BACKGROUND Complement overactivation is a major driver of lupus nephritis(LN).Impaired interactions of C-reactive protein(CRP)with complement factor H(CFH)have been shown as a pathogenic mechanism that contributes to ...BACKGROUND Complement overactivation is a major driver of lupus nephritis(LN).Impaired interactions of C-reactive protein(CRP)with complement factor H(CFH)have been shown as a pathogenic mechanism that contributes to the overactivation of complement in LN.However,genetic variations of neither CRP nor CFH show consistent influences on the risk of LN.AIM To examine whether genetic variations of CRP and CFH in combination can improve the risk stratification in Chinese population.METHODS We genotyped six CRP single nucleotide polymorphisms(SNPs)(rs1205,rs3093062,rs2794521,rs1800947,rs3093077,and rs1130864)and three CFH SNPs(rs482934,rs1061170,and rs1061147)in 270 LN patients and 303 healthy subjects.RESULTS No linkage was found among CRP and CFH SNPs,indicating lack of genetic interactions between the two genes.Moreover,CRP and CFH SNPs,neither individually nor in combination,are associated with the risk or clinical manifestations of LN.Given the unambiguous pathogenic roles of the two genes.CONCLUSION These findings suggest that the biological effects of most genetic variations of CRP and CFH on their expressions or activities are not sufficient to influence the disease course of LN.展开更多
AIM: Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world and complement factor H (CFH) polymorphism has been found to associate with the AMD. To investigate whether the Y402...AIM: Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world and complement factor H (CFH) polymorphism has been found to associate with the AMD. To investigate whether the Y402H variant in CFH is associated with AMD in Chinese populations, a systematic review and meta-analysis were performed to estimate the magnitude of the gene effect and the possible mode of action. METHODS: A meta-analysis was performed using data available from ten case-control studies assessing association between the CFH Y402H polymorphism and AMD in Chinese populations involving 1538 AMD. Data extraction and study quality assessment were performed in duplicate. Summary odds ratios (ORs) and 95% confidence intervals (CIs) an allele contrast and genotype contrast were estimated usingfixed- effects models. The Q-statistic test was used to assess heterogeneity, and Funnel plot was used to evaluate publication bias. RESULTS: Seven of ten case-control studies were neovascular AMD, and few studies came from west and north of China. There was strong evidence for association between CFH and AMD in Chinese population, with those having risk allele C 2.35 times more likely to have AMD than subjects with T allele. Evidence of publication bias was not observed in our meta-analysis. CONCLUSION: This meta-analysis summarizes the strong evidence for an association between CFH and AMD in Chinese and indicates each C allele increasing the odds of AMD by 2.33-fold. But more evidences about the relation between CFH polymorphism and different type of Chinese AMD from various district were needed.展开更多
Angiogenesis,the process of formation of new capillaries from existing blood vessels,is required for multiple physiological and pathological processes.Complement factorH(CFH)is a plasma protein that inhibits the alter...Angiogenesis,the process of formation of new capillaries from existing blood vessels,is required for multiple physiological and pathological processes.Complement factorH(CFH)is a plasma protein that inhibits the alternative pathway of the complement system.Loss of CFH enhances the alternative pathway and increases complement activation fragments with pro-angiogenic capacity,including complement 3a,complement 5a,and membrane attack complex.CFH protein contains binding sites for C-reactive protein,malondialdehyde,and endothelial heparan sulfates.Dysfunction of CFH prevents its interaction with these molecules and initiates pro-angiogenic events.Mutations in the CFH gene have been found in patients with age-related macular degeneration characterized by choroidal neovascularization.The Cfh-deficient mice show an increase in angiogenesis,which is decreased by administration of recombinant CFH protein.In this review,we summarize the molecular mechanisms of the anti-angiogenic effects of CFH and the regulatory mechanisms of CFH expression.The therapeutic potential of recombinant CFH protein in angiogenesisrelated diseases has also been discussed.展开更多
