such as TG, diglycerides, cholesteryl esters, and retinyl esters. HSL is the major enzyme responsible for the hydrolysis of stored TG in adipose tissue and has a pivotal role in the mobilization of fatty acids in many other tissues, including liver and muscle (9, 10). Whereas many studies have focused on the posttranslational mechanisms in HSL regulation and demonstrated the importance of the HSL protein phosphorylation in enzyme activity (11), relatively fewer investigations have been carried out in terms of the transcriptional regulation of the HSL gene.The HSL gene is known to be involved in various metabolic disorders. For example, HSL knockout mice develop hyperglycemia and hyperinsulinemia, suggesting that lack of HSL leads to impaired insulin sensitivity (12, 13). The insulin resistance was observed in skeletal muscle and liver in those studies. Human studies also support a role for HSL in insulin sensitivity and show that maximum stimulated lipolysis is defective in patients with the insulin-resistance syndrome (14, 15), and decreased expression and function of HSL are present in fat cells from obese subjects (16). Furthermore, genetic studies suggest that the polygenic background of HSL may be involved in the pathogenesis of type 2 diabetes (17,18).Based on the importance of both PPAR␥ and HSL in metabolism and insulin sensitivity, we studied the regulatory effects of PPAR␥ and its agonists on the HSL gene expression. In this report, we show the evidence that expression of the HSL gene is up-regulated by PPAR␥ and PPAR␥ agonists, which requires the involvement of the transcription factor specificity protein-1 (Sp1).

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A series of benzo[de][1,7]naphthyridin-7(8H)-ones possessing a functionalized long-chain appendage have been designed and evaluated as novel PARP1 inhibitors. The initial effort led to the first-generation PARP1 inhibitor 26 bearing a terminal phthalazin-1(2H)-one framework and showing remarkably high PARP1 inhibitory activity (0.31 nM) but only moderate potency in the cell. Further effort generated the second-generation lead 41, showing high potency against both the PARP1 enzyme and BRCA-deficient cells, especially for the BRCA1-deficient MDA-MB-436 cells (CC50 < 0.26 nM). Mechanistic studies revealed that the new PARP1 inhibitors significantly inhibited H2O2-triggered PARylation in SKOV3 cells, induced cellular accumulation of DNA double-strand breaks, and impaired cell-cycle progression in BRCA2-deficient cells. Significant potentiation on the cytotoxicity of Temozolomide was also observed. The unique structural character and exceptionally high potency of 41 made it stand out as a promising drug candidate worthy for further evaluation.

1 The aim of this study was to investigate the capacity of chiglitazar to improve insulin resistance and dyslipidemia in monosodium L-glutamate (MSG) obese rats and to determine whether its lipidlowering effect is mediated through its activation of PPARa. 2 Chiglitazar is a PPARa/g dual agonist.3 The compound improved impaired insulin and glucose tolerance; decreased plasma insulin level and increased the insulin sensitivity index and decreased HOMA index. Euglycemic hyperinsulinemic clamp studies showed chiglitazar increased the glucose infusion rate in MSG obese rats. 4 Chiglitazar inhibited alanine gluconeogenesis, lowered the hepatic glycogen level in MSG obese rats. Like rosiglitazone, chiglitazar promoted the differentiation of adipocytes and decreased the maximal diameter of adipocytes. In addition, chiglitazar decreased the fibrosis and lipid accumulation in the islets and increased the size of islets. 5 Chiglitazar reduced plasma triglyceride, total cholesterol (TCHO), nonesterified fatty acids (NEFA) and low density lipoprotein-cholesterol levels; lowered hepatic triglyceride and TCHO contents; decreased muscular NEFA level. Unlike rosiglitazone, chiglitazar showed significant increase of mRNA expression of PPARa, CPT1, BIFEZ, ACO and CYP4A10 in the liver of MSG obese rats. 6 These data suggest that PPARa/g coagonist, such as chiglitazar, affect lipid homeostasis with different mechanisms from rosiglitazone, chiglitazar may have better effects on lipid homeostasis in diabetic patients than selective PPARg agonists.