摘要:
Retinoid-related orphan receptor alpha (RORalpha) is involved in tumor development. However, the mechanisms underlying RORalpha inhibiting epithelial-to-mesenchymal transition (EMT) and invasion are poorly understood in gastric cancer (GC). This study revealed that the decreased expression of RORalpha is associated with GC development, progression, and prognosis. RORalpha suppressed cell proliferation, EMT, and invasion in GC cells through inhibition of the Wnt/beta-catenin pathway. RORalpha overexpression resulted in the decreased Wnt1 expression and the increased RORalpha interaction with beta-catenin, which could lead to the decreased intranuclear beta-catenin and p-beta-catenin levels, concomitant with downregulated T-cell factor-4 (TCF-4) expression and the promoter activity of c-Myc. The inhibition of Wnt/beta-catenin pathway was coupled with the reduced expression of Axin, c-Myc, and c-Jun. RORalpha downregulated vimentin and Snail and upregulated E-cadherin protein levels in vitro and in vivo. Inversely, knockdown of RORalpha attenuated its inhibitory effects on Wnt/beta-catenin pathway and its downstream gene expression, facilitating cell proliferation, EMT, migration, and invasion in GC cells. Therefore, RORalpha could play a crucial role in repressing GC cell proliferation, EMT, and invasion via downregulating Wnt/beta-catenin pathway.
作者机构:
[Dong Zhongyi; Liu, Li; Li, Wenwen; Sun, Qingcan; Hou, Jin-Lin; Wu, Dehua; Song, Yang; Hou, JL; Liu, L; Xiao, Lushan; Cao, Hui-Chuan; Zhou, Zixiao; Sun, Jingyuan] Southern Med Univ, Nan Fang Hosp, State Key Lab Organ Failure Res, Guangzhou 510515, Guangdong, Peoples R China.;[Liu, Li; Li, Wenwen; Sun, Qingcan; Hou, Jin-Lin; Song, Yang; Hou, JL; Liu, L; Xiao, Lushan; Zhou, Zixiao] Southern Med Univ, Nan Fang Hosp, Guangdong Prov Key Lab Viral Hepatitis Res, Guangzhou 510515, Guangdong, Peoples R China.;[Liu, Li; Li, Wenwen; Zhu, Hongbo; Sun, Qingcan; Hou, Jin-Lin; Song, Yang; Hou, JL; Liu, L; Xiao, Lushan; Zhou, Zixiao] Southern Med Univ, Nan Fang Hosp, Dept Infect Dis, Guangzhou 510515, Guangdong, Peoples R China.;[Dong Zhongyi; Wu, Dehua; Cao, Hui-Chuan; Sun, Jingyuan] Southern Med Univ, Nan Fang Hosp, Dept Radiat Oncol, Guangzhou 510515, Guangdong, Peoples R China.;[Peng, Jie] Guizhou Med Univ, Affiliated Hosp 2, Dept Oncol, Kaili, Peoples R China.
通讯机构:
[Hou, JL; Liu, L] S;Southern Med Univ, Nan Fang Hosp, State Key Lab Organ Failure Res, Guangzhou 510515, Guangdong, Peoples R China.;Southern Med Univ, Nan Fang Hosp, Guangdong Prov Key Lab Viral Hepatitis Res, Guangzhou 510515, Guangdong, Peoples R China.;Southern Med Univ, Nan Fang Hosp, Dept Infect Dis, Guangzhou 510515, Guangdong, Peoples R China.
