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
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
Rapeseed(Brassica napus L.)is a global oil crop.Salinity stress impedes the growth of rapeseed,especially during seed germination.The key genes mediating salinity stress response during seed germination in B.napus rem...Rapeseed(Brassica napus L.)is a global oil crop.Salinity stress impedes the growth of rapeseed,especially during seed germination.The key genes mediating salinity stress response during seed germination in B.napus remain largely unknown.Here,we found that all six paralogs of C2H2 zinc finger transcription factor WIP DOMAIN PROTEIN 2(BnaWIP2)showed increased expression during the initial 12 hours of germination,and expression was further enhanced by salinity stress.Under NaCl treatment,knocking out all six BnaWIP2 paralogs in B.napus led to significantly reduced germination,while overexpression of BnaC06.WIP2 promoted germination.Transcriptomic analysis revealed that BnaC06.WIP2 downregulated a series of genes related to abscisic acid(ABA)biosynthesis and signaling,among which BnaA05.NCED3,BnaC04.ABI5-2,BnaA03.EM6,and BnaA05.EM6 were directly repressed by BnaC06.WIP2.Further analysis showed that in germinating seeds,BnaC06.WIP2 was induced by ABA and in turn restrained ABA production,indicating that BnaC06.WIP2 forms a negative feedback loop with ABA to promote seed germination under salinity stress in B.napus.Collectively,these results enhance our understanding of the novel function of BnaWIP2 and provide valuable genetic resources for breeding salinity-tolerant rapeseed varieties.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
目的探讨血清半乳糖缺陷型IgA1(galactose-deficient IgA1,Gd-IgA1)、补体C4、补体因子H(complement factor H,CFH)和补体因子H相关蛋白(complement factor H related proteins,CFHRP)1、3、5在IgA肾病(IgA nephropathy,IgAN)中的诊断...目的探讨血清半乳糖缺陷型IgA1(galactose-deficient IgA1,Gd-IgA1)、补体C4、补体因子H(complement factor H,CFH)和补体因子H相关蛋白(complement factor H related proteins,CFHRP)1、3、5在IgA肾病(IgA nephropathy,IgAN)中的诊断价值。方法本研究为回顾性研究,收集2021年11月1日至2023年12月31日在雅安市人民医院行肾穿刺活检诊断为原发性IgAN的患者58例,同期其他肾小球疾病患者48例和健康志愿者20名作为对照,采用酶联免疫吸附分析法检测上述对象血清IgA、补体C4、Gd-IgA1、CFH、CFHRP1、3、5浓度并行组间比较,绘制受试者工作特征曲线评估血清Gd-IgA1、Gd-IgA1/CFH、CFHRP1/CFH、CFHRP5/CFH在IgAN中的诊断价值,筛选出受试者工作特征曲线的曲线下面积较大的指标Gd-IgA1、CFHRP1/CFH、CFHRP5/CFH,重点研究Gd-IgA1分别联合检测CFHRP1/CFH、CFHRP5/CFH对IgAN的诊断价值。结果原发性IgAN组患者血清IgA[1.568(1.344,1.705)g/L比1.177(0.618,1.893)g/L、0.538(0.433,0.732)g/L]、补体C4[0.547(0.494,0.643)g/L比0.396(0.312,0.515)g/L、0.289(0.186,0.356)g/L]、Gd-IgA1[0.003(0.002,0.004)g/L比0.002(0.001,0.003)g/L、0.0017(0.0010,0.0020)g/L]、CFHRP1[0.013(0.011,0.015)g/L比0.010(0.009,0.013)g/L、0.011(0.009,0.012)g/L]水平及Gd-IgA1/CFH[0.023(0.017,0.030)比0.012(0.009,0.021)mmol/L、0.005(0.004,0.007)mmol/L]、CFHRP1/CFH[0.115(0.091,0.161)比0.093(0.061,0.108)、0.038(0.028,0.043)]比值明显高于其他肾小球疾病组和健康组(P<0.05),血清CFH[0.000109(0.000089,0.000110)g/L比0.000285(0.000259,0.000347)g/L]浓度低于健康组(P<0.05);血清Gd-IgA1联合CFHRP1/CFH、CFHRP5/CFH诊断原发性IgAN的曲线下面积分别为0.946(95%CI:0.908~0.985)、0.926(95%CI:0.874~0.978),灵敏度分别为80%、90%,特异度分别为93.9%、86.3%。结论Gd-IgA1联合检测CFHRP1/CFH、CFHRP5/CFH对于诊断原发性IgAN具有较好价值,或可作为诊断IgAN的潜在无创性生物标志物。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
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.
