摘要:
It is well-recognized that hyperlipidemia and lipid peroxidation contribute to the progression of diabetic nephropathy (DN), which is associated with oxidative stress (OS) and fibrotic lesions. Ibrolipim, a specific lipoprotein lipase activator, has been proved to reduce hyperglycemia and hyperlipidemia, suppress renal lipid deposition, and also protect renal damage. However, the underlying mechanisms of its renoprotective effect are not clearly elaborated. Herein, the present study was to identify whether the putative mechanism of Ibrolipim was related to OS and fibrogenesis in diabetic minipigs fed by high-sucrose and high-fat diet (HSFD) with or without Ibrolipim for 5 months. Compared with the normal control diet, nutrient stress induced by HSFD caused moderate glomerulosclerosis and tubulointerstitial fibrosis, and promoted renal ultrastructural and functional abnormalities. These abnormalities were correlated with renal OS and fibrogenesis characterized by the increased levels of reactive oxygen species (ROS), malondialdehyde, hydroxyproline, collagen type Ⅳ alpha 1 and fibronectin, and decreased contents of reduced glutathione and total antioxidant capacity in kidneys. Ibrolipim significantly ameliorated these abnormalities in HSFD-fed minipigs. In addition, Ibrolipim diminished HSFD-induced nicotinamide-adenine dinucleotide phosphate oxidase-4 activation to reduce ROS production, and enhanced the expression and activity of antioxidant enzymes (i.e. superoxide dismutase 1, catalase and glutathione peroxidase 1) to increase ROS elimination, resulting in obvious suppression of renal OS. Meanwhile, Ibrolipim not only inhibited the upregulation of transforming growth factor-β1 but also partially reversed the downregulation of matrix metalloproteinase 2, and then prevented extracellular matrix (ECM) accumulation. Taken together, Ibrolipim exhibits anti-oxidative and anti-fibrotic effects via modulating the rebalance of renal ROS and ECM metabolism, and ultimately attenuates the progression of nephropathy in diet-induced diabetic minipigs.
摘要:
Atherosclerotic lesions are characterized by the accumulation of abundant lipids and chronic inflammation. Previous researches have indicated that macrophage-derived lipoprotein lipase (LPL) promotes atherosclerosis progression by accelerating lipid accumulation and proinflammatory cytokine secretion. Although apelin-13 has been regarded as an atheroprotective factor, it remains unclear whether it can regulate the expression of LPL. The aim of this study was to explore the effects of apelin-13 on the expression of LPL and the underlying mechanism in THP-1 macrophage-derived foam cells. Apelin-13 significantly decreased cellular levels of total cholesterol, free cholesterol, and cholesterol ester at the concentrations of 10 and 100 nM. ELISA analysis confirmed that treatment with apelin-13 reduced pro-inflammatory cytokine secretion, such as interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α). It was also found that apelin-13 inhibited the expression of LPL as revealed by western blot and real-time PCR analyses. Bioinformatics analyses and dual-luciferase reporter assay indicated that miR-361-5p directly downregulated the expression of LPL by targeting the 3'UTR of LPL. In addition, apelin-13 + miR-361-5p mimic significantly downregulated the expression of LPL in cells. Finally, we demonstrated that apelin-13 downregulated the expression of LPL through activating the activity of PKCa. Taken together, our results showed that apelin-13 downregulated the expression of LPL via activating the APJ/PKCa/miR-361 -5p signaling pathway in THP-1 macrophage-derived foam cells, leading to inhibition of lipid accumulation and proinflammatory cytokine secretion. Therefore, our studies provide important new insight into the inhibition of lipid accumulation and pro-inflammatory cytokine secretion by apelin-13, and high-light appelin-13 as a promising therapeutic target in atherosclerosis.
作者机构:
[He, Shuya; Xiao, Xiao; Fu, Liang; Ma, Yun; Tian, Shuai] Univ South China, Dept Biochem & Biol, 28 Western Changsheng Rd, Hengyang City 421001, Hunan, Peoples R China.;[Wang, Zongbao; He, Shuya; Lei, Xiaoyong; Ma, Yun; Lei, XY] Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, 28 Western Changsheng Rd, Hengyang City 421001, Hunan, Peoples R China.;[Chen, Qiong] Cent S Univ, Xiangya Hosp, Dept Resp, Dept Geriatr Med, Changsha 410008, Hunan, Peoples R China.