关键词:
CBX8;HCC;HCC proliferation;YBX1;cyclin D1
摘要:
Polycomb group (PcG) proteins have recently been identified as critical regulators in tumor initiation and development. However, the function of CBX8 in human hepatocellular carcinoma (HCC) remains largely unknown. Our study was designed to explore the biological function and clinical implication of CBX8 in HCC. We investigated the interplay between CBX8 and cell cycle through Gene Set Enrichment Analysis and western blotting. Bioinformatics tools and co-immunoprecipitation were used to explore cell cycle regulation. Finally, we studied the expression and clinical significance of CBX8 in HCC through 3 independent datasets. CBX8 was upregulated in HCC and its expression correlated with cell cycle progression. CyclinD1 was downregulated by CBX8 knockdown but upregulated by CBX8 overexpression. YBX1 interacted with CBX8 and regulated the cell cycle. Moreover, targeting YBX1 with specific siRNA impaired CBX8-mediated regulation of CyclinD1. CBX8 overexpression boosted HCC cell growth, while CBX8 knockdown suppressed cell proliferation. Further, YBX1 interacted with CBX8. YBX1 knockdown compromised the proliferation of CBX8 overexpressing cells. CBX8 promotes HCC cell proliferation through YBX1 mediated cell cycle progression and is related to poor HCC prognoses. Therefore, CBX8 may serve as a potential target for the diagnosis and treatment of HCC.
作者机构:
[Cen, Lian; Yu, Xu-Dong; Tian, Shao-Wen; Yu, XD] Univ South China, Hengyang Med Coll, Dept Physiol, Hengyang 421001, Hunan, Peoples R China.;[Xiao, Zhi-Yong] Univ South China, Dept Anesthesiol, Affiliated Hosp 1, Hengyang 421001, Hunan, Peoples R China.
通讯机构:
[Tian, SW; Yu, XD] U;Univ South China, Hengyang Med Coll, Dept Physiol, Hengyang 421001, Hunan, Peoples R China.
关键词:
GLT1;Glutamate;Astrocyte;Learning;Memory
摘要:
Glutamate transporter GLT1 mediates glutamate uptake, and maintains glutamate homeostasis in the synaptic cleft. Previous studies suggest that blockade of glutamate uptake affects synaptic transmission and plasticity. However, the effect of GLT1 blockade on learning and memory still receives little attention. In the present study, we examined the effect of unilateral intracerebroventricular injection of dihydrokainic acid (DHK), a GLT-1 inhibitor, on novel object recognition (NOR) memory performance. The NOR task involved three sessions including habituation, sampling and test. In experiment 1, DHK injection 0.5 h pre-sampling impaired short-term NOR memory performance. In experiment 2, DHK injection 0.5 h pre-sampling impaired long-term NOR memory acquisition. In experiment 3, DHK injection immediately but not 6h post-sampling impaired long-term NOR memory consolidation. In experiment 4, DHK injection 0.5 h pre-test impaired long-term NOR memory retrieval. Furthermore, DHK-induced memory performance impairment was not due to its effects on nonspecific responses such as locomotor activity and exploratory behavior. The current findings further extend previous studies on the effects of disruption of glutamate homeostasis on learning and memory.
通讯机构:
[Fu, Mingui] U;Univ Missouri, Sch Med, Dept Biomed Sci, 2411 Holmes St, Kansas City, MO 64108 USA.;Univ Missouri, Sch Med, Shock Trauma Res Ctr, 2411 Holmes St, Kansas City, MO 64108 USA.
关键词:
Endothelial activation;Inhibitors of MALT1;VCAM-1;MCPIP1, vascular inflammation
摘要:
Mucosa associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is not only an intracellular signaling scaffold protein but also a paracaspase that plays a key role in the signal transduction and cellular activation of lymphocytes and macrophages. However, its role in endothelial cells remains unknown. Here we report that pharmacological inhibition of MALT1 protease activity strongly suppresses endothelial activation via enhancing MCPIP1 expression. Treatment with MALT1 protease inhibitors selectively inhibited TNFα-induced VCAM-1 expression in HUVECs and LPS-induced VCAM-1 expression in mice. In addition, Inhibition of MALT1 protease activity also significantly inhibited TNFα-induced adhesion of THP-1 monocytic cells to HUVECs. To explore the mechanisms, MALT1 inhibitors does not affect the activation of NF-κB signaling pathway in HUVEC. However, they can stabilize MCPIP1 protein and significantly enhance MCPIP1 protein level in endothelial cells. These results suggest that MALT1 paracaspase also targets MCPIP1 and degrade MCPIP1 protein in endothelial cells similar as it does in immune cells. Taken together, the study suggest inhibition of MALT1 protease activity may represent a new strategy for prevention/therapy of vascular inflammatory diseases such as atherosclerosis.