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.
基金supported by the Biological Breeding-National Science and Technology Major Project(2022ZD04010)Scientific and Technological Innovation Team of Shaanxi Province(2024RS-CXTD-69)+1 种基金Key Research and Development Program of Shaanxi Province(2021LLRH-07)a grant from the Yang Ling Seed Industry Innovation Center(K3031122024).
文摘Rapeseed(Brassica napus L.)is a global oil crop.Salinity stress impedes the growth of rapeseed,especially during seed germination.The key genes mediating salinity stress response during seed germination in B.napus remain largely unknown.Here,we found that all six paralogs of C2H2 zinc finger transcription factor WIP DOMAIN PROTEIN 2(BnaWIP2)showed increased expression during the initial 12 hours of germination,and expression was further enhanced by salinity stress.Under NaCl treatment,knocking out all six BnaWIP2 paralogs in B.napus led to significantly reduced germination,while overexpression of BnaC06.WIP2 promoted germination.Transcriptomic analysis revealed that BnaC06.WIP2 downregulated a series of genes related to abscisic acid(ABA)biosynthesis and signaling,among which BnaA05.NCED3,BnaC04.ABI5-2,BnaA03.EM6,and BnaA05.EM6 were directly repressed by BnaC06.WIP2.Further analysis showed that in germinating seeds,BnaC06.WIP2 was induced by ABA and in turn restrained ABA production,indicating that BnaC06.WIP2 forms a negative feedback loop with ABA to promote seed germination under salinity stress in B.napus.Collectively,these results enhance our understanding of the novel function of BnaWIP2 and provide valuable genetic resources for breeding salinity-tolerant rapeseed varieties.
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.
文摘目的探讨血清半乳糖缺陷型IgA1(galactose-deficient IgA1,Gd-IgA1)、补体C4、补体因子H(complement factor H,CFH)和补体因子H相关蛋白(complement factor H related proteins,CFHRP)1、3、5在IgA肾病(IgA nephropathy,IgAN)中的诊断价值。方法本研究为回顾性研究,收集2021年11月1日至2023年12月31日在雅安市人民医院行肾穿刺活检诊断为原发性IgAN的患者58例,同期其他肾小球疾病患者48例和健康志愿者20名作为对照,采用酶联免疫吸附分析法检测上述对象血清IgA、补体C4、Gd-IgA1、CFH、CFHRP1、3、5浓度并行组间比较,绘制受试者工作特征曲线评估血清Gd-IgA1、Gd-IgA1/CFH、CFHRP1/CFH、CFHRP5/CFH在IgAN中的诊断价值,筛选出受试者工作特征曲线的曲线下面积较大的指标Gd-IgA1、CFHRP1/CFH、CFHRP5/CFH,重点研究Gd-IgA1分别联合检测CFHRP1/CFH、CFHRP5/CFH对IgAN的诊断价值。结果原发性IgAN组患者血清IgA[1.568(1.344,1.705)g/L比1.177(0.618,1.893)g/L、0.538(0.433,0.732)g/L]、补体C4[0.547(0.494,0.643)g/L比0.396(0.312,0.515)g/L、0.289(0.186,0.356)g/L]、Gd-IgA1[0.003(0.002,0.004)g/L比0.002(0.001,0.003)g/L、0.0017(0.0010,0.0020)g/L]、CFHRP1[0.013(0.011,0.015)g/L比0.010(0.009,0.013)g/L、0.011(0.009,0.012)g/L]水平及Gd-IgA1/CFH[0.023(0.017,0.030)比0.012(0.009,0.021)mmol/L、0.005(0.004,0.007)mmol/L]、CFHRP1/CFH[0.115(0.091,0.161)比0.093(0.061,0.108)、0.038(0.028,0.043)]比值明显高于其他肾小球疾病组和健康组(P<0.05),血清CFH[0.000109(0.000089,0.000110)g/L比0.000285(0.000259,0.000347)g/L]浓度低于健康组(P<0.05);血清Gd-IgA1联合CFHRP1/CFH、CFHRP5/CFH诊断原发性IgAN的曲线下面积分别为0.946(95%CI:0.908~0.985)、0.926(95%CI:0.874~0.978),灵敏度分别为80%、90%,特异度分别为93.9%、86.3%。结论Gd-IgA1联合检测CFHRP1/CFH、CFHRP5/CFH对于诊断原发性IgAN具有较好价值,或可作为诊断IgAN的潜在无创性生物标志物。
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.
