作者机构：
[Zhang, Chi; Tang, Yan-Yan; Xie, Wei; Lv, Yun-Cheng; Li, Yuan; Zhang, Min; Peng, Juan; Shi, Jin-Feng; He, Ping-Ping; Lan, Gan] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China;[Yin, Wei-Dong] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China. Electronic address: wdy20042004@126.com;[Tang, Chao-Ke] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China. Electronic address: tangchaoke@qq.com;[Peng, Juan] Yongzhou Vocational and Technical College, Yongzhou, Hunan 425000, China;[Zheng, Xi-Long] Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, The University of Calgary, 3330 Hospital Dr NW, Calgary, Alberta T2N 4N1, Canada
通讯机构：
[Tang, Chao-Ke; Yin, Wei-Dong] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China. Electronic address:
摘要：
Background: Atherosclerosis is a major cause of coronary artery disease, which is characterized by cellular lipid accumulation. Lipoprotein lipase (LPL) is a key enzyme in lipid metabolism. Studies have shown that macrophage-derived LPL exhibits proatherogenic properties, and plays a major role in lipid accumulation in macrophages. Evidence suggests that oxidative stress can effectively enhance macrophage LPL production. Betulinic acid (BA) is a pentacyclic lupane triterpene with a potent antioxidant activity. In this study, we investigated whether BA affects the expression of macrophage LPL and how it regulates cellular lipid accumulation. Methods and results: We revealed that BA downregulated H2O2-simulated macrophage LPL protein, mRNA levels and its activity in both concentration- and time-dependent manners. Furthermore, BA decreased LPL-involved total cholesterol and triglyceride levels in macrophages. In addition, cellular lipid staining by Oil Red 0 showed that BA decreased cellular lipid droplet deposition. Next, we confirmed that pretreatment with BA decreased H2O2-induced production of intracellular reactive oxygen species in a concentration-dependent manner. Further studies demonstrated that BA inhibited H2O2-induced membrane translocation of PKC, phosphorylation of ERK1/2 and c-Fos. Finally, the induction of LPL production and activity by H2O2 was abolished by BA, inhibition of PKC or ERK or depletion c-Fos, respectively. Conclusions: BA, through its role of antioxidant activity, attenuated macrophage-derived LPL expression and activity induced by oxidative stress, and effectively reduced cellular lipid accumulation, likely through inhibition of the pathways involving PKC, ERK and c-Fos. These effects of BA may contribute to its mitigation of atherosclerosis and help develop BA as a therapeutic compound in treatment of atherosclerosis. (C) 2015 Published by Elsevier B.V.
摘要：
LPL (lipoprotein lipase) is a rate-limiting enzyme involved in the hydrolysis of triglycerides. Previous studies have shown that microRNA (miR)-467b regulates hepatic LPL expression and plays a role in the progression of steatosis or abnormal lipid retention in obese mice. Macrophage-derived LPL has been shown to promote atherosclerosis. However, if miR-476b influences macrophage LPL expression and the subsequent effects are unknown. Here, we utilized oxLDL-treatment RAW 264.7 macrophages that were transfected with miR-467b mimics or inhibitors to investigate the potential roles of macrophage miR-476b. We found that miR-467b significantly decreased lipid accumulation and IL-6, IL-1 beta, TNF-alpha and MCP-1 secretions. Furthermore, our studies suggested an additional explanation for the regulatory mechanism of miR-467b on its functional target, LPL in RAW 264.7 macrophages. Thus, our findings indicate that miR-467b may regulate lipid accumulation and proinflammatory cytokine secretion in oxLDL-stimulated RAW 264.7 macrophages by targeting the LPL gene. (C) 2012 Elsevier Masson SAS. All rights reserved.