目的筛选家系早发冠心病血瘀证的特异性蛋白,为今后临床早期诊断和预防疾病提供潜在生物标志物。方法通过同位素相对标记与绝对定量技术(isobaric tags for relative and absolute quantification,i TRAQ)分析家系早发冠心病血瘀证患者...目的筛选家系早发冠心病血瘀证的特异性蛋白,为今后临床早期诊断和预防疾病提供潜在生物标志物。方法通过同位素相对标记与绝对定量技术(isobaric tags for relative and absolute quantification,i TRAQ)分析家系早发冠心病血瘀证患者、家系早发冠心病非血瘀证患者及健康人的血浆蛋白表达,数据分析后得到各组间的差异蛋白表达情况,再经差异蛋白筛选标准初步得到疾病的预测蛋白,并使用Western blot验证预测蛋白。结果通过i TRAQ技术共得到差异蛋白75个,其中家系早发冠心病血瘀证组与健康对照组之间共得到32个差异蛋白,包括22个上调蛋白与10个下调蛋白,共涉及429个生物学过程,其与角质化、皮肤发展、蛋白质激活级联反应等关系最为密切;在代谢途径金黄色葡萄球菌感染、补体和凝血级联、血小板激活等KEGG通路上富集。与健康对照组相比,家系早发冠心病血瘀证组差异蛋白补体因子H(complement factor H,CFH)表达水平差异有统计学意义(P<0.01)。结论经差异蛋白筛选标准得到的CFH蛋白,可作为家系早发冠心病血瘀证早期诊断的潜在生物标志物。展开更多
Complement proteins in blood recognize charged particles.The anionic phospholipid(aPL)cardiolipin binds both complement proteins C1q and factor H.C1q is an activator of the complement classical pathway,while factor H ...Complement proteins in blood recognize charged particles.The anionic phospholipid(aPL)cardiolipin binds both complement proteins C1q and factor H.C1q is an activator of the complement classical pathway,while factor H is an inhibitor of the alternative pathway.To examine opposing effects of C1q and factor H on complement activation by aPL,we surveyed C1q and factor H binding,and complement activation by aPL,either coated on microtitre plates or in liposomes.Both C1q and factor H bound to all aPL tested,and competed directly with each other for binding.All the aPL activated the complement classical pathway,but negligibly the alternative pathway,consistent with accepted roles of C1q and factor H.However,in this system,factor H,by competing directly with C1q for binding to aPL,acts as a direct regulator of the complement classical pathway.This regulatory mechanism is distinct from its action on the alternative pathway.Regulation of classical pathway activation by factor H was confirmed by measuring C4 activation by aPL in human sera in which the C1q:factor H molar ratio was adjusted over a wide range.Thus factor H,which is regarded as a down-regulator only of the alternative pathway,has a distinct role in downregulating activation of the classical complement pathway by aPL.A factor H homologue,β2-glycoprotein-1,also strongly inhibits C1q binding to cardiolipin.Recombinant globular domains of C1q A,B and C chains bound aPL similarly to native C1q,confirming that C1q binds aPL via its globular heads.展开更多
Proteins of the complement system are known to interact with many charged substances.We recently characterized binding of C1q and factor H to immobilized and liposomal anionic phospholipids.Factor H inhibited C1q bind...Proteins of the complement system are known to interact with many charged substances.We recently characterized binding of C1q and factor H to immobilized and liposomal anionic phospholipids.Factor H inhibited C1q binding to anionic phospholipids,suggesting a role for factor H in regulating activation of the complement classical pathway by anionic phospholipids.To extend this finding,we examined interactions of C1q and factor H with lipid A,a well-characterized activator of the classical pathway.We report that C1q and factor H both bind to immobilized lipid A,lipid A liposomes and intact Escherichia coli TG1.Factor H competes with C1q for binding to these targets.Furthermore,increasing the factor H:C1q molar ratio in serum diminished C4b fixation,indicating that factor H diminishes classical pathway activation.The recombinant forms of the Cterminal,globular heads of C1q A,B and C chains bound to lipid A and E.coli in a manner qualitatively similar to native C1q,confirming that C1q interacts with these targets via its globular head region.These observations reinforce our proposal that factor H has an additional complement regulatory role of down-regulating classical pathway activation in response to certain targets.This is distinct from its role as an alternative pathway downregulator.We suggest that under physiological conditions,factor H may serve as a downregulator of bacterially-driven inflammatory responses,thereby finetuning and balancing the inflammatory response in infections with Gram-negative bacteria.展开更多
