Liver injury represents a continuum of pathophysiological processes involving a complex interplay between hepatocytes, macrophages, and hepatic stellate cells. The mechanism whereby these intercellular interactions co...Liver injury represents a continuum of pathophysiological processes involving a complex interplay between hepatocytes, macrophages, and hepatic stellate cells. The mechanism whereby these intercellular interactions contribute to liver injury and fibrosis is not completely understood. We report here that angiogenic factor with G patch and FHA domains 1(Aggfl) was downregulated in the livers of cirrhotic patients compared to healthy controls and in primary hepatocytes in response to carbon tetrachloride(CC14) stimulation. Overexpression of Aggfl attenuated macrophage chemotaxis. Aggfl interacted with NF-κB to block its binding to the Ccl2 gene promoter and repressed Ccl2 transcription in hepatocytes. Macrophages cultured in the conditioned media collected from Aggfloverexpressing hepatocytes antagonized HSC activation. Taken together, our data illustrate a novel role for Aggfl in regulating hepatic inflammation and provide insights on the development of interventional strategies against cirrhosis.展开更多
The class A scavenger receptor, encoded by the macrophage scavenger receptor 1 (MSR1) gene, is a pattern recognition receptor (PPR) primarily expressed in macrophages. It has been reported that genetic polymorphis...The class A scavenger receptor, encoded by the macrophage scavenger receptor 1 (MSR1) gene, is a pattern recognition receptor (PPR) primarily expressed in macrophages. It has been reported that genetic polymorphisms of MSR1 are significantly associated with the number of diseased vessels and coronary artery narrowing greater than 20% in Caucasians. However, whether it links genetically to coronary artery disease (CAD) in Chinese is not defined. Here, we performed an independent case-control study in a Chinese population consisting of 402 CAD cases and 400 controls by genotyping ten single nucleotide polymorphisms (SNPs) of MSR1. We found that rs416748 and rs13306541 were significantly associated with an increased risk of CAD with per allele odds ratio (OR) of 1.56 [95% confidence interval (CI) = 1.28-1.90; P 〈 0.001] and 1.70 (95% CI = 1.27-2.27; P 〈 0.001), re- spectively. Our results indicate that genetic variants of MSR1 may serve as predictive markers for the risk of CAD / in combination with traditional risk factors of CAD in Chinese population.展开更多
Hydrogen sulfide (H2S) is a gasotransmitter that regulates cardiovascular functions. The present study aimed to determine the protective effect of slow-releasing H2S donor GYY4137 on myocardial ischemia and reperfus...Hydrogen sulfide (H2S) is a gasotransmitter that regulates cardiovascular functions. The present study aimed to determine the protective effect of slow-releasing H2S donor GYY4137 on myocardial ischemia and reperfusion (I/R) injury and to investigate the possible signaling mechanisms involved. Male Sprague-Dawley rats were treated with GYY4137 at 12.5 mg/(kg.day), 25 mg/(kg.day) or 50 mg/(kg.day) intraperitoneally for 7 days. Then, rats were subjected to 30 minutes of left anterior descending coronary artery occlusion followed by reperfusion for 24 hours. We found that GYY4137 increased the cardiac ejection fraction and fractional shortening, reduced the ischemia area, alleviated histological injury and decreased plasma creatine kinase after myocardial I/R. Both H2S concentration in plasma and cystathionine-γ-lyase (CSE) activity in the myocardium were enhanced in the GYY4137 treated groups. GYY4137 also decreased malondialdehyde and myeloperoxidase levels in serum, attenuated superoxide anion level and suppressed phosphorylation of mitogen activated protein kinases in the myocardium after I/R. Meanwhile, GYY4137 increased the expression of Bcl-2 but decreased the expression of Bax, caspase-3 activity and apoptosis in the myocardium. The data suggest that GYY4137 protects against myocardial ischemia and reperfusion injury by attenuating oxidative stress and apoptosis.展开更多
Atherosclerosis is a progressive human pathology that encompasses several stages of development. Endothelial dysfunction represents an early sign of lesion within the vasculature. A number of risk factors for atherosc...Atherosclerosis is a progressive human pathology that encompasses several stages of development. Endothelial dysfunction represents an early sign of lesion within the vasculature. A number of risk factors for atherosclero- sis, including hyperlipidemia, diabetes, and hypertension, target the vascular endothelium by re-programming its transcriptome. These profound alterations taking place on the chromatin rely on the interplay between sequence specific transcription factors and the epigenetic machinery. The epigenetic machinery, in turn, tailor individual transcription events key to atherogenesis to intrinsic and extrinsic insults dictating the development of atheroscle- rotic lesions. This review summarizes our current understanding of the involvement of the epigenetic machinery in endothelial injury during atherogenesis.展开更多
