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.
作者机构：
[Zhang, Xianshuo] Anyang Normal Univ, Sch Chem & Chem Engn, Anyang 455000, Henan, Peoples R China.;[Li, Xiaochen; Wei, Hua; Ma, Liwei; Zhang, Xianshuo; Liu, Fangjun; Tian, Yunfei] Lanzhou Univ, State Key Lab Appl Organ Chem, Key Lab Nonferrous Met Chem & Resources Utilizat, Lanzhou 730000, Gansu, Peoples R China.;[Li, Xiaochen; Wei, Hua; Ma, Liwei; Zhang, Xianshuo; Liu, Fangjun; Tian, Yunfei] Lanzhou Univ, Coll Chem & Chem Engn, Lanzhou 730000, Gansu, Peoples R China.;[Wei, Hua; Yu, Cuiyun; Wei, H] Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Hengyang 421001, Peoples R China.;[Wei, Hua; Yu, Cuiyun; Wei, H] Univ South China, Dept Pharm & Pharmacol, Hengyang 421001, Peoples R China.
通讯机构：
[Wei, Hua] L;[Yu, CY; Wei, H] U;Lanzhou Univ, State Key Lab Appl Organ Chem, Key Lab Nonferrous Met Chem & Resources Utilizat, Lanzhou 730000, Gansu, Peoples R China.;Lanzhou Univ, Coll Chem & Chem Engn, Lanzhou 730000, Gansu, Peoples R China.;Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Hengyang 421001, Peoples R China.
摘要：
Crosslinking based on triethoxysilyl-/ trimethoxysilyl functionality has been repeatedly highlighted to be the most frequently used strategy for producing crosslinked organic/ inorganic hybrid nanovehicles with enhanced stability for drug delivery applications. However, the permeability of the developed nanocarriers is another critical characteristic and should be simultaneously manipulated to realize sufficient release of the loaded therapeutic cargo in order to give an efficient therapeutic dose. The mainstream strategy to control the permeability of a hybrid nanocontainer is probably a modulation of its crosslinking degree via controlled living polymerization techniques. However, this strategy governed from a macromolecular level still suffered from limited and unsatisfactorily regulation. To exert more precise engineering of the permeability of the hybrid nanocarriers at a molecular level, a novel reducible silica monomer, 2-((2(methacryloyloxy) ethyl) disulfanyl) ethyl (3-(diethoxymethylsilyl) propyl) carbamate (DESSPMA), with diethoxysilyl groups for in situ crosslinking was designed and synthesized in this study, to produce a lower crosslinking density and greater permeability. In addition to a reducible double-head agent comprising a hydroxyl group and a reversible addition-fragmentation chain transfer (RAFT) agent, a dual reductionsensitive triblock copolymer, poly(e-caprolactone)-SS-poly(DESSPMA)-b-poly(oligoethyleneglycol methacrylate) (PCL-SS-PDESSPMA-b-POEGMA), with disulfide bridges located in both the block junction of the polymer backbone and the side chain containing the crosslinking units was prepared by integrated ring-opening polymerization and RAFT polymerization. Notably, greater drug loading capacity and in vitro cytotoxicity of the DESSPMA-based shell crosslinked micelles relative to those of the 2-((2-(methacryloyloxy) ethyl) disulfanyl) ethyl (3-(triethoxysilyl) propyl) carbamate (TESSPMA)-based analogues were realized, which were attributed to the enhanced permeability because of a lower crosslinking density without compromised micelle stability. Therefore the novel diethoxymethylsilyl-based crosslinking strategy developed herein provides a facile and robust route to engineer organic/ inorganic hybrid nanocarriers with enhanced therapeutic efficacy.
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：
Formaldehyde (FA) is a common environmental contaminant that has toxic effects on the central nervous system (CNS). Our previous data demonstrated that hydrogen sulfide (H2S), the third endogenous gaseous mediator, has protective effects against FA-induced neurotoxicity. As is known to all, Brain-derived neurotropic factor (BDNF), a member of the neurotrophin gene family, mediates its neuroprotective properties via various intracellular signaling pathways triggered by activating the tyrosine kinase receptor B (TrkB). Intriguingly, our previous data have illustrated the upregulatory role of H2S on BDNF protein expression in the hippocampus of rats. Therefore, in this study, we hypothesized that H2S provides neuroprotection against FA toxicity by regulating BDNF-TrkB pathway. In the present study, we found that NaHS, a donor of H2S, upregulated the level of BDNF protein in PC12 cells, and significantly rescued FA-induced downregulation of BDNF levels. Furthermore, we found that pretreatment of PC12 cells with K252a, an inhibitor of the BDNF receptor TrkB, markedly reversed the inhibition of NaHS on FA-induced cytotoxicity and ablated the protective effects of NaHS on FA-induced oxidative stress, including the accumulation of intracellular reactive oxygen species (ROS), 4-hydroxy-2-trans-nonenal (4-HNE), and malondialdehyde (MDA). We also showed that K252a abolished the inhibition of NaHS on FA-induced apoptosis, as well as the activation of caspase-3 in PC12 cells. In addition, K252a reversed the protection of H2S against FA-induced downregulation of Bcl-2 protein expression and upregulation of Bax protein expression in PC12 cells. These data indicate that the BDNF-TrkB pathway mediates the neuroprotection of H2S against FA-induced cytotoxicity, oxidative stress and apoptosis in PC12 cells. These findings provide a novel mechanism underlying the protection of H2S against FA-induced neurotoxicity.
摘要：
The chronic unpredictable mild stress (CUMS) model is a widely used experimental model of depression. Exogenous stress-induced neuronal cell death in the hippocampus is closely associated with the pathogenesis of depression. Excessive and prolonged endoplasmic reticulum (ER) stress triggers cell death. Hydrogen sulfide (H2S), the third endogenous signaling gasotransmitter, plays an important role in brain functions as a neuromodulator and a neuroprotectant. We hypothesized that the disturbance of endogenous H2S generation and ER stress in the hippocampus might be involved in CUMS-induced depression-like behaviors. Thus, the present study focused on whether CUMS disturbs the generation of endogenous H2S and up-regulates ER stress in the hippocampus and whether exogenous H2S prevents CUMS-induced depressive-like behaviors. Results showed that CUMS-treated rats exhibit depression-like behavior and hippocampal ER stress responses including up-regulated levels of glucose-regulated protein 78, CCAAT/enhancer binding protein homologous protein, and cleaved caspase-12 expression, while the endogenous generation of H2S in the hippocampus is suppressed in CUMS-treated rats. Furthermore, exogenous H2S prevents CUMS-induced depression-like behavior. These data indicated that CUMS-induced depression-like behaviors are related to the disturbance of endogenous H2S generation and ER stress in the hippocampus and suggested that endogenous H2S and ER stress are novel treatment targets of depression.
摘要：
Depression is highly prevalent in individuals with diabetes, and depressive symptoms are less responsive to current antidepressant therapies. Oxidative stress plays a major role both in the pathogenesis of diabetes and in major depression and anxiety disorders. Hydrogen sulfide (H2S), the third gaseous mediator, is a novel signaling molecule in the brain that has both antioxidative activity and antidepressant-like and anxiolytic-like effects. We hypothesized that H2S could produce antidepressant-like and anxiolytic-like effects in diabetic patients through its antioxidative effect. To test this hypothesis, we generated streptozotocin (STZ)-induced diabetic rats. We found that H2S alleviated depressive-like behaviors of STZ-induced diabetic rats in the forced swimming and tail suspension tests and reduced their anxiety-like behaviors in the elevated plus maze test. We also found that H2S significantly reduced levels of malondialdehyde and 4-hydroxynonenal and elevated levels of superoxide dismutase and reduced glutathione in the hippocampus of STZ-induced diabetic rats. The results provide evidence for antidepressant-like and anxiolytic-like effects of H2S in STZ-induced diabetic rats and suggest that the therapeutic effects may result from inhibition of hippocampal oxidative stress. These findings suggest that elevating H2S signaling is a potential target for treatment of depressive and anxiety disorders related to diabetes.
摘要：
Corticosterone, one of the glucocorticoids, is toxic to neurons and plays an important role in depressive-like behavior and depression. We previously showed that hydrogen sulfide (H2S), a novel physiological mediator, plays an inhibitory role in depression. However, the mechanism underlying H2S-triggered antidepressant-like role is not clearly known. Brain-derived neurotrophic factor (BDNF), a neurotrophic factor, plays a neuroprotective role that is mediated by its high-affinity tropomysin-related kinase B (TrkB) receptor. In this study, to investigate the underlying mechanism of H2S-induced antidepressant-like role, we explored whether H2S could protect neurons against corticosterone-mediated cyctotoxicity and whether this protective role of H2S was involved in the regulation of BDNF-TrkB pathway. Our data demonstrated that sodium hydrosulfide (NaHS), the donor of H2S, could prevent corticosterone-induced cytotoxicity, apoptosis, accumulation of intracellular reactive oxygen species (ROS) and loss of mitochondrial membrane potential (MMP) in PC12 cells. NaHS not only induced the up-regulation of BDNF but also prevented the down-regulation of BDNF by corticosterone. It was also found that blocking BDNF-TrkB pathway by K252a, an inhibitor of TrkB, abolished the protection of H2S against corticosterone-induced cytotoxicity, apoptosis, accumulation of ROS, and loss of MMP. These results suggest that H2S protects against the neurotoxicity of corticosterone by modulation of the BDNF-TrkB pathway.
摘要：
Aims: This study aims to examine the possible associations between high density lipoprotein (HDL) subclass distribution and APOA5-1131T>C polymorphism in hypertriglyceridemia. Methods: The distribution of HDL subclasses was quantified by 2-dimensional electrophoresis in conjunction with immunodetection method. The APOA5-1131T>C polymorphism was identified in 95 hypertriglyceridemic (HTG) patients and 102 healthy subjects by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Results: The APOA5-1131C (C) allele frequency was higher in the HTG group than in the control group. Plasma triglycerides (TG) were significantly higher and apoA5 was significantly lower in patients with the C allele when compared to patients with the APOA5-1131T (T) allele, even more dramatically so in the APOA5-1131CC homozygote. In both the HTG group and the control group, the frequency of the C allele was positively correlated with levels of TG, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and apolipoprotein B100 (apoB100), and negatively correlated with levels of high density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (apoA1) and apolipoprotein A5 (apoA5) (P < 0.001). In all subjects, the frequency of the C allele was positively correlated with the level of small-sized HDL (pre beta(1)-HDL and HDL3a), and negatively correlated with levels of HDL2a and HDL2b. Conclusion: Changes in HDL subclass distributions in HTG may be related to the APOA5-1131T>C polymorphism. This polymorphism leads to a general shift towards smaller-sized HDL. (c) 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