作者机构：
[Yao, Feng; Tang, Yan-Yan; Xie, Wei; Yin, Wei-Dong; Lv, Yun-Cheng; Li, Yuan; Zhao, Guo-Jun; Zhang, Min; Peng, Juan; Chen, Wu-Jun; Tian, Guo-Ping; Ouyang, Xin-Ping; He, Ping-Ping; Liu, Xiang-Yu; Tang, Yu Lin; Wu, Jian-Feng; Huang, Liang] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China;[Yin, Wei-Dong] Pharmacy and Biological Science College, University of South China, Hengyang, Hunan 421001, China. Electronic address: wdy20042004@126.com;[Wang, Zong-Bao] Pharmacy and Biological Science College, University of South China, Hengyang, Hunan 421001, China;[Tang, Chao-Ke] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China. Electronic address: tangchaoke@qq.com;[Tian, Guo-Ping] Second Affiliated Hospital of University of South China, Hengyang, Hunan 421001, China
通讯机构：
[Tang, Chao-Ke] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China. Electronic address:;[Yin, Wei-Dong] Pharmacy and Biological Science College, University of South China, Hengyang, Hunan 421001, China. Electronic address:
摘要：
Background: Accumulating evidence suggests that microRNA-590 (miR-590) has protective effects on cardiovascular diseases, but the mechanism is unknown. Interestingly, previous studies from our laboratory and others have shown that macrophage-derived lipoprotein lipase (LPL) might accelerate atherosclerosis by promoting lipid accumulation and inflammatory response. However, the regulation of LPL at the post-transcriptional level by microRNAs has not been fully understood. In this study, we explored whether miR-590 affects the expression of LPL and its potential subsequent effects on lipid accumulation and pro-inflammatory cytokine secretion in human THP-1 macrophages. Methods and results: Using bioinformatics analyses and dual-luciferase reporter assays, we found that miR-590 directly inhibited LPL protein and mRNA expression by targeting LPL 3'UTR. LPL Activity Assays showed that miR-590 reduced LPL activity in the culture media. Oil Red 0 staining and high-performance liquid chromatography assays showed that miR-590 had inhibitory effects on the lipid accumulation in human THP-1 macrophages. We also illustrated that miR-590 alleviated pro-inflammatory cytokine secretion in human THP-1 macrophages as measured by ELISA. With the method of small interfering RNA, we found that LPL siRNA can inhibit the miR-590 inhibitor-induced increase in lipid accumulation and secretion of pro-inflammatory cytokines in oxLDL-treated human THP-1 macrophages. Conclusions: MiR-590 attenuates lipid accumulation and pro-inflammatory cytokine secretion by targeting LPL gene in human THP-1 macrophages. Therefore, targeting miR-590 may offer a promising strategy to treat atherosclerotic cardiovascular diseases. (C) 2014 Elsevier B.V. and Societe francaise de biochimie et biologie Moleculaire (SFBBM). All rights reserved.
作者机构：
[Huang, Chong; Yao, Feng; Xie, Wei; Yin, Wei-Dong; Li, Liang; Tan, Yu-Lin; Tang, Chao-Ke; Lv, Yun-Cheng; Li, Yuan; Liu, Dan; Zhang, Min; Lan, Gang; He, Ping-Ping; Cheng, Hai-Peng; OuYang, Xin-Ping; Gong, Duo] Institute of Cardiovascular Research, Key Laboratory for Atherosclerologyof Hunan Province,Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China,Hengyang, Hunan 421001, China;[Zhong, Hui-Juan] Department of Cardiovascular Medicine, The Liwan Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510170, China;[Yin, Wei-Dong; Wang, Zong-Bao; Tang, Chao-Ke; He, Ping-Ping; OuYang, Xin-Ping] Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, 28 West Changsheng Road, Hengyang 421001, Hunan, China;[Yin, Wei-Dong; Wang, Zong-Bao] Pharmacy and Biological Science College, University of South China, Hengyang, Hunan, 421001, China;[Li, Zhao-Xia; He, Ping-Ping] Nursing School, University of South China, Hengyang 421001, Hunan, China
通讯机构：
[Yin, WD] Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Key Lab Atherosclerol Hunan Prov, Inst Cardiovasc Res, Hengyang 421001, Hunan, Peoples R China.