Tumor necrosis factor alpha(TNF-a) is a cytokine that can potently stimulate the synthesis of a range of proinflammatory mediators in macrophages. The underlying epigenetic mechanism, however, is underexplored. Here w...Tumor necrosis factor alpha(TNF-a) is a cytokine that can potently stimulate the synthesis of a range of proinflammatory mediators in macrophages. The underlying epigenetic mechanism, however, is underexplored. Here we report that the transcriptional modulator megakaryocytic leukemia 1(MKL1) is associated with a histone H3 K4 methyltransferase activity. Re-ChIP assay suggests that MKL1 interacts with and recruits WDR5, a component of the COMPASS complex responsible for H3 K4 methylation, to the promoter regions of pro-inflammatory genes in macrophages treated with TNF-α. WDR5 enhances the ability of MKL1 to stimulate the promoter activities of proinflammatory genes. In contrast, silencing of WDR5 attenuates TNF-a induced production of pro-inflammatory mediators and erases the H3 K4 methylation from the gene promoters. Of interest, the chromatin remodeling protein BRG1 also plays an essential role in maintaining H3 K4 methylation on MKL1 target promoters by interacting with WDR5. MKL1 knockdown disrupts the interaction between BRG1 and WDR5. Together, our data illustrate a role for MKL1 in moderating the crosstalk between BRG1 and WDR5 to activate TNF-a induced pro-inflammatory transcription in macrophages.展开更多
Excessive fibrogenesis disrupts normal liver structure,impairs liver function,and precipitates the development of cirrhosis,an irreversible end-stage liver disease.A host of factors including nutrition surplus contrib...Excessive fibrogenesis disrupts normal liver structure,impairs liver function,and precipitates the development of cirrhosis,an irreversible end-stage liver disease.A host of factors including nutrition surplus contribute to liver fibrosis but the underlying mechanism is not fully understood.In the present study,we investigated the involvement of protein inhibitor for activated stat 4(PIAS4)in liver fibrosis in a mouse model of non-alcoholic steatohepatitis(NASH).We report that PIAS4 silencing using short hairpin RNA(shRNA)attenuated high-fat high-carbohydrate(HFHC)diet induced liver fibrosis in mice.Quantitative PCR and Western blotting analyses confirmed that PIAS4 knockdown downregulated a panel of pro-fibrogenic genes including type I and type III collagens,smooth muscle actin,and tissue inhibitors of metalloproteinase.Mechanistically,PIAS4 silencing blocked the recruitment of SMAD3,a potent pro-fibrogenic transcription factor,to the promoter regions of pro-fibrogenic genes and dampened SMAD3 acetylation likely by upregulating SIRT1 expression.In conclusion,PIAS4 may contribute to liver fibrosis by modulating SIRT1-dependent SMAD3 acetylation.展开更多
Glycine is a well-documented cytoprotective agent.However,whether it has a protective effect against myocar-dial ischemia-reperfusion injury in vivo is still unknown.By using an open-chest anesthetized rat model,we fo...Glycine is a well-documented cytoprotective agent.However,whether it has a protective effect against myocar-dial ischemia-reperfusion injury in vivo is still unknown.By using an open-chest anesthetized rat model,we found that glycine reduced the infarct size by 21% in ischemia-reperfusion injury rats compared with that in the vehicle-treated MI/R rats.The left ventricular ejection fraction and fractional shortening were increased by 19.11% and 30.98%,respectively,in glycine-treated rats.The plasma creatine kinase levels in ischemia-reperfusion injury rats decreased following glycine treatment.Importantly,administration of glycine significantly inhibited apoptosis in post-ischemia-reperfusion myocardium,which was accompanied by suppression of phosphorylated p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase,as well as the Fas ligand.These results suggest that gly-cine attenuates myocardial ischemia-reperfusion injury in vivo by inhibiting cardiomyocytes apoptosis.展开更多
Metformin(MET), an antidiabetic agent, also has antioxidative effects in metabolic-related hypertension.This study was designed to determine whether MET has anti-hypertensive effects in salt-sensitive hypertensive rat...Metformin(MET), an antidiabetic agent, also has antioxidative effects in metabolic-related hypertension.This study was designed to determine whether MET has anti-hypertensive effects in salt-sensitive hypertensive rats by inhibiting oxidative stress in the hypothalamic paraventricular nucleus(PVN). Salt-sensitive rats received a highsalt(HS) diet to induce hypertension, or a normal-salt(NS)diet as control. At the same time, they received intracerebroventricular(ICV) infusion of MET or vehicle for 6 weeks. We found that HS rats had higher oxidative stress levels and mean arterial pressure(MAP) than NS rats. ICV infusion of MET attenuated MAP and reduced plasma norepinephrine levels in HS rats. It also decreased reactive oxygen species and the expression of subunits of NAD(P)H oxidase, improved the superoxide dismutase activity,reduced components of the renin-angiotensin system, and altered neurotransmitters in the PVN. Our findings suggest that central MET administration lowers MAP in saltsensitive hypertension via attenuating oxidative stress,inhibiting the renin-angiotensin system, and restoring the balance between excitatory and inhibitory neurotransmitters in the PVN.展开更多
