期刊：
JOURNAL OF MEMBRANE BIOLOGY,2020年253(2):101-108 ISSN：0022-2631
通讯作者：
Long, Shi-yin;Zhang, CP
作者机构：
[Wang, Chu-yao; Long, Shi-yin; Long, SY; Li, Bo-jie; Zhang, Cai-ping; Jiang, Su-su] Univ South China, Dept Biochem & Mol Biol, Med Coll, Hengyang 421001, Hunan, Peoples R China.;[Chen, Hao] Univ South China, Affiliated Hosp 1, Dept Clin Lab, Hengyang 421001, Hunan, Peoples R China.;[Tuo, Qin-hui] Hunan Univ Chinese Med, State Key Lab Chinese Med Powder & Med Innovat Hu, Div Stem Cell Regulat & Applicat, Changsha 410208, Hunan, Peoples R China.;[Liao, Duan-fang] Hunan Univ Chinese Med, State Key Lab Chinese Med Powder & Med Innovat Hu, Changsha 410208, Hunan, Peoples R China.
通讯机构：
[Long, SY; Zhang, CP ] U;Univ South China, Dept Biochem & Mol Biol, Med Coll, Hengyang 421001, Hunan, Peoples R China.
关键词：
KIF16B;Kinesin;Endocytic trafficking;Cholesterol transport
摘要：
As a member of the kinesin-3 family, kinesin family member 16B (KIF16B) has a characteristic PhoX homology (PX) domain that binds to membranes containing phosphatidylinositol-3-phosphate (PI(3)P) and moves along microtubule filaments to the plus end via a process regulated by coiled coils in the stalk region in various cell types. The physiological function of KIF16B supports the transport of intracellular cargo and the formation of endosomal tubules. Ras-related protein (Rab) coordinates many steps of membrane transport and are involved in the regulation of KIF16B-mediated vesicle trafficking. Data obtained from clinical research suggest that KIF16B has a potential effect on the disease processes in intellectual disability, abnormal lipid metabolism, and tumor brain metastasis. In this review, we summarize recent advances in the structural and physiological characteristics of KIF16B as well as diseases associated with KIF16B disorders, and speculating its role as a potential adaptor for intracellular cholesterol trafficking. Graphic
作者机构：
[Yang, Hui-xian] Univ South China, Med Coll, Inst Cardiovasc Dis, 28 Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.;[Liao, Duan-fang; Chen, Jian-xiong; Tuo, Qin-hui] Hunan Univ Chinese Med, Div Stem Cell Regulat & Applicat, State Key Lab Chinese Med Powder & Med Innovat Hu, 300 Xueshi Rd, Changsha 410208, Hunan, Peoples R China.;[Liao, DF; Tian, Ying; Long, Shi-yin; Yang, Hui-xian; Zhang, Cai-ping; Zhang, Min] Univ South China, Med Coll, 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.
通讯机构：
[Liao, DF ; Zhang, CP] U;Univ South China, Med Coll, Dept Biochem & Mol Biol, 28 W Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.
关键词：
Dyslipidemia;IDOL;LDL-C;LDLR;PCSK9;SREBP2
摘要：
The SREBP2/LDLR pathway is sensitive to cholesterol content in the endoplasmic reticulum (ER), while membrane low-density lipoprotein receptor (LDLR) is influenced by sterol response element binding protein 2 (SREBP2), pro-protein convertase subtilisin/kexin type 9 (PCSK9) and inducible degrader of LDLR (IDOL). LDL-C, one of the risk factors in cardiovascular disease, is cleared through endocytosis recycling of LDLR. Therefore, we propose that a balance between LDLR endocytosis recycling and PCSK9-mediated and IDOL-mediated lysosomal LDLR degradation is responsible for cholesterol homeostasis in the ER. For statins that decrease serum LDL-C levels via cholesterol synthesis inhibition, the mechanism by which the statins increase the membrane LDLR may be regulated by cholesterol homeostasis in the ER.