INTRODUCTIONInsulin-like growth factor Ⅱ(IGF-Ⅱ) is a mitogenic peptide of 74 kD and is mostly synthesized in fetal liver tissue .IGF-Ⅱ is believed to play an important role in fetal growth and development and is in...INTRODUCTIONInsulin-like growth factor Ⅱ(IGF-Ⅱ) is a mitogenic peptide of 74 kD and is mostly synthesized in fetal liver tissue .IGF-Ⅱ is believed to play an important role in fetal growth and development and is involved in cellular proliferation and differentiation[1-5]. Recently ,several researchers have reported increased expression of the IGF-Ⅱgene in human hepatocellular carcinoma (HCC) and adjacent non-cancerous liver tissues [6-10].展开更多
文摘BACKGROUND Complement overactivation is a major driver of lupus nephritis(LN).Impaired interactions of C-reactive protein(CRP)with complement factor H(CFH)have been shown as a pathogenic mechanism that contributes to the overactivation of complement in LN.However,genetic variations of neither CRP nor CFH show consistent influences on the risk of LN.AIM To examine whether genetic variations of CRP and CFH in combination can improve the risk stratification in Chinese population.METHODS We genotyped six CRP single nucleotide polymorphisms(SNPs)(rs1205,rs3093062,rs2794521,rs1800947,rs3093077,and rs1130864)and three CFH SNPs(rs482934,rs1061170,and rs1061147)in 270 LN patients and 303 healthy subjects.RESULTS No linkage was found among CRP and CFH SNPs,indicating lack of genetic interactions between the two genes.Moreover,CRP and CFH SNPs,neither individually nor in combination,are associated with the risk or clinical manifestations of LN.Given the unambiguous pathogenic roles of the two genes.CONCLUSION These findings suggest that the biological effects of most genetic variations of CRP and CFH on their expressions or activities are not sufficient to influence the disease course of LN.
文摘AIM: Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world and complement factor H (CFH) polymorphism has been found to associate with the AMD. To investigate whether the Y402H variant in CFH is associated with AMD in Chinese populations, a systematic review and meta-analysis were performed to estimate the magnitude of the gene effect and the possible mode of action. METHODS: A meta-analysis was performed using data available from ten case-control studies assessing association between the CFH Y402H polymorphism and AMD in Chinese populations involving 1538 AMD. Data extraction and study quality assessment were performed in duplicate. Summary odds ratios (ORs) and 95% confidence intervals (CIs) an allele contrast and genotype contrast were estimated usingfixed- effects models. The Q-statistic test was used to assess heterogeneity, and Funnel plot was used to evaluate publication bias. RESULTS: Seven of ten case-control studies were neovascular AMD, and few studies came from west and north of China. There was strong evidence for association between CFH and AMD in Chinese population, with those having risk allele C 2.35 times more likely to have AMD than subjects with T allele. Evidence of publication bias was not observed in our meta-analysis. CONCLUSION: This meta-analysis summarizes the strong evidence for an association between CFH and AMD in Chinese and indicates each C allele increasing the odds of AMD by 2.33-fold. But more evidences about the relation between CFH polymorphism and different type of Chinese AMD from various district were needed.
基金supported by the National Nature Science Foundation of China (82171318,82241030,82011530024)the State Program of Scientific Research“Natural resources and the Environment” (3.01,2020–2021,Belarus)Academic Promotion Program of Shandong First Medical University (2019QL014)and Shandong Taishan Scholarship (J.L).
文摘Angiogenesis,the process of formation of new capillaries from existing blood vessels,is required for multiple physiological and pathological processes.Complement factorH(CFH)is a plasma protein that inhibits the alternative pathway of the complement system.Loss of CFH enhances the alternative pathway and increases complement activation fragments with pro-angiogenic capacity,including complement 3a,complement 5a,and membrane attack complex.CFH protein contains binding sites for C-reactive protein,malondialdehyde,and endothelial heparan sulfates.Dysfunction of CFH prevents its interaction with these molecules and initiates pro-angiogenic events.Mutations in the CFH gene have been found in patients with age-related macular degeneration characterized by choroidal neovascularization.The Cfh-deficient mice show an increase in angiogenesis,which is decreased by administration of recombinant CFH protein.In this review,we summarize the molecular mechanisms of the anti-angiogenic effects of CFH and the regulatory mechanisms of CFH expression.The therapeutic potential of recombinant CFH protein in angiogenesisrelated diseases has also been discussed.
文摘Complement proteins in blood recognize charged particles.The anionic phospholipid(aPL)cardiolipin binds both complement proteins C1q and factor H.C1q is an activator of the complement classical pathway,while factor H is an inhibitor of the alternative pathway.To examine opposing effects of C1q and factor H on complement activation by aPL,we surveyed C1q and factor H binding,and complement activation by aPL,either coated on microtitre plates or in liposomes.Both C1q and factor H bound to all aPL tested,and competed directly with each other for binding.All the aPL activated the complement classical pathway,but negligibly the alternative pathway,consistent with accepted roles of C1q and factor H.However,in this system,factor H,by competing directly with C1q for binding to aPL,acts as a direct regulator of the complement classical pathway.This regulatory mechanism is distinct from its action on the alternative pathway.Regulation of classical pathway activation by factor H was confirmed by measuring C4 activation by aPL in human sera in which the C1q:factor H molar ratio was adjusted over a wide range.Thus factor H,which is regarded as a down-regulator only of the alternative pathway,has a distinct role in downregulating activation of the classical complement pathway by aPL.A factor H homologue,β2-glycoprotein-1,also strongly inhibits C1q binding to cardiolipin.Recombinant globular domains of C1q A,B and C chains bound aPL similarly to native C1q,confirming that C1q binds aPL via its globular heads.
文摘Proteins of the complement system are known to interact with many charged substances.We recently characterized binding of C1q and factor H to immobilized and liposomal anionic phospholipids.Factor H inhibited C1q binding to anionic phospholipids,suggesting a role for factor H in regulating activation of the complement classical pathway by anionic phospholipids.To extend this finding,we examined interactions of C1q and factor H with lipid A,a well-characterized activator of the classical pathway.We report that C1q and factor H both bind to immobilized lipid A,lipid A liposomes and intact Escherichia coli TG1.Factor H competes with C1q for binding to these targets.Furthermore,increasing the factor H:C1q molar ratio in serum diminished C4b fixation,indicating that factor H diminishes classical pathway activation.The recombinant forms of the Cterminal,globular heads of C1q A,B and C chains bound to lipid A and E.coli in a manner qualitatively similar to native C1q,confirming that C1q interacts with these targets via its globular head region.These observations reinforce our proposal that factor H has an additional complement regulatory role of down-regulating classical pathway activation in response to certain targets.This is distinct from its role as an alternative pathway downregulator.We suggest that under physiological conditions,factor H may serve as a downregulator of bacterially-driven inflammatory responses,thereby finetuning and balancing the inflammatory response in infections with Gram-negative bacteria.
基金Project supported by the National Nature Science Foundation of China,No.39470774
文摘INTRODUCTIONInsulin-like growth factor Ⅱ(IGF-Ⅱ) is a mitogenic peptide of 74 kD and is mostly synthesized in fetal liver tissue .IGF-Ⅱ is believed to play an important role in fetal growth and development and is involved in cellular proliferation and differentiation[1-5]. Recently ,several researchers have reported increased expression of the IGF-Ⅱgene in human hepatocellular carcinoma (HCC) and adjacent non-cancerous liver tissues [6-10].
