Background Heat stress(HS)is posing as a tremendous threat to the swine industry,due to the thermos-sensitive gonads of boars.Testes are immune-privileged organs in which spermatogenesis needs to remain undisturbed,wh...Background Heat stress(HS)is posing as a tremendous threat to the swine industry,due to the thermos-sensitive gonads of boars.Testes are immune-privileged organs in which spermatogenesis needs to remain undisturbed,whereas immune cells are thermo-sensitive,especially macrophages,which are the most abundant testicular immune cells.Our study aimed to unveil the underlying immune responses and assess their consequences on the semen quality of boars under HS.The results will aid in addressing environmental temperature-related seasonal infertility and in selecting the best boar for use in artificial insemination.Methods The 3-week experiment assigned 268-week-old Rongchang male pigs into thermal neutral pair-feed(TN-PF)and HS groups.During the last 2 weeks,which served as the HS period,the HS group was subjected to 14-day 35±1℃,while the TN-PF group was kept at 26±1℃.Pig gonad tissues were sampled at the end of HS period for assessments and measurements.Results Our findings confirmed HS-related reactions such as elevated respiration rate(P<0.05)and elevated heat shock protein 60(HSP60;P<0.05)and heat shock protein 90(HSP90;P<0.05)expression levels.Sperm motility(P=0.06)and progressive sperms(P=0.08)were decreased under HS as was a significant reduction in average straight-line velocity(VSL;P<0.05).Additionally,total abnormality levels increased(P<0.05).Fibrosis,caspase-3 expression,and accumulations of tumor necrosis factor-α(TNF-α;P<0.05)and interleukin-1β(IL-1β;P<0.05),along with an elevated macrophage composition(P<0.05)characterized the orchitis under HS.Single cell RNA sequencing(scRNA-seq)revealed fluctuations in engulfing and inflammatory signals in testicular macrophages(TMs).In particular,the complement cascade was promoted by CD163+macrophages,resulting in membrane attack complex(C5b-9)assembly(P<0.05).Linear regressions further revealed a negative correlation between C5b-9 and sperm motility(P<0.05),as well as near-negative correlations between the C5b-9 and both progressive motility(P=0.08)and VSL(P=0.06).Conclusions Our findings highlighted the relationship between HS,the onset of orchitis,and the activation of the complement system,all of which decreased the boar semen quality.展开更多
Insects represent emerging sources of bioactive peptides and functional materials.Mantidis Oötheca(Sang-Piao-Xiao in Chinese,SPX)serves as an insect-derived medicine for treating kidney disease.This study demonst...Insects represent emerging sources of bioactive peptides and functional materials.Mantidis Oötheca(Sang-Piao-Xiao in Chinese,SPX)serves as an insect-derived medicine for treating kidney disease.This study demonstrated that supernatant(SPX)improved kidney function in adriamycin(ADR)-induced nephropathy mice model.Transcriptomic analysis revealed that SPX inhibited complement activation by targeting the MASP1-C3/C3a receptor(C3aR)pathway.Peptidomic analysis identified 304 peptides from SPX,with 49 peptides selected for evaluation using prediction tools and molecular docking with complement core protein C3.Three peptides(PMGFPFDR,FNDPK,AAQFFNR)exhibiting docking scores below-8.0 were synthesized to verify complement inhibition and anti-fibrotic activities.The synthetic peptide AAQFFNR demonstrated complement inhibitory activity,with an inhibitory complement hemolytic 50%(ICH_(50))value of 24.54μmol·L^(-1),and exhibited superior protective effects in ADR-induced HK-2 cells.Surface plasmon resonance(SPR)assay revealed direct interaction between AAQFFNR and complement C3 with K_(d)value of 16.8μmol·L^(-1).The reno-protective effect of AAQFFNR was subsequently verified in ADR-induced mice.This research provides initial evidence that complement C3-inhibiting peptides from insects demonstrate potential in preventing nephropathy through in silico and in vivo validation approaches.展开更多
Activation of spinal cord neural stem cells(NSCs)and subsequent neurogenesis holds a promising alternative for spinal cord injury(SCI)repair.Our previous study demonstrated that complement C3a,derived from reactive as...Activation of spinal cord neural stem cells(NSCs)and subsequent neurogenesis holds a promising alternative for spinal cord injury(SCI)repair.Our previous study demonstrated that complement C3a,derived from reactive astrocytes,inhibits NSC proliferation by suppressing protein aggregate clearance through the deubiquitinating enzyme ubiquitin carboxy-terminal hydrolase L1(UCHL1)-proteasome system post-SCI.However,the potential molecular mechanism by which C3a modulates NSC activation via this pathway remains