Angiotensin(Ang)-(1–7) is an important biologically-active peptide of the renin-angiotensin system. This study was designed to determine whether inhibition of Ang-(1–7) in the hypothalamic paraventricular nucleus(PV...Angiotensin(Ang)-(1–7) is an important biologically-active peptide of the renin-angiotensin system. This study was designed to determine whether inhibition of Ang-(1–7) in the hypothalamic paraventricular nucleus(PVN) attenuates sympathetic activity and elevates blood pressure by modulating pro-inflammatory cytokines(PICs)and oxidative stress in the PVN in salt-induced hypertension. Rats were fed either a high-salt(8% NaCl) or a normal salt diet(0.3% NaCl) for 10 weeks, followed by bilateral microinjections of the Ang-(1–7) antagonist A-779 or vehicle into the PVN. We found that the mean arterial pressure(MAP), renal sympathetic nerve activity(RSNA), and plasma norepinephrine(NE) were significantly increased in salt-induced hypertensive rats. The high-salt diet also resulted in higher levels of the PICs interleukin-6, interleukin-1 beta, tumor necrosis factor alpha, and monocyte chemotactic protein-1, as well as higher gp91 phoxexpression and superoxide production in the PVN. Microinjection of A-779(3 nmol/50 nL) into the bilateral PVN of hypertensive rats not only attenuated MAP, RSNA, and NE, but also decreased the PICs and oxidative stress in the PVN. These results suggest that the increased MAP and sympathetic activity in salt-induced hypertension can be suppressed by blockade of endogenous Ang-(1–7) in the PVN, through modulation of PICs and oxidative stress.展开更多
Class A scavenger receptor (SR-A) plays an important role in macrophage adhesion. However, the underlying mechanism remains unclear. We previously found that 78 kDa glucose-regulated protein (GRP78) inhibited SR- ...Class A scavenger receptor (SR-A) plays an important role in macrophage adhesion. However, the underlying mechanism remains unclear. We previously found that 78 kDa glucose-regulated protein (GRP78) inhibited SR- A-mediated ligand internalization into macrophage by binding to SR-A. The aim of the study was to investigate whether GRP78 could regulate SR-A-mediated cell adhesion. We demonstrated that GRP78 bound directly to SR-A by fluorescence resonance energy transfer (FRET) assay. Overexpression of GRP78 inhibited macrophage adhesion via SR-A. These results suggest that GRP78 may act as an inhibitor of macrophage adhesion via SR-A.展开更多
Experimental autoimmune prostatitis(EAP)-induced persistent inflammatory immune response can significantly upregulate the expression of N-methyl-D-aspartic acid(NMDA)receptors in the paraventricular nucleus(PVN).Howev...Experimental autoimmune prostatitis(EAP)-induced persistent inflammatory immune response can significantly upregulate the expression of N-methyl-D-aspartic acid(NMDA)receptors in the paraventricular nucleus(PVN).However,the mechanism has not yet been elucidated.Herein,we screened out the target prostate-derived inflammation cytokines(PDICs)by comparing the inflammatory cytokine levels in peripheral blood and cerebrospinal fluid(CSF)between EAP rats and their controls.After identifying the target PDIC,qualified males in initial copulatory behavior testing(CBT)were subjected to implanting tubes onto bilateral PVN.Next,they were randomly divided into four subgroups(EAP-1,EAP-2,Control-1,and Control-2).After 1-week recovery,EAP-1 rats were microinjected with the target PDIC inhibitor,Control-1 rats were microinjected with the target PDIC,while the EAP-2 and Control-2 subgroups were only treated with the same amount of artificial CSF(aCSF).Results showed that only interleukin-1β(IL-1β)had significantly increased mRNA-expression in the prostate of EAP rats compared to the controls(P<0.001)and significantly higher protein concentrations in both the serum(P=0.001)and CSF(P<0.001)of the EAP groups compared to the Control groups.Therefore,IL-1βwas identified as the target PDIC which crosses the blood-brain barrier,thereby influencing the central nervous system.Moreover,the EAP-1 subgroup displayed a gradually prolonged ejaculation latency(EL)in the last three CBTs(all P<0.01)and a significantly lower expression of NMDA NR1 subunit in the PVN(P=0.043)compared to the respective control groups after a 10-day central administration of IL-1βinhibitors.However,the Control-1 subgroup showed a gradually shortened EL(P<0.01)and a significantly higher NR1 expression(P=0.004)after homochronous IL-1βadministration.Therefore,we identified IL-1βas the primary PDIC which shortens EL in EAP rats.However,further studies should be conducted to elucidate the specific molecular mechanisms through which IL-1βupregulates NMDA expression.展开更多