摘要：
Recent studies have suggested that miR-590 may play critical roles in cardiovascular disease. This study was designed to determine the effects of miR-590 on lipoprotein lipase (LPL) expression and development of atherosclerosis in apolipoprotein E knockout (apoE(-/-)) mice and explore the potential mechanisms. En face analysis of the whole aorta revealed that miR-590 significantly decreased aortic atherosclerotic plaque size and lipid content in apoE (-/-) mice. Double immunofluorescence staining in cross-sections of the proximal aorta showed that miR-590 agomir reduced CD68 and LPL expression in macrophages in atherosclerotic lesions. MiR-590 agomir down-regulated LPL mRNA and protein expression as analyzed by RT-qPCR and western blotting analyses, respectively. Consistently, miR-590 decreased the expression of CD36 and scavenger receptor A1 (SRA1) mRNA and protein. High-performance liquid chromatography (HPLC) analysis confirmed that treatment with miR-590 agomir reduced lipid levels either in plasma orinabdominal cavity macrophages of apoE(-/-) mice. ELISA analysis showed that miR-590 agomir decreased plasma levels of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), monocyte chemotactic protein-1 (MCP-1), interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6). In contrast, treatment with miR-590 antagomir prevented or reversed these effects. Taken together, these results reveal a novel mechanism of miR-590 effects, and may provide new insights into the development of strategies for attenuating lipid accumulation and pro-inflammatory cytokine secretion.
作者机构：
[Yin, WD] Department of Biochemistry and Molecular Biology, Nanhua University School of Life Sciences and Technology, Hengyang, 421001, Hunan, China. wdy20012001@yahoo.com
通讯机构：
[Yin, Weidong] Department of Biochemistry and Molecular Biology, Nanhua University School of Life Sciences and Technology, Hengyang, 421001, Hunan, China.
摘要：
The synthetic compound NO-1886 is a lipoprotein lipase activator that has been proven to be highly effective in lowering plasma triglycerides and elevating high-density lipoprotein cholesterol. Recently, we found that NO-1886 also had a plasma glucose-reducing action in high-fat/high-sucrose diet-induced diabetic rabbits. In the current study we investigated the effects of NO-1886 on the morphology of adipocytes, plasma levels of tumor necrosis factor-alpha (TNF-alpha) and free fatty acids (FFA) in miniature pigs fed a high-fat/high-sucrose diet. Our results showed that feeding a high-fat/high-sucrose diet to miniature pigs increased the size of adipocytes, and the plasma levels of TNF-alpha, FFA, and glucose. This diet also induced insulin resistance and impaired the acute insulin response to glucose loading. Supplementing 1% NO-1886 to the high-fat/high-sucrose diet inhibited adipocyte enlargement, and suppressed plasma levels of TNF-alpha, FFA, and glucose. The decrease in plasma TNF-alpha and FFA was simultaneous with the decrease in plasma glucose. We also found an increased whole body glucose clearance and an increased acute insulin response to intravenous glucose loading by NO-1886 supplementation. These data suggest that NO-1886 improves the glucose metabolism in high-fat/high-sucrose diet-induced diabetic minipigs by decreasing fat deposit, and suppressing plasma TNF-alpha and FFA levels. Therefore, NO-1886 is potentially beneficial for the treatment of insulin-resistant syndrome. (C) 2003 Elsevier Ltd. All rights reserved.
摘要：
Background: Lipoprotein lipase (LPL) expressed in macrophages plays an important role in promoting the development of atherosclerosis or atherogenesis. MicroRNA-182 (miR-182) is involved in the regulation of lipid metabolism and inflammation. However, it remains unclear how miR-182 regulates LPL and atherogenesis. Methods and Results: Using bioinformatics analyses and a dual-luciferase reporter assay, we identified histone deacetylase 9 (HDAC9) as a target gene of miR-182. Moreover, miR-182 upregulated LPL expression by directly targeting HDAC9 in THP-1 macrophages. Hematoxylin-eosin (H&E), Oil Red O and Masson's trichrome staining showed that apolipoprotein E (ApoE)-knockout (KO) mice treated with miR-182 exhibited more severe atherosclerotic plaques. Treatment with miR-182 increased CD68 and LPL expression in atherosclerotic lesions in ApoE-KO mice, as indicated by double immunofluorescence staining in the aortic sinus. Increased miR-182-induced increases in LPL expression in ApoE-KO mice was confirmed by real-time quantitative polymerase chain reaction and western blotting analyses. Treatment with miR-182 also increased plasma concentrations of proinflammatory cytokines and lipids in ApoE-KO mice. Conclusions: The results of the present study suggest that miR-182 upregulates LPL expression, promotes lipid accumulation in atherosclerotic lesions, and increases proinflammatory cytokine secretion, likely through targeting HDAC9, leading to an acceleration of atherogenesis in ApoE-KO mice.