unclear.Here,we revealed that C3a/C3a receptor(C3aR)signaling activated NF-κB p65,which in turn inhibited Nrf2 activity and UCHL1 expression,resulting in diminished proteasome activity and the accumulation of protein aggregates,and ultimately impaired NSC activation.Both knockdown of NF-κB p65 and Nrf2 upregulation restored UCHL1 expression and proteasome activity in vitro,promoting NSC activation by enhancing protein aggregate clearance.Mechanistically,we found that NF-κB p65 regulated Nrf2 activity through a dual mechanism:(1)promoting Keap1-dependent ubiquitination and proteasome degradation of Nrf2;(2)inhibiting protein kinase C-mediated Nrf2 phosphorylation and nuclear translocation.Using the dual-luciferase reporter assay and chromatin immunoprecipitation(ChIP)analysis,we further identified UCHL1 as a direct transcriptional target of Nrf2.Importantly,in vivo experiments using SCI mice confirmed that either C3aR blockade,NF-κB p65 knockdown,or Nrf2 overexpression could rescue SCI-induced UCHL1 downregulation.Together,this study uncovers the C3a-NF-κB p65-Nrf2-UCHL1-proteasome axis as a critical regulator of NSC activation after SCI.This may provide novel molecular targets and intervention strategies for SCI repair.展开更多
BACKGROUND Complement-mediated thrombotic microangiopathy(TMA)is a rare endothelial injury syndrome caused by dysregulated activation of the alternative complement pathway,often linked to genetic abnormalities in comp...BACKGROUND Complement-mediated thrombotic microangiopathy(TMA)is a rare endothelial injury syndrome caused by dysregulated activation of the alternative complement pathway,often linked to genetic abnormalities in complement factor H(CFH),complement factor I,or complement factor H-related(CFHR)proteins.Both renal transplantation and pregnancy are independent triggers for recurrence.This case highlights a genetically high-risk patient who achieved a successful term pregnancy after renal transplantation without complement inhibition,emphasizing individualized risk stratification,close surveillance,and multidisciplinary management for favourable maternal and graft outcomes.CASE SUMMARY A 32-year-old woman with end-stage renal disease secondary to genetically confirmed complement-mediated TMA—homozygous CFH exon 17 deletion and CFHR3-CFHR1 duplication—was maintained on dialysis for 2.5 years before undergoing a successful live-donor kidney transplant from her mother.Post-transplant immunosuppression included tacrolimus,mycophenolate mofetil,and prednisolone,later modified to azathioprine during pregnancy planning.One-year post-transplant,she conceived spontaneously.Pregnancy was complicated by transient gestational hypertension,controlled with nifedipine,labetalol,and amlodipine.Proteinuria remained<150 mg/day;white blood cell counts 5.8-7.2×109/L without cytopenia.Serum creatinine ranged 0.9-1.1 mg/dL,and tacrolimus trough levels 5-7 ng/mL.At 36 weeks,she delivered a healthy 3 kg infant by elective caesarean section.Postpartum follow-up at three months confirmed stable maternal and graft function.CONCLUSION High-risk complement-mediated TMA patients can achieve successful pregnancy post-transplant through individualized care without mandatory complement blockade.展开更多
AIM:To investigate the prognostic role of invariant natural killer T(iNKT) cells and antibody-dependent cell-mediated cytotoxicity(ADCC) in wild type KRAS metastatic colorectal cancer(mC RC) patients treated with cetu...AIM:To investigate the prognostic role of invariant natural killer T(iNKT) cells and antibody-dependent cell-mediated cytotoxicity(ADCC) in wild type KRAS metastatic colorectal cancer(mC RC) patients treated with cetuximab.METHODS: Forty-one KRAS wt mC RC patients,treated with cetuximab and irinotecan-based chemotherapy in Ⅱ and Ⅲ lines were analyzed. Genotyping of single nucleotide polymorphism(SNP)s in the FCGR2A,FCGR3A and in the 3' untranslated regions of KRAS and mutational analysis for KRAS,BRAF and NRAS genes was determined either by sequencing or allelic discrimination assays. Enriched NK cells were obtained from lymphoprepperipheral blood mononuclear cell and iN KT cells were defined by co-expression of CD3,TCRVα24,TCRVβ11. ADCC was evaluated as ex vivo NK-dependent activity,measuring lactate dehydrogenase release.RESULTS: At basal,mCRC patients performing ADCC activity above the median level(71%) showed an improved overall survival(OS) compared to patients with ADCC below(median 16 vs 8 mo;P=0.026). We did not find any significant correlation of iN KT cells with OS(P=0.19),albeit we observed a trend to a longer survival after 10 mo in patients with iN KT above median basal level(0.382 cells/microliter). Correlation of OS and progression-free survival(PFS) with interesting SNPs involved in ADCC ability revealed not to be significant. Patients carrying alleles both with A in FCGR2 A and TT in FCGR3A presented a trend of longer PFS(median 9 vs 5 mo;P=0.064). Chemotherapy impacted both iN KT cells and ADCC activity. Their prognostic values get lost when we analysed them after 2 and 4 mo of treatment.CONCLUSION: Our results suggest a link between iN KT cells,basal ADCC activity,genotypes in FCGR2A and FCGR3A,and efficacy of cetuximab in KRAS wt mC RC patients.展开更多
Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus,leading to long-term cognitive impairment.However,the mechanism underlying this neurogenesis impairment remains unknown.In ...Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus,leading to long-term cognitive impairment.However,the mechanism underlying this neurogenesis impairment remains unknown.In this study,we established a male mouse model of repetitive traumatic brain injury and performed long-term evaluation of neurogenesis of the hippocampal dentate gyrus after repetitive traumatic brain injury.Our results showed that repetitive traumatic brain injury inhibited neural stem cell proliferation and development,delayed neuronal maturation,and reduced the complexity of neuronal dendrites and spines.Mice with repetitive traumatic brain injuryalso showed deficits in spatial memory retrieval.Moreover,following repetitive traumatic brain injury,neuroinflammation was enhanced in the neurogenesis microenvironment where C1q levels were increased,C1q binding protein levels were decreased,and canonical Wnt/β-catenin signaling was downregulated.An inhibitor of C1 reversed the long-term impairment of neurogenesis induced by repetitive traumatic brain injury and improved neurological function.These findings suggest that repetitive traumatic brain injury–induced C1-related inflammation impairs long-term neurogenesis in the dentate gyrus and contributes to spatial memory retrieval dysfunction.展开更多
Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery...Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery in this population.Following the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation,a similar role for complement in spinal neuroinflammation is a focus of ongoing research.In this work,we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins,triggers of complement activation,and role of effector functions in the pathology.We study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris,and or activation via antibody binding to damage-associated molecular patterns.Several effector functions of complement have been implicated in spinal cord injury,and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord injury.Following this pathophysiological review,we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human subjects.This review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury,to evaluate the phases of involvement of opsonins and anaphylatoxins,and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.展开更多
The complement system is crucial for maintaining immunological homeostasis in the liver,playing a significant role in both innate and adaptive immune responses.Dysregulation of this system is closely linked to the pat...The complement system is crucial for maintaining immunological homeostasis in the liver,playing a significant role in both innate and adaptive immune responses.Dysregulation of this system is closely linked to the pathogenesis of various liver diseases.Modulating the complement system can affect the progression of these conditions.To provide insights into treating liver injury by targeting the regu-lation of the complement system,we conducted a comprehensive search of major biomedical databases,including MEDLINE,PubMed,EMBASE,and Web of Science,to identify articles on complement and liver injury and reviewed the functions and mechanisms of the complement system in liver injury.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)surveillance is crucial for patients with compensated cirrhosis(CC)and decompensated cirrhosis(DC).Increasing evidence has revealed a connection between thyroid hormone(TH)and H...BACKGROUND Hepatocellular carcinoma(HCC)surveillance is crucial for patients with compensated cirrhosis(CC)and decompensated cirrhosis(DC).Increasing evidence has revealed a connection between thyroid hormone(TH)and HCC,although this relationship remains contentious.Complements and immunoglobulin(Ig),which serve as surrogates of cirrhosis-associated immune dysfunc-tion,are associated with the severity and outcomes of liver cirrhosis(LC).To date,there is a lack of evidence supporting the recommendation of TH,Ig,and com-plement tests in patients at high risk of HCC.AIM To assess the predictive value of TH,Ig,and complements for HCC