Cardiac fibrosis represents an adoptive response in the heart exposed to various stress cues. While resolution of the fibrogenic response heralds normalization of heart function, persistent fibrogenesis is usually ass...Cardiac fibrosis represents an adoptive response in the heart exposed to various stress cues. While resolution of the fibrogenic response heralds normalization of heart function, persistent fibrogenesis is usually associated with progressive loss of heart function and eventually heart failure. Cardiac fibrosis is regulated by a myriad of factors that converge on the transcription of genes encoding extracellular matrix proteins, a process the epigenetic machinery plays a pivotal role. In this minireview, we summarize recent advances regarding the epigenetic regulation of cardiac fibrosis focusing on the role of histone and DNA modifications and non-coding RNAs.展开更多
Intermedin/adrenomedullin-2(IMD/AM2), a member of the calcitonin gene-related peptide/AM family,plays an important role in protecting the cardiovascular system. However, its role in the enhanced sympathoexcitation in ...Intermedin/adrenomedullin-2(IMD/AM2), a member of the calcitonin gene-related peptide/AM family,plays an important role in protecting the cardiovascular system. However, its role in the enhanced sympathoexcitation in obesity-related hypertension is unknown. In this study, we investigated the effects of IMD in the paraventricular nucleus(PVN) of the hypothalamus on sympathetic nerve activity(SNA), and lipopolysaccharide(LPS)-induced sympathetic activation in obesity-related hypertensive(OH)rats induced by a high-fat diet for 12 weeks. Acute experiments were performed under anesthesia. The dynamic alterations of sympathetic outflow were evaluated as changes in renal SNA and mean arterial pressure(MAP) in response to specific drugs. Male rats were fed a control diet(12% kcal as fat) or a high-fat diet(42% kcal as fat) for 12 weeks to induce OH. The results showed that IMD protein in the PVN was downregulated, but Toll-like receptor 4(TLR4) and plasma norepinephrine(NE, indicating sympathetic hyperactivity) levels, and systolic blood pressure were increased in OH rats. LPS(0.5 lg/50 nL)-induced enhancement of renal SNA and MAP was greater in OH rats than in obese or control rats. Bilateral PVN microinjection of IMD(50 pmol)caused greater decreases in renal SNA and MAP in OH rats than in control rats, and inhibited LPS-induced sympatheticactivation, and these were effectively prevented in OH rats by pretreatment with the AM receptor antagonist AM22-52.The mitogen-activated protein kinase/extracellular signalregulated kinase(ERK) inhibitor U0126 in the PVN partially reversed the LPS-induced enhancement of SNA. However,IMD in the PVN decreased the LPS-induced ERK activation,which was also effectively prevented by AM22-52. Chronic IMD administration resulted in significant reductions in the plasma NE level and blood pressure in OH rats. Moreover,IMD lowered the TLR4 protein expression and ERK activation in the PVN, and decreased the LPS-induced sympathetic overactivity. These results indicate that IMD in the PVN attenuates SNA and hypertension, and decreases the ERK activation implicated in the LPS-induced enhancement of SNA in OH rats, and this is mediated by AM receptors.展开更多
Differences in intravaginal ejaculation latency reflect normal biological variation, but the causes are poorly understood. Here, we investigated whether variation in ejaculation latency in an experimental rat model is...Differences in intravaginal ejaculation latency reflect normal biological variation, but the causes are poorly understood. Here, we investigated whether variation in ejaculation latency in an experimental rat model is related to altered sympathetic nervous system (SNS) activity and expression of N-methyI-D-aspartic acid (NMDA) receptors in the paraventricular nucleus of the hypothalamus (PVN). Male rats were classified as "sluggish," "normal," and "rapid" ejaculators on the basis of ejaculation frequency during copulatory behavioral testing. The lumbar splanchnic nerve activity baselines in these groups were not significantly different at 1460±480 mV, 1660±600 mV, and 1680±490 mV, respectively (P = 0.71). However, SNS sensitivity was remarkably different between the groups (P 〈 0.01), being 28.9% ± 8.1% in "sluggish," 48.4%±7.5% in "normal," and 88.7% ~ 7.4% in "rapid" groups. Compared with "normal" ejaculators, the percentage of neurons expressing NMDA receptors in the PVN of "rapid" ejaculators was significantly higher, whereas it was significantly lower in "sluggish" ejaculators (P = 0.01). In addition, there was a positive correlation between the expression of NMDA receptors in the PVN and SNS sensitivity (r = 0.876, P = 0.02). This study shows that intravaginal ejaculatory latency is associated with SNS activity and is mediated by NMDA receptors in the PVN.展开更多
In adult mammals, including humans, the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone of the dentate gyms (DG) show ongoing neurogenesis. Cerebral ischemic insults trigger neurogenes...In adult mammals, including humans, the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone of the dentate gyms (DG) show ongoing neurogenesis. Cerebral ischemic insults trigger neurogenesis from neural stem cells or progenitor cells located in the SVZ and DG. Newborn neurons are then functionally recruited into the circuitry of the CA1 region, striatum and DG granule cell layer.展开更多