摘要：
Inflammation, closely associated with obesity, is emerging as an important risk factor for the pathophysiological development of atherosclerosis and diabetes mellitus. Fat balance is critical in the aetiology of obesity. Lipoprotein lipase is an important enzyme in lipid metabolism. The aim of this study was to investigate the long-term effect of the lipoprotein lipase activator, NO-1886, on inflammation cytokines, adiposity and related diseases in miniature pigs fed a high-fat/high-sucrose/high-cholesterol diet (HFSC diet). Chinese Bama-miniature pigs were fed a control diet or HFSC diet with or without NO-1886 for 5 months. The levels of inflammation-associated cytokines were determined using the antibody arrays. Feeding of the HFSC diet to miniature pigs markedly increased the expression of inflammatory cytokines. On the other hand, supplementation of NO-1886 to HFSC diet decreased the expression of inflammatory cytokines significantly, protecting against the development of atherosclerosis and diabetes mellitus. NO-1886 may have a beneficial effect on the most inflammation-associated cytokines, and this effect may contribute to improving atherosclerosis and diabetes mellitus. (c) 2006 Elsevier B.V All rights reserved.
摘要：
Evidences indicate that a complex relationship exists among sleep disorders, obesity and insulin resistance. NEU-P11 is a novel melatonin agonist used in treatment of psychophysiological insomnia, and in animal studies NEU-P11 showed sleep-promoting effect. In this study, we applied NEU-P11 on obese rats to assess its potential melatoninergic effects in vivo. Obese models were established using high-fat/high-sucrose-fed for 5 months. NEU-P11 (10 mg/kg)/melatonin (4 mg/kg)/vehicle were administered by a daily intraperitoneal injection respectively for 8 weeks. Our results showed that NEU-P11 or melatonin inhibited both body weight gain and deposit of abdominal fat with no influence on food intake. The impaired insulin sensitivity and antioxidative potency were improved and the levels of plasma glucose, total cholesterol (TC), triglycerides (TG) decreased with an increased in HDL-cholesterol (HDL-c) after NEU-P11 or melatonin administration. These data suggest that NEU-P11, like melatonin, decreased body weight gain and improved insulin sensitivity and metabolic profiles in obese rats. We conclude that NEU-P11 has a melatoninergic effect on regulating body weight in obese rats and also improving metabolic profiles and efficiently enhancing insulin sensitivity. (C) 2009 Elsevier Ltd. All rights reserved.
期刊：
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,2016年472(3):410-417 ISSN：0006-291X
通讯作者：
Tang, CK
作者机构：
[Liu, Dan; Zhang, Min; Huang, Chong; Lan, Gang; Xie, Wei; Li, Liang; Cheng, Hai-Peng; Tan, Yu-Lin; Gong, Duo] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, 421001, Hunan, China;[Yin, Wei-Dong] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, 421001, Hunan, China. Electronic address: yysweets@126.com;[Zheng, Xi-Long] Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, The University of Calgary, Health Sciences Center, 3330 Hospital Dr NW, Calgary, Alberta, T2N 4N1, Canada;[Tang, Chao-Ke] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, 421001, Hunan, China. Electronic address: tangchaoke@qq.com
通讯机构：
[Tang, Chao-Ke; Yin, Wei-Dong] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, 421001, Hunan, China. Electronic address:
摘要：
Angiopoietin-like 4 (Angptl4), a secreted protein, is an important regulator to irreversibly inhibit lipoprotein lipase (LPL) activity. Macrophage LPL contributes to foam cell formation via a so-called"molecular bridge" between lipoproteins and receptors on cell surface. It has been reported that macrophage ANGPTL4 suppresses LPL activity, foam cell formation and inflammatory gene expression to reduce atherosclerosis development. Recently, some studies demonstrated that microRNA-134 is upregulated in atherosclerotic macrophages. Here we demonstrate that miR-134 directly binds to 3'UTR of ANGPTL4 mRNA to suppression the expression of ANGPTL4. To investigate the potential roles of macrophage miR-134, THP-1 macrophages were transfected with miR-134 mimics or inhibitors. Our results showed that LPL activity and protein were dramatically increased. We also found that miR-134 activated LPL-mediated lipid accumulation. Collectively, our findings indicate that miR-134 may regulate lipid accumulation and proinfiammatory cytokine secretion in macrophages by targeting the ANGPTL4 gene. Our results have also suggested a promising and potential therapeutic target for atherosclerosis. (C) 2016 Elsevier Inc. All rights reserved.
