· AIM: To investigate the expression of complement factors in the posterior scleral fibroblasts of guinea pigs with negative lens-defocused myopia.· METHODS: Eighteen guinea pigs were assigned randomly to tw...· AIM: To investigate the expression of complement factors in the posterior scleral fibroblasts of guinea pigs with negative lens-defocused myopia.· METHODS: Eighteen guinea pigs were assigned randomly to two groups: the negative lens-defocused group(NLD group, n =9) and the normal control without treatment group(NC group, n =9). The effect of myopic induction was compared in three subgroups: eyes treated with a-10.00 D negative lens in the NLD group(NL group), eyes treated with a plano(0 D) lens in the NLD group(PL group), and untreated right eyes in the NC group(NC group). The following analyses were conducted at four weeks: examination of the refractive error via retinoscopy, assessment of complement C5b-9expression in the posterior scleral fibroblasts using immunohistochemistry, and measurements of complement C1 q and C3 protein levels in the posterior sclera by Western blot.·RESULTS: After an induction period of four weeks, a significant myopic shift was detected in the eyes of the NL group, relative to that of the PL and NC groups(P 【0.05). Data analysis showed a significant increase in the percentage of C5b-9 immunopositive fibroblasts in the posterior sclera of the NL group eyes, compared to the PL group(q =11.50, P 【0.001). Significantly higher levels of C1q(q =4.94, P =0.01) and C3(q =4.07, P =0.03)protein were detected in the posterior sclera of NL group eyes, compared to the PL group. There were no significant difference between the PL and NC groups for C5b-9(q =2.44, P =0.10), C1q(q =1.55, P =0.53) and C3(q =0.98, P =0.77) in the posterior sclera.·CONCLUSION: The data from present study provide evidence of the up-regulation of C5b-9, C1 q and C3 in the posterior scleral fibroblasts in a NLD myopic animal model. The results suggest that the complement system may be involved in the development of myopia.展开更多
AIM： To systematically review the association between complement factors I （CFI） polymorphisms and age- related macular degeneration （AMD） and to explore whether CFI polymorphisms are associated with AMD, METHODS...AIM： To systematically review the association between complement factors I （CFI） polymorphisms and age- related macular degeneration （AMD） and to explore whether CFI polymorphisms are associated with AMD, METHODS： Meta-analysis of articles published from 1995 to January 2015 of articles involved with AMD and polymorphisms of the CFI gene. Eligible data were pooled in a Meta-analysis, analyzing using STATA software （version 12.0）, Review Manager （version 5.2） and different models based on the heterogeneity of effect sizes. Egger＇s test, Begg＇s rank correlation methods were used to evaluate for publication bias.~ RESULTS： Thirteen articles were eligible, describing two loci polymorphisms of the CFI gene （of which 12 articles focus on rs10033900T〉C and 3 articles focus on rs2285714C〉T）. For rs10033900T〉C, the results of our study revealed that having a mutant allele C, TC, CC and TC＋CC was associated with a decreased risk of AMD in all population groups studied （C versus T models, OR=0.84, 95%Ch 0.72-0.99, P=0.04; TC versus TT models OR= 0.89, 95%Ch 0.88-0.99, P=0.04;CC versus ＂1-1＂ models, OR=0.76, 95%Ch 0.60-0.98, P=-0.03; TC＋CC versus TT models, OR=0.81, 95%Ch0.65-0.99, P=0.04）. We found that C allele were related to lower AMD risk in the Caucasian population by subgroup analysis, but there was no association with AMD under the allele and genotypes comparison in Asian studies. For rs2285714 C〉T, the TC, TT genotypes contributed to a higher risk of AMD, compared with the CC carriers and CT＋CC （OR=1.34, 95%Ch 1.09-1.63, P=0.004; OR=1.50, 95%Ch 1.25-1.80, P〈0.0001）. CONCLUSION： This Meta-analysis suggests that CFI rs10033900T〉C and rs2285714C〉T polymorphisms may contribute to AMD.展开更多
AIM:To determine whether single nucleotide polymorphism(SNP)rs641153 is associated with the risk of age-related macular degeneration(AMD),we performed a systematic meta-analysis of 15 eligible studies.SNP in the compl...AIM:To determine whether single nucleotide polymorphism(SNP)rs641153 is associated with the risk of age-related macular degeneration(AMD),we performed a systematic meta-analysis of 15 eligible studies.SNP in the complement factor B(CFB)gene is considered to have significant association with AMD susceptibility,but there is great discrepancy in these results.METHODS:The eligible studies were identified by searching the databases of PubMed,EMBASE,and Web of Science.Odds ratios(ORs)with 95%confidence intervals(CIs)were used to assess the association.All data were analyzed using Stata software.RESULTS:The association between rs641153 and AMD risk was statistically significant under the homozygous model(AA vs GG:OR=0.26,95%CI=0.15-0.45,P_h=0.973,/~2=0.0%,fixed effects),dominant model(AA+GA vsGG:OR=0.49,95%CI=0.40-0.59,P_h=0.004,/~2=56.4%,random effects)and recessive model(AA vs GA+GG:OR=0.30,95%CI=0.17-0.51,R_n=0.983,I^2=0.0%,fixed effects).The same results were also observed in the stratified analyses by ethnicity,source of control and sample size.CONCLUSION:Our meta-analysis suggests that rs641153 in the CFB gene may play a protective role in AMD susceptibility,the late AMD in particular,both in Caucasians and in Asians.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
Diabetic cardiomyopathy is a disorder of the cardiac muscle that affects patients with diabetes.The exact mechanisms underlying diabetic cardiomyopathy are mostly unknown,but several factors have been implicated in th...Diabetic cardiomyopathy is a disorder of the cardiac muscle that affects patients with diabetes.The exact mechanisms underlying diabetic cardiomyopathy are mostly unknown,but several factors have been implicated in the pathogenesis of the disease and its progression towards heart failure,including endothelial dysfunction,autonomic neuropathy,metabolic alterations,oxidative stress,and alterations in ion homeostasis,especially calcium transients[1].In Military Medical Research,Jiang et al.[2]sought to determine the functional role of complement factor D(Adipsin)in the pathophysiology of diabetic cardiomyopathy.展开更多
BACKGROUND Colon cancer(CC)occurrence and progression are considerably influenced by the tumor microenvironment.However,the exact underlying regulatory mechanisms remain unclear.AIM To investigate immune infiltration-...BACKGROUND Colon cancer(CC)occurrence and progression are considerably influenced by the tumor microenvironment.However,the exact underlying regulatory mechanisms remain unclear.AIM To investigate immune infiltration-related differentially expressed genes(DEGs)in CC and specifically explored the role and potential molecular mechanisms of complement factor I(CFI).METHODS Immune infiltration-associated DEGs were screened for CC using bioinformatics.Quantitative reverse transcription polymerase chain reaction was used to examine hub DEGs expression in the CC cell lines.Stable CFI-knockdown HT29 and HCT116 cell lines were constructed,and the diverse roles of CFI in vitro were assessed using CCK-8,5-ethynyl-2’-deoxyuridine,wound healing,and transwell assays.Hematoxylin and eosin staining and immunohistochemistry staining were employed to evaluate the influence of CFI on the tumorigenesis of CC xenograft models constructed using BALB/c male nude mice.Key proteins associated with glycolysis and the Wnt pathway were measured using western blotting.RESULTS Six key immune infiltration-related DEGs were screened,among which the expression of CFI,complement factor B,lymphoid enhancer binding factor 1,and SRY-related high-mobility-group box 4 was upregulated,whereas that of fatty acid-binding protein 1,and bone morphogenic protein-2 was downregulated.Furthermore,CFI could be used as a diagnostic biomarker for CC.Functionally,CFI silencing inhibited CC cell proliferation,migration,invasion,and tumor growth.Mechanistically,CFI knockdown downregulated the expression of key glycolysis-related proteins(glucose transporter type 1,hexokinase 2,lactate dehydrogenase A,and pyruvate kinase M2)and the Wnt pathway-related proteins(β-catenin and c-Myc).Further investigation indicated that CFI knockdown inhibited glycolysis in CC by blocking the Wnt/β-catenin/c-Myc pathway.CONCLUSION The findings of the present study demonstrate that CFI plays a crucial role in CC development by influencing glycolysis and the Wnt/β-catenin/c-Myc pathway,indicating that it could serve as a promising target for therapeutic intervention in CC.展开更多
Atypical hemolytic-uremic syndrome(a HUS) is a rare disease of complement dysregulation leading to thrombotic microangiopathy(TMA). Renal involvement and progression to end-stage renal disease are common in untreated ...Atypical hemolytic-uremic syndrome(a HUS) is a rare disease of complement dysregulation leading to thrombotic microangiopathy(TMA). Renal involvement and progression to end-stage renal disease are common in untreated patients. We report a 52-year-old female patient who presented with severe acute kidney injury, microangiopathic hemolytic anemia, and thrombocytopenia. She was managed with steroid, plasma exchange, and dialysis. Kidney biopsy shows TMA and renal cortical necrosis. Genetic analysis reveals heterozygous complement factor Ⅰ(CFI) mutation. Eculizumab was initiated after 3 mo of presentation, continued for 9 mo, and stopped because of sustained hematologic remission, steady renal function, and cost issues. Despite this, the patient continued to be in hematologic remission and showed signs of renal recovery, and peritoneal dialysis was stopped 32 mo after initiation. We report a case of a HUS due to CFI mutation, which, to the best of our knowledge, has not been reported before in Saudi Arabia. Our case illustrates the challenges related to the diagnosis and management of this condition, in which a high index of suspicion and prompt treatment are usually necessary.展开更多
AIM:To evaluate whether recombinant complement factor B(CFB)short hairpin RNA(sh RNA)reduces laserinduced choroidal neovascularization(CNV)in rats.METHODS:Laser-induced rat CNV model was established,and then the anima...AIM:To evaluate whether recombinant complement factor B(CFB)short hairpin RNA(sh RNA)reduces laserinduced choroidal neovascularization(CNV)in rats.METHODS:Laser-induced rat CNV model was established,and then the animals underwent fundus fluorescence angiography(FFA)and hematoxylin and eosin(HE)staining.On day 3 and 7 after photocoagulation,the expression of CFB and membrane attack complex(MAC)was detected by immunhischemistry.A recombinant CFBsh RNA plasmid was constructed.CFB and scrambled sh RNA plasmids were intravenous injected into rats via the tail vein on the day of laser treatment,respectively.On day 7,the incidence of CNV was determined by FFA,and the expression of CFB and vascular endothelial growth factor(VEGF)in retinal pigment epithelium(RPE)/choroidal tissues was detected by immunhischemistry,Western blot and/or semi-quantitative reverse transcription-polymerase chain reaction(RT-PCR)in CFB and scrambled sh RNA groups.The possible adverse effects of CFB-sh RNA injection were assessed by transmission electron microscopy and electroretinography.RESULTS:FFA and HE results indicated that a laserinduced rat CNV model was successfully established on day 7 after photocoagulation.The expression of CFB and MAC was extremely weak in normal retina and choroid,and increased on day 3 after photocoagulation.However,it started to reduce on day 7.CFB sh RNA plasmid was successfully constructed and induced CFB knockdown in the retinal and choroidal tissues.FFA showed CFB knockdown significantly inhibited incidence of CNV in rats.Moreover,CFB knockdown significantly inhibited the expression of VEGF in RPE/choroidal tissues.CFB sh RNA caused no obvious side effects in eyes.CONCLUSION:CFB knockdown significantly inhibits the formation and development of CNV in vivo through reducing the expression of VEGF,which is a potential therapy target.The alternative pathway of complement activation plays an important role in CNV formation.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
AIM: To investigate the molecular mechanisms underlying the reversal effect of emodin on platinum resistance in hepatocellular carcinoma. METHODS: After the addition of 10 μmol/L emodin to HepG2/oxaliplatin (OXA) cel...AIM: To investigate the molecular mechanisms underlying the reversal effect of emodin on platinum resistance in hepatocellular carcinoma. METHODS: After the addition of 10 μmol/L emodin to HepG2/oxaliplatin (OXA) cells, the inhibition rate (IR), 50% inhibitory concentration (IC 50 ) and reversal index (IC 50 in experimental group/IC 50 in control group) were calculated. For HepG2, HepG2/OXA, HepG2/OXA/T, each cell line was divided into a control group, OXA group, OXA + fibroblast growth factor 7 (FGF7) group and OXA + emodin group, and the final concentrations of FGF7, emodin and OXA in each group were 5 ng/mL, 10 μg/mL and 10 μmol/L, respectively. Single-cell gel electrophoresis was conducted to detect DNA damage, and the fibroblast growth factor receptor 2 (FGFR2), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) and excision repair cross-complementing gene 1 (ERCC1) protein expression levels in each group were examined by Western blotting. RESULTS: Compared with the IC50 of 120.78 μmol/L in HepG2/OXA cells, the IC 50 decreased to 39.65 μmol/L after treatment with 10 μmol/L emodin; thus, the reversal index was 3.05. Compared with the control group, the tail length and Olive tail length in the OXA group, OXA + FGF7 group and OXA + emodin group were significantly increased, and the differences were statistically significant (P < 0.01). The tail length and Olive tail length were lower in the OXA + FGF7 group than in the OXA group, and this difference was also statistically significant. Compared with the OXA + FGF7 group, the tail extent, the Olive tail moment and the percentage of tail DNA were significantly increased in the OXA + emodin group, and these differences were statistically significant (P < 0.01). In comparison with its parental cell line HepG2, the HepG2/OXA cells demonstrated significantly increased FGFR2, p-ERK1/2 and ERCC1 expression levels, whereas the expression of all three molecules was significantly inhibited in HepG2/ OXA/T cells, in which FGFR2 was silenced by FGFR2 shRNA. In the examined HepG2 cells, the FGFR2, p-ERK1/2 and ERCC1 expression levels demonstrated increasing trends in the OXA group and OXA + FGF7 group. Compared with the OXA group and OXA + FGF7 group, the FGFR2, p-ERK1/2, and ERCC1 expression levels were significantly lower in the OXA + emodin group, and these differences were statistically significant. In the HepG2/OXA/T cell line that was transfected with FGFR2 shRNA, the FGFR2, p-ERK1/2 and ERCC1 expression levels were significantly inhibited, but there were no significant differences in these expression levels among the OXA, OXA + FGF7 and OXA + emodin groups. CONCLUSION: Emodin markedly reversed OXA resistance by enhancing OXA DNA damage in HepG2/OXA cells, and the molecular mechanism was related to the inhibitory effect on ERCC1 expression being mediated by the FGFR2/ERK1/2 signaling pathway.展开更多
Recent studies have shown that tea polyphenols can cross the blood-brain barrier, inhibit apoptosis and play a neuroprotective role against cerebral ischemia. Furthermore, tea polyphenols can decrease DNA damage cause...Recent studies have shown that tea polyphenols can cross the blood-brain barrier, inhibit apoptosis and play a neuroprotective role against cerebral ischemia. Furthermore, tea polyphenols can decrease DNA damage caused by free radicals. We hypothesized that tea polyphenols repair DNA damage and inhibit neuronal apoptosis during global cerebral ischemia/reperfusion. To test this hypothesis, we employed a rat model of global cerebral ischemia/reperfusion. We demonstrated that intraperitoneal injection of tea polyphenols immediately after reperfusion significantly reduced apoptosis in the hippocampal CA1 region; this effect started 6 hours following reperfusion. Immunohistochemical staining showed that tea polyphenols could reverse the ischemia/reperfusion-induced reduction in the expression of DNA repair proteins, X-ray repair cross-complementing protein 1 and apudnic/apyrimidinic endonuclease/redox factor-1 starting at 2 hours. Both effects lasted at least 72 hours. These experimental findings suggest that tea polyphenols promote DNA damage repair and protect against apoptosis in the brain.展开更多
Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD includes soft drusen and pigmentary changes in the retinal pigment epithelium (RPE). ...Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD includes soft drusen and pigmentary changes in the retinal pigment epithelium (RPE). As people age, such soft confluent drusen can progress into two forms of advanced AMD, geographic atrophy (GA, or dry AMD) or choroidal neovascularization (CNV, or wet AMD) and result in the loss of central vision. The exact mechanism for developing early AMD and progressing to advanced stage of disease is still largely unknown. However, significant evidence exists demonstrating a complex interplay of genetic and environmental factors as the cause of AMD progression. Together, complement factor H (CFH) and HTRA1/ARMS polymorphisms contribute to more than 50% of the genetic risk for AMD. Environmentally, oxidative stress from activities such as smoking has also demonstrated a powerful contribution to AMD progression. To extend our previous finding that genetic polymorphisms in CFH results in OxPLs and the risk-form of CFH (CFH Y402H) has reduced affinity for oxidized phospholipids, and subsequent diminished capacity which subsequently diminishes the capability to attenuate the inflammatory effects of these molecules, we compared the binding properties of CFH and CFH related protein 1 (CFHR1), which is also associated with disease risk, to OxPLs and their effects on modulating inflammation and lipids uptake. As both CFH-402H and CFHR1 are associated with increased risk to AMD, we hypothesized that like CFH-402H, CFHR1 contribution to AMD risk may also be due to its diminished affinity for OxPLs. Interestingly, we found that association of CFHR1 with OxPLs was not statistically different than CFH. However, binding of CFHR1 did not elicit the same protective benefits as CFH in that both inflammation and lipid uptake are unaffected by CFHR1 association with OxPLs. These findings demonstrate a novel and interesting complexity to the potential interplay between the complement system and oxidative stress byproducts, such as OxPLs, in the mechanistic contribution to AMD. Future work will aim to identify the molecular distinctions between CFH and CFHR1 which confer protection by the former, but not latter molecules. Understanding the molecular domains necessary for protection could provide interventional insights in the generation of novel therapeutics for AMD and other diseases associated with oxidative stress.展开更多
The complement system plays a crucial role in the innate immune system of animals. It can be activated by distinct yet overlapping classical, alternative and lectin pathways. In the alternative pathway, complement fac...The complement system plays a crucial role in the innate immune system of animals. It can be activated by distinct yet overlapping classical, alternative and lectin pathways. In the alternative pathway, complement factor B(Bf) serves as the catalytic subunit of complement component 3(C3) convertase, which plays the central role among three activation pathways. In this study, the Bf gene in sea cucumber(Apostichopus japonicus), termed Aj Bf, was obtained by rapid amplification of c DNA ends(RACE). The full-length c DNA of Aj Bf was 3231 bp in length barring the poly(A) tail. It contained an open reading frame(ORF) of 2742 bp encoding 913 amino acids, a 105 bp 5'-UTR(5'-terminal untranslated region) and a 384 bp 3'-UTR. Aj Bf was a mosaic protein with six CCP(complement control protein) domains, a VWA(von Willebrand factor A) domain, and a serine protease domain. The deduced molecular weight of Aj Bf protein was 101 k Da. Quantitative real time PCR(q RT-PCR) analysis indicated that the expression level of Aj Bf in A. japonicus was obviously higher at larval stage than that at embryonic stage. Expression detection in different tissues showed that Aj Bf expressed higher in coelomocytes than in other four tissues. In addation, Aj Bf expression in different tissues was induced significantly after LPS or Poly I:C challenge. These results indicated that Aj Bf plays an important role in immune responses to pathogen infection.展开更多
Researchers reported that intravenously injected PEGylated colloidal drug carriers lose their long-circulating characteristic and accumulated extensively in liver when they are administrated twice in the same animal w...Researchers reported that intravenously injected PEGylated colloidal drug carriers lose their long-circulating characteristic and accumulated extensively in liver when they are administrated twice in the same animal with certain intervals. This phenomenon was referred to as the 'accelerated blood clearance(ABC) phenomenon'. Some former studies had found that complement-mediated phagocytosis, activated by antigen–antibody complex, was responsible for inducing the phenomenon. According to the theory, we have used cobra venom factor to deplete complement in vivo and to investigate the effect of complement inhibition on the ABC phenomenon. Rats were administered by injection of cobra venom factor solution to build up the model of complement exhaustion/inhibition, and the effect of the inhibition of complement on ABC phenomenon was carried out. It seemed that inhibition of complement didn’t affect the pharmacokinetic of the first infection. By contrast, in rats of which complement had been depleted, the second dose of PEGylated nanoemulsions showed enhanced circulation time compared with normal rats in a complement inhibition-independent manner, but the ABC phenomenon was not completely eliminated. It indicated that complement inhibition could certainly weaken the accelerated clearance;meanwhile, there were other factors causing the ABC effect.These findings provide novel insights into the attenuating of ABC phenomenon and lay foundation for further study of immune mechanism.展开更多
Complement (C) activation-related hypersensitivity reactions (HSRs) represent an unsolved adverse immune effect of many i.v. administered “nanomedicines”, such as liposomal doxorubicin (Doxil/Caelyx). Because these ...Complement (C) activation-related hypersensitivity reactions (HSRs) represent an unsolved adverse immune effect of many i.v. administered “nanomedicines”, such as liposomal doxorubicin (Doxil/Caelyx). Because these pseudoallergic reactions can be severe or even lethal, it is an important clinical objective to find biomarkers for proneness for C activation by reactogenic nanoparticles that will allow the prediction of in vivo reactions by in vitro assays. With this goal in mind we identified a normal human blood donor who consistently showed high sensitivity to Caelyx-induced C activation in vitro, whose plasma (Caelyx sensitive plasma, CSP) was subjected to proteome profiling with a library of human plasma proteome specific mAbs. The chip (PlasmaScan-380TM) contained 380 non redundant (with respect to epitopes) mAbs. The analysis revealed 8 proteins that were differentially represented in CSP in comparison with Caelyx-insensitive control plasma. These proteins were identified by mass spectrometry and Western blot analyses to represent factor H (decreased in CSP), factor H related protein, serum amyloid P component, fibronectin, complement component C4, Apo B100, prothrombin and alpha-2-HS glycoprotein (all increased in CSP). Some of these protein changes are consistent with proneness for increased C activation, suggesting the potential use of this method in the search for biomarkers for liposome-induced or other types of nanomedicine-induced HSRs.展开更多
BACKGROUND： Certain components of tetramethylpyrazine, a traditional Chinese medicine, exhibit protective effects against brain injury. OBJECTIVE： To investigate the effects of different Naoxintong doses on expressi...BACKGROUND： Certain components of tetramethylpyrazine, a traditional Chinese medicine, exhibit protective effects against brain injury. OBJECTIVE： To investigate the effects of different Naoxintong doses on expression of nuclear factor-kappa B （ kB）, interleukin-6, tumor necrosis factor-α, and complement 3 in rats following focal cerebral ischemia. DESIGN, TIME AND SETTING： The randomized experiment was performed at the Laboratory of Neurology, Second Hospital of Hebei Medical University from June 2004 to June 2006. MATERIALS： A total of 150 adult, healthy, male, Sprague Dawley rats, weighing 280-320g, were selected. Naoxintong powder （mainly comprising szechwan lovage rhizome, milkvetch root, danshen root, and radix angelicae sinensis） was obtained from Buchang Pharmacy Co., Ltd. in Xianyang City of Shanxi Province of China, lot number 040608. METHODS： The rats were randomly assigned into sham operation, saline, high-dose Naoxintong, moderate-dose Naoxintong, and low-dose Naoxintong groups, with 30 rats in each group. Rat models of middle cerebral artery occlusion were established using the suture method, with the exception of the sham operation group. Rats in the high-dose, moderate-dose and low-dose Naoxintong groups received 4, 2, and 1 g/kg Naoxintong respectively, by gavage. Rats in the saline group were treated with 1 mL saline by gavage All rats were administered by gavage at 5 and 23 hours following surgery, and subsequently, once per day. MAIN OUTCOME MEASURES： At 6, 24, 48, 72 hours, and 7 days following model establishment, brain water content was measured. Histopathological changes in brain tissues were detected using hematoxylin-eosin staining. Expression of nuclear factor- kB, interleukin-6, tumor necrosis factor- α, and complement 3 was examined by immunohistochemistry. RESULTS： A total of 150 rats were included in the final analysis with no loss. Brain water content was significantly increased in the ischemic hemisphere of rats from the saline, as well as the high-dose, moderate-dose, and low-dose Naoxintong groups at 24 hours, which reached a peak at 48 hours. At 6, 24, 48, 72 hours, and 7 days, brain water content was greater in the ischemic hemisphere of rats from the saline, as well as the high-dose, moderate-dose, and low-dose Naoxintong groups, compared with the sham operation group （P 〈 0.05）. At 24 and 48 hours, brain water content was reduced in the high-dose and moderate-dose Naoxintong groups, compared to the saline and low-dose Naoxintong groups （P 〈 0.05）. In the saline, as well as high-dose, moderate-dose, and low-dose Naoxintong groups, neuronal edema was observed at 6 hours surrounding the ischemic sites. Inflammatory cells appeared at 24 hours, reached a peak at 48 hours, and gradually diminished. A small amount of glial cell proliferation and neuronal degeneration were observed in the hippocampus at 72 hours following infarction. Microglial proliferation and aggregation were detected at 7 days after infarction. Expression of nuclear factor- kB, interleukin-6, tumor necrosis factor-α, and complement 3 was significantly less in the high-dose, moderate-dose, and low-dose Naoxintong groups, compared to the sham operation group （P 〈 0.05）. Expression of the above-mentioned inflammatory cytokines was lower in rat brain tissues of the high-dose Naoxintong group, compared to the low-dose Naoxintong group （P 〈 0.05）. CONCLUSION： High-dose Naoxintong and moderate-dose Naoxintong significantly alleviated rat brain edema and decreased expression of nuclear factor-kB, interleukin-6, tumor necrosis factor-α, and complement 3 in brain tissues. The protective effect of high-dose Naoxintong was most significant.展开更多
in this paper, the major Bf allotypes were detected and analyzed from 460 unrelated healthy adults of Han nationality in Guangdong, China with the method and nomenclature of the international Complement Reference Labo...in this paper, the major Bf allotypes were detected and analyzed from 460 unrelated healthy adults of Han nationality in Guangdong, China with the method and nomenclature of the international Complement Reference Laboratory. Four Bf phenotypes of BF SS(79. 13%),BF FF(2. 39%), BF FS(18. 04%), and BF SS07 (0.43%) were found with the allelic frequencies of 0. 8837 for BF*S, 0. 1141 for BF*F and 0. 0022 for BF*S07. The BF phenotype frequency distributions were in agreement with the Hardy-Weinberg equilibrium law. The characteristics of the gene frequency distributions were basically the same with those from Wuhan and Shanghai cities. The distribution of BF allotypes among three major human races and the discrepancies of the rare variants in different areas were discussed.展开更多
基金Supported by the National Natural Science Foundation of China(No.81070755)
文摘· AIM: To investigate the expression of complement factors in the posterior scleral fibroblasts of guinea pigs with negative lens-defocused myopia.· METHODS: Eighteen guinea pigs were assigned randomly to two groups: the negative lens-defocused group(NLD group, n =9) and the normal control without treatment group(NC group, n =9). The effect of myopic induction was compared in three subgroups: eyes treated with a-10.00 D negative lens in the NLD group(NL group), eyes treated with a plano(0 D) lens in the NLD group(PL group), and untreated right eyes in the NC group(NC group). The following analyses were conducted at four weeks: examination of the refractive error via retinoscopy, assessment of complement C5b-9expression in the posterior scleral fibroblasts using immunohistochemistry, and measurements of complement C1 q and C3 protein levels in the posterior sclera by Western blot.·RESULTS: After an induction period of four weeks, a significant myopic shift was detected in the eyes of the NL group, relative to that of the PL and NC groups(P 【0.05). Data analysis showed a significant increase in the percentage of C5b-9 immunopositive fibroblasts in the posterior sclera of the NL group eyes, compared to the PL group(q =11.50, P 【0.001). Significantly higher levels of C1q(q =4.94, P =0.01) and C3(q =4.07, P =0.03)protein were detected in the posterior sclera of NL group eyes, compared to the PL group. There were no significant difference between the PL and NC groups for C5b-9(q =2.44, P =0.10), C1q(q =1.55, P =0.53) and C3(q =0.98, P =0.77) in the posterior sclera.·CONCLUSION: The data from present study provide evidence of the up-regulation of C5b-9, C1 q and C3 in the posterior scleral fibroblasts in a NLD myopic animal model. The results suggest that the complement system may be involved in the development of myopia.
基金Supported by the Scientific Research Project of Traditional Chinese Medicine of Health and Family Planning Commission of Chongqing (ZY20150243)
文摘AIM： To systematically review the association between complement factors I （CFI） polymorphisms and age- related macular degeneration （AMD） and to explore whether CFI polymorphisms are associated with AMD, METHODS： Meta-analysis of articles published from 1995 to January 2015 of articles involved with AMD and polymorphisms of the CFI gene. Eligible data were pooled in a Meta-analysis, analyzing using STATA software （version 12.0）, Review Manager （version 5.2） and different models based on the heterogeneity of effect sizes. Egger＇s test, Begg＇s rank correlation methods were used to evaluate for publication bias.~ RESULTS： Thirteen articles were eligible, describing two loci polymorphisms of the CFI gene （of which 12 articles focus on rs10033900T〉C and 3 articles focus on rs2285714C〉T）. For rs10033900T〉C, the results of our study revealed that having a mutant allele C, TC, CC and TC＋CC was associated with a decreased risk of AMD in all population groups studied （C versus T models, OR=0.84, 95%Ch 0.72-0.99, P=0.04; TC versus TT models OR= 0.89, 95%Ch 0.88-0.99, P=0.04;CC versus ＂1-1＂ models, OR=0.76, 95%Ch 0.60-0.98, P=-0.03; TC＋CC versus TT models, OR=0.81, 95%Ch0.65-0.99, P=0.04）. We found that C allele were related to lower AMD risk in the Caucasian population by subgroup analysis, but there was no association with AMD under the allele and genotypes comparison in Asian studies. For rs2285714 C〉T, the TC, TT genotypes contributed to a higher risk of AMD, compared with the CC carriers and CT＋CC （OR=1.34, 95%Ch 1.09-1.63, P=0.004; OR=1.50, 95%Ch 1.25-1.80, P〈0.0001）. CONCLUSION： This Meta-analysis suggests that CFI rs10033900T〉C and rs2285714C〉T polymorphisms may contribute to AMD.
文摘AIM:To determine whether single nucleotide polymorphism(SNP)rs641153 is associated with the risk of age-related macular degeneration(AMD),we performed a systematic meta-analysis of 15 eligible studies.SNP in the complement factor B(CFB)gene is considered to have significant association with AMD susceptibility,but there is great discrepancy in these results.METHODS:The eligible studies were identified by searching the databases of PubMed,EMBASE,and Web of Science.Odds ratios(ORs)with 95%confidence intervals(CIs)were used to assess the association.All data were analyzed using Stata software.RESULTS:The association between rs641153 and AMD risk was statistically significant under the homozygous model(AA vs GG:OR=0.26,95%CI=0.15-0.45,P_h=0.973,/~2=0.0%,fixed effects),dominant model(AA+GA vsGG:OR=0.49,95%CI=0.40-0.59,P_h=0.004,/~2=56.4%,random effects)and recessive model(AA vs GA+GG:OR=0.30,95%CI=0.17-0.51,R_n=0.983,I^2=0.0%,fixed effects).The same results were also observed in the stratified analyses by ethnicity,source of control and sample size.CONCLUSION:Our meta-analysis suggests that rs641153 in the CFB gene may play a protective role in AMD susceptibility,the late AMD in particular,both in Caucasians and in Asians.
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National Institutes of Health(NIH):National Heart,Lung,and Blood Institute(NHLBI:R01-HL164772,R01-HL159062,R01-HL146691,T32-HL144456)National Institute of Diabetes and Digestive and Kidney Diseases(NIDDK:R01-DK123259,R01-DK033823)+2 种基金National Center for Advancing Translational Sciences(NCATS:UL1-TR002556-06,UM1-TR004400)(to Gaetano Santulli)Diabetes Action Research and Education Foundation(to Gaetano Santulli)Monique Weill-Caulier and Irma T.Hirschl Trusts(to Gaetano Santulli).
文摘Diabetic cardiomyopathy is a disorder of the cardiac muscle that affects patients with diabetes.The exact mechanisms underlying diabetic cardiomyopathy are mostly unknown,but several factors have been implicated in the pathogenesis of the disease and its progression towards heart failure,including endothelial dysfunction,autonomic neuropathy,metabolic alterations,oxidative stress,and alterations in ion homeostasis,especially calcium transients[1].In Military Medical Research,Jiang et al.[2]sought to determine the functional role of complement factor D(Adipsin)in the pathophysiology of diabetic cardiomyopathy.
文摘BACKGROUND Colon cancer(CC)occurrence and progression are considerably influenced by the tumor microenvironment.However,the exact underlying regulatory mechanisms remain unclear.AIM To investigate immune infiltration-related differentially expressed genes(DEGs)in CC and specifically explored the role and potential molecular mechanisms of complement factor I(CFI).METHODS Immune infiltration-associated DEGs were screened for CC using bioinformatics.Quantitative reverse transcription polymerase chain reaction was used to examine hub DEGs expression in the CC cell lines.Stable CFI-knockdown HT29 and HCT116 cell lines were constructed,and the diverse roles of CFI in vitro were assessed using CCK-8,5-ethynyl-2’-deoxyuridine,wound healing,and transwell assays.Hematoxylin and eosin staining and immunohistochemistry staining were employed to evaluate the influence of CFI on the tumorigenesis of CC xenograft models constructed using BALB/c male nude mice.Key proteins associated with glycolysis and the Wnt pathway were measured using western blotting.RESULTS Six key immune infiltration-related DEGs were screened,among which the expression of CFI,complement factor B,lymphoid enhancer binding factor 1,and SRY-related high-mobility-group box 4 was upregulated,whereas that of fatty acid-binding protein 1,and bone morphogenic protein-2 was downregulated.Furthermore,CFI could be used as a diagnostic biomarker for CC.Functionally,CFI silencing inhibited CC cell proliferation,migration,invasion,and tumor growth.Mechanistically,CFI knockdown downregulated the expression of key glycolysis-related proteins(glucose transporter type 1,hexokinase 2,lactate dehydrogenase A,and pyruvate kinase M2)and the Wnt pathway-related proteins(β-catenin and c-Myc).Further investigation indicated that CFI knockdown inhibited glycolysis in CC by blocking the Wnt/β-catenin/c-Myc pathway.CONCLUSION The findings of the present study demonstrate that CFI plays a crucial role in CC development by influencing glycolysis and the Wnt/β-catenin/c-Myc pathway,indicating that it could serve as a promising target for therapeutic intervention in CC.
文摘Atypical hemolytic-uremic syndrome(a HUS) is a rare disease of complement dysregulation leading to thrombotic microangiopathy(TMA). Renal involvement and progression to end-stage renal disease are common in untreated patients. We report a 52-year-old female patient who presented with severe acute kidney injury, microangiopathic hemolytic anemia, and thrombocytopenia. She was managed with steroid, plasma exchange, and dialysis. Kidney biopsy shows TMA and renal cortical necrosis. Genetic analysis reveals heterozygous complement factor Ⅰ(CFI) mutation. Eculizumab was initiated after 3 mo of presentation, continued for 9 mo, and stopped because of sustained hematologic remission, steady renal function, and cost issues. Despite this, the patient continued to be in hematologic remission and showed signs of renal recovery, and peritoneal dialysis was stopped 32 mo after initiation. We report a case of a HUS due to CFI mutation, which, to the best of our knowledge, has not been reported before in Saudi Arabia. Our case illustrates the challenges related to the diagnosis and management of this condition, in which a high index of suspicion and prompt treatment are usually necessary.
文摘AIM:To evaluate whether recombinant complement factor B(CFB)short hairpin RNA(sh RNA)reduces laserinduced choroidal neovascularization(CNV)in rats.METHODS:Laser-induced rat CNV model was established,and then the animals underwent fundus fluorescence angiography(FFA)and hematoxylin and eosin(HE)staining.On day 3 and 7 after photocoagulation,the expression of CFB and membrane attack complex(MAC)was detected by immunhischemistry.A recombinant CFBsh RNA plasmid was constructed.CFB and scrambled sh RNA plasmids were intravenous injected into rats via the tail vein on the day of laser treatment,respectively.On day 7,the incidence of CNV was determined by FFA,and the expression of CFB and vascular endothelial growth factor(VEGF)in retinal pigment epithelium(RPE)/choroidal tissues was detected by immunhischemistry,Western blot and/or semi-quantitative reverse transcription-polymerase chain reaction(RT-PCR)in CFB and scrambled sh RNA groups.The possible adverse effects of CFB-sh RNA injection were assessed by transmission electron microscopy and electroretinography.RESULTS:FFA and HE results indicated that a laserinduced rat CNV model was successfully established on day 7 after photocoagulation.The expression of CFB and MAC was extremely weak in normal retina and choroid,and increased on day 3 after photocoagulation.However,it started to reduce on day 7.CFB sh RNA plasmid was successfully constructed and induced CFB knockdown in the retinal and choroidal tissues.FFA showed CFB knockdown significantly inhibited incidence of CNV in rats.Moreover,CFB knockdown significantly inhibited the expression of VEGF in RPE/choroidal tissues.CFB sh RNA caused no obvious side effects in eyes.CONCLUSION:CFB knockdown significantly inhibits the formation and development of CNV in vivo through reducing the expression of VEGF,which is a potential therapy target.The alternative pathway of complement activation plays an important role in CNV formation.
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.