development.METHODS Data from 142 patients,comprising 72 patients with CC and 70 patients with DC,were analysed as a training set.Among them,100 patients who underwent complement and Ig tests were considered for internal validation.Logistic regression was employed to identify independent risk factors for HCC development.RESULTS The median follow-up duration was 32(24-37 months)months.The incidence of HCC was significantly higher in the DC group(16/70,22.9%)compared to the CC group(3/72,4.2%)(χ^(2)=10.698,P<0.01).Patients with DC exhibited lower total tetraiodothyronine(TT4),total triiodothyronine(TT3),free triiodothyronine,complement C3,and C4(all P<0.01),and higher IgA and IgG(both P<0.01).In both CC and DC patients,TT3 and TT4 positively correlated with alanine transaminase(ALT),aspartate transaminase(AST),and gamma-glutamyl transpeptidase(GGT).IgG positively correlated with IgM,IgA,ALT,and AST,while it negatively correlated with C3 and C4.Multivariable analysis indicated that age,DC status,and GGT were independent risk factors for HCC development.CONCLUSION The predictive value of TH,Ig,and complements for HCC development is suboptimal.Age,DC,and GGT emerge as more significant factors during HCC surveillance in hepatitis B virus-related LC.展开更多
Antibody-mediated rejection(AMR)represents a major challenge in kidney transplantation,significantly contributing to tissue injury and graft failure.AMR is primarily driven by donor-specific alloantibodies(DSAs),which...Antibody-mediated rejection(AMR)represents a major challenge in kidney transplantation,significantly contributing to tissue injury and graft failure.AMR is primarily driven by donor-specific alloantibodies(DSAs),which recognize and bind to specific target antigens present within the transplanted kidney tissue.Upon binding,these DSAs commonly initiate activation of the complement system within the graft.The activation of the complement cascade sets off a powerful inflammatory response characterized by the recruitment and activation of immune cells,endothelial damage,and subsequent tissue injury.This inflammation underlies many clinical and histological manifestations of AMR,making complement activation a critical player in the disease process.Advancements in our understanding of how complement pathways contribute to kidney graft injury have opened new avenues for therapeutic intervention.Recent research has facilitated the development and application of novel therapies specifically designed to inhibit complement activation.Such targeted complement-inhibitory strategies have shown promise in improving graft outcomes by inhibiting complement-mediated damage and extending graft survival.This review comprehensively discusses the critical role of complement activation in inducing kidney graft injury with a focus on its role in AMR.By elucidating the detailed mechanisms and contributions of complement pathways,the review seeks to enhance the understanding necessary for developing targeted therapeutic interventions to prevent or treat AMR effectively.展开更多
We deal with the properties of incompressible and pairwise incompressible surfaces in knot complements through the application of relevant properties of almost simple topological graphs.We analyze the topological grap...We deal with the properties of incompressible and pairwise incompressible surfaces in knot complements through the application of relevant properties of almost simple topological graphs.We analyze the topological graph invariants associated with surfaces embedded in the complements of alternating and almost alternating knots.Specifically,we prove that the characteristic numbers of these graphs remain invariant under two fundamental transformations(R-move and S^(2)-move).Leveraging the interplay between characteristic numbers and Euler characteristics,and further connecting Euler characteristics to surface genus,we derive novel results regarding the genus of incompressible pairwise incompressible surfaces.Additionally,we establish a discriminant criterion to determine when such surfaces in knot complements admit genus zero.展开更多