期刊：
Clinica chimica acta; international journal of clinical chemistry,2016年453:107-113 ISSN：0009-8981
通讯作者：
Yin, Wei-Dong;Tang, Chao-Ke
作者机构：
[Xie, Wei; Li, Liang] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, Hunan, China;[Xie, Wei] Department of Anatomy, University of South China, Hengyang 421001, Hunan, China;[Yin, Wei-Dong] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, Hunan, China. Electronic address: wdy20042004@126.com;[Zheng, Xi-Long] Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, The University of Calgary, Health Sciences Center, 3330 Hospital Dr NW, Calgary, Alberta T2N 4N1, Canada;[Li, Liang] Department of Pathophysiology, University of South China, Hengyang 421001, Hunan, China
通讯机构：
[Tang, Chao-Ke; Yin, Wei-Dong] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, Hunan, China. Electronic address:
摘要：
Cardiovascular diseases, such as atherosclerosis and hypertension, are the major cause of mortality and morbidity in the world. Adropin was first discovered in 2008 by Kumar and his coworkers. Adropin, encoded by the Energy Homeostasis Associated gene, is expressed in many tissues and organs, such as pancreatic tissue, liver, brain, kidney, endocardium, myocardium, and epicardium. In this review, we have summarized recent data suggesting the roles of adropin in several major cardiovascular diseases. Increasing evidence suggests that adropin is a potential regulator of cardiovascular functions and plays a protective role in the pathogenesis and development of cardiovascular diseases. However, further studies are needed to elucidate the specific mechanisms underlying the association between adropin and cardiovascular diseases. (C) 2015 Elsevier B.V. All rights reserved.
作者机构：
[Yao, Feng; Xie, Wei; Yin, Wei-Dong; Li, Liang; Zhao, Zhen-Wang; Tan, Yu-Lin; Tang, Chao-Ke; Liu, Dan; Zhang, Min; Lan, Gang; Ouyang, Xin-Ping; He, Ping-Ping; Cheng, Hai-Peng; Gong, Duo] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan, China;[Xie, Wei; Lv, Yun-Cheng] Laboratory of Clinical Anatomy, University of South China, Hengyang, Hunan, China;[Li, Liang] Department of Pathophysiology, University of South China, Hengyang, Hunan, China;[Zheng, Xi-Long] Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, The University of Calgary, Health Sciences Center, Hospital Dr NW, Calgary, Alberta, Canada
通讯机构：
[Tang, CK] Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan Prov,Med Res Ctr, Hengyang, Hunan, Peoples R China.