摘要:
Hyperglycemia‐induced neurotoxicity involves in the pathogenesis of diabetic encephalopathy and neuronal senescence is one of the worst effects of hyperglycemic neurotoxicity. Cannabinoid receptor type 1 (CB1) has neuroprotective function in a series of neuropathy. Spermidine (Spd) has anti‐aging function in many tissues. However, the role of Spd in hyperglycemia‐induced neuronal senescence remains unexplored. Therefore, we used high glucose (HG)‐treated HT‐22 cell as vitro model to investigate whether Spd protects neurons against hyperglycemia‐induced senescence and the mediatory role of CB1 receptor. The HT‐22 cells were cultured in HG condition in the presence of different dose of Spd. Then, the viability of cells was measured by Cell Counting Kit‐8 (CCK‐8) assay. The senescence of cells was detected by Senescence‐associated β‐galactosidase (SA‐β‐Gal) staining. The expressions of P16INK4a, p21CIP¹ and CB1 receptor were measured by Western blot. We found that Spd inhibited HG‐induced neurotoxicity (the loss of cell viability) and senescence (the increase of SA‐β‐Gal positive cells, the upregulation of P16INK4a and p21CIP¹) in HT‐22 cells. Also, Spd prevented the HG‐induced the downregulation of CB1 receptor in HT‐22 cells. Furthermore, we demonstrated that AM251 (a specific inhibitor of the CB1 receptor) reversed the protective effects of Spd on HG‐induced neurotoxicity and senescence. These results indicated that Spd prevents HG‐induced neurotoxicity and senescence via the upregulation of CB1 receptor. Our findings provide a promising future of Spd‐based preventions and therapies for diabetic encephalopathy. This article is protected by copyright. All rights reserved.
作者机构:
[Wang, Ai-Ping; Wei, Hai-Jun; Wang, Chun-Yan; Li, Man-Hong; Tang, Xiao-Qing; Zou, Wei; Li, Xiang; Tang, Yi-Yun; Zhang, Ping] Univ South China, Inst Neurosci, Med Coll, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Hengyang 421001, Hunan, Peoples R China.;[Wei, Hai-Jun; Tang, Xiao-Qing; Tang, Yi-Yun] Univ South China, Dept Physiol, Med Coll, 28 W Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.;[Wang, Ai-Ping] Univ South China, Dept Anat, Med Coll, Hengyang 421001, Hunan, Peoples R China.;[Li, Man-Hong; Tang, Xiao-Qing; Zou, Wei; Zhang, Ping] Univ South China, Nanhua Affiliated Hosp, Dept Neurol, 336 E Dongfeng Rd, Hengyang 421001, Hunan, Peoples R China.;[Li, Xiang] Univ South China, Dept Anaesthesiol, Affiliated Hosp 1, Hengyang 421001, Hunan, Peoples R China.
通讯机构:
[Tang, Xiao-Qing; Zou, Wei] U;Univ South China, Dept Physiol, Med Coll, 28 W Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Nanhua Affiliated Hosp, Dept Neurol, 336 E Dongfeng Rd, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Inst Neurosci, Med Coll, 28 W Changsheng Rd, Hengyang, Hunan, Peoples R China.