基金supported,in part, by grants from the Natural Science Foundation of China (81402550)the Natural Science Foundation of Jiangsu Province (BK20140906)+2 种基金the Natural Science Foundation of Jiangsu Higher Education Institutions(14KJB310007)the Science & Technology Development Foundation of Nanjing Medical University (2013NJMU015)funding from Jiangsu Jiankang Vocational University (JK201405)
文摘Liver injury represents a continuum of pathophysiological processes involving a complex interplay between hepatocytes, macrophages, and hepatic stellate cells. The mechanism whereby these intercellular interactions contribute to liver injury and fibrosis is not completely understood. We report here that angiogenic factor with G patch and FHA domains 1(Aggfl) was downregulated in the livers of cirrhotic patients compared to healthy controls and in primary hepatocytes in response to carbon tetrachloride(CC14) stimulation. Overexpression of Aggfl attenuated macrophage chemotaxis. Aggfl interacted with NF-κB to block its binding to the Ccl2 gene promoter and repressed Ccl2 transcription in hepatocytes. Macrophages cultured in the conditioned media collected from Aggfloverexpressing hepatocytes antagonized HSC activation. Taken together, our data illustrate a novel role for Aggfl in regulating hepatic inflammation and provide insights on the development of interventional strategies against cirrhosis.
基金supported by the 973 Project of National Basic Research Program (No. 2012CB517503 and 2011CB503903)National Natural Science Foundation of China (No. 81070120)
文摘The class A scavenger receptor, encoded by the macrophage scavenger receptor 1 (MSR1) gene, is a pattern recognition receptor (PPR) primarily expressed in macrophages. It has been reported that genetic polymorphisms of MSR1 are significantly associated with the number of diseased vessels and coronary artery narrowing greater than 20% in Caucasians. However, whether it links genetically to coronary artery disease (CAD) in Chinese is not defined. Here, we performed an independent case-control study in a Chinese population consisting of 402 CAD cases and 400 controls by genotyping ten single nucleotide polymorphisms (SNPs) of MSR1. We found that rs416748 and rs13306541 were significantly associated with an increased risk of CAD with per allele odds ratio (OR) of 1.56 [95% confidence interval (CI) = 1.28-1.90; P 〈 0.001] and 1.70 (95% CI = 1.27-2.27; P 〈 0.001), re- spectively. Our results indicate that genetic variants of MSR1 may serve as predictive markers for the risk of CAD / in combination with traditional risk factors of CAD in Chinese population.
基金supported by grants from the National Natural Science Foundation of China(Grant No.81170083,81400203)Universities Natural Science Research Project of Jiangsu Province(No.10KJA310033)+1 种基金Major Science and Technology Development Fund Project of Nanjing Medical University(2011NJMU264)the Priority Academic Program Development(PAPD)of Jiangsu Higher Education Institutions
文摘Hydrogen sulfide (H2S) is a gasotransmitter that regulates cardiovascular functions. The present study aimed to determine the protective effect of slow-releasing H2S donor GYY4137 on myocardial ischemia and reperfusion (I/R) injury and to investigate the possible signaling mechanisms involved. Male Sprague-Dawley rats were treated with GYY4137 at 12.5 mg/(kg.day), 25 mg/(kg.day) or 50 mg/(kg.day) intraperitoneally for 7 days. Then, rats were subjected to 30 minutes of left anterior descending coronary artery occlusion followed by reperfusion for 24 hours. We found that GYY4137 increased the cardiac ejection fraction and fractional shortening, reduced the ischemia area, alleviated histological injury and decreased plasma creatine kinase after myocardial I/R. Both H2S concentration in plasma and cystathionine-γ-lyase (CSE) activity in the myocardium were enhanced in the GYY4137 treated groups. GYY4137 also decreased malondialdehyde and myeloperoxidase levels in serum, attenuated superoxide anion level and suppressed phosphorylation of mitogen activated protein kinases in the myocardium after I/R. Meanwhile, GYY4137 increased the expression of Bcl-2 but decreased the expression of Bax, caspase-3 activity and apoptosis in the myocardium. The data suggest that GYY4137 protects against myocardial ischemia and reperfusion injury by attenuating oxidative stress and apoptosis.
文摘Atherosclerosis is a progressive human pathology that encompasses several stages of development. Endothelial dysfunction represents an early sign of lesion within the vasculature. A number of risk factors for atherosclero- sis, including hyperlipidemia, diabetes, and hypertension, target the vascular endothelium by re-programming its transcriptome. These profound alterations taking place on the chromatin rely on the interplay between sequence specific transcription factors and the epigenetic machinery. The epigenetic machinery, in turn, tailor individual transcription events key to atherogenesis to intrinsic and extrinsic insults dictating the development of atheroscle- rotic lesions. This review summarizes our current understanding of the involvement of the epigenetic machinery in endothelial injury during atherogenesis.
