通讯机构：
[Yin, WD; Tang, CK ] U;Univ South China, Med Res Expt Ctr, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Inst Cardiovasc Dis,Key Lab Arteriosclerol Hunan, Hengyang 421001, Hunan, Peoples R China.
关键词：
AS;CCDC80;DNA methylation;LPL;TET2
摘要：
Recent studies showed that coiled-coil domain-containing 80 (CCDC80) has a positive link with atherosclerosis and that plasma CCDC80 levels are positively correlated with the levels of fasting plasma triglycerides (TG) in obese individuals. The underlying mechanisms, however, are unclear. Using Hematoxylin-eosin (H&E) and Oil Red O staining, we found that CCDC80 overexpression in vivo significantly increased plasma lipid contents, decreased the expression and activity of lipoprotein lipase (LPL), and accelerated the development of atherosclerosis. Conversely, knockdown of CCDC80 decreased plaque lesions area. In vitro, qRT-PCR and western blot results showed that CCDC80 overexpression significantly decreased, while CCDC80 knockdown increased, LPL expression in cultured vascular smooth muscle cells (VSMCs). Further, we found that CCDC80 reduced LPL expression via inhibiting the phosphorylation of extracellular regulated protein kinase 1/2 (ERK1/2) and also increased the methylation of LPL promoter via down-regulating Tet methylcytosine dioxygenase 2 (TET2). Our results also revealed that CCDC80 significantly down-regulated TET2 expression through decreasing the phosphorylation of ERK1/2. In addition, we found that CCDC80 decreased binding of TET2 to forkhead box O3 (FOXO3a) but had no effect on FOXO3a expression. On the other hand, and that FOXO3a was partially involved in TET2-regulated LPL expression. CCDC80 down-regulated ERK1/2 phosphorylation and decreased expression of TET2 and its interaction with FOXO3a, leading to a reduction of LPL expression and acceleration of atherosclerosis.
通讯机构：
[Yin, Wei-Dong; Mo, Zhong-Cheng] U;Univ South China, Inst Cardiovasc Dis, Sch Med, 28W Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Sch Med, Dept Histol & Embryol, 28W Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.
关键词：
cholesterol;follitropin;insulin;liver X receptor alpha;liver X receptor beta;peroxisome proliferator activated receptor alpha;peroxisome proliferator activated receptor delta;peroxisome proliferator activated receptor gamma;retinoid X receptor alpha;retinoid X receptor beta;retinoid X receptor gamma;scavenger receptor BI;sex hormone;cholesterol;sterol 14alpha demethylase;cholesterol metabolism;cholesterol transport;human;male;metabolic regulation;nonhuman;Review;Sertoli cell;spermatogenesis;gene expression regulation;genetics;lipid metabolism;metabolism;Sertoli cell;spermatogenesis;testis;Cholesterol;Gene Expression Regulation, Developmental;Humans;Lipid Metabolism;Male;Sertoli Cells;Spermatogenesis;Sterol 14-Demethylase;Testis
摘要：
The Sertoli cell, which is the supporting cell of spermatogenesis, has an important role in the endocrine and paracrine control of spermatogenesis. Functionally, it provides the cells of the seminiferous epithelium with nutrition, conveys mature spermatids to the lumen of seminiferous tubules, secretes androgen-binding protein and interacts with endocrine Leydig cells. In addition, the levels of cholesterol, as well as its intermediates, vary greatly between nongonadal tissues and the male reproductive system. Throughout spermatogen-esis, a dynamic and constant alteration in the membrane lipid composition of Sertoli cells occurs. In several mammalian species, testis meiosis-activating sterol and desmosterol, as well as other cholesterol precursors, accumulate in the testes and spermatozoa. In addition, certain cholesterogenic genes exhibit stage-specific expression patterns during spermato-genesis, including the cytochrome P450 enzyme lanosterol 14α-demethylase. Inconsistency in the patterns of gene expression during spermatogenesis indicates a cell-type specific and complex temporary modulation of lipids and cholesterol, which also implicates the dynamic interactions between Sertoli cells and germ cells. Furthermore, in the female reproductive tract and during epididymal transit, which is a prerequisite for valid fertilization, the modulation of cholesterol occurring in spermatozoal membranes further indicates the functional importance of sterol compounds in spermatogenesis. However, the exact role of cholesterol metabolism in Sertoli cells in sperm production is unknown. The present review article describes the progress made in the research regarding the characteristics of the Sertoli cell, particularly the regulation of its cholesterol metabolism during spermatogenesis.