Objectives:Colorectal cancer(CRC)remains a major contributor to global cancer mortality,ranking second worldwide for cancer-related deaths in 2022,and is characterized by marked heterogeneity in prognosis and therapeu...Objectives:Colorectal cancer(CRC)remains a major contributor to global cancer mortality,ranking second worldwide for cancer-related deaths in 2022,and is characterized by marked heterogeneity in prognosis and therapeutic response.We sought to construct a machine-learning prognosticmodel based on a complement-related risk signature(CRRS)and to situate this signature within the CRC immune microenvironment.Methods:Transcriptomic profiles with matched clinical annotations from TCGA and GEO CRC cohorts were analyzed.Prognostic CRRS genes were screened using Cox proportional hazards modeling alongside machine-learning procedures.A random survival forest(RSF)predictor was trained and externally validated.Comparisons of immune infiltration,mutational burden,pathway enrichment,and drug sensitivity were made between risk groups.The function of FAM84A,a key model gene,was examined in CRC cell lines.Results:The six-gene CRRS model accurately stratified patients by survival outcomes.Low-risk patients exhibited greater immune cell infiltration and higher predicted response to immunotherapy and chemotherapy,while high-risk patients showed enrichment of complement activation and matrix remodeling pathways.FAM84A was shown to promote CRC cell proliferation,migration,and epithelial–mesenchymal transition.Conclusion:CRRS is a critical modulator of the CRC immune microenvironment.The developed model enables precise risk prediction and supports individualized therapeutic decisions in CRC.展开更多
目的探究血清网膜素-1(Omentin-1)、补体/C1q肿瘤坏死因子相关蛋白9(CTRP-9)水平与急性脑梗死(ACI)神经功能康复的相关性。方法选取2022年11月至2024年2月于该院治疗的ACI患者106例作为研究组,其中包括ACI神经功能康复良好患者62例(良好...目的探究血清网膜素-1(Omentin-1)、补体/C1q肿瘤坏死因子相关蛋白9(CTRP-9)水平与急性脑梗死(ACI)神经功能康复的相关性。方法选取2022年11月至2024年2月于该院治疗的ACI患者106例作为研究组,其中包括ACI神经功能康复良好患者62例(良好组)和康复不良患者44例(不良组)。采用酶联免疫吸附试验检测所有研究对象的血清Omentin-1、CTRP-9水平;采用Spearman相关性分析血清Omentin-1、CTRP-9水平与ACI患者入院时的美国国立卫生研究院卒中量表(NIHSS)评分及脑梗死体积的相关性;采用多因素Logistic回归分析ACI患者神经功能康复不良的影响因素;采用受试者工作特征(ROC)曲线分析血清Omentin-1、CTRP-9水平对ACI患者神经功能康复不良的诊断价值。结果良好组血清Omentin-1、CTRP-9水平明显高于不良组(P<0.05),入院时NIHSS评分、脑梗死面积和发病90 d时改良Rankin量表(mRS)评分明显低于不良组(P<0.05);Spearman相关性分析显示,血清Omentin-1、CTRP-9水平与90 d mRS评分呈负相关(r=-0.648,-0.573,均P<0.001);多因素Logistic回归分析结果显示,90 d mRS评分是ACI患者神经功能康复不良的危险因素(P<0.05),血清Omentin-1、CTRP-9水平是ACI患者神经功能康复不良的保护因素(P<0.05);ROC曲线分析结果显示,血清Omentin-1、CTRP-9水平诊断ACI患者神经功能康复不良的曲线下面积(AUC)为0.843、0.828,二者联合诊断的AUC为0.937,明显大于二者单独诊断(Z_(二者联合-Omentin-1)=2.321,P=0.020;Z_(二者联合-CTRP-9)=2.532,P=0.011)。结论ACI神经功能康复不良患者血清Omentin-1、CTRP-9水平明显降低,且Omentin-1、CTRP-9水平与90 d mRS评分呈负相关,与神经功能康复情况密切相关。展开更多
基金supported by the Projects of The National Natural Science Foundation of China(U21A20255)Strategic Priority Research Program of the National Center of Technology Innovation for Pigs(NCTIPXD/B04)+3 种基金The National Natural Science Foundation of China(32573270)The National Natural Science Foundation of China(3227291)National Modern Agricultural Industry Technology System Sichuan Pig innovation team(SCSZTD-2024-08)the National Key R&D Program of China(2023YFD1300804)。
文摘Background Heat stress(HS)is posing as a tremendous threat to the swine industry,due to the thermos-sensitive gonads of boars.Testes are immune-privileged organs in which spermatogenesis needs to remain undisturbed,whereas immune cells are thermo-sensitive,especially macrophages,which are the most abundant testicular immune cells.Our study aimed to unveil the underlying immune responses and assess their consequences on the semen quality of boars under HS.The results will aid in addressing environmental temperature-related seasonal infertility and in selecting the best boar for use in artificial insemination.Methods The 3-week experiment assigned 268-week-old Rongchang male pigs into thermal neutral pair-feed(TN-PF)and HS groups.During the last 2 weeks,which served as the HS period,the HS group was subjected to 14-day 35±1℃,while the TN-PF group was kept at 26±1℃.Pig gonad tissues were sampled at the end of HS period for assessments and measurements.Results Our findings confirmed HS-related reactions such as elevated respiration rate(P<0.05)and elevated heat shock protein 60(HSP60;P<0.05)and heat shock protein 90(HSP90;P<0.05)expression levels.Sperm motility(P=0.06)and progressive sperms(P=0.08)were decreased under HS as was a significant reduction in average straight-line velocity(VSL;P<0.05).Additionally,total abnormality levels increased(P<0.05).Fibrosis,caspase-3 expression,and accumulations of tumor necrosis factor-α(TNF-α;P<0.05)and interleukin-1β(IL-1β;P<0.05),along with an elevated macrophage composition(P<0.05)characterized the orchitis under HS.Single cell RNA sequencing(scRNA-seq)revealed fluctuations in engulfing and inflammatory signals in testicular macrophages(TMs).In particular,the complement cascade was promoted by CD163+macrophages,resulting in membrane attack complex(C5b-9)assembly(P<0.05).Linear regressions further revealed a negative correlation between C5b-9 and sperm motility(P<0.05),as well as near-negative correlations between the C5b-9 and both progressive motility(P=0.08)and VSL(P=0.06).Conclusions Our findings highlighted the relationship between HS,the onset of orchitis,and the activation of the complement system,all of which decreased the boar semen quality.
基金supported by the National Natural Science Foundation of China(No.82104353)China Postdoctoral Science Foundation funded project(No.2022M711680).
文摘Insects represent emerging sources of bioactive peptides and functional materials.Mantidis Oötheca(Sang-Piao-Xiao in Chinese,SPX)serves as an insect-derived medicine for treating kidney disease.This study demonstrated that supernatant(SPX)improved kidney function in adriamycin(ADR)-induced nephropathy mice model.Transcriptomic analysis revealed that SPX inhibited complement activation by targeting the MASP1-C3/C3a receptor(C3aR)pathway.Peptidomic analysis identified 304 peptides from SPX,with 49 peptides selected for evaluation using prediction tools and molecular docking with complement core protein C3.Three peptides(PMGFPFDR,FNDPK,AAQFFNR)exhibiting docking scores below-8.0 were synthesized to verify complement inhibition and anti-fibrotic activities.The synthetic peptide AAQFFNR demonstrated complement inhibitory activity,with an inhibitory complement hemolytic 50%(ICH_(50))value of 24.54μmol·L^(-1),and exhibited superior protective effects in ADR-induced HK-2 cells.Surface plasmon resonance(SPR)assay revealed direct interaction between AAQFFNR and complement C3 with K_(d)value of 16.8μmol·L^(-1).The reno-protective effect of AAQFFNR was subsequently verified in ADR-induced mice.This research provides initial evidence that complement C3-inhibiting peptides from insects demonstrate potential in preventing nephropathy through in silico and in vivo validation approaches.
基金supported by the National Natural Science Foundation of China(82071362 and 82270669)Key Project of the Regional Joint Fund of Guangdong Province(2023B1515120077)+3 种基金Basic Research Program of Shenzhen Science and Technology Innovation Commission(JCYJ20210324123001003 and JCYJ20220530144801003)Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research(ZDSYS20230626091402006)the Innovation and Entrepreneurship Training Program for College Students,Sun Yat-sen University(20242150)the Leading Innovation and Entrepreneurship Team Program of Zhejiang Province,China(2023R01005).
文摘Activation of spinal cord neural stem cells(NSCs)and subsequent neurogenesis holds a promising alternative for spinal cord injury(SCI)repair.Our previous study demonstrated that complement C3a,derived from reactive astrocytes,inhibits NSC proliferation by suppressing protein aggregate clearance through the deubiquitinating enzyme ubiquitin carboxy-terminal hydrolase L1(UCHL1)-proteasome system post-SCI.However,the potential molecular mechanism by which C3a modulates NSC activation via this pathway remains unclear.Here,we revealed that C3a/C3a receptor(C3aR)signaling activated NF-κB p65,which in turn inhibited Nrf2 activity and UCHL1 expression,resulting in diminished proteasome activity and the accumulation of protein aggregates,and ultimately impaired NSC activation.Both knockdown of NF-κB p65 and Nrf2 upregulation restored UCHL1 expression and proteasome activity in vitro,promoting NSC activation by enhancing protein aggregate clearance.Mechanistically,we found that NF-κB p65 regulated Nrf2 activity through a dual mechanism:(1)promoting Keap1-dependent ubiquitination and proteasome degradation of Nrf2;(2)inhibiting protein kinase C-mediated Nrf2 phosphorylation and nuclear translocation.Using the dual-luciferase reporter assay and chromatin immunoprecipitation(ChIP)analysis,we further identified UCHL1 as a direct transcriptional target of Nrf2.Importantly,in vivo experiments using SCI mice confirmed that either C3aR blockade,NF-κB p65 knockdown,or Nrf2 overexpression could rescue SCI-induced UCHL1 downregulation.Together,this study uncovers the C3a-NF-κB p65-Nrf2-UCHL1-proteasome axis as a critical regulator of NSC activation after SCI.This may provide novel molecular targets and intervention strategies for SCI repair.
文摘BACKGROUND Complement-mediated thrombotic microangiopathy(TMA)is a rare endothelial injury syndrome caused by dysregulated activation of the alternative complement pathway,often linked to genetic abnormalities in complement factor H(CFH),complement factor I,or complement factor H-related(CFHR)proteins.Both renal transplantation and pregnancy are independent triggers for recurrence.This case highlights a genetically high-risk patient who achieved a successful term pregnancy after renal transplantation without complement inhibition,emphasizing individualized risk stratification,close surveillance,and multidisciplinary management for favourable maternal and graft outcomes.CASE SUMMARY A 32-year-old woman with end-stage renal disease secondary to genetically confirmed complement-mediated TMA—homozygous CFH exon 17 deletion and CFHR3-CFHR1 duplication—was maintained on dialysis for 2.5 years before undergoing a successful live-donor kidney transplant from her mother.Post-transplant immunosuppression included tacrolimus,mycophenolate mofetil,and prednisolone,later modified to azathioprine during pregnancy planning.One-year post-transplant,she conceived spontaneously.Pregnancy was complicated by transient gestational hypertension,controlled with nifedipine,labetalol,and amlodipine.Proteinuria remained<150 mg/day;white blood cell counts 5.8-7.2×109/L without cytopenia.Serum creatinine ranged 0.9-1.1 mg/dL,and tacrolimus trough levels 5-7 ng/mL.At 36 weeks,she delivered a healthy 3 kg infant by elective caesarean section.Postpartum follow-up at three months confirmed stable maternal and graft function.CONCLUSION High-risk complement-mediated TMA patients can achieve successful pregnancy post-transplant through individualized care without mandatory complement blockade.
基金the Fondazione Veronesi that granted Daniela Vivenza and Martino Monteverde with PostDoctoral Fellowship Veronesithe Fondazione Cassa Risparmio of Cuneo for partially supporting the study
文摘AIM:To investigate the prognostic role of invariant natural killer T(iNKT) cells and antibody-dependent cell-mediated cytotoxicity(ADCC) in wild type KRAS metastatic colorectal cancer(mC RC) patients treated with cetuximab.METHODS: Forty-one KRAS wt mC RC patients,treated with cetuximab and irinotecan-based chemotherapy in Ⅱ and Ⅲ lines were analyzed. Genotyping of single nucleotide polymorphism(SNP)s in the FCGR2A,FCGR3A and in the 3' untranslated regions of KRAS and mutational analysis for KRAS,BRAF and NRAS genes was determined either by sequencing or allelic discrimination assays. Enriched NK cells were obtained from lymphoprepperipheral blood mononuclear cell and iN KT cells were defined by co-expression of CD3,TCRVα24,TCRVβ11. ADCC was evaluated as ex vivo NK-dependent activity,measuring lactate dehydrogenase release.RESULTS: At basal,mCRC patients performing ADCC activity above the median level(71%) showed an improved overall survival(OS) compared to patients with ADCC below(median 16 vs 8 mo;P=0.026). We did not find any significant correlation of iN KT cells with OS(P=0.19),albeit we observed a trend to a longer survival after 10 mo in patients with iN KT above median basal level(0.382 cells/microliter). Correlation of OS and progression-free survival(PFS) with interesting SNPs involved in ADCC ability revealed not to be significant. Patients carrying alleles both with A in FCGR2 A and TT in FCGR3A presented a trend of longer PFS(median 9 vs 5 mo;P=0.064). Chemotherapy impacted both iN KT cells and ADCC activity. Their prognostic values get lost when we analysed them after 2 and 4 mo of treatment.CONCLUSION: Our results suggest a link between iN KT cells,basal ADCC activity,genotypes in FCGR2A and FCGR3A,and efficacy of cetuximab in KRAS wt mC RC patients.
