摘要：
OBJECTIVE: Hypertension is closely associated with profound vascular remodeling, especially proliferation and hyperplasia of vascular smooth muscle cells (VSMCs). Aberrant Wnt5a signaling has been related to vascular diseases, but its role on the proliferation of VSMCs is unclear. The study evaluated the effect of Wnt5a on the proliferation of VSMCs and its possible mechanism. DESIGN AND METHOD: The capability of cell proliferation was detected by the assays of MTT, colony formation and EdU cell proliferation. Flow cytometry detections were applied to evaluate the cell cycle. The expressions of specific proteins were detected by western blotting. Immunofluorescence analysis was utilized to observe the localization of Wnt5a and Ror2. RESULTS: The data show that serum induced proliferation of VSMC in a time-dependent manner, accompanied with a significant decrease of Wnt5a expression. Treatment with recombinant mouse Wnt5a or overexpression of Wnt5a leads to the proliferative inhibition of VSMCs and cell cycle arrest at G0/G1 phase, which related to the down-regulation of CyclinD1 and up-regulation of p53. Whereas knockdown of Wnt5a has an opposite effect. Both of Wnt5a and Ror2 are co-localized in the membrane surface. Additionally, knockdown of Ror2 decreases Wnt5a expression and the phenotype of cell proliferation induced by Wnt5a overexpression are rescued. Moreover, Wnt5a promotes Ror2 expression, which has been shown to specifically interact with the non-canonical Wnt signaling pathway. Therefore, protein kinase C (PKC) signaling was activated by Wnt5a in VSMCs, which was also accompanied with upregulation of p53 and reduction of CyclinD1. A positive feedback loop between Wnt5a and phospho-PKC to regulate CyclinD1 expression was also revealed. Furthermore, knockdown of p53 dramatically increases CyclinD1 expression. CONCLUSIONS: Taken together, Wnt5a exerts its beneficial effects on VSMCs proliferation and vascular remodeling. Wnt5a/Ror2/PKC signaling pathway is involved in suppression of VSMC proliferation by down-regulating and up-regulating the expression of CyclinD1 and p53 respectively.(Figure is included in full-text article.).
通讯机构：
[Qin, Li] H;Hunan Univ Chinese Med, Sch Pharm, 300 Xueshi Rd, Changsha 410208, Hunan, Peoples R China.
关键词：
Long noncoding RNAs;Nuclear receptor;SRA;Transcriptional coactivator
摘要：
Steroid receptor RNA activator (SRA) is a type of long noncoding RNA (lncRNA) which coordinates the functions of various transcription factors, enhances steroid receptor-dependent gene expression, and also serves as a distinct scaffold. The novel, profound and expanded roles of SRA are emerging in critical aspects of coactivation of nuclear receptors (NRs). As a nuclear receptor coactivator, SRA can coactivate androgen receptor (AR), estrogen receptor α (ERα), ERβ, progesterone receptor (PR), glucocorticoid receptor (GR), thyroid hormone receptor and retinoic acid receptor (RAR). Although SRA is one of the least well-understood molecules, increasing studies have revealed that SRA plays a key role in both biological processes, such as myogenesis and steroidogenesis, and pathological changes, including obesity, cardiomyopathy, and tumorigenesis. Furthermore, the SRA-related signaling pathways, such as the mitogen-activated protein kinase (p38 MAPK), Notch and tumor necrosis factor α (TNFα) pathways, play critical roles in the pathogenesis of estrogen-dependent breast cancers. In addition, the most recent data demonstrates that SRA expression may serve as a new prognostic marker in patients with ER-positive breast cancer. Thus, elucidating the molecular mechanisms underlying SRA-mediated functions is important to develop proper novel strategies to target SRA in the diagnosis and treatment of human diseases.
作者机构：
[Dong-qian Yi; Nian Fu; Yang Hu; Ting Cao; Xue-feng Yang; Qing Wu] Department of Digestion Internal Medicine, the Affiliated Nanhua Hospital of University of South China, Hengyang 421000, Hunan, China;[Duan-fang Liao] Department of Pathology, Hunan University of Chinese Medicine, Changsha 410208, China
关键词：
autophagy;hepatic fibrosis;fatty liver;viral hepatitis;liver cancer
摘要：
In recent years, increasingly evidences show that autophagy plays an important role in the pathogenesis and development of liver diseases, and the relationship between them has increasingly become a focus of concern. Autophagy refers to the process through which the impaired organelles, misfolded protein, and intruding microorganisms is degraded by lysosomes to maintain stability inside cells. This article states the effect of autophagy on liver diseases (hepatic fibrosis, fatty liver, viral hepatitis, and liver cancer), which aims to provide a new direction for the treatment of liver diseases.
作者：
Bu, Yiwen;Cai, Guoshuai;Shen, Yi;Huang, Chenfei;Zeng, Xi;...
期刊：
Cancer Letters,2016年383(2):261-271 ISSN：0304-3835
通讯作者：
Cao, Deliang;Liao, Duan-Fang
作者机构：
[Huang, Chenfei; Shen, Yi; Cao, Yu; Bu, Yiwen; Cao, Deliang] Southern Illinois Univ, Sch Med, Simmons Canc Inst, Dept Med Microbiol Immunol & Cell Biol, 913 N Rutledge St, Springfield, IL 62794 USA.;[Cai, Guoshuai] Geisel Sch Med Dartmouth, Dept Genet, Hanover, NH 03755 USA.;[Zeng, Xi] Univ South China, Canc Res Inst, Hengyang 421001, Hunan, Peoples R China.;[Wang, Yuhong; Cao, Deliang; Huang, Dan; Liao, Duan-Fang; Cai, Chuan] 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 Tradit Chinese Med, Div Stem Cell Regulat & Applicat, 1 Xiangzui Rd, Changsha 410208, Hunan, Peoples R China.
通讯机构：
[Cao, Deliang] S;[Liao, Duan-Fang] H;Southern Illinois Univ, Sch Med, Simmons Canc Inst, Dept Med Microbiol Immunol & Cell Biol, 913 N Rutledge St, Springfield, IL 62794 USA.;Hunan Univ Tradit Chinese Med, Div Stem Cell Regulat & Applicat, 1 Xiangzui Rd, Changsha 410208, Hunan, Peoples R China.
关键词：
NF-kappa B RelA/p65;ABCC6;RITA;Chemoresistance
摘要：
Inactivation of p53 occurs frequently in various cancers. RITA is a promising anticancer small molecule that dissociates p53-MDM2 interaction, reactivates p53 and induces exclusive apoptosis in cancer cells, but acquired RITA resistance remains a major drawback. This study found that the site-differential phosphorylation of nuclear factor-kappa B (NF-kappa B) RelA/p65 creates a barcode for RITA chemosensitivity in cancer cells. In naive MCF7 and HCT116 cells where RITA triggered vast apoptosis, phosphorylation of RelA/p65 increased at Ser536, but decreased at Ser276 and Ser468; oppositely, in RITA-resistant cells, RelA/p65 phosphorylation decreased at Ser536, but increased at Ser276 and Ser468. A phosphomimetic mutation at Ser536 (p65/S536D) or silencing of endogenous RelA/p65 resensitized the RITA-resistant cells to RITA while the phosphomimetic mutant at Ser276 (p65/S276D) led to RITA resistance of naive cells. In mouse xenografts, intratumoral delivery of the phosphomimetic p65/S536D mutant increased the antitumor activity of RITA. Furthermore, in the RITA-resistant cells ATP-binding cassette transporter ABCC6 was upregulated, and silencing of ABCC6 expression in these cells restored RITA sensitivity. In the naive cells, ABCC6 delivery led to RITA resistance and blockage of p65/S536D mutant-induced RITA sensitivity. Taken together, these data suggest that the site-differential phosphorylation of RelA/p65 modulates RITA sensitivity in cancer cells, which may provide an avenue to manipulate RITA resistance. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
通讯机构：
[Xia, B.-H.] S;School of Pharmacy, Hunan University of Chinese Medicine, Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Changsha, China
摘要：
Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, effectively reduces plasma cholesterol, but its effect on atherosclerosis is unclear. Foam cell formation has been implicated as a key mediator during the development of atherosclerosis. The purpose of this study was to investigate the effects of ezetimibe on foam cell formation and explore the underlying mechanism. Our results showed that ezetimibe reduced atherosclerotic lesions in apolipoprotein E deficient (apoE-/-) mice by lowering cholesterol levels. Treatment of macrophages with Chol:MβCD resulted in foam cell formation, which was concentration-dependently inhibited by the presence of ezetimibe. Mechanically, ezetimibe treatment downregulated the expression of CD36 and scavenger receptor class B1 (SR-B1), but upregulated the expression of apoE and caveolin-1 in macrophage-derived foam cells, which kept consistent with our microarray results. Moreover, treatment with ezetimibe abrogated the increase of phospho-extracellular signal regulated kinase (ERK) 1/2 and their nuclear accumulation in foam cells. Inhibition of the MAPK pathway by the MEK inhibitor PD98059 attenuated the inhibitory effect of ezetimibe on the expression of p-ERK1/2 and caveolin-1. Taken together, our results showed that ezetimibe suppressed foam cell formation via the caveolin-1/MAPK signaling pathway, suggesting that inhibition of foam cell formation might be a novel mechanism underlying the anti-atherosclerotic effect of ezetimibe. This article is protected by copyright. All rights reserved.
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