摘要：
Type 2 diabetes mellitus (T2DM) is a chronic degenerative endocrine and metabolic disease with high mortality and morbidity, yet lacks effective therapeutics. We recently generated a novel fusion peptide INSR-IgG4Fc, Yiminsu (YMS), to facilitate the high-affinity binding and transportation of insulin. Thus, the aim of the present study was to determine whether the novel recombinant peptide, YMS, could contribute to restoring insulin sensitivity and glycaemic control in insulin resistance models and revealing its underlying mechanism. Palmitic acid (PA)-treated LO2 cells and high fat diet (HFD)-fed mice were treated with YMS. Therapeutic effects of YMS were measured using Western blotting, ELISA, qPCR, Histology and transmission electron microscopy. We observed that YMS treatment effectively improved insulin signaling in PA-treated LO2 cells and HFD-fed mice. Notably, YMS could significantly reduce serum levels of glucose, triglycerides, fatty acids and cholesterol without affecting the serum insulin levels. Moreover, our data demonstrated that YMS could restore glucose and lipid homeostasis via facilitating insulin transportation and reactivating PI3K/Akt signaling in both PA-treated cells and liver, gastrocnemius and brown fat of HFD-fed mice. Additionally, we noticed that the therapeutic effects of YMS was similar as rosiglitazone, a well-recognized insulin sensitizer. Our findings suggested that YMS is a potentially candidate for pharmacotherapy for metabolic disorders associated with insulin resistance, particularly in T2DM.
摘要：
Obesity is defined as a chronic and excessive growth of adipose tissue. It has been associated with a high risk for development and progression of obesity-associated malignancies, while adipokines may mediate this association. Adiponectin is an adipose tissue-derived adipokines, with significant anti-diabetic, anti-inflammatory, anti-atherosclerotic and anti-proliferative properties. Plasma adiponectin levels are decreased in obese individuals, and this feature is closely correlated with development of several metabolic, immunological and neoplastic diseases. Recent studies have shown that prostate cancer patients have lower serum adiponectin levels and decreased expression of adiponectin receptors in tumor tissues, which suggests plasma adiponectin level is a risk factor for prostate cancer. Furthermore, exogenous adiponectin has exhibited therapeutic potential in animal models. In this review, we focus on the potential role of adiponectin and the underlying mechanism of adiponectin in the development and progression of prostate cancer. Exploring the signaling pathways linking adiponectin with tumorigenesis might provide a potential target for therapy.
摘要：
A variety of cardiovascular diseases is accompanied by the loss of vascular contractility. This study sought to investigate the effects of curcumin, a natural polyphenolic compound present in turmeric, on mouse vascular contractility and the underlying mechanisms. After mice were administered curcumin (100 mg.kg(-1).d(-1), ig) for 6 weeks, the contractile responses of the thoracic aorta to KCl and phenylephrine were significantly enhanced compared with the control group. Furthermore, the contractility of vascular smooth muscle (SM) was significantly enhanced after incubation in curcumin (25 mu mol/L) for 4 d, which was accompanied by upregulated expression of SM marker contractile proteins SM22 alpha and SM alpha-actin. In cultured vascular smooth muscle cells (VSMCs), curcumin (10, 25, 50 mu mol/L) significantly increased the expression of myocardin, a "master regulator" of SM gene expression. Curcumin treatment also significantly increased the levels of caveolin-1 in VSMCs. We found that as a result of the upregulation of caveolin-1, curcumin blocked the activation of Notch1 and thereby abolished Notch1-inhibited myocardin expression. Knockdown of caveolin-1 or activation of Notch1 signaling with Jagged1 (2 mu g/mL) diminished these effects of curcumin in VSMCs. These findings suggest that curcumin induces the expression of myocardin in mouse smooth muscle cells via a variety of mechanisms, including caveolin-1-mediated inhibition of Notch1 activation and Notch1-mediated repression of myocardin expression. This may represent a novel pathway, through which curcumin protects blood vessels via the beneficial regulation of SM contractility.
期刊：
Medical Hypotheses,2016年86:138-142 ISSN：0306-9877
通讯作者：
Liao, DF
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, DF] Hunan Univ Chinese Med, 1 Xiangzui Rd, Changsha 410208, Hunan, Peoples R China.
通讯机构：
[Liao, DF ] H;Hunan Univ Chinese Med, 1 Xiangzui Rd, Changsha 410208, Hunan, Peoples R China.
关键词：
atorvastatin;ESCRT protein;ezetimibe;hydroxymethylglutaryl coenzyme A reductase inhibitor;inducible degrader of low density lipoprotein receptor;kexin;liver X receptor;low density lipoprotein cholesterol;low density lipoprotein receptor;peptidase;proprotein convertase subtilisin kexin 9;rosuvastatin;serine proteinase;sterol regulatory element binding protein 2;ubiquitin protein ligase E3;ubiquitin specific peptidase 8;unclassified drug;antilipemic agent;low density lipoprotein receptor;MYLIP protein, human;ubiquitin protein ligase;Article;atherogenesis;cell surface;cholesterol blood level;coronary artery atherosclerosis;dyslipidemia;familial hypercholesterolemia;genetic association;Han Chinese;human;hyperlipidemia;lipid metabolism;multivesicular body;nonhuman;protein localization;protein targeting;single nucleotide polymorphism;biological model;drug effects;Dyslipidemias;metabolism;Dyslipidemias;Humans;Hypolipidemic Agents;Models, Biological;Receptors, LDL;Ubiquitin-Protein Ligases
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.
期刊：
Biochemical and Biophysical Research Communications,2016年480(1):139-145 ISSN：0006-291X
通讯作者：
Chen, Jianxiong;Tuo, QH
作者机构：
[Xu, Guina; Sun, Shaowei; Wen, Juan; Xiong, Guozuo; Li, Tianping; Zhang, Caiping] Univ South China, Inst Pharm & Pharmacol, Sch Life Sci & Technol, Hengyang 421001, Hunan, Peoples R China.;[Chen, Jianxiong; Chen, JX; Sun, Shaowei; Tuo, Qinhui; Qiu, Fei; Nie, Juan; Liao, Duangfang] Hunan Univ Chinese Med, Sch Med, 300 Xueshi Rd, Changsha 410208, Hunan, Peoples R China.;[Yin, Yufang] Southern Illinois Univ, Dept Pharmacol, Sch Med, Springfield, IL 62702 USA.;[Chen, Jianxiong] Univ Mississippi, Med Ctr, Dept Pharmacol & Toxicol, Jackson, MS 39216 USA.
通讯机构：
[Chen, JX; Tuo, QH ] H;Hunan Univ Chinese Med, Sch Med, 300 Xueshi Rd, Changsha 410208, Hunan, Peoples R China.
关键词：
*Androgen receptor;*Cholesterol;*Fas death domain-associated protein;*SCAP;*SREBP
摘要：
Daxx is a highly conserved nuclear transcriptional factor, which has been implicated in many nuclear processes including transcription and cell cycle regulation. Our previous study demonstrated Daxx also plays a role in regulation of intracellular cholesterol content. Daxx contains several domains that are essential for interaction with a growing number of proteins. To delineate the underlying mechanism of hypocholesterolemic activity of Daxx, we constructed a set of plasmids which can be used to overexpress different fragments of Daxx and transfected to HepG2 cells. We found that the C-terminal region Daxx626-740 clearly reduced intracellular cholesterol levels and inhibited the expression of SREBPs and SCAR. In GST pull-down experiments and Double immunofluorescence assays, Daxx626-740 was demonstrated to bind directly to androgen receptor (AR). Our findings suggest that the interaction of Daxx626-740 and AR abolishes the AR-mediated activation of SCAP/SREBPs pathway, which suppresses the de novo cholesterol synthesis. Thus, C-terminal domain of Daxx acts as a potential regulator of intracellular cholesterol content in HepG2 cells. (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：
[孙四玉; 邱飞; 杨冬梅] School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China;[阳巍; 张彩平; 熊国祚] Institute of Pharmacy and Pharmacology, University of South China, Hengyang Hunan, 421001, China;[陈剑雄] Integrative Heart and Brain Disease Prevention and Control Laboratory, Hunan University of Chinese Medicine, Changsha, 410208, China;School of Medicine, Hunan University of Chinese Medicine, Changsha, 410208, China;[庹勤慧] Institute of Pharmacy and Pharmacology, University of South China, Hengyang Hunan, 421001, China, School of Medicine, Hunan University of Chinese Medicine, Changsha, 410208, China
作者机构：
[Zhang Cai-Ping] Univ South China, Coll Med, Hengyang 421001, Peoples R China.;[Liao, DF; Lin Li-Mei; Tuo Qin-Hui; Sun Shao-Wei; Gong Yong-Zhen; Liao Duan-Fang] Hunan Univ Chinese Med, State Key Lab Chinese Med Powder & Med Innovat Hu, Div Stem Cell Regulat & Applicat, Changsha 410205, Hunan, Peoples R China.;[Zhang Cai-Ping; Zheng Xing; Sun Shao-Wei; Ou Lu; Lei Xiao-Yong] Univ South China, Coll Pharm & Biol Sci, Hengyang 421001, Peoples R China.;[Tuo Qin-Hui; Gong Yong-Zhen; Liao Duan-Fang] Hunan Univ China, Sinoluxembourg Cooperat Res Ctr Chinese Med, Med, Changsha 410208, Hunan, Peoples R China.
通讯机构：
[Liao, DF ] H;Hunan Univ Chinese Med, State Key Lab Chinese Med Powder & Med Innovat Hu, Div Stem Cell Regulat & Applicat, Changsha 410205, Hunan, Peoples R China.