基金the National Natural Science Foundation of China (81570420) supported by the Qinglan Project of the Education Commission of Jiangsu Province
文摘Tumor necrosis factor alpha(TNF-a) is a cytokine that can potently stimulate the synthesis of a range of proinflammatory mediators in macrophages. The underlying epigenetic mechanism, however, is underexplored. Here we report that the transcriptional modulator megakaryocytic leukemia 1(MKL1) is associated with a histone H3 K4 methyltransferase activity. Re-ChIP assay suggests that MKL1 interacts with and recruits WDR5, a component of the COMPASS complex responsible for H3 K4 methylation, to the promoter regions of pro-inflammatory genes in macrophages treated with TNF-α. WDR5 enhances the ability of MKL1 to stimulate the promoter activities of proinflammatory genes. In contrast, silencing of WDR5 attenuates TNF-a induced production of pro-inflammatory mediators and erases the H3 K4 methylation from the gene promoters. Of interest, the chromatin remodeling protein BRG1 also plays an essential role in maintaining H3 K4 methylation on MKL1 target promoters by interacting with WDR5. MKL1 knockdown disrupts the interaction between BRG1 and WDR5. Together, our data illustrate a role for MKL1 in moderating the crosstalk between BRG1 and WDR5 to activate TNF-a induced pro-inflammatory transcription in macrophages.
基金supported by the Natural Science Foundation of China(No.81500441)
文摘Excessive fibrogenesis disrupts normal liver structure,impairs liver function,and precipitates the development of cirrhosis,an irreversible end-stage liver disease.A host of factors including nutrition surplus contribute to liver fibrosis but the underlying mechanism is not fully understood.In the present study,we investigated the involvement of protein inhibitor for activated stat 4(PIAS4)in liver fibrosis in a mouse model of non-alcoholic steatohepatitis(NASH).We report that PIAS4 silencing using short hairpin RNA(shRNA)attenuated high-fat high-carbohydrate(HFHC)diet induced liver fibrosis in mice.Quantitative PCR and Western blotting analyses confirmed that PIAS4 knockdown downregulated a panel of pro-fibrogenic genes including type I and type III collagens,smooth muscle actin,and tissue inhibitors of metalloproteinase.Mechanistically,PIAS4 silencing blocked the recruitment of SMAD3,a potent pro-fibrogenic transcription factor,to the promoter regions of pro-fibrogenic genes and dampened SMAD3 acetylation likely by upregulating SIRT1 expression.In conclusion,PIAS4 may contribute to liver fibrosis by modulating SIRT1-dependent SMAD3 acetylation.
基金supported by the National Natural Science Foundation of China(No.81070120,81000118 and 81100857)the National Basic Research Program(973 Program,No.2012CB517503 and 2011CB503903)
文摘Glycine is a well-documented cytoprotective agent.However,whether it has a protective effect against myocar-dial ischemia-reperfusion injury in vivo is still unknown.By using an open-chest anesthetized rat model,we found that glycine reduced the infarct size by 21% in ischemia-reperfusion injury rats compared with that in the vehicle-treated MI/R rats.The left ventricular ejection fraction and fractional shortening were increased by 19.11% and 30.98%,respectively,in glycine-treated rats.The plasma creatine kinase levels in ischemia-reperfusion injury rats decreased following glycine treatment.Importantly,administration of glycine significantly inhibited apoptosis in post-ischemia-reperfusion myocardium,which was accompanied by suppression of phosphorylated p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase,as well as the Fas ligand.These results suggest that gly-cine attenuates myocardial ischemia-reperfusion injury in vivo by inhibiting cardiomyocytes apoptosis.
基金supported by the National Natural Science Foundation of China(81600333,81770426,81800372,91439120,and 91639105)the Postdoctoral Science Foundation of China(2016M602835,2017M620457)the Postdoctoral Science Foundation of Shaanxi Province,China(2016BSHEDZZ91)
文摘Metformin(MET), an antidiabetic agent, also has antioxidative effects in metabolic-related hypertension.This study was designed to determine whether MET has anti-hypertensive effects in salt-sensitive hypertensive rats by inhibiting oxidative stress in the hypothalamic paraventricular nucleus(PVN). Salt-sensitive rats received a highsalt(HS) diet to induce hypertension, or a normal-salt(NS)diet as control. At the same time, they received intracerebroventricular(ICV) infusion of MET or vehicle for 6 weeks. We found that HS rats had higher oxidative stress levels and mean arterial pressure(MAP) than NS rats. ICV infusion of MET attenuated MAP and reduced plasma norepinephrine levels in HS rats. It also decreased reactive oxygen species and the expression of subunits of NAD(P)H oxidase, improved the superoxide dismutase activity,reduced components of the renin-angiotensin system, and altered neurotransmitters in the PVN. Our findings suggest that central MET administration lowers MAP in saltsensitive hypertension via attenuating oxidative stress,inhibiting the renin-angiotensin system, and restoring the balance between excitatory and inhibitory neurotransmitters in the PVN.