摘要：
Atherosclerotic lesions are lipometabolic disorder characterized by chronic progressive inflammation in arterial walls. Previous studies have shown that macrophage-derived lipoprotein lipase (LPL) might be a key factor that promotes atherosclerosis by accelerating lipid accumulation and proinflammatory cytokine secretion. Increasing evidence indicates that microRNA-27 (miR-27) has beneficial effects on lipid metabolism and inflammatory response. However, it has not been fully understood whether miR-27 affects the expression of LPL and subsequent development of atherosclerosis in apolipoprotein E knockout (apoE KO) mice. To address these questions and its potential mechanisms, oxidized low-density lipoprotein (ox-LDL)-treated THP-1 macrophages were transfected with the miR-27 mimics/inhibitors and apoE KO mice fed high-fat diet were given a tail vein injection with miR-27 agomir/antagomir, followed by exploring the potential roles of miR-27. MiR-27 agomir significantly down-regulated LPL expression in aorta and peritoneal macrophages by western blot and real-time PCR analyses. We performed LPL activity assay in the culture media and found that miR-27 reduced LPL activity. ELISA showed that miR-27 reduced inflammatory response as analyzed in vitro and in vivo experiments. Our results showed that miR-27 had an inhibitory effect on the levels of lipid both in plasma and in peritoneal macrophages of apoE KO mice as examined by HPLC. Consistently, miR-27 suppressed the expression of scavenger receptors associated with lipid uptake in ox-LDL-treated THP-1 macrophages. In addition, transfection with LPL siRNA inhibited the miR-27 inhibitor-induced lipid accumulation and proinflammatory cytokines secretion in ox-LDL-treated THP-1 macrophages. Finally, systemic treatment revealed that miR-27 decreased aortic plaque size and lipid content in apoE KO mice. The present results provide evidence that a novel antiatherogenic role of miR-27 was closely related to reducing lipid accumulation and inflammatory response via downregulation of LPL gene expression, suggesting a potential strategy to the diagnosis and treatment of atherosclerosis.
摘要：
P>MicroRNAs (miRNAs) play essential roles in many biological processes. It is known that aberrant miRNA expression contributes to some pathological conditions. However, it is not known whether miRNAs play any role in the development of insulin resistance in adipocytes, a key pathophysiological link between obesity and diabetes. To investigate the function of miRNAs in the development of insulin resistance, using miRNA microarray analysis we compared miRNA expression profiles between normal insulin-sensitive 3T3-L1 adipocytes and 3T3-L1 adipocytes rendered insulin resistant following treatment with high glucose (25 mmol/L) and high insulin (1 mu mol/L). Furthermore, adipocytes were transfected with specific antisense oligonucleotides against miRNA-320 (anti-miR-320 oligo) and the effects on the development of insulin resistance were evaluated. We identified 50 upregulated and 29 downregulated miRNAs in insulin-resistant (IR) adipocytes, including a 50-fold increase in miRNA-320 (miR-320) expression. Using bioinformatic techniques, the p85 subunit of phosphatidylinositol 3-kinase (PI3-K) was found to be a potential target of miR-320. In experiments with anti-miR-320 oligo, insulin sensitivity was increased in IR adipocytes, as evidenced by increases in p85 expression, phosphorylation of Akt and the protein expression of the glucose transporter GLUT-4, as well as insulin-stimulated glucose uptake. These beneficial effects of anti-miR-320 oligo were observed only in IR adipocytes and not in normal adipocytes. In conclusion, the miRNA profile changes in IR adipocytes compared with normal 3T3-L1 adipocytes. Anti-miR-320 oligo was found to regulate insulin resistance in adipocytes by improving insulin-PI3-K signalling pathways. The findings provide information regarding a potentially new therapeutic strategy to control insulin resistance.
期刊：
CELL BIOCHEMISTRY AND BIOPHYSICS,2013年67(3):1239-1248 ISSN：1085-9195
通讯作者：
Xu, GL
作者机构：
[Cao, Zhao-hui; Feng, Shao-long; Yin, Wei-dong] Univ South China, Sch Pharm & Life Sci, Hengyang 421001, Peoples R China.;[Cao, Zhao-hui; Xu, Gui-lian] Third Mil Med Univ, Dept Immunol, Chongqing 400038, Peoples R China.;[Cao, Zhao-hui; Zhang, Ke-qin; Zheng, Quan-you] Third Mil Med Univ, Inst Surg Res, Daping Hosp, Dept Urol, Chongqing 400042, Peoples R China.
通讯机构：
[Xu, GL] Third Mil Med Univ, Dept Immunol, Chongqing 400038, Peoples R China.
摘要：
TNF-alpha and IFN-gamma are the major pro-inflammatory cytokines in the beta-cell destruction. However, the underlying mechanism remains unclear. The present study used a murine insulinoma cell line MIN6 for further investigation of the effect of Caspase-3 on the cytokines-induced pancreatic beta-cell apoptosis and analyzed the mechanisms involved in the activation of Caspase-3. It was showed that the combination of IFN-gamma and TNF-alpha significantly reduced the viability of MIN6 cells and the observed cells growth inhibition was due to cell apoptosis as judged by the morphological changes under a confocal laser scanning microscopy and FACS assay of Annexin-V/7-AAD double staining. Accompanying with NF-kappa B activation and Bcl-2 downregulation, both the cleaved Caspase-3 and PARP, a known substrate of Caspase-3 in vivo, were observed at 24 and 12 h, respectively, after cells exposure to IFN-gamma and TNF-alpha treatment. Pretreatment of Caspase-3 inhibitors remarkably attenuated IFN-gamma- and TNF-alpha-induced cells apoptosis. Inhibition of NF-kappa B activation led to the increase in Bcl-2 expression, a significant attenuation in Caspase-3 activity, and an obvious amelioration in cells viability in IFN-gamma- and TNF-alpha-treated MIN6 cells. Taken together, our results indicate that Caspase-3 is critical for the induction of MIN6 cells apoptosis and it's activation is further confirmed to be related to the NF-kappa B-mediated Bcl-2 downregulation, which may be the underlying mechanism of IFN-gamma- and TNF-alpha-mediated MIN6 cells apoptosis.
期刊：
Die Pharmazie,2011年66(10):798-803 ISSN：0031-7144
通讯作者：
Wang, ZB
作者机构：
[Zeng, Huaicai] Univ S China, Sch Publ Hlth, Hengyang 421001, Peoples R China.;[Wang, Yueting; Yin, Weidong; Zhang, Sujun; Zhang, Yali; Yu, Jian; Wang, Zongbao; Xiao, Guohua] Univ S China, Inst Biochem & Mol Biol, Hengyang 421001, Peoples R China.;[Wang, Zongbao] Univ S China, Dept Lab Anim Sci, Hengyang 421001, Peoples R China.
通讯机构：
[Wang, ZB] Univ S China, Inst Biochem & Mol Biol, Hengyang 421001, Peoples R China.
摘要：
OBJECTIVE: Endothelial dysfunction is a key event in the onset and progression of atherosclerosis associated with diabetes. Increasing cell apoptosis may lead to endothelial dysfunction and contribute to vascular complications. Therefore, we aimed to elucidate the possible role and mechanism of ibrolipim in preventing endothelial dysfunction induced by high glucose. METHODS: Human umbilical vein endothelial cells (HUVECs) were cultured respectively under normal glucose level (5.5mM), high glucose level (33mM), and high glucose level with ibrolipim treatment. Endothelial dysfunction was identified by the expression of ET-1 and vWF through reverse transcription PCR (RT-PCR). HUVECs apoptosis was assessed by fluorescent staining with Hoechst 33258. Akt activity was analyzed by western blot. RESULTS: High glucose condition significantly increased the rate of apoptotic cells, weakened cell viability, and decreased the expression of ET-1 and vWF. Ibrolipim treatment significantly attenuated these alterations of endothelial dysfunction. The lower concentrations (2, 4, 8 microM) of ibrolipim inhibited apoptosis of cultured HUVECs, improved cell viability, down-regulated the mRNA levels of ET-1, vWF, and attenuated the cytotoxicity; however, higher concentration (16, 32 microM) of ibrolipim aggravated the damage of HUVECs cultured under high glucose level. Meanwhile, high glucose induced a decrease of Akt activity which led to apoptosis, and ibrolipim prevented the decrease and attenuated apoptotic effect induced by high glucose. Furthermore, the PI3K inhibitor LY294002 significantly abolished the anti-apoptotic effect of ibrolipim, and decreased Akt phosphorylation. Although, the expression of Akt mRNA and total protein were not altered in cultured HUVECs. CONCLUSION: Ibrolipim at lower concentrations can inhibit high glucose-induced apoptosis in cultured HUVECs, which might be related to the alternation of Akt activity. Ibrolipim has the potential to attenuate endothelial dysfunction and lower the risk of diabetes-associated vascular diseases. And it might be a therapeutic agent for diabetic vascular complications.
作者机构：
[Chen, Si-guo; Xiao, Ji; Cui, Li-bao; Mo, Zhong-cheng; Jiang, Jin; Yin, Kai; Yin, Wei-dong; Liu, Xie-hong; Tan, Chun-zhi; Liu, Mei-mei; Tang, Chao-ke; Zhao, Guo-jun] Univ S China, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan Prov, Life Sci Res Ctr, Hengyang 421001, Peoples R China.;[Chen, Si-guo] Xiangnan Univ, Dept Physiol, Chenzhou 423000, Peoples R China.;[Xiao, Ji] Univ S China, Dept Anesthesiol, Affiliated Hosp 2, Hengyang 421001, Peoples R China.
通讯机构：
[Tang, CK] Univ S China, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan Prov, Life Sci Res Ctr, Hengyang 421001, Peoples R China.
关键词：
ATP-binding membrane cassette transporter A-1;ATP-binding membrane cassette transporter G-1;ibrolipim;liver X receptor a;atherosclerosis;RNA interference;high density lipoprotein;apolipoprotein;cholesterol
摘要：
Aim: To determine the effects and potential mechanisms of ibrolipim on ATP-binding membrane cassette transporter A-1 (CA1) and ATP-binding membrane cassette transporter G-1 (CG1) expression from human macrophage foam cells, which may play a critical role in atherogenesis. Methods: Human THP-1 cells pre-incubated with ox-LDL served as foam cell models. Specific mRNA was quantified using real-time RT-PCR and protein expression using Western blotting. Cellular cholesterol handling was studied using cholesterol efflux experiments and high performance liquid chromatography assays. Results: Ibrolipim 5 and 50 μmol/L significantly increased cholesterol efflux from THP-1 macrophage-derived foam cells to apo A-I or HDL. Moreover, it upregulated the expression of CA1 and CG1. In addition, LXRa was also upregulated by the ibrolipim treatment. In addition, LXRa small interfering RNA completely abolished the promotion effect that was induced by ibrolipim. Conclusion: Ibrolipim increased CA1 and CG1 expression and promoted cholesterol efflux, which was mediated by the LXRa signaling pathway
摘要：
Lipoprotein lipase (LPL) is a rate-limiting enzyme that hydrolyzes circulating triglyceride-rich lipoproteins such as very low-density lipoproteins and chylomicrons. A decrease in LPL activity is associated with an increase in plasma triglycerides (TG) and a decrease in plasma high-density lipoprotein cholesterol (HDL-C). The increase in plasma TG and decrease in plasma HDL-C are risk factors for cardiovascular disease. Tsutsumi et al. hypothesized that elevating LPL activity would cause a reduction of plasma TG and an increase in plasma HDL-C, resulting in protection against the development of atherosclerosis. To test this hypothesis, Otsuka Pharmaceutical Factory, Inc. synthesized the LPL activator NO-1886. NO-1886 increased LPL mRNA and LPL activity in adipose tissue, myocardium and skeletal muscle, resulting in an elevation of postheparin plasma LPL activity and LPL mass in rats. NO-1886 also decreased plasma TG concentration and caused a concomitant rise in plasma HDL-C. Long-term administration of NO-1886 to rats and rabbits with experimental atherosclerosis inhibited the development of atherosclerotic lesions in coronary arteries and aortas. Multiple regression analysis suggested that the increase in plasma HDL-C and the decrease in plasma TG protect from atherosclerosis. The atherogenic lipid profile is changed to an antiatherogenic profile by increasing LPL activity, resulting in protection from atherosclerosis. Therefore, the LPL activator NO-1886 or other possible LPL activating agents are potentially beneficial for the treatment of hypertriglyceridemia, hypo-HDL cholesterolemia, and protection from atherosclerosis.