通讯机构:
[He, Shuya] U;[Ma, Y; Lei, XY] H;Univ South China, Dept Biochem & Biol, 28 Western Changsheng Rd, Hengyang City 421001, Hunan, Peoples R China.;Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, 28 Western Changsheng Rd, Hengyang City 421001, Hunan, Peoples R China.
关键词:
miR-19b;FXR1;RAB18;USP32;Dusp6
摘要:
The biological effects of microRNAs (miRNAs) in the Fragile X Syndrome (FXS) have been widely studied. Dysregulation of miRNAs plays a critical role in the progression of nervous system diseases and in cell proliferation and differentiation. Our previous study validated that miR-19b-3p was associated with FXR1 (Fragile X related gene I), one of homologous genes of FMR1 (Fragile X mental retardation 1). The purpose of this study was to investigate the relationship of FXR1 and miR-19b-3p, and the crucial role of miR-19b-3p in FXS and to validate whether miR-19b-3p could regulate the growth of SH-SY5Y cells. We determined that miR-19b-3p could regulate the expression of not only USP32, RAB18 and Dttsp6 but also FXR1, and FXR1 could in turn regulate the expression of miR-19b-3p. What's more, the overexpression of miR-19b-3p significantly inhibited the proliferation, contributed the apoptosis and slowed down the cycle of SH-SY5Y cells. Taken together, our results indicate that miR-19b-3p plays a significant role in the molecular pathology of FXS by interacting with FXR1 and influencing the growth of SH-SY5Y cells. (C) 2016 Elsevier B.V. All rights reserved.
通讯机构:
[Ma, Y; He, SY] U;Univ South China, Dept Biochem & Biol, 28 Western Changshen Rd, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Inst Pharmaceut & Biol Sci, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Hengyang 421001, Hunan, Peoples R China.
关键词:
fragile X related protein 1;CMP-N-acetylneuraminic acid synthetase;fragile X syndrome;GM1
摘要:
Fragile X mental retardation protein (FMRP), fragile X related 1 protein (FXR1P) and FXR2P are the members of the FMR protein family. These proteins contain two KH domains and a RGG box, which are characteristic of RNA binding proteins. The absence of FMRP, causes fragile X syndrome (FXS), the leading cause of hereditary mental retardation. FXR1P is expressed throughout the body and important for normal muscle development, and its absence causes cardiac abnormality. To investigate the functions of FXR1P, a screen was performed to identify FXR1P-interacting proteins and determine the biological effect of the interaction. The current study identified CMP-N-acetylneuraminic acid synthetase (CMAS) as an interacting protein using the yeast two-hybrid system, and the interaction between FXR1P and CMAS was validated in yeast using a beta-galactosidase assay and growth studies with selective media. Furthermore, co-immunoprecipitation was used to analyze the FXR1P/CMAS association and immunofluorescence microscopy was performed to detect expression and intracellular localization of the proteins. The results of the current study indicated that FXR1P and CMAS interact, and colocalize in the cytoplasm and the nucleus of HEK293T and HeLa cells. Accordingly, a fragile X related 1 (FXR1) gene overexpression vector was constructed to investigate the effect of FXR1 overexpression on the level of monosialotetrahexosyl-ganglioside 1 (GM1). The results of the current study suggested that FXR1P is a tissue-specific regulator of GM1 levels in SH-SY5Y cells, but not in HEK293T cells. Taken together, the results initially indicate that FXR1P interacts with CMAS, and that FXR1P may enhance the activation of sialic acid via interaction with CMAS, and increase GM1 levels to affect the development of the nervous system, thus providing evidence for further research into the pathogenesis of FXS.
摘要:
A novel series of iodo-chrysin derivatives with resorcinol as raw materials were synthesized according to Baker-Venkataraman reaction and their inhibitory activities in vitro against thyroid cancer cell lines (SW-579 and TT) were evaluated by the standard methyl thiazole tetrazolium (MTT) method. Biological test results showed that these derivatives possessed stronger anti-thyroid cancer activities than 5-FU. Compound 21 showed the strongest activity against SW-579 cell lines with IC50 value of 3.4μM and compound 10 showed the strongest activity against TT cell lines with IC50 value of 6.2μM, it was better than 5-FU (59.3μΜ, 18.4μM respectively).