关键词:
Hydrogen sulfide;Homocysteine;Silent mating type information regulation 2 homolog 1;Endoplasmic reticulum stress;Cognitive dysfunction
摘要:
Homocysteine (Hcy) causes cognitive deficits and hippocampal endoplasmic reticulum (ER) stress. Our previous study has confirmed that Hydrogen sulfide (H2S) attenuates Hcy-induced cognitive dysfunction and hippocampal ER stress. Silent information regulator 1 (Sirt-1) is indispensable in the formation of learning and memory. Therefore, the aim of this study was to explore the role of Sirt-1 in the protective effect of H2S against Hcy-induced cognitive dysfunction. We found that NaHS (a donor of H2S) markedly up-regulated the expression of Sirt-1 in the hippocampus of Hcy-exposed rats. Sirtinol, a specific inhibitor of Sirt-1, reversed the improving role of NaHS in the cognitive function of Hcy-exposed rats, as evidenced by that sirtinol increased the escape latency and the swim distance in the acquisition trial of morris water maze (MWM) test, decreased the times crossed through and the time spent in the target quadrant in the probe trail of MWM test, and reduced the discrimination index in the novel object recognition test (NORT) in the rats cotreated with NaHS and Hcy. We also found that sirtinol reversed the protection of NaHS against Hcy-induced hippocampal ER-stress, as evidenced by up-regulating the expressions of GRP78, CHOP, and cleaved caspase-12 in the hippocampus of rats cotreated with NaHS and Hcy. These results suggested the contribution of upregulation of hippocampal Sirt-1 to the improving role of H2S in the cognitive function of Hcy-exposed rats, which involves suppression of hippocampal ER stress. Our finding provides a new insight into the mechanism underlying the inhibitory role of H2S in Hcy-induced cognitive dysfunction.
摘要:
The peptide apelin and its receptor APJ are found to express in multiple brain regions, especially in the regions such as the hippocampus and hypothalamus that play important roles in stress and depression. The distribution of apelin and APJ suggests that the apelinergic signaling may be a key mediator in the development of stress-related depressive behavior. We recently demonstrated that intracerebroventricular (i.c.v) injection of apelin-13 exerts an antidepressant-like activity in the rat forced swimming test (FST). However, the possible brain region mediating apelin-13's antidepressant-like activity remains unclear. In the present study, we determined whether the hippocampus and hypothalamus are the possible regions mediating antidepressant-like activity of apelin-13. We found that forced swimming exposure upregulated apelin and APJ protein expression levels in the hippocampus but not hypothalamus in rats. Further, intrahippocampal injection of apelin-13 exerted an antidepressant-like activity (as indicated by a decreased immobility behavior), and intrahippocampal infusion of APJ receptor antagonist F13A blocked the antidepressant-like activity produced by i.c.v injection of apelin-13 in the FST. Moreover, intrahypothalamic injection of apelin-13 did not affect the immobility behavior in the FST. These findings suggest that the hippocampus, but not hypothalamus, is a critical site mediating antidepressant-like activity of apelin-13 in rats. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.
摘要:
The Sertoli cell, which is the supporting cell of spermatogenesis, has an important role in the endocrine and paracrine control of spermatogenesis. Functionally, it provides the cells of the seminiferous epithelium with nutrition, conveys mature spermatids to the lumen of seminiferous tubules, secretes androgen-binding protein and interacts with endocrine Leydig cells. In addition, the levels of cholesterol, as well as its intermediates, vary greatly between nongonadal tissues and the male reproductive system. Throughout spermatogen-esis, a dynamic and constant alteration in the membrane lipid composition of Sertoli cells occurs. In several mammalian species, testis meiosis-activating sterol and desmosterol, as well as other cholesterol precursors, accumulate in the testes and spermatozoa. In addition, certain cholesterogenic genes exhibit stage-specific expression patterns during spermato-genesis, including the cytochrome P450 enzyme lanosterol 14α-demethylase. Inconsistency in the patterns of gene expression during spermatogenesis indicates a cell-type specific and complex temporary modulation of lipids and cholesterol, which also implicates the dynamic interactions between Sertoli cells and germ cells. Furthermore, in the female reproductive tract and during epididymal transit, which is a prerequisite for valid fertilization, the modulation of cholesterol occurring in spermatozoal membranes further indicates the functional importance of sterol compounds in spermatogenesis. However, the exact role of cholesterol metabolism in Sertoli cells in sperm production is unknown. The present review article describes the progress made in the research regarding the characteristics of the Sertoli cell, particularly the regulation of its cholesterol metabolism during spermatogenesis.