基金supported by the National Natural Science Foundation of China(81600333,81770426,91439120,and 91639105)the China Postdoctoral Science Foundation(2016M602835 and 2016M592802)the Shaanxi Postdoctoral Science Foundation(2016BSHEDZZ91)
文摘Angiotensin(Ang)-(1–7) is an important biologically-active peptide of the renin-angiotensin system. This study was designed to determine whether inhibition of Ang-(1–7) in the hypothalamic paraventricular nucleus(PVN) attenuates sympathetic activity and elevates blood pressure by modulating pro-inflammatory cytokines(PICs)and oxidative stress in the PVN in salt-induced hypertension. Rats were fed either a high-salt(8% NaCl) or a normal salt diet(0.3% NaCl) for 10 weeks, followed by bilateral microinjections of the Ang-(1–7) antagonist A-779 or vehicle into the PVN. We found that the mean arterial pressure(MAP), renal sympathetic nerve activity(RSNA), and plasma norepinephrine(NE) were significantly increased in salt-induced hypertensive rats. The high-salt diet also resulted in higher levels of the PICs interleukin-6, interleukin-1 beta, tumor necrosis factor alpha, and monocyte chemotactic protein-1, as well as higher gp91 phoxexpression and superoxide production in the PVN. Microinjection of A-779(3 nmol/50 nL) into the bilateral PVN of hypertensive rats not only attenuated MAP, RSNA, and NE, but also decreased the PICs and oxidative stress in the PVN. These results suggest that the increased MAP and sympathetic activity in salt-induced hypertension can be suppressed by blockade of endogenous Ang-(1–7) in the PVN, through modulation of PICs and oxidative stress.
基金supported by grants from the National Basic ResearchProgram(973)(No.2012CB517503,No.2011CB503903,and No.2012CB945003)National Natural Science Foundation of China(No.81070120)to Qi Chen+1 种基金National Natural Science Foundation ofChina(No.81000118)University Natural Science Foundation ofJiangsu(No.10KJB310005)to Jingjing Ben
文摘Class A scavenger receptor (SR-A) plays an important role in macrophage adhesion. However, the underlying mechanism remains unclear. We previously found that 78 kDa glucose-regulated protein (GRP78) inhibited SR- A-mediated ligand internalization into macrophage by binding to SR-A. The aim of the study was to investigate whether GRP78 could regulate SR-A-mediated cell adhesion. We demonstrated that GRP78 bound directly to SR-A by fluorescence resonance energy transfer (FRET) assay. Overexpression of GRP78 inhibited macrophage adhesion via SR-A. These results suggest that GRP78 may act as an inhibitor of macrophage adhesion via SR-A.
基金This work was supported by the National Natural Science Foundation of China(Grant No.81501245 and No.81971377)Fellowship of China Postdoctoral Science Foundation(Grant No.2020M671393)Jiangsu Province Postdoctoral Research Support Project(Grant No.2020Z134).
文摘Experimental autoimmune prostatitis(EAP)-induced persistent inflammatory immune response can significantly upregulate the expression of N-methyl-D-aspartic acid(NMDA)receptors in the paraventricular nucleus(PVN).However,the mechanism has not yet been elucidated.Herein,we screened out the target prostate-derived inflammation cytokines(PDICs)by comparing the inflammatory cytokine levels in peripheral blood and cerebrospinal fluid(CSF)between EAP rats and their controls.After identifying the target PDIC,qualified males in initial copulatory behavior testing(CBT)were subjected to implanting tubes onto bilateral PVN.Next,they were randomly divided into four subgroups(EAP-1,EAP-2,Control-1,and Control-2).After 1-week recovery,EAP-1 rats were microinjected with the target PDIC inhibitor,Control-1 rats were microinjected with the target PDIC,while the EAP-2 and Control-2 subgroups were only treated with the same amount of artificial CSF(aCSF).Results showed that only interleukin-1β(IL-1β)had significantly increased mRNA-expression in the prostate of EAP rats compared to the controls(P<0.001)and significantly higher protein concentrations in both the serum(P=0.001)and CSF(P<0.001)of the EAP groups compared to the Control groups.Therefore,IL-1βwas identified as the target PDIC which crosses the blood-brain barrier,thereby influencing the central nervous system.Moreover,the EAP-1 subgroup displayed a gradually prolonged ejaculation latency(EL)in the last three CBTs(all P<0.01)and a significantly lower expression of NMDA NR1 subunit in the PVN(P=0.043)compared to the respective control groups after a 10-day central administration of IL-1βinhibitors.However,the Control-1 subgroup showed a gradually shortened EL(P<0.01)and a significantly higher NR1 expression(P=0.004)after homochronous IL-1βadministration.Therefore,we identified IL-1βas the primary PDIC which shortens EL in EAP rats.However,further studies should be conducted to elucidate the specific molecular mechanisms through which IL-1βupregulates NMDA expression.
基金Supported by Innovative Collaboration Center for Cardio-vascular Translational Medicine
文摘Cardiac fibrosis represents an adoptive response in the heart exposed to various stress cues. While resolution of the fibrogenic response heralds normalization of heart function, persistent fibrogenesis is usually associated with progressive loss of heart function and eventually heart failure. Cardiac fibrosis is regulated by a myriad of factors that converge on the transcription of genes encoding extracellular matrix proteins, a process the epigenetic machinery plays a pivotal role. In this minireview, we summarize recent advances regarding the epigenetic regulation of cardiac fibrosis focusing on the role of histone and DNA modifications and non-coding RNAs.
基金supported by the National Natural Science Foundation of China(81000106 and81470539)
文摘Intermedin/adrenomedullin-2(IMD/AM2), a member of the calcitonin gene-related peptide/AM family,plays an important role in protecting the cardiovascular system. However, its role in the enhanced sympathoexcitation in obesity-related hypertension is unknown. In this study, we investigated the effects of IMD in the paraventricular nucleus(PVN) of the hypothalamus on sympathetic nerve activity(SNA), and lipopolysaccharide(LPS)-induced sympathetic activation in obesity-related hypertensive(OH)rats induced by a high-fat diet for 12 weeks. Acute experiments were performed under anesthesia. The dynamic alterations of sympathetic outflow were evaluated as changes in renal SNA and mean arterial pressure(MAP) in response to specific drugs. Male rats were fed a control diet(12% kcal as fat) or a high-fat diet(42% kcal as fat) for 12 weeks to induce OH. The results showed that IMD protein in the PVN was downregulated, but Toll-like receptor 4(TLR4) and plasma norepinephrine(NE, indicating sympathetic hyperactivity) levels, and systolic blood pressure were increased in OH rats. LPS(0.5 lg/50 nL)-induced enhancement of renal SNA and MAP was greater in OH rats than in obese or control rats. Bilateral PVN microinjection of IMD(50 pmol)caused greater decreases in renal SNA and MAP in OH rats than in control rats, and inhibited LPS-induced sympatheticactivation, and these were effectively prevented in OH rats by pretreatment with the AM receptor antagonist AM22-52.The mitogen-activated protein kinase/extracellular signalregulated kinase(ERK) inhibitor U0126 in the PVN partially reversed the LPS-induced enhancement of SNA. However,IMD in the PVN decreased the LPS-induced ERK activation,which was also effectively prevented by AM22-52. Chronic IMD administration resulted in significant reductions in the plasma NE level and blood pressure in OH rats. Moreover,IMD lowered the TLR4 protein expression and ERK activation in the PVN, and decreased the LPS-induced sympathetic overactivity. These results indicate that IMD in the PVN attenuates SNA and hypertension, and decreases the ERK activation implicated in the LPS-induced enhancement of SNA in OH rats, and this is mediated by AM receptors.
文摘Differences in intravaginal ejaculation latency reflect normal biological variation, but the causes are poorly understood. Here, we investigated whether variation in ejaculation latency in an experimental rat model is related to altered sympathetic nervous system (SNS) activity and expression of N-methyI-D-aspartic acid (NMDA) receptors in the paraventricular nucleus of the hypothalamus (PVN). Male rats were classified as "sluggish," "normal," and "rapid" ejaculators on the basis of ejaculation frequency during copulatory behavioral testing. The lumbar splanchnic nerve activity baselines in these groups were not significantly different at 1460±480 mV, 1660±600 mV, and 1680±490 mV, respectively (P = 0.71). However, SNS sensitivity was remarkably different between the groups (P 〈 0.01), being 28.9% ± 8.1% in "sluggish," 48.4%±7.5% in "normal," and 88.7% ~ 7.4% in "rapid" groups. Compared with "normal" ejaculators, the percentage of neurons expressing NMDA receptors in the PVN of "rapid" ejaculators was significantly higher, whereas it was significantly lower in "sluggish" ejaculators (P = 0.01). In addition, there was a positive correlation between the expression of NMDA receptors in the PVN and SNS sensitivity (r = 0.876, P = 0.02). This study shows that intravaginal ejaculatory latency is associated with SNS activity and is mediated by NMDA receptors in the PVN.
文摘In adult mammals, including humans, the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone of the dentate gyms (DG) show ongoing neurogenesis. Cerebral ischemic insults trigger neurogenesis from neural stem cells or progenitor cells located in the SVZ and DG. Newborn neurons are then functionally recruited into the circuitry of the CA1 region, striatum and DG granule cell layer.