通讯机构：
[Tang, Shengsong] H;[Tang, Shengsong] U;Hunan Univ Med, Biomed Res Ctr, Huaihua 418000, Peoples R China.;Univ South China, Inst Pharm & Pharmacol, Dept Histol & Embryol, Hengyang 421001, Peoples R China.
关键词：
Macrophage colony-stimulating factor;chemoresistance;apoptosis;autophagy;breast cancer
摘要：
Macrophage colony-stimulating factor is a vital factor in maintaining the biological function of monocyte–macrophage lineage. It is expressed in many tumor tissues and cancer cells. Recent findings indicate that macrophage colony-stimulating factor might contribute to chemoresistance, but the precise mechanisms are unclear. This study was to explore the effect of macrophage colony-stimulating factor on doxorubicin resistance in MCF-7 breast cancer cells and the possible mechanism. In the study, the human breast cancer cells, MCF-7, were transfected with macrophage colony-stimulating factor. We document that cytoplasmic macrophage colony-stimulating factor induces doxorubicin resistance and inhibits apoptosis in MCF-7 cells. Further studies demonstrated that cytoplasmic macrophage colony-stimulating factor-mediated apoptosis inhibition was dependent on the activation of PI3K/Akt/Survivin pathway. More importantly, we found that macrophage colony-stimulating factor-induced autophagic cell death in doxorubicin-treated MCF-7 cells. Taken together, we show for the first time that macrophage colony-stimulating factor-induced doxorubicin resistance is associated with the changes in cell death response with defective apoptosis and promotion of autophagic cell death.
期刊：
Medical Hypotheses,2016年86:138-142 ISSN：0306-9877
通讯作者：
Liao, Duan-fang
作者机构：
[Zhang, Cai-ping] Univ South China, Coll Med, 28 W Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.;[Liao, Duan-fang; Chen, Jian-xiong; Tuo, Qin-hui] Hunan Univ Chinese Med, State Key Lab Chinese Med Powder & Med Innovat Hu, Div Stem Cell Regulat & Applicat, 300 Xueshi Rd, Changsha 410208, Hunan, Peoples R China.;[Tian, Ying; Zhang, Cai-ping; Zhang, Min] Univ South China, Dept Biochem & Mol Biol, 28 W Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.;[Chen, Jian-xiong] Univ Mississippi, Med Ctr, Dept Pharmacol & Toxicol, University, MS 38677 USA.;[Liao, Duan-fang] Hunan Univ Chinese Med, 1 Xiangzui Rd, Changsha 410208, Hunan, Peoples R China.
通讯机构：
[Liao, Duan-fang] H;Hunan Univ Chinese Med, 1 Xiangzui Rd, Changsha 410208, Hunan, Peoples R China.
摘要：
Low-density lipoprotein cholesterol (LDL-C) is the hall marker for the atherosclerotic cardiovascular disease (ASCVD). It has been shown that over 70% of circulating LDL-C is metabolized through binding and activation of hepatic LDL receptor (LDLR). Genetic LDLR mutations cause hypercholesterolemia in the patients. Therefore, elevation of LDLR levels is beneficial for the treatment of dyslipidemia. LDLR expression is regulated by the SREBP2/PCSK9 pathways. Targeting SREBP2/PCSK9 pathways by statins and human monoclonal PCSK9 antibody has been shown to reduce the progression of ASVCD. Recent studies identified that inducible degrader of LDLR (IDOL) is a novel regulator of LDLR. IDOL is an E3-ubiquitin ligase regulated via liver X receptors (LXRs) binding to the upstream of translation start site of IDOL. IDOL modulates LDLR distribution through ubiquitination and degradation of LDLR in lysosomes. Genome-wide association studies (GWAS) have revealed that the nonsynonymous substitution rs9370867 of IDOL probably contributes to the variability of circulating LDL levels. Recently studies also demonstrated that IDOL influences PCSK9 expression in a LDLR/SREBP2-dependent manner. Based upon these novel findings, we hypothesize that IDOL and PCSK9 would have a synergistic effect on LDLR distribution. Specifically, loss of IDOL increases LDLR distribution in the hepatic cell, and subsequently reduces serum LDL-C levels in dyslipidemic patients. IDOL might be a potential therapeutic target for the treatment of ASCVD. (C) 2015 Elsevier Ltd. All rights reserved.
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.
摘要：
Rationale: Previous studies have shown that apolipoprotein-1 (apoA-1) binding protein (AIBP) is highly associated with the regulation of apoA-1 metabolism, suggesting its role in the treatment of atherosclerosis. However, how AIBP regulates foam cell formation remains largely unexplored. Objective: To investigate the mechanisms underlying AIBP inhibition of foam cell formation from macrophages. Methods and results: THP-1-derived macrophages were incubated without or with apoA-1 and AIBP, followed by assessing the formation of foam cells and the potential mechanisms. Our results showed that AIBP and apoA-1 enhanced cholesterol efflux, altered the levels of cellular free cholesterol and cholesterol ester and prevented lipid accumulation so as to reduce the formation of foam cells. Meanwhile, lack of AIBP 115-123 amino acids resulted in the loss of AIBP binding to apoA-1. Moreover, our chemiluminescent analysis showed that AIBP promoted biotin-labeled apoA-1 binding to macrophages. Besides with AIBP, more apoA-1 bound to ABCA1, a key transporter responsible for cholesterol efflux to apoA-1, as indicated by our co-immunoprecipitation assay. Our results also showed that AIBP did not regulate ABCA1 mRNA expression, but stabilized its protein from CSN2-mediated degradation. Conclusions: AIBP promotes apoA-1 binding to ABCA1 on the cell membrane of macrophages and prevents ABCA1 protein from CSN2-mediated degradation so as to prevent foam cell formation. AIBP 115-123 amino acids is at least partially responsible for its binding to apoA-1. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
摘要：
Macrophage-activating lipopeptide-2 (MALP-2) has been shown to promote the development of atherosclerosis. ATP-binding cassette transporter A1 (ABCA1), a transmembrane protein, plays a critical role in mediating cholesterol export from macrophages to apolipoprotein A-I (apoA-I). However, whether MALP-2 can regulate the expression of ABCA1 is still largely unknown. The aim of this study was to explore the effects of MALP-2 on ABCA1 expression in THP-1 macrophages and the underlying mechanisms. Our results showed that the treatment of cells with MALP-2 decreased ABCA1 level and suppressed cholesterol efflux in both concentration- and time-dependent manners. The contents of intracellular cholesterol were significantly increased in the presence of MALP-2. Moreover, MALP-2-mediated inhibition of ABCA1 expression was abolished by siRNA of either Toll-like receptor 2 (TLR2) or nuclear factor κB (NF-κB). A similar effect was produced by treatment with the NF-κB inhibitor pyrrolidine dithiocarbamate. In addition, MALP-2-induced activation of NF-κB markedly increased zinc finger protein 202 (ZNF202) level, and ZNF202 siRNA impaired the effects of MALP-2 on ABCA1 expression. Taken together, these results suggest that MALP-2 can decrease ABCA1 expression and subsequent cholesterol efflux through activation of the TLR2/NF-κB/ZNF202 signaling pathway in THP-1 macrophages.
作者：
Cui Li-Bao;Yu Xiao-Hua;Jiang Chong-Hui;Tang Ya-Ling;Ouyang Xin-Ping;...
期刊：
生物化学与生物物理进展,2015年42(9):866-876 ISSN：1000-3282
通讯作者：
Tang Chao-Ke
作者机构：
[Ouyang Xin-Ping; Yao Feng; Yu Xiao-Hua; Cui Li-Bao; He Ping-Ping; Tang Chao-Ke; Lu Yun-Cheng; Zhang Min; Tang Ya-Ling] Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Key Lab Atherosclerol Hunan Prov, Inst Cardiovasc Res,Life Sci Res Ctr, Hengyang 421001, Peoples R China.;[Jiang Chong-Hui; Cui Li-Bao] Cent Hosp Hengyang, Dept Pharm, Hengyang 421001, Peoples R China.
通讯机构：
[Tang Chao-Ke] U;Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Key Lab Atherosclerol Hunan Prov, Inst Cardiovasc Res,Life Sci Res Ctr, Hengyang 421001, Peoples R China.
关键词：
ABCA1;ABCG5;ABCG8;Atherosclerosis;HDL-C;Inflammation;Probucol;SR-B I
摘要：
Probucol is a potent hypolipidemic drug that decreases plasma high-density lipoprotein cholesterol (HDL-C) levels but attenuates atherosclerosis. However, the detailed mechanisms are not fully understood. The aim of this study was to explore the molecular mechanisms of the HDL-C-lowering and antiatherogenic effects of probucol. New Zealand white rabbits were randomly divided into normal diet group, normal diet+probucol group, high fat diet (HFD) group and HFD+probucol (HFD+P) group. After 7 weeks of treatments, the extent of the atherosclerotic lesions, hepatic lipid accumulation and plasma levels of triglycerides, total cholesterol, low-density lipoprotein cholesterol and HDL-C were significantly reduced in HFD+P group as compared to HFD group. Probucol effectively inhibited down-regulation of hepatic scavenger receptor class B type I (SR-B I) expression, and ATP-binding cassette (ABC) transporters G5 (ABCG5) and G8 (ABCG8) expression in the liver and small intestine induced by HFD but further promoted HFD-induced reduction in hepatic ABC transporter A1 (ABCA1) expression. In addition, probucol also significantly prevented HFD-induced increases of tumor necrosis factor-alpha, interleukin-1, interleukin-6 and monocyte chemotactic protein-1 levels in the aortic arch and plasma. Thus, our data provide strong evidence that probucol alleviates atherosclerosis through regulating ABCA I, SR-B I, ABCG5 and ABCG8 expression and inhibiting the secretion of proinflammatory cytokines in hypercholesterolemic rabbits.
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：
[Zhang, Min; Liu, Dan; Tang, Chao-ke; Tan, Yu-lin; Lv, Yun-cheng; Li, Liang; He, Ping-ping; Xie, Wei; Tang, Yan-yan; Ouyang, Xin-ping; Yao, Feng] Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan,Prov Life Sci Res Ctr, Hengyang 421001, Hunan, Peoples R China.;[Lv, Yun-cheng; Xie, Wei] Univ South China, Lab Clin Anat, Hengyang 421001, Hunan, Peoples R China.;[Yang, Jing] Univ South China, Dept Endocrinol & Metab, Affiliated Hosp 1, Hengyang 421001, Hunan, Peoples R China.;[Yao, Feng] Univ South China, Dept Lab Anim Sci, Hengyang 421001, Hunan, Peoples R China.;[Cayabyab, Francisco S.] Univ Saskatchewan, Coll Med, Dept Surg, Saskatoon, SK S7N 0W0, Canada.
通讯机构：
[Tang, Chao-ke] U;Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan,Prov Life Sci Res Ctr, Hengyang 421001, Hunan, Peoples R China.
关键词：
ABCA1;Atherosclerosis;Cholesterol efflux;Diosgenin;Macrophage foam cells;Reverse cholesterol transport
摘要：
Rationale: Diosgenin (Dgn), a structural analogue of cholesterol, has been reported to have the hypolipidemic and antiatherogenic properties, but the underlying mechanisms are not fully understood. Given the key roles of macrophages in cholesterol metabolism and atherogenesis, it is critical to investigate macrophage cholesterol efflux and development of atherosclerotic lesion after Dgn treatment. Objective: This study was designed to evaluate the potential effects of Dgn on macrophage cholesterol metabolism and the development of aortic atherosclerosis, and to explore its underlying mechanisms. Methods and Results: Dgn significantly up-regulated the expression of ATP-binding cassette transporter A1 (ABCA1) protein, but didn't affect liver X receptor a levels in foam cells derived from human THP-1 macrophages and mouse peritoneal macrophages (MPMs) as determined by western blotting. The miR-19b levels were markedly down-regulated in Dgn-treated THP-1 macrophages/MPM-derived foam cells. Cholesterol transport assays revealed that treatment with Dgn alone or together with miR-19b inhibitor notably enhanced ABCA1-dependent cholesterol efflux, resulting in the reduced levels of total cholesterol, free cholesterol and cholesterol ester as determined by high-performance liquid chromatography. The fecal H-3-sterol originating from cholesterol-laden MPMs was increased in apolipoprotein E knockout mice treated with Dgn or both Dgn and antagomiR-19b. Treatment with Dgn alone or together with antagomiR-19b elevated plasma high-density lipoprotein levels, but reduced plasma low-density lipoprotein levels. Accordingly, aortic lipid deposition and plaque area were reduced, and collagen content and ABCA1 expression were increased in mice treated with Dgn alone or together with antagomiR-19b. However, miR-19b overexpression abrogated the lipid-lowering and atheroprotective effects induced by Dgn. Conclusion: The present study demonstrates that Dgn enhances ABCA1-dependent cholesterol efflux and inhibits aortic atherosclerosis progression by suppressing macrophage miR-19b expression. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
作者机构：
[L(U) Yun-cheng; TANG Yan-yan; ZHAO Guo-jun; YAO Feng; XIE Wei; OU-YANG Xin-ping; JUAN Peng; ZHANG Min; LIU Dan; TANG Chao-ke] Institute of Cardiovascular Research,Life Science Research Center,University of South China,Hengyang 421001,China;[L(U) Yun-cheng; XIE Wei] Laboratory of Clinical Anatomy,University of South China,Hengyang 421001,China