基金Supported by National Natural Sciences Foundation of China,No. 81001067the Ministry of Science and Technology International Cooperation Project, No. 2010DFA31870the AstraZeneca Special Research Foundation for Targeted Therapy of the Wu Jieping Medical Foundation, No. 320.6700.09068
文摘AIM: To investigate the molecular mechanisms underlying the reversal effect of emodin on platinum resistance in hepatocellular carcinoma. METHODS: After the addition of 10 μmol/L emodin to HepG2/oxaliplatin (OXA) cells, the inhibition rate (IR), 50% inhibitory concentration (IC 50 ) and reversal index (IC 50 in experimental group/IC 50 in control group) were calculated. For HepG2, HepG2/OXA, HepG2/OXA/T, each cell line was divided into a control group, OXA group, OXA + fibroblast growth factor 7 (FGF7) group and OXA + emodin group, and the final concentrations of FGF7, emodin and OXA in each group were 5 ng/mL, 10 μg/mL and 10 μmol/L, respectively. Single-cell gel electrophoresis was conducted to detect DNA damage, and the fibroblast growth factor receptor 2 (FGFR2), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) and excision repair cross-complementing gene 1 (ERCC1) protein expression levels in each group were examined by Western blotting. RESULTS: Compared with the IC50 of 120.78 μmol/L in HepG2/OXA cells, the IC 50 decreased to 39.65 μmol/L after treatment with 10 μmol/L emodin; thus, the reversal index was 3.05. Compared with the control group, the tail length and Olive tail length in the OXA group, OXA + FGF7 group and OXA + emodin group were significantly increased, and the differences were statistically significant (P < 0.01). The tail length and Olive tail length were lower in the OXA + FGF7 group than in the OXA group, and this difference was also statistically significant. Compared with the OXA + FGF7 group, the tail extent, the Olive tail moment and the percentage of tail DNA were significantly increased in the OXA + emodin group, and these differences were statistically significant (P < 0.01). In comparison with its parental cell line HepG2, the HepG2/OXA cells demonstrated significantly increased FGFR2, p-ERK1/2 and ERCC1 expression levels, whereas the expression of all three molecules was significantly inhibited in HepG2/ OXA/T cells, in which FGFR2 was silenced by FGFR2 shRNA. In the examined HepG2 cells, the FGFR2, p-ERK1/2 and ERCC1 expression levels demonstrated increasing trends in the OXA group and OXA + FGF7 group. Compared with the OXA group and OXA + FGF7 group, the FGFR2, p-ERK1/2, and ERCC1 expression levels were significantly lower in the OXA + emodin group, and these differences were statistically significant. In the HepG2/OXA/T cell line that was transfected with FGFR2 shRNA, the FGFR2, p-ERK1/2 and ERCC1 expression levels were significantly inhibited, but there were no significant differences in these expression levels among the OXA, OXA + FGF7 and OXA + emodin groups. CONCLUSION: Emodin markedly reversed OXA resistance by enhancing OXA DNA damage in HepG2/OXA cells, and the molecular mechanism was related to the inhibitory effect on ERCC1 expression being mediated by the FGFR2/ERK1/2 signaling pathway.
基金supported by the National Natural Science Foundation of China, No. 30571790
文摘Recent studies have shown that tea polyphenols can cross the blood-brain barrier, inhibit apoptosis and play a neuroprotective role against cerebral ischemia. Furthermore, tea polyphenols can decrease DNA damage caused by free radicals. We hypothesized that tea polyphenols repair DNA damage and inhibit neuronal apoptosis during global cerebral ischemia/reperfusion. To test this hypothesis, we employed a rat model of global cerebral ischemia/reperfusion. We demonstrated that intraperitoneal injection of tea polyphenols immediately after reperfusion significantly reduced apoptosis in the hippocampal CA1 region; this effect started 6 hours following reperfusion. Immunohistochemical staining showed that tea polyphenols could reverse the ischemia/reperfusion-induced reduction in the expression of DNA repair proteins, X-ray repair cross-complementing protein 1 and apudnic/apyrimidinic endonuclease/redox factor-1 starting at 2 hours. Both effects lasted at least 72 hours. These experimental findings suggest that tea polyphenols promote DNA damage repair and protect against apoptosis in the brain.
文摘Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD includes soft drusen and pigmentary changes in the retinal pigment epithelium (RPE). As people age, such soft confluent drusen can progress into two forms of advanced AMD, geographic atrophy (GA, or dry AMD) or choroidal neovascularization (CNV, or wet AMD) and result in the loss of central vision. The exact mechanism for developing early AMD and progressing to advanced stage of disease is still largely unknown. However, significant evidence exists demonstrating a complex interplay of genetic and environmental factors as the cause of AMD progression. Together, complement factor H (CFH) and HTRA1/ARMS polymorphisms contribute to more than 50% of the genetic risk for AMD. Environmentally, oxidative stress from activities such as smoking has also demonstrated a powerful contribution to AMD progression. To extend our previous finding that genetic polymorphisms in CFH results in OxPLs and the risk-form of CFH (CFH Y402H) has reduced affinity for oxidized phospholipids, and subsequent diminished capacity which subsequently diminishes the capability to attenuate the inflammatory effects of these molecules, we compared the binding properties of CFH and CFH related protein 1 (CFHR1), which is also associated with disease risk, to OxPLs and their effects on modulating inflammation and lipids uptake. As both CFH-402H and CFHR1 are associated with increased risk to AMD, we hypothesized that like CFH-402H, CFHR1 contribution to AMD risk may also be due to its diminished affinity for OxPLs. Interestingly, we found that association of CFHR1 with OxPLs was not statistically different than CFH. However, binding of CFHR1 did not elicit the same protective benefits as CFH in that both inflammation and lipid uptake are unaffected by CFHR1 association with OxPLs. These findings demonstrate a novel and interesting complexity to the potential interplay between the complement system and oxidative stress byproducts, such as OxPLs, in the mechanistic contribution to AMD. Future work will aim to identify the molecular distinctions between CFH and CFHR1 which confer protection by the former, but not latter molecules. Understanding the molecular domains necessary for protection could provide interventional insights in the generation of novel therapeutics for AMD and other diseases associated with oxidative stress.
基金supported by the National Natural Science Foundation of China(Nos.31272687 and 30972 272)Science and Technology Project of Liaoning Province(2014203006)+1 种基金Ocean and Fisheries Project of Liaoning Province(201301)Science and Technology Project of Dalian City(2013J21DW025)
文摘The complement system plays a crucial role in the innate immune system of animals. It can be activated by distinct yet overlapping classical, alternative and lectin pathways. In the alternative pathway, complement factor B(Bf) serves as the catalytic subunit of complement component 3(C3) convertase, which plays the central role among three activation pathways. In this study, the Bf gene in sea cucumber(Apostichopus japonicus), termed Aj Bf, was obtained by rapid amplification of c DNA ends(RACE). The full-length c DNA of Aj Bf was 3231 bp in length barring the poly(A) tail. It contained an open reading frame(ORF) of 2742 bp encoding 913 amino acids, a 105 bp 5'-UTR(5'-terminal untranslated region) and a 384 bp 3'-UTR. Aj Bf was a mosaic protein with six CCP(complement control protein) domains, a VWA(von Willebrand factor A) domain, and a serine protease domain. The deduced molecular weight of Aj Bf protein was 101 k Da. Quantitative real time PCR(q RT-PCR) analysis indicated that the expression level of Aj Bf in A. japonicus was obviously higher at larval stage than that at embryonic stage. Expression detection in different tissues showed that Aj Bf expressed higher in coelomocytes than in other four tissues. In addation, Aj Bf expression in different tissues was induced significantly after LPS or Poly I:C challenge. These results indicated that Aj Bf plays an important role in immune responses to pathogen infection.
基金supported by the National Natural Science Foundation of China(Grant No.81373334)
文摘Researchers reported that intravenously injected PEGylated colloidal drug carriers lose their long-circulating characteristic and accumulated extensively in liver when they are administrated twice in the same animal with certain intervals. This phenomenon was referred to as the 'accelerated blood clearance(ABC) phenomenon'. Some former studies had found that complement-mediated phagocytosis, activated by antigen–antibody complex, was responsible for inducing the phenomenon. According to the theory, we have used cobra venom factor to deplete complement in vivo and to investigate the effect of complement inhibition on the ABC phenomenon. Rats were administered by injection of cobra venom factor solution to build up the model of complement exhaustion/inhibition, and the effect of the inhibition of complement on ABC phenomenon was carried out. It seemed that inhibition of complement didn’t affect the pharmacokinetic of the first infection. By contrast, in rats of which complement had been depleted, the second dose of PEGylated nanoemulsions showed enhanced circulation time compared with normal rats in a complement inhibition-independent manner, but the ABC phenomenon was not completely eliminated. It indicated that complement inhibition could certainly weaken the accelerated clearance;meanwhile, there were other factors causing the ABC effect.These findings provide novel insights into the attenuating of ABC phenomenon and lay foundation for further study of immune mechanism.
文摘Complement (C) activation-related hypersensitivity reactions (HSRs) represent an unsolved adverse immune effect of many i.v. administered “nanomedicines”, such as liposomal doxorubicin (Doxil/Caelyx). Because these pseudoallergic reactions can be severe or even lethal, it is an important clinical objective to find biomarkers for proneness for C activation by reactogenic nanoparticles that will allow the prediction of in vivo reactions by in vitro assays. With this goal in mind we identified a normal human blood donor who consistently showed high sensitivity to Caelyx-induced C activation in vitro, whose plasma (Caelyx sensitive plasma, CSP) was subjected to proteome profiling with a library of human plasma proteome specific mAbs. The chip (PlasmaScan-380TM) contained 380 non redundant (with respect to epitopes) mAbs. The analysis revealed 8 proteins that were differentially represented in CSP in comparison with Caelyx-insensitive control plasma. These proteins were identified by mass spectrometry and Western blot analyses to represent factor H (decreased in CSP), factor H related protein, serum amyloid P component, fibronectin, complement component C4, Apo B100, prothrombin and alpha-2-HS glycoprotein (all increased in CSP). Some of these protein changes are consistent with proneness for increased C activation, suggesting the potential use of this method in the search for biomarkers for liposome-induced or other types of nanomedicine-induced HSRs.
基金Supported by: the Scientific Technology Research and Development Plan of Hebei Province, No. 06276103Dthe Natural Science Foundation of Hebei Province, No. C2006000915
文摘BACKGROUND： Certain components of tetramethylpyrazine, a traditional Chinese medicine, exhibit protective effects against brain injury. OBJECTIVE： To investigate the effects of different Naoxintong doses on expression of nuclear factor-kappa B （ kB）, interleukin-6, tumor necrosis factor-α, and complement 3 in rats following focal cerebral ischemia. DESIGN, TIME AND SETTING： The randomized experiment was performed at the Laboratory of Neurology, Second Hospital of Hebei Medical University from June 2004 to June 2006. MATERIALS： A total of 150 adult, healthy, male, Sprague Dawley rats, weighing 280-320g, were selected. Naoxintong powder （mainly comprising szechwan lovage rhizome, milkvetch root, danshen root, and radix angelicae sinensis） was obtained from Buchang Pharmacy Co., Ltd. in Xianyang City of Shanxi Province of China, lot number 040608. METHODS： The rats were randomly assigned into sham operation, saline, high-dose Naoxintong, moderate-dose Naoxintong, and low-dose Naoxintong groups, with 30 rats in each group. Rat models of middle cerebral artery occlusion were established using the suture method, with the exception of the sham operation group. Rats in the high-dose, moderate-dose and low-dose Naoxintong groups received 4, 2, and 1 g/kg Naoxintong respectively, by gavage. Rats in the saline group were treated with 1 mL saline by gavage All rats were administered by gavage at 5 and 23 hours following surgery, and subsequently, once per day. MAIN OUTCOME MEASURES： At 6, 24, 48, 72 hours, and 7 days following model establishment, brain water content was measured. Histopathological changes in brain tissues were detected using hematoxylin-eosin staining. Expression of nuclear factor- kB, interleukin-6, tumor necrosis factor- α, and complement 3 was examined by immunohistochemistry. RESULTS： A total of 150 rats were included in the final analysis with no loss. Brain water content was significantly increased in the ischemic hemisphere of rats from the saline, as well as the high-dose, moderate-dose, and low-dose Naoxintong groups at 24 hours, which reached a peak at 48 hours. At 6, 24, 48, 72 hours, and 7 days, brain water content was greater in the ischemic hemisphere of rats from the saline, as well as the high-dose, moderate-dose, and low-dose Naoxintong groups, compared with the sham operation group （P 〈 0.05）. At 24 and 48 hours, brain water content was reduced in the high-dose and moderate-dose Naoxintong groups, compared to the saline and low-dose Naoxintong groups （P 〈 0.05）. In the saline, as well as high-dose, moderate-dose, and low-dose Naoxintong groups, neuronal edema was observed at 6 hours surrounding the ischemic sites. Inflammatory cells appeared at 24 hours, reached a peak at 48 hours, and gradually diminished. A small amount of glial cell proliferation and neuronal degeneration were observed in the hippocampus at 72 hours following infarction. Microglial proliferation and aggregation were detected at 7 days after infarction. Expression of nuclear factor- kB, interleukin-6, tumor necrosis factor-α, and complement 3 was significantly less in the high-dose, moderate-dose, and low-dose Naoxintong groups, compared to the sham operation group （P 〈 0.05）. Expression of the above-mentioned inflammatory cytokines was lower in rat brain tissues of the high-dose Naoxintong group, compared to the low-dose Naoxintong group （P 〈 0.05）. CONCLUSION： High-dose Naoxintong and moderate-dose Naoxintong significantly alleviated rat brain edema and decreased expression of nuclear factor-kB, interleukin-6, tumor necrosis factor-α, and complement 3 in brain tissues. The protective effect of high-dose Naoxintong was most significant.
文摘in this paper, the major Bf allotypes were detected and analyzed from 460 unrelated healthy adults of Han nationality in Guangdong, China with the method and nomenclature of the international Complement Reference Laboratory. Four Bf phenotypes of BF SS(79. 13%),BF FF(2. 39%), BF FS(18. 04%), and BF SS07 (0.43%) were found with the allelic frequencies of 0. 8837 for BF*S, 0. 1141 for BF*F and 0. 0022 for BF*S07. The BF phenotype frequency distributions were in agreement with the Hardy-Weinberg equilibrium law. The characteristics of the gene frequency distributions were basically the same with those from Wuhan and Shanghai cities. The distribution of BF allotypes among three major human races and the discrepancies of the rare variants in different areas were discussed.
