Prolactin(PRL)is a polypeptide hormone that is mainly synthesized and secreted by the lactotroph cells of the pituitary.There are two main isoforms of PRL:23-kDa PRL(named full-l ength PRL)and vasoinhibins(including ...Prolactin(PRL)is a polypeptide hormone that is mainly synthesized and secreted by the lactotroph cells of the pituitary.There are two main isoforms of PRL:23-kDa PRL(named full-l ength PRL)and vasoinhibins(including 5.6–18 kDa fragments).Both act as circulating hormones and cytokines to stimulate or inhibit vascular formation at different stages and neovascularization,including endothelial cell proliferation and migration,protease production,and apoptosis.However,their effects on vascular function and cardiovascular diseases are different or even contrary.In addition to the structure,secretion regulation,and signal transduction of PRL/vasoinhibins,this review focuses on the pathological mechanism and clinical significance of PRL/vasoinhibins in cardiovascular diseases.展开更多
Circular RNAs(circRNAs)are endogenous RNAs with a covalently closed single-stranded transcript.They are a novel class of genomic regulators that are linked to many important development and disease processes and are b...Circular RNAs(circRNAs)are endogenous RNAs with a covalently closed single-stranded transcript.They are a novel class of genomic regulators that are linked to many important development and disease processes and are being pursued as clinical and therapeutic targets.Using the most powerful RNA sequencing and bioinformatics techniques,a large number of circRNAs have been identified and further functional studies have been performed.It is known that circRNAs act as potential biomarkers,sponges for microRNAs(miRNAs)and RNA-binding proteins(RBPs),and regulators of mRNA transcription.They also participate in the translation of peptides or proteins.Many types of circRNAs are dysregulated in plasma or lung tissues,and they may be involved in regulating the proliferation and apoptosis of pulmonary artery endothelial cells(PAECs)and pulmonary artery smooth muscle cells(PASMCs),leading to pulmonary vascular remodeling in pulmonary hypertension(PH).One possible mechanism is that circRNAs can regulate the function of PAECs and PASMCs by acting as miRNA sponge.However,other potential mechanisms of action of circRNAs are still being actively explored in PH.This paper presents a systematic review of the biogenesis,biological characterization,relevant underlying functions,and future perspectives for studies of circRNAs in the pathogenesis of PH.展开更多
Background:Aberrant expression of microRNAs(miRNAs)has been associated with the pathogenesis of pulmonary hypertension(PH).It is,however,not clear whether miRNAs are involved in estrogen rescue of PH.Methods:Fresh pla...Background:Aberrant expression of microRNAs(miRNAs)has been associated with the pathogenesis of pulmonary hypertension(PH).It is,however,not clear whether miRNAs are involved in estrogen rescue of PH.Methods:Fresh plasma samples were prepared from 12 idiopathic pulmonary arterial hypertension(IPAH)patients and 12 healthy controls undergoing right heart cath-eterization in Shanghai Pulmonary Hospital.From each sample,5μg of total RNA was tagged and hybridized on microRNA microarray chips.Monocrotaline-induced PH(MCT-PH)male rats were treated with 17β-estradiol(E_(2))or vehicle.Subgroups were cotreated with estrogen receptor(ER)antagonist or with antagonist of miRNA.Results:Many circulating miRNAs,including miR-21-5p and miR-574-5p,were mark-edly expressed in patients and of interest in predicting mean pulmonary arterial pres-sure elevation in patients.The expression of miR-21-5p in the lungs was significantly upregulated in MCT-PH rats compared with the controls.However,miR-574-5p showed no difference in the lungs of MCT-PH rats and controls.miR-21-5p was se-lected for further analysis in rats as E_(2) strongly regulated it.E_(2) decreased miR-21-5p expression in the lungs of MCT-PH rats by ERβ.E_(2) reversed miR-21-5p target gene FilGAP downregulation in the lungs of MCT-PH rats.The abnormal expression of RhoA,ROCK2,Rac1 and c-Jun in the lungs of MCT-PH rats was inhibited by E_(2) and miR-21-5p antagonist.Conclusions:miR-21-5p level was remarkably associated with PH severity in patients.Moreover,the miR-21-5p/FilGAP signaling pathway modulated the protective effect of E_(2) on MCT-PH through ERβ.展开更多
[Objectives] To study the effects and mechanism of notoginsenoside Rg1 on the spatial learning and memory and phosphorylated tau protein in the AD( Alzheimer's Disease) model rat. [Methods]The AD model rat was rep...[Objectives] To study the effects and mechanism of notoginsenoside Rg1 on the spatial learning and memory and phosphorylated tau protein in the AD( Alzheimer's Disease) model rat. [Methods]The AD model rat was replicated by injection of Aβ_(25-35) in the left lateral ventricles of SD rats. The low dose( 25 mg/kg),middle dose( 50 mg/kg) and high dose( 100 mg/kg) notoginsenoside Rg1 was used for intragastric administration,respectively,two times every day. After 4 weeks,the Morris water maze test was done to detect the learning and memory capacity,and the immunoblotting,immunohistochemical methods were used to detect the changes in the phosphorylation level and distribution of tau protein in hippocampus of the rats. [Results] After the intracerebroventricular injection of Aβ_(25-35),the learning and memory capacity of the model rats was significantly lower than the learning and memory capacity of the normal control rats. The immunoblotting test results showed that the phosphorylation level of tau protein threonine 231 site( Thr231) in hippocampus was significantly increased,and the nonphosphorylation level was significantly decreased. The morphological testing results showed that the phosphorylation level of tau protein Thr231 of AD model rats was increased markedly in region of DG,CA1 and CA3 of the hippocampus. The intervention of the middle dose notoginsenoside Rg1 could significantly improve the learning and memory capacity of the model rats in Morris water maze. The notoginsenoside Rg1 in three different doses could all reduce the phosphorylation level of tau protein Thr231 in the hippocampal DG,CA1,CA3 regions,and there were no significant differences among the three doses. [Conclusions]The notoginsenoside Rg1 could improve Aβ_(25-35)-induced spatial learning and memory impairment of the AD model rats,and decreased the phosphorylation level of tau protein in hippocampus.展开更多
Objective:This study aimed at examining the alterations in metabolomic profiles caused by treatment of H.pylori infection,and the associations between key plasma metabolites and the risk of gastric lesion progression ...Objective:This study aimed at examining the alterations in metabolomic profiles caused by treatment of H.pylori infection,and the associations between key plasma metabolites and the risk of gastric lesion progression during follow-up after treatment.Methods:An intervention trial was performed in 183 participants,117 of whom were H.pylori positive participants receiving treatment for H.pylori infection.H.pylori positive participants were prospectively followed for 182 to 1,289 days.Untargeted metabolomics assays were conducted on plasma samples collected at baseline,6 months after treatment,and during continued follow-up.Results:We identified 59 metabolites with differential posttreatment changes between participants with successful and failed H.pylori eradication,17 metabolites significantly distinguished participants with successful vs.failed eradication.Two metabolites[PC(18:1(11Z)/14:1(9Z))and(2S)-6-amino-2-formamidohexanamide]showed posttreatment changes positively associated with successful H.pylori eradication,and were inversely associated with the risk of gastric lesion progression among participants with successful eradication.In contrast,9-decenoic acid showed posttreatment changes inversely associated with successful eradication:its level was positively associated with the risk of gastric lesion progression among participants with successful eradication.Although the identified metabolites showed a temporary but significant decline after treatment,the trend generally reversed during continued follow-up,and pretreatment levels were restored.Conclusions:Treatment of H.pylori infection significantly altered plasma metabolic profiles in the short term,and key metabolites were capable of distinguishing participants with successful vs.failed eradication,but might not substantially affect metabolic regulation in the long term.Several plasma metabolites were differentially associated with the risk of gastric lesion progression among participants with successful or failed eradication.展开更多
Both in nature and in aquaculture,fish may experience periods of food scarcity or hunger.The metabolic regulation of fish when nutritional state changes is a complex process that involves many factors.To study glucose...Both in nature and in aquaculture,fish may experience periods of food scarcity or hunger.The metabolic regulation of fish when nutritional state changes is a complex process that involves many factors.To study glucose metabolism adaptability during fasting and re-feeding in the black carp(Mylopharyngodon piceus),we measured changes in some biochemical indicators related to glucose metabolism.Five fish were sampled on days 0,1,3,5,and 10 of fasting(F,S1,S3,S5,and S10,respectively)and days 1,3,and 5 of re-feeding(RF1,RF3,and RF5,respectively).The serum glucose concentration decreased significantly at S1,reached the lowest point at S10,and increased significantly at RF1(P<0.05).The concentration of liver glycogen decreased significantly at S1 and reached the lowest level at S3,whereas the muscle glycogen level decreased significantly at S5 and reached the lowest value at S10(P<0.05).Both liver and muscle glycogen levels returned to the pre-fasting level at RF5(P<0.05).Regarding glycolysis,the concentrations of pyruvate kinase(PK)and hexokinase(HK)decreased significantly at S5 and increased significantly at RF5 and RF1,respectively(P<0.05).The concentrations of glucokinase(GCK)and insulin decreased significantly at S1 and increased significantly at RF1 and RF3,respectively(P<0.05).The mRNA expression levels of liver GCK and glucose transporter 2(GLUT2)decreased significantly at S1 and increased significantly at RF1 and RF5,respectively(P<0.05).As for gluconeogenesis,the concentration of glucose-6-phosphatase(G6PC)increased significantly at S1 and decreased significantly at RF1(P<0.05).The concentrations of glucagon and glucocorticoid(GC)increased significantly at S3 and significantly decreased at RF1 and RF5,respectively(P<0.05).The mRNA expression levels of liver G6PC and phosphoenolpyruvate carboxykinase(PEPCK)increased significantly at S3 and S1,and both decreased significantly at RF1(P<0.05).These results indicate that coordination between glycolysis and gluconeogenesis might be crucial for glucose homeostasis during fasting and re-feeding in the black carp.展开更多
Background:Our previous study found that mouse embryonic neural stem cell(NSC)-derived exosomes(EXOs)regulated NSC differentiation via the miR-9/Hes1 axis.However,the effects of EXOs on brain microvascular endothelial...Background:Our previous study found that mouse embryonic neural stem cell(NSC)-derived exosomes(EXOs)regulated NSC differentiation via the miR-9/Hes1 axis.However,the effects of EXOs on brain microvascular endothelial cell(BMEC)dysfunction via the miR-9/Hes1 axis remain unknown.Therefore,the current study aimed to determine the effects of EXOs on BMEC proliferation,migration,and death via the miR-9/Hes1 axis.Methods:Immunofluorescence,quantitative real-time polymerase chain reaction,cell counting kit-8 assay,wound healing assay,calcein-acetoxymethyl/propidium iodide staining,and hematoxylin and eosin staining were used to determine the role and mechanism of EXOs on BMECs.Results:EXOs promoted BMEC proliferation and migration and reduced cell death under hypoxic conditions.The overexpression of miR-9 promoted BMEC prolifera-tion and migration and reduced cell death under hypoxic conditions.Moreover,miR-9 downregulation inhibited BMEC proliferation and migration and also promoted cell death.Hes1 silencing ameliorated the effect of amtagomiR-9 on BMEC proliferation and migration and cell death.Hyperemic structures were observed in the regions of the hippocampus and cortex in hypoxia-induced mice.Meanwhile,EXO treatment improved cerebrovascular alterations.Conclusion:NSC-derived EXOs can promote BMEC proliferation and migra-tion and reduce cell death via the miR-9/Hes1 axis under hypoxic conditions.Therefore,EXO therapeutic strategies could be considered for hypoxia-induced vascular injury.展开更多
Zinc levels are high in pancreatic β-cells, and zinc is involved in the synthesis, processing and secretion of insulin in these cells. However, precisely how cellular zinc homeostasis is regulated in pancreatic β-ce...Zinc levels are high in pancreatic β-cells, and zinc is involved in the synthesis, processing and secretion of insulin in these cells. However, precisely how cellular zinc homeostasis is regulated in pancreatic β-cells is poorly understood. By screening the expression of 14 Slc39a metal importer family member genes, we found that the zinc transporter Slc39a5 is significantly downregulated in pancreatic β-cells in diabetic db/db mice, obese ob/ob mice and high-fat diet-fed mice. Moreover,β-cell-specific Slc39a5 knockout mice have impaired insulin secretion. In addition, Slc39a5-deficient pancreatic islets have reduced glucose tolerance accompanied by reduced expression of Pgc-1α and its downstream target gene Glut2. The down-regulation of Glut2 in Slc39a5-deficient islets was rescued using agonists of Sirt1, Pgc-1α and Ppar-γ. At the mechanistic level, we found that Slc39a5-mediated zinc influx induces Glut2 expression via Sirt1-mediated Pgc-1α activation. These findings suggest that Slc39a5 may serve as a possible therapeutic target for diabetes-related conditions.展开更多
基金National Natural Science Foundation of China,Grant/Award Number:81700045,81870042 and 81900050Natural Science Foundation of Shanghai,Grant/Award Number:22ZR1452400+1 种基金Shanghai Municipal Commission of Health,Grant/Award Number:20204Y0384Shanghai Pulmonary Hospital,Grant/Award Number:fk18003 and fkyq1605。
文摘Prolactin(PRL)is a polypeptide hormone that is mainly synthesized and secreted by the lactotroph cells of the pituitary.There are two main isoforms of PRL:23-kDa PRL(named full-l ength PRL)and vasoinhibins(including 5.6–18 kDa fragments).Both act as circulating hormones and cytokines to stimulate or inhibit vascular formation at different stages and neovascularization,including endothelial cell proliferation and migration,protease production,and apoptosis.However,their effects on vascular function and cardiovascular diseases are different or even contrary.In addition to the structure,secretion regulation,and signal transduction of PRL/vasoinhibins,this review focuses on the pathological mechanism and clinical significance of PRL/vasoinhibins in cardiovascular diseases.
基金supported by the Program of National Natural Science Foundation of China (81870042 and 81900050)Program of Natural Science Foundation of Shanghai (21ZR1453800)Program of Shanghai Pulmonary Hospital (FKLY20005)
文摘Circular RNAs(circRNAs)are endogenous RNAs with a covalently closed single-stranded transcript.They are a novel class of genomic regulators that are linked to many important development and disease processes and are being pursued as clinical and therapeutic targets.Using the most powerful RNA sequencing and bioinformatics techniques,a large number of circRNAs have been identified and further functional studies have been performed.It is known that circRNAs act as potential biomarkers,sponges for microRNAs(miRNAs)and RNA-binding proteins(RBPs),and regulators of mRNA transcription.They also participate in the translation of peptides or proteins.Many types of circRNAs are dysregulated in plasma or lung tissues,and they may be involved in regulating the proliferation and apoptosis of pulmonary artery endothelial cells(PAECs)and pulmonary artery smooth muscle cells(PASMCs),leading to pulmonary vascular remodeling in pulmonary hypertension(PH).One possible mechanism is that circRNAs can regulate the function of PAECs and PASMCs by acting as miRNA sponge.However,other potential mechanisms of action of circRNAs are still being actively explored in PH.This paper presents a systematic review of the biogenesis,biological characterization,relevant underlying functions,and future perspectives for studies of circRNAs in the pathogenesis of PH.
基金National Natural Science Foundation of China,Grant/Award Number:8 1870042Natural Science Foundation of Shanghai,Grant/Award Number:21ZR1453800。
文摘Background:Aberrant expression of microRNAs(miRNAs)has been associated with the pathogenesis of pulmonary hypertension(PH).It is,however,not clear whether miRNAs are involved in estrogen rescue of PH.Methods:Fresh plasma samples were prepared from 12 idiopathic pulmonary arterial hypertension(IPAH)patients and 12 healthy controls undergoing right heart cath-eterization in Shanghai Pulmonary Hospital.From each sample,5μg of total RNA was tagged and hybridized on microRNA microarray chips.Monocrotaline-induced PH(MCT-PH)male rats were treated with 17β-estradiol(E_(2))or vehicle.Subgroups were cotreated with estrogen receptor(ER)antagonist or with antagonist of miRNA.Results:Many circulating miRNAs,including miR-21-5p and miR-574-5p,were mark-edly expressed in patients and of interest in predicting mean pulmonary arterial pres-sure elevation in patients.The expression of miR-21-5p in the lungs was significantly upregulated in MCT-PH rats compared with the controls.However,miR-574-5p showed no difference in the lungs of MCT-PH rats and controls.miR-21-5p was se-lected for further analysis in rats as E_(2) strongly regulated it.E_(2) decreased miR-21-5p expression in the lungs of MCT-PH rats by ERβ.E_(2) reversed miR-21-5p target gene FilGAP downregulation in the lungs of MCT-PH rats.The abnormal expression of RhoA,ROCK2,Rac1 and c-Jun in the lungs of MCT-PH rats was inhibited by E_(2) and miR-21-5p antagonist.Conclusions:miR-21-5p level was remarkably associated with PH severity in patients.Moreover,the miR-21-5p/FilGAP signaling pathway modulated the protective effect of E_(2) on MCT-PH through ERβ.
基金Supported by National Natural Science Foundation of China(81673856,81573865)China Postdoctoral Science Foundation(2016M592319,2017T100542)+1 种基金Youth Project of Hubei University of Traditional Chinese Medicine(Zhong Yi Xiao Zi2015182)PhD Research Foundation of Hubei University of Traditional Chinese Medicine(Zhong Yi Dang Zi201425)
文摘[Objectives] To study the effects and mechanism of notoginsenoside Rg1 on the spatial learning and memory and phosphorylated tau protein in the AD( Alzheimer's Disease) model rat. [Methods]The AD model rat was replicated by injection of Aβ_(25-35) in the left lateral ventricles of SD rats. The low dose( 25 mg/kg),middle dose( 50 mg/kg) and high dose( 100 mg/kg) notoginsenoside Rg1 was used for intragastric administration,respectively,two times every day. After 4 weeks,the Morris water maze test was done to detect the learning and memory capacity,and the immunoblotting,immunohistochemical methods were used to detect the changes in the phosphorylation level and distribution of tau protein in hippocampus of the rats. [Results] After the intracerebroventricular injection of Aβ_(25-35),the learning and memory capacity of the model rats was significantly lower than the learning and memory capacity of the normal control rats. The immunoblotting test results showed that the phosphorylation level of tau protein threonine 231 site( Thr231) in hippocampus was significantly increased,and the nonphosphorylation level was significantly decreased. The morphological testing results showed that the phosphorylation level of tau protein Thr231 of AD model rats was increased markedly in region of DG,CA1 and CA3 of the hippocampus. The intervention of the middle dose notoginsenoside Rg1 could significantly improve the learning and memory capacity of the model rats in Morris water maze. The notoginsenoside Rg1 in three different doses could all reduce the phosphorylation level of tau protein Thr231 in the hippocampal DG,CA1,CA3 regions,and there were no significant differences among the three doses. [Conclusions]The notoginsenoside Rg1 could improve Aβ_(25-35)-induced spatial learning and memory impairment of the AD model rats,and decreased the phosphorylation level of tau protein in hippocampus.
基金supported by grants from the Capital’s Funds for Health Improvement and Research(Grant No.CFH 2020-2-1026)Michigan Medicine-PKUHSC Joint Institute for Translational and Clinical Research(Grant No.BMU2020JI004)+1 种基金Beijing Talents foundation(Grant No.2018000021223ZK01)PKU-Baidu Fund(Grant No.2020BD034).
文摘Objective:This study aimed at examining the alterations in metabolomic profiles caused by treatment of H.pylori infection,and the associations between key plasma metabolites and the risk of gastric lesion progression during follow-up after treatment.Methods:An intervention trial was performed in 183 participants,117 of whom were H.pylori positive participants receiving treatment for H.pylori infection.H.pylori positive participants were prospectively followed for 182 to 1,289 days.Untargeted metabolomics assays were conducted on plasma samples collected at baseline,6 months after treatment,and during continued follow-up.Results:We identified 59 metabolites with differential posttreatment changes between participants with successful and failed H.pylori eradication,17 metabolites significantly distinguished participants with successful vs.failed eradication.Two metabolites[PC(18:1(11Z)/14:1(9Z))and(2S)-6-amino-2-formamidohexanamide]showed posttreatment changes positively associated with successful H.pylori eradication,and were inversely associated with the risk of gastric lesion progression among participants with successful eradication.In contrast,9-decenoic acid showed posttreatment changes inversely associated with successful eradication:its level was positively associated with the risk of gastric lesion progression among participants with successful eradication.Although the identified metabolites showed a temporary but significant decline after treatment,the trend generally reversed during continued follow-up,and pretreatment levels were restored.Conclusions:Treatment of H.pylori infection significantly altered plasma metabolic profiles in the short term,and key metabolites were capable of distinguishing participants with successful vs.failed eradication,but might not substantially affect metabolic regulation in the long term.Several plasma metabolites were differentially associated with the risk of gastric lesion progression among participants with successful or failed eradication.
基金supported by China Agriculture Research System of MOF and MARA(CARS-45-03).
文摘Both in nature and in aquaculture,fish may experience periods of food scarcity or hunger.The metabolic regulation of fish when nutritional state changes is a complex process that involves many factors.To study glucose metabolism adaptability during fasting and re-feeding in the black carp(Mylopharyngodon piceus),we measured changes in some biochemical indicators related to glucose metabolism.Five fish were sampled on days 0,1,3,5,and 10 of fasting(F,S1,S3,S5,and S10,respectively)and days 1,3,and 5 of re-feeding(RF1,RF3,and RF5,respectively).The serum glucose concentration decreased significantly at S1,reached the lowest point at S10,and increased significantly at RF1(P<0.05).The concentration of liver glycogen decreased significantly at S1 and reached the lowest level at S3,whereas the muscle glycogen level decreased significantly at S5 and reached the lowest value at S10(P<0.05).Both liver and muscle glycogen levels returned to the pre-fasting level at RF5(P<0.05).Regarding glycolysis,the concentrations of pyruvate kinase(PK)and hexokinase(HK)decreased significantly at S5 and increased significantly at RF5 and RF1,respectively(P<0.05).The concentrations of glucokinase(GCK)and insulin decreased significantly at S1 and increased significantly at RF1 and RF3,respectively(P<0.05).The mRNA expression levels of liver GCK and glucose transporter 2(GLUT2)decreased significantly at S1 and increased significantly at RF1 and RF5,respectively(P<0.05).As for gluconeogenesis,the concentration of glucose-6-phosphatase(G6PC)increased significantly at S1 and decreased significantly at RF1(P<0.05).The concentrations of glucagon and glucocorticoid(GC)increased significantly at S3 and significantly decreased at RF1 and RF5,respectively(P<0.05).The mRNA expression levels of liver G6PC and phosphoenolpyruvate carboxykinase(PEPCK)increased significantly at S3 and S1,and both decreased significantly at RF1(P<0.05).These results indicate that coordination between glycolysis and gluconeogenesis might be crucial for glucose homeostasis during fasting and re-feeding in the black carp.
基金Program of Natural Science Foundation of Shanghai,Grant/Award Number:21ZR1453800 and 22ZR1452400Program of National Natural Science Foundation of China,Grant/Award Number:82370057+3 种基金Fundamental Research Funds for the Central Universities,Grant/Award Number:22120220562Program of Shanghai Municipal Health Commission,Grant/Award Number:20204Y0384Program of National Key Research and Development Project of China,Grant/Award Number:2023YFC2509500。
文摘Background:Our previous study found that mouse embryonic neural stem cell(NSC)-derived exosomes(EXOs)regulated NSC differentiation via the miR-9/Hes1 axis.However,the effects of EXOs on brain microvascular endothelial cell(BMEC)dysfunction via the miR-9/Hes1 axis remain unknown.Therefore,the current study aimed to determine the effects of EXOs on BMEC proliferation,migration,and death via the miR-9/Hes1 axis.Methods:Immunofluorescence,quantitative real-time polymerase chain reaction,cell counting kit-8 assay,wound healing assay,calcein-acetoxymethyl/propidium iodide staining,and hematoxylin and eosin staining were used to determine the role and mechanism of EXOs on BMECs.Results:EXOs promoted BMEC proliferation and migration and reduced cell death under hypoxic conditions.The overexpression of miR-9 promoted BMEC prolifera-tion and migration and reduced cell death under hypoxic conditions.Moreover,miR-9 downregulation inhibited BMEC proliferation and migration and also promoted cell death.Hes1 silencing ameliorated the effect of amtagomiR-9 on BMEC proliferation and migration and cell death.Hyperemic structures were observed in the regions of the hippocampus and cortex in hypoxia-induced mice.Meanwhile,EXO treatment improved cerebrovascular alterations.Conclusion:NSC-derived EXOs can promote BMEC proliferation and migra-tion and reduce cell death via the miR-9/Hes1 axis under hypoxic conditions.Therefore,EXO therapeutic strategies could be considered for hypoxia-induced vascular injury.
基金supported by research grants from the National Natural Science Foundation of China(31600953 to X.Wang31530034 and 31330036 to F.Wang,31570791 and 91542205 to J.Min)+2 种基金the National Key R&D Program of China(2018YFA0507801 to J.Min and 2018YFA0507802 to F.Wang)the Zhejiang Provincial Natural Science Foundation of China(LQ15C110002 to X.Wang and LZ15H160002 to J.Min)the Nation Science and Technology Major Projects for Major New Drugs Innovation and Develop 2017ZX09101-005-004-002(L.Chen).
文摘Zinc levels are high in pancreatic β-cells, and zinc is involved in the synthesis, processing and secretion of insulin in these cells. However, precisely how cellular zinc homeostasis is regulated in pancreatic β-cells is poorly understood. By screening the expression of 14 Slc39a metal importer family member genes, we found that the zinc transporter Slc39a5 is significantly downregulated in pancreatic β-cells in diabetic db/db mice, obese ob/ob mice and high-fat diet-fed mice. Moreover,β-cell-specific Slc39a5 knockout mice have impaired insulin secretion. In addition, Slc39a5-deficient pancreatic islets have reduced glucose tolerance accompanied by reduced expression of Pgc-1α and its downstream target gene Glut2. The down-regulation of Glut2 in Slc39a5-deficient islets was rescued using agonists of Sirt1, Pgc-1α and Ppar-γ. At the mechanistic level, we found that Slc39a5-mediated zinc influx induces Glut2 expression via Sirt1-mediated Pgc-1α activation. These findings suggest that Slc39a5 may serve as a possible therapeutic target for diabetes-related conditions.
基金The work was supported by the National Natural Science Foundation of China （No. 81502955）, the Doctoral Scientific Research Foundation of Shanghai Ocean University （No. A2030214300077）, the Young Teachers Training Program of Shanghai （No. A12056160002）, and the Project Funded by Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening.