摘要:
Perivascular adipose tissue (PVAT), the adipose tissue that surrounds most of the vasculature, has emerged as an active component of the blood vessel wall regulating vascular homeostasis and affecting the pathogenesis of atherosclerosis. Although PVAT characteristics resemble both brown and white adipose tissues, recent evidence suggests that PVAT develops from its own distinct precursors implying a closer link between PVAT and vascular system. Under physiological conditions, PVAT has potent anti-atherogenic properties mediated by its ability to secrete various biologically active factors that induce non-shivering thermogenesis and metabolize fatty acids. In contrast, under pathological conditions (mainly obesity), PVAT becomes dysfunctional, loses its thermogenic capacity and secretes pro-inflammatory adipokines that induce endothelial dysfunction and infiltration of inflammatory cells, promoting atherosclerosis development. Since PVAT plays crucial roles in regulating key steps of atherosclerosis development, it may constitute a novel therapeutic target for the prevention and treatment of atherosclerosis. Here, we review the current literature regarding the roles of PVAT in the pathogenesis of atherosclerosis.
摘要:
OBJECTIVE: To compare dorsal penile nerve block (DPNB) and eutectic mixture of local anesthetics (EMLA) cream for pain relief in infants during circumcision. METHODS: We systematically searched Medline via PubMed, Embase, CNKI and the Cochrane Library Center Register to identify randomized controlled trials up to March 2018. Effect estimates were performed in random effect models. Mean neonate infant pain scale (NIPS) scores, incidence of hematoma, edema and erythema, mean heart rate were conducted to assessed the effect of analgesia. We found that the EMLA had significantly higher pain scores compared to DPNB (SMD = 3.72, 95% CI 1.27-6.17, P = 0.003). In DPNB group, the incidence of hematoma was significantly higher than EMLA group, OR = 0.03, 95% CI 0.00-0.24, P = 0.001. The analysis did not show any significant differences in mean heart rate and the risk of edema and erythema between EMLA and DPNB group (SMD = 21.71, 95% CI = -0.88-44.30, P = 0.06 & OR = 0.40, 95% CI 0.15-1.07, P = 0.07 & OR = 7.33, 95% CI 0.84-64.07, P = 0.07). CONCLUSION: Based on the pooled results from the included studies, we found that DPNB was significantly more effective in pain relief as indicated by mean NIPS score than EMLA in infants during circumcision. However, use of DPNB significantly increased the risk of hematoma.
摘要:
In the present study, the interaction of proteins in the microenvironment of gastric mucosal atypical hyperplasia was analyzed. The stromata of normal gastric mucosa (NGM) and gastric mucosal atypical hyperplasia (GMAH) tissues were purified with laser capture microdissection (LCM). The differentially expressed GMAH proteins of the NGM and GMAH tissues were identified by quantitative proteomic techniques with isotope labeling. The cross-talk between differentially expressed proteins in NGM and GMAH tissues was then analyzed by bioinformatics. There were 165 differentially expressed proteins identified from the stromata of NGM and GMAH tissues. Among them, 99 proteins were upregulated and 66 were downregulated in GMAH tissue. The present study demonstrated that these proteins in gastric mucosal atypical hyperplasia were involved in cancer-associated signaling pathways, including the p53, mitogen-activated protein kinase (MAPK), cell cycle and apoptosis signaling pathways, and were involved in cellular growth, cellular proliferation, apoptosis and the humoral immune response. The results of the present study suggest that the 165 differentially expressed proteins, including S100 calcium-binding protein A6 (S100A6) and superoxide dismutase 3 (SOD3) in the microenvironment of gastric mucosal atypical hyperplasia, are involved in the p53, MAPK, cell cycle and apoptosis signaling pathways, and serve a function in the pathogenesis of gastric cancer.