Disturbances in nitric oxide synthase (NOS) and cyclooxygenase (COX) isozyme systems, manifested by the excessive NO and prostaglandin (PGE2) generation, are well-recognized features of gastric mucosal inflammatory re...Disturbances in nitric oxide synthase (NOS) and cyclooxygenase (COX) isozyme systems, manifested by the excessive NO and prostaglandin (PGE2) generation, are well-recognized features of gastric mucosal inflammatory responses to H. pylori infection. In this study, we report that H. pylori LPS-induced enhancement in gastric mucosal inducible (i) iNOS expression and COX-2 activation was accompanied by the impairment in constitutive (c) cNOS phosphorylation, up-regulation in the inhibitory κB kinase-β (IKKβ) activation and the increase in the transcriptional factor, NF-κB, nuclear translocation. Further, we show that abrogation of cNOS control over NF-κB activation has lead to induction of iNOS expression and COX-2 activation through S-nitrosylation. Moreover, we demonstrate that the modulatory effect of peptide hormone, ghrelin, on the LPS-induced changes was reflected in the increase in Src/Akt-dependent cNOS activation through phosphorylation and the suppression of IKK-β activity through cNOS-mediated IKK-β protein S-nitrosylation. As a result, ghrelin exerted the inhibitory effect on NF-κB nuclear translocation, thus causing the repression of iNOS gene induction and the inhibition in COX-2 activation through iNOS-dependent S-nitrosylation. Our findings point to cNOS activation as a pivotal element in the signaling cascade by which ghrelin exerts modulatory control over proinflammatory events triggered in gastric mucosa by H. pylori infection.展开更多
目的 探讨吸烟和戒烟对2型糖尿病大鼠IKK-β磷酸化的影响.方法 6周龄Wistar大鼠42只,随机分为4组：正常对照组（NC,7只）、糖尿病对照组（DC,7只）、糖尿病吸烟组（DS,14只）、糖尿病戒烟组（SC,14只）.糖尿病吸烟组分为吸烟8周组（DS8,...目的 探讨吸烟和戒烟对2型糖尿病大鼠IKK-β磷酸化的影响.方法 6周龄Wistar大鼠42只,随机分为4组：正常对照组（NC,7只）、糖尿病对照组（DC,7只）、糖尿病吸烟组（DS,14只）、糖尿病戒烟组（SC,14只）.糖尿病吸烟组分为吸烟8周组（DS8,7只）和12周组（DS12,7只）,糖尿病戒烟组分为吸烟8周戒烟组（SC8,7只）和吸烟12周戒烟组（SC12,7只）.吸烟组进行8周或12周被动吸烟,戒烟组在8周或12周的被动吸烟后停止吸烟4周.Western blot方法检测各组大鼠骨骼肌中IKK-β磷酸化的程度.结果 与NC组比较,DC组IKK-β磷酸化程度增强（0.16±0.05 vs 0.30±0.08,P〈0.01）;与DC组和SC8组比较,DS8组IKK-β磷酸化程度有增强趋势,但差异无统计学意义（0.30±0.08,0.36±0.10 vs 0.40±0.09,P〉0.05）;DS12组IKK-β磷酸化程度明显增强,显著高于DC组和SC12组（0.74±0.11 vs 0.30±0.08,0.35±0.07,P〈0.01）.结论 随吸烟时间延长2型糖尿病大鼠IKK-β磷酸化程度增强,戒烟后IKK-β磷酸化程度减弱,提示IKK-β磷酸化水平与吸烟致2型糖尿病的发生发展机制有关.展开更多
Objective:To explore the anti-cancer activity of maslinic acid against colorectal cancer(CRC)cell lines and its possible mechanism.Methods:The inhibitory effect of maslinic acid was screened against five CRC cell line...Objective:To explore the anti-cancer activity of maslinic acid against colorectal cancer(CRC)cell lines and its possible mechanism.Methods:The inhibitory effect of maslinic acid was screened against five CRC cell lines(HT-29,HCT 116,SW480,SW48,and LS 174 T)via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.Apoptosis and cell cycle analyses were carried out using annexinⅤ-FITC/propidium iodide staining and propidium iodide staining,respectively and subjected to fluorescence-activated cell sorting analysis.Protein expression studies of inhibitor ofκB kinase-β(IKK-β),checkpoint kinase 1(Chk1)and cyclin D1 were conducted using the JESS system.Results:Maslinic acid exhibited growth inhibitory effect in a doseand time-dependent manner in HT-29 and HCT 116 cell lines.A more prominent apoptosis induced by maslinic acid was observed in HCT 116 cell line.However,in HT-29 cell line,maslinic acid induced cell cycle arrest by inhibiting the G1-S transition,which was accompanied by the downregulation of cyclin D1.The expression of unphosphorylated IKK-βprotein was increased in both(HT-29 and HCT 116)cell lines after maslinic acid treatment.Conclusions:Maslinic acid inhibits the growth of HT-29 and HCT 116 cells in a different manner,induces cell cycle arrest in HT-29 cells and causes apoptosis in HCT 116 cells partially via NF-κB pathway inhibition.展开更多
Herpes simplex virus type 1(HSV-1)is a ubiquitous and widespread human pathogen,which gives rise to a range of diseases,including cold sores,corneal blindness,and encephalitis.Currently,the use of nucleoside analogs,s...Herpes simplex virus type 1(HSV-1)is a ubiquitous and widespread human pathogen,which gives rise to a range of diseases,including cold sores,corneal blindness,and encephalitis.Currently,the use of nucleoside analogs,such as acyclovir and penciclovir,in treating HSV-1 infection often presents limitation due to their side effects and low efficacy for drug-resistance strains.Therefore,new anti-herpetic drugs and strategies should be urgently developed.Here,we reported that baicalein,a naturally derived compound widely used in Asian countries,strongly inhibited HSV-1 replication in several models.Baicalein was effective against the replication of both HSV-1/F and HSV-1/Blue(an acyclovir-resistant strain)in vitro.In the ocular inoculation mice model,baicalein markedly reduced in vivo HSV-1/F replication,receded inflammatory storm and attenuated histological changes in the cornea.Consistently,baicalein was found to reduce the mortality of mice,viral loads both in nose and trigeminal ganglia in HSV-1 intranasal infection model.Moreover,an ex vivo HSV-1-EGFP infection model established in isolated murine epidermal sheets confirmed that baicalein suppressed HSV-1 replication.Further investigations unraveled that dual mechanisms,inactivating viral particles and inhibiting IκB kinase beta(IKK-β)phosphorylation,were involved in the anti-HSV-1 effect of baicalein.Collectively,our findings identified baicalein as a promising therapy candidate against the infection of HSV-1,especially acyclovir-resistant strain.展开更多
文摘Disturbances in nitric oxide synthase (NOS) and cyclooxygenase (COX) isozyme systems, manifested by the excessive NO and prostaglandin (PGE2) generation, are well-recognized features of gastric mucosal inflammatory responses to H. pylori infection. In this study, we report that H. pylori LPS-induced enhancement in gastric mucosal inducible (i) iNOS expression and COX-2 activation was accompanied by the impairment in constitutive (c) cNOS phosphorylation, up-regulation in the inhibitory κB kinase-β (IKKβ) activation and the increase in the transcriptional factor, NF-κB, nuclear translocation. Further, we show that abrogation of cNOS control over NF-κB activation has lead to induction of iNOS expression and COX-2 activation through S-nitrosylation. Moreover, we demonstrate that the modulatory effect of peptide hormone, ghrelin, on the LPS-induced changes was reflected in the increase in Src/Akt-dependent cNOS activation through phosphorylation and the suppression of IKK-β activity through cNOS-mediated IKK-β protein S-nitrosylation. As a result, ghrelin exerted the inhibitory effect on NF-κB nuclear translocation, thus causing the repression of iNOS gene induction and the inhibition in COX-2 activation through iNOS-dependent S-nitrosylation. Our findings point to cNOS activation as a pivotal element in the signaling cascade by which ghrelin exerts modulatory control over proinflammatory events triggered in gastric mucosa by H. pylori infection.
文摘目的 探讨吸烟和戒烟对2型糖尿病大鼠IKK-β磷酸化的影响.方法 6周龄Wistar大鼠42只,随机分为4组：正常对照组（NC,7只）、糖尿病对照组（DC,7只）、糖尿病吸烟组（DS,14只）、糖尿病戒烟组（SC,14只）.糖尿病吸烟组分为吸烟8周组（DS8,7只）和12周组（DS12,7只）,糖尿病戒烟组分为吸烟8周戒烟组（SC8,7只）和吸烟12周戒烟组（SC12,7只）.吸烟组进行8周或12周被动吸烟,戒烟组在8周或12周的被动吸烟后停止吸烟4周.Western blot方法检测各组大鼠骨骼肌中IKK-β磷酸化的程度.结果 与NC组比较,DC组IKK-β磷酸化程度增强（0.16±0.05 vs 0.30±0.08,P〈0.01）;与DC组和SC8组比较,DS8组IKK-β磷酸化程度有增强趋势,但差异无统计学意义（0.30±0.08,0.36±0.10 vs 0.40±0.09,P〉0.05）;DS12组IKK-β磷酸化程度明显增强,显著高于DC组和SC12组（0.74±0.11 vs 0.30±0.08,0.35±0.07,P〈0.01）.结论 随吸烟时间延长2型糖尿病大鼠IKK-β磷酸化程度增强,戒烟后IKK-β磷酸化程度减弱,提示IKK-β磷酸化水平与吸烟致2型糖尿病的发生发展机制有关.
基金supported by Fundamental Research Grant Scheme Grant(FRGS/1/2018/SKK08/UTAR/01/2)from Ministry of Higher Education(MOHE),Malaysia
文摘Objective:To explore the anti-cancer activity of maslinic acid against colorectal cancer(CRC)cell lines and its possible mechanism.Methods:The inhibitory effect of maslinic acid was screened against five CRC cell lines(HT-29,HCT 116,SW480,SW48,and LS 174 T)via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.Apoptosis and cell cycle analyses were carried out using annexinⅤ-FITC/propidium iodide staining and propidium iodide staining,respectively and subjected to fluorescence-activated cell sorting analysis.Protein expression studies of inhibitor ofκB kinase-β(IKK-β),checkpoint kinase 1(Chk1)and cyclin D1 were conducted using the JESS system.Results:Maslinic acid exhibited growth inhibitory effect in a doseand time-dependent manner in HT-29 and HCT 116 cell lines.A more prominent apoptosis induced by maslinic acid was observed in HCT 116 cell line.However,in HT-29 cell line,maslinic acid induced cell cycle arrest by inhibiting the G1-S transition,which was accompanied by the downregulation of cyclin D1.The expression of unphosphorylated IKK-βprotein was increased in both(HT-29 and HCT 116)cell lines after maslinic acid treatment.Conclusions:Maslinic acid inhibits the growth of HT-29 and HCT 116 cells in a different manner,induces cell cycle arrest in HT-29 cells and causes apoptosis in HCT 116 cells partially via NF-κB pathway inhibition.
基金partly supported by National Natural Science Foundation of China(Grant Nos.U1801284,81573675,81622050,81873209 and 81673709)National Key Research and Development Program of China(Grant No.2017YFC1700404)+5 种基金the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(Grant No.2017BT01Y036,China)GDUPS(2019,China)the Guangdong Science and Technology Foundation(Grant No.2017A030306004)the Program of Hong Kong Scholar(XJ2016017,China)Science and Technology Program of Guangzhou(Grant No.201903010062,China)the Youth Top-notch Talent Support Program of Guangdong Province(Grant No.2016TQ03R586,China)
文摘Herpes simplex virus type 1(HSV-1)is a ubiquitous and widespread human pathogen,which gives rise to a range of diseases,including cold sores,corneal blindness,and encephalitis.Currently,the use of nucleoside analogs,such as acyclovir and penciclovir,in treating HSV-1 infection often presents limitation due to their side effects and low efficacy for drug-resistance strains.Therefore,new anti-herpetic drugs and strategies should be urgently developed.Here,we reported that baicalein,a naturally derived compound widely used in Asian countries,strongly inhibited HSV-1 replication in several models.Baicalein was effective against the replication of both HSV-1/F and HSV-1/Blue(an acyclovir-resistant strain)in vitro.In the ocular inoculation mice model,baicalein markedly reduced in vivo HSV-1/F replication,receded inflammatory storm and attenuated histological changes in the cornea.Consistently,baicalein was found to reduce the mortality of mice,viral loads both in nose and trigeminal ganglia in HSV-1 intranasal infection model.Moreover,an ex vivo HSV-1-EGFP infection model established in isolated murine epidermal sheets confirmed that baicalein suppressed HSV-1 replication.Further investigations unraveled that dual mechanisms,inactivating viral particles and inhibiting IκB kinase beta(IKK-β)phosphorylation,were involved in the anti-HSV-1 effect of baicalein.Collectively,our findings identified baicalein as a promising therapy candidate against the infection of HSV-1,especially acyclovir-resistant strain.