基金supported by the Fundamental Research Program of Shanxi Province of China,No.20210302124277the Science Foundation of Shanxi Bethune Hospital,No.2021YJ13(both to JW)。
文摘Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus,leading to long-term cognitive impairment.However,the mechanism underlying this neurogenesis impairment remains unknown.In this study,we established a male mouse model of repetitive traumatic brain injury and performed long-term evaluation of neurogenesis of the hippocampal dentate gyrus after repetitive traumatic brain injury.Our results showed that repetitive traumatic brain injury inhibited neural stem cell proliferation and development,delayed neuronal maturation,and reduced the complexity of neuronal dendrites and spines.Mice with repetitive traumatic brain injuryalso showed deficits in spatial memory retrieval.Moreover,following repetitive traumatic brain injury,neuroinflammation was enhanced in the neurogenesis microenvironment where C1q levels were increased,C1q binding protein levels were decreased,and canonical Wnt/β-catenin signaling was downregulated.An inhibitor of C1 reversed the long-term impairment of neurogenesis induced by repetitive traumatic brain injury and improved neurological function.These findings suggest that repetitive traumatic brain injury–induced C1-related inflammation impairs long-term neurogenesis in the dentate gyrus and contributes to spatial memory retrieval dysfunction.
基金supported by the Department of Veterans Affairs(VA Merit Award BX004256)(to AMA)Emory Department of Neurosurgery Catalyst GrantEmory Medical Care Foundation Grant(to AMA and JG)。
文摘Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery in this population.Following the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation,a similar role for complement in spinal neuroinflammation is a focus of ongoing research.In this work,we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins,triggers of complement activation,and role of effector functions in the pathology.We study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris,and or activation via antibody binding to damage-associated molecular patterns.Several effector functions of complement have been implicated in spinal cord injury,and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord injury.Following this pathophysiological review,we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human subjects.This review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury,to evaluate the phases of involvement of opsonins and anaphylatoxins,and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.
基金Supported by the Science and Technology Planning Projects of Guizhou Province,No.QKHJC-ZK[2022]YB642the Science and Technology Planning Projects of Zunyi City,No.ZSKHHZ(2022)344+4 种基金the WBE Liver Fibrosis Foundation,No.CFHPC2025028the Chinese Foundation for Hepatitis Prevention and Control Muxin Research Fund of CHB,No.MX202404Beijing Liver and Gallbladder Mutual Aid Public Welfare Foundation Artificial Liver Special Fund,No.iGandanF-1082024-Rgg018the Graduate Research Fund Project of Zunyi Medical University,No.ZYK246the Student Innovation and Entrepreneurship Training Program of Zunyi Medical University,No.2024106610923 and No.S202310661028.
文摘The complement system is crucial for maintaining immunological homeostasis in the liver,playing a significant role in both innate and adaptive immune responses.Dysregulation of this system is closely linked to the pathogenesis of various liver diseases.Modulating the complement system can affect the progression of these conditions.To provide insights into treating liver injury by targeting the regu-lation of the complement system,we conducted a comprehensive search of major biomedical databases,including MEDLINE,PubMed,EMBASE,and Web of Science,to identify articles on complement and liver injury and reviewed the functions and mechanisms of the complement system in liver injury.
基金Supported by The Research Foundation of Jiangsu Province Administration of Traditional Chinese Medicine,No.MS2023088The Science and Technology Project of Changzhou,No.CE20225040+1 种基金The Research Foundation of Nanjing Medical University Changzhou Medical Center,No.CMCC202311Leading Talent of Changzhou“The 14th Five-Year Plan”High-Level Health Talents Training Project,No.2022CZLJ021.
文摘BACKGROUND Hepatocellular carcinoma(HCC)surveillance is crucial for patients with compensated cirrhosis(CC)and decompensated cirrhosis(DC).Increasing evidence has revealed a connection between thyroid hormone(TH)and HCC,although this relationship remains contentious.Complements and immunoglobulin(Ig),which serve as surrogates of cirrhosis-associated immune dysfunc-tion,are associated with the severity and outcomes of liver cirrhosis(LC).To date,there is a lack of evidence supporting the recommendation of TH,Ig,and com-plement tests in patients at high risk of HCC.AIM To assess the predictive value of TH,Ig,and complements for HCC development.METHODS Data from 142 patients,comprising 72 patients with CC and 70 patients with DC,were analysed as a training set.Among them,100 patients who underwent complement and Ig tests were considered for internal validation.Logistic regression was employed to identify independent risk factors for HCC development.RESULTS The median follow-up duration was 32(24-37 months)months.The incidence of HCC was significantly higher in the DC group(16/70,22.9%)compared to the CC group(3/72,4.2%)(χ^(2)=10.698,P<0.01).Patients with DC exhibited lower total tetraiodothyronine(TT4),total triiodothyronine(TT3),free triiodothyronine,complement C3,and C4(all P<0.01),and higher IgA and IgG(both P<0.01).In both CC and DC patients,TT3 and TT4 positively correlated with alanine transaminase(ALT),aspartate transