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.;[Tian, Ying; Long, Shi-yin; Yang, Hui-xian; Zhang, Cai-ping; Zhang, Min; Liao, DF] 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：
[Zhang, CP; Liao, DF] 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.
期刊：
International braz j urol,2019年45(2):220-228 ISSN：1677-5538
通讯作者：
Cao, Zhaohui
作者机构：
[Cao, Zhaohui; Hu, Xiaobo] Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Hengyang, Peoples R China.;[Hu, Cong; Cao, Zhaohui; Hu, Xiaobo; Long, Shiyin; Zhang, Caiping; Zhang, Min] Univ South China, Sch Pharm & Biosci, Dept Biotechnol, Hengyang, Peoples R China.
通讯机构：
[Cao, Zhaohui] U;Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Hengyang, Peoples R China.
关键词：
ABSTRACT 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. Keywords: Prostatic Neoplasms;Obesity;Stress, Physiological
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 KCI 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 pmol/L) for 4 d, which was accompanied by upregulated expression of SM marker contractile proteins SM22a and SM a-actin. In cultured vascular smooth muscle cells (VSMCs), curcumin (10, 25, 50 µmol/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 Notch 1 and thereby abolished Notchl-inhibited myocardin expression. Knockdown of caveolin-1 or activation of Notch 1 signaling with Jagged 1 (2 pg/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-l-mediated inhibition of Notch 1 activation and Notch 1-mediated repression of myocardin expression. This may represent a novel pathway, through which curcumin protects blood vessels via the beneficial regulation of SM contractility.
作者机构：
Dept of Genetics, Changde Maternal and Child Health-Care Hospital, Changde, Hunan, 415000, China;[张敏; Yu X.-X.; 田英; Duan U.-R.; 龙石银; 麻燕妮; 张彩平] Dept of Biotechnology, University of South China, Hengyang, Hunan, 421001, China;[刘英] Dept of Medicine, Changde Vocational Technical College, Changde, Hunan, 415000, China;[欧露] Dept of Genetics, Changde Maternal and Child Health-Care Hospital, Changde, Hunan, 415000, China, Dept of Biotechnology, University of South China, Hengyang, Hunan, 421001, China
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.
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.;[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 Duan-Fang] 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.
