通讯机构：
[Yin, WD; Tang, CK] U;Univ South China, Inst Cardiovasc Res, Hengyang 421001, Hunan, Peoples R China.
关键词：
MALAT1, miR-141-3p/200a-3p, CCDC80, LPL
摘要：
OBJECTIVE: Our previous study showed that Coiled-Coil Domain Containing 80 (CCDC80) accelerates the development of atherosclerosis by decreasing lipoprotein lipase (LPL) expression and activity in apoE knockout mice. However, the regulatory mechanism for CCDC80 expression is unclear. This study was designed to evaluate whether non-coding RNAs involved the regulation of CCDC80 expression in vascular smooth muscle cells (VSMCs). METHODS AND RESULTS: Bioinformatics prediction and luciferase reporter gene results showed that miR-141-3p/200a-3p bound to the 3'UTR of CCDC80. Further, miR-141-3p/200a-3p mimics decreased the expression of CCDC80 but increased LPL expression. Opposite results were observed with miR-141-3p/200a-3p inhibitors. We also found that lncRNA metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) interacted with the sequences of miR-141-3p/200a-3p and decreased their expression. RT-qPCR and western blotting results showed that MALAT1 overexpression increased CCDC80 expression and decreased LPL expression, while MALAT1 knockdown displayed an opposite phenotype. The effects of both MALAT1 overexpression and knockdown were blocked by miR-141-3p/200a-3p mimics or inhibitors. CONCLUSIONS: Thus, we demonstrated that lncRNA MALAT1 regulates CCDC80 and LPL expression through miR-141-3p/200a-3p.
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.
摘要：
BACKGROUND AND AIMS: Kruppel-like factor 14 (KLF14) is known to play a role in atherosclerosis, but the underlying mechanisms are still largely unknown. The aim of our study was to explore the effects of KLF14 on lipid metabolism and inflammatory response, providing a potential target for lowering the risk of atherosclerosis-causing disease. METHODS AND RESULTS: mRNA and protein levels of KLF14 were significantly decreased in oxidized low-density lipoprotein (oxLDL)-treated macrophages and in the atherosclerotic lesion area. Chromatin immunoprecipitation (ChIP) and luciferase reporter gene assays were used to confirm that KLF14 positively regulated miR-27a expression by binding to its promoter. We also found that KLF14 could restored appropriate cellular lipid homeostasis and inflammatory responses via negatively regulating lipoprotein lipase (LPL) expression in THP1-derived macrophages through miR-27a. In addition, gypenosides (GP), a KLF14 activator, delayed the development of atherosclerosis in apolipoprotein E deficient (apoE(-/-)) mice. CONCLUSIONS: KLF14 plays an antiatherogenic role via the miR-27a-dependent down-regulation of LPL and subsequent inhibition of proinflammatory cytokine secretion and lipid accumulation.
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
摘要：
The Krüppel-like factor (KLF) family, as the SP/XKLF transcription factors, plays important roles in regulating the expression of genes required for the proper execution of important biological and pathological processes. Recent studies have demonstrated that KLF14, a member of the KLF family, participates in the initiation and progression of atherosclerotic cardiovascular disease (CVD). From the molecular function aspect, this review focuses on the impact of KLF14-mediated regulation in major atherosclerosis-related diseases and pathological processes, such as insulin resistance, type 2 diabetes, dyslipidemia, inflammation, obesity, metabolic syndrome, cell proliferation and differentiation. This review was designed to help understand the roles of KLF14 in the pathogenesis of atherosclerosis and define KLF14 as a potential disease biomarker and a novel therapeutic target in CVD.
作者机构：
[Zhengming Li; Xiuping Li] Department of Laboratory, Hunan University of Medicine, Huaihua 418000, China;[Xing Li] Basic Medical Sciences, Hunan University of Medicine, Huaihua 418000, China;[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;[Moshe Laudon] Neurim Pharmaceuticals Ltd., Tel-Aviv 69710, Israel
通讯机构：
[Cai, S.] B;Basic Medical Sciences, Hunan University of Medicine, Huaihua, 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.
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：
Recombinant immunotoxin HA22, composed of an anti-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 of PE38 containing lysosomal protease cleavage sites deleted, leaving only furin 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-silencing 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-L010 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.
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.
作者机构：
College of Laboratory Medicine, Hunan University of Medicine, Huaihua, Hunan 418000, China;Division of Basic Medical Sciences, Hunan University of Medicine, Huaihua, Hunan 418000, China;Institute of Cardiovascular Disease, University of South China Medical College, Hengyang, Hunan 412000, China;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, Hunan University of Medicine, Huaihua, Hunan, China
作者：
Su, Zehong;Lian, Gaojian;Mawatari, Kazuaki;Tang, Ping;He, Shuya;...
期刊：
Photochemistry and Photobiology,2015年91(5):1165-1172 ISSN：0031-8655
通讯作者：
Yin, Weidong
作者机构：
[He, Shuya; Lian, Gaojian; Su, Zehong; Tang, Ping; Yin, Weidong] Univ South China, Sch Pharmacol & Life Sci & Technol, Dept Biotechnol, Hengyang, Peoples R China.;[Mawatari, Kazuaki; Su, Zehong; Takahashi, Akira; Shimohata, Takaaki] Univ Tokushima, Grad Sch, Inst Hlth Biosci, Dept Prevent Environm & Nutr, Tokushima 770, Japan.;[Wu, Yimou] Univ South China, Dept Microbiol & Immunol, Hengyang, Peoples R China.
通讯机构：
[Yin, Weidong] U;Univ South China, Sch Pharmacol & Life Sci & Technol, Dept Biotechnol, Hengyang, Peoples R China.
摘要：
Photoreactivation is an error‐free mechanism of DNA repair, utilized by prokaryotes and most eukaryotes and is catalyzed by specific enzymes called DNA photolyases. Photoreactivation has been reported in Vibrio parahaemolyticus WP28; however, information on photolyases in V. parahaemolyticus (V.p) strains has not been reported. This study examined the photoreactivation in V.p RIMD2210633. The photolyase responsible for repairing cyclobutane pyrimidine dimer (CPD) in DNA was identified, and the corresponding gene was determined as VPA1471. The protein was overexpressed in Escherichia coli and was purified for functional assessment in vitro. The mRNA level and protein expression level of this gene increased after ultraviolet A (UVA) illumination following ultraviolet C (UVC) irradiation. In vitro experiments confirmed that the protein encoded by VPA1471 could reduce the quantity of CPD in DNA. We designated the corresponding gene and protein of VPA1471 phr and Phr, respectively, although the function of two other photolyase/cryptochrome family members, VPA0203 and VPA0204, remains unclear. UV (ultraviolet) irradiation experiments suggest that these two genes possess some photorepairing ability. Therefore, we hypothesize that VPA0203 and VPA0204 encode (6‐4) photolyase in V. parahaemolyticus RIMD2210633. Vibrio parahaemolyticus possesses the photoreactivation ability when it utilizes blue light as energy. However, ΔVPA1471 abolished this capacity completely, whereas complementation of VPA1417 could make this ability recover partly. Some cells of UVC radiated VPA0203 KO and VPA0204 KO strains recovered by the following UVA illumination.
作者机构：
Department of Laboratory, Hunan University of Medicine, Huaihua, Hunan 418000, China;Division of Basic Medical Sciences, Hunan University of Medicine, Huaihua, Hunan 418000, China;Institute of Cardiovascular Disease, University of South China Medical School, Hengyang, Hunan 412000, China;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, Hunan University of Medicine, Huaihua, Hunan, China