作者：
Shi J.-F.;Zhang X.-H.;Li M.-X.;She M.-H.;He P.-C.;...
期刊：
中国药理学通报,2017年33(5):637-641 ISSN：1001-1978
作者机构：
[Shi J.-F.; Tian Q.-X.; Li M.-X.] Institute of Cardiovascular Disease, Institute of Pharmaceutical and Biological Sciences, University of South China, Hengyang Hunan, 421001, China;[He P.-C.; She M.-H.] Dept. of Biotechnology, Institute of Pharmaceutical and Biological Sciences, University of South China, Hengyang Hunan, 421001, China;[Zhang X.-H.] Aier Eye Hospital of Hengyang, Hengyang Hunan, 421001, China;[Zhang Y.] First People's Hospital of Changde, Changde Hunan, 415000, China;[Moshe L.] Neurim Pharmaceuticals Ltd., Israel
作者机构：
[Zhengming Li; Xiuping Li] Department of Laboratory, Hunan University of Medicine, Huaihua 418000, China;[Shichang Cai] Basic Medical Sciences, Hunan University of Medicine, Huaihua 418000, China caishichang2008@163.com;[Xiaobo Hu; Weidong Yin] Institute of Cardiovascular Disease, Key Laboratory Arteriosclerology of Hunan Province, University of South China, Hengyang 412000, China;[Sujun Zhang] Department of Experimental Animal, University of South China, Hengyang 412000, China;[Xing Li] Basic Medical Sciences, Hunan University of Medicine, Huaihua 418000, China
通讯机构：
[Shichang Cai *] 2;2 Basic Medical Sciences , Hunan University of Medicine , Huaihua 418000 , China
关键词：
胰岛素抵抗;调控作用;信号通路;2型糖尿病;分泌能力;患病率;高血糖;细胞
摘要：
The prevalence of Type 2 diabetes (T2D) has been globally increased since the last decade. T2D is a condition of relative insulin insufficiency, in which hyperglycemia develops when the insulin secretory capacity of β-cells is no longer sufficient to meet the insulin requirement in the setting of insulin resistance. Previous studies have shown that there is a close correlation between T2D and insulin receptor substrate-1 (IRS-1) levels, and that lack of expression or abnormal phosphorylation of IRS-1 can lead to insulin resistance. Phosphoinositide 3-kinase (PI3K) plays a key role in insulin signaling and its activity has been shown to be blunted in tissues from T2D subjects. PI3K activation is critical for insulin-mediated metabolic effects such as increased glucose uptake and glycogen synthesis. Glycogen synthase kinase-3β (GSK3β), a downstream target of insulin signaling, is activated by phosphorylated (p) Akt. Phosphorylation by p-Akt inhibits the activity of GSK3β. GSK3β phosphorylation and inactivation are considered to be important mechanisms of cell survival. Melatonin (Mel) is a circulating hormone that is predominantly released from the pineal gland. Some studies suggest that Mel may potentially play a role in diabetes and its associated metabolic disturbances by regulating insulin secretion. Luzindole is a nonspecific Mel receptor antagonist that can block some Mel functions. Although Mel has an extensive range of biological effects, studies have revealed that it is rapidly metabolized with a half-life of 20–30 min once it gets ingested in humans. Therefore, the effect of Mel cannot be studied from direct administration of this drug. Moreover, extraction and synthesis of Mel is complicated and a high dose of Mel is associated with side effects. Neu-P11 is a novel type of nonselective agonist of Mel. It has several characteristics including the ease with which it can be synthesized in vitro and administered effectively for a longer time with fewer side effects. It can also substitute for Mel to interact with its receptors and consequently has an extensive range of biological actions.
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.
摘要：
Recombinant immunotoxin HA22, composed of an an-ti-CD22 Fv fragment fused to PE38, a truncated portion of Pseudomonas Exotoxin A (PE), has been developed for targeted treatment of various B-cell malignancies. As a foreign, internalized macromolecule, PE38 often induces lysosomal degradation and neutralizing antibodies to limit the efficacy of treating B-cell malignancies. The region ofPE38 containing lysosomal protease cleavage sites deleted, leaving onlyfiirin processing site. The resulting immunotoxin HA22-LR (lysosome resistant) retains excellent biologic activity and removes immunogenic epitopes as an additional benefit. Another approach for avoiding immunogenicity is to identify B-cell epitopes and remove them by mutagenesis. Previously, to determine B-cell epitopes on PE38, murine Ab as a model, 7 major mouse-specific B-cell epitope groups with 13 subgroups were identified and located through a series of point mutations. Two new mutants, HA22-8X and HA22-LR-8X, were prepared, containing 8 epitope-silenc-ing mutations which greatly reduced immunogenicity in mice. Later, by phage-display assay, human Fvs against PE toxin were isolated and human-specific B-cell epitopes were located by alanine scanning mutagenesis. HA22-LR as a scaffold, HA22-LR-LO10 with 7 point mutations was constructed, has low reactivity with human antisera, yet has high cytotoxic and antitumor activity. In this review, theoretical aspects and experimental evidence for the removal of B-cell epitope is discussed.
作者机构：
[Shi J.-F.] Institute of Cardiovascular Diseases, University of South China, Hengyang Hunan, 421001, China;[She M.-H.; Yang J.] Dept of Biotechnology, Institute of Pharmaceutical and Biological Sciences, University of South China, Hengyang Hunan, 421001, China;[Zhang X.-H.] Aier Eye Hospital, Hengyang Hunan, 421001, China;First People's Hospital of Changde, Changde Hunan, 415003, China;[Moshe L.] Neurim Pharmaceuticals Ltd., Israel
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.
作者：
Li X.-P.;Cai S.-C.;Yin W.-D.;Zhang S.-J.;Lu Q.;...
期刊：
海军军医大学学报,2016年37(9):1184-1186 ISSN：2097-1338
通讯作者：
Cai, S.-C.
作者机构：
[Li X.-P.] College of Laboratory Medicine, Hunan University of Medicine, Huaihua, Hunan 418000, China;[Cai S.-C.; Lu Q.; Li X.] Division of Basic Medical Sciences, Hunan University of Medicine, Huaihua, Hunan 418000, China;[Yin W.-D.] Institute of Cardiovascular Disease, University of South China Medical College, Hengyang, Hunan 412000, China;[Zhang S.-J.] Department of Experimental Animal, University of South China, Hengyang, Hunan 412000, China;[Moshe L.] Neurim Pharmaceuticals Ltd, Tel-Aviv, 69710, Israel
通讯机构：
[Cai, S.-C.] D;Division of Basic Medical Sciences, China
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.
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.
作者机构：
[Li X.-P.; Hu R.] Department of Laboratory, Hunan University of Medicine, Huaihua, Hunan 418000, China;[Li X.; Cai S.-C.] Division of Basic Medical Sciences, Hunan University of Medicine, Huaihua, Hunan 418000, China;[Yin W.-D.] Institute of Cardiovascular Disease, University of South China Medical School, Hengyang, Hunan 412000, China;[Zhang S.-J.] Division of Experimental Animal, University of South China, Hengyang, Hunan 412000, China;[Moshe L.] Neurim Pharmaceuticals Ltd., Tel-Aviv, 69710, Israel
通讯机构：
[Cai, S.-C.] D;Division of Basic Medical Sciences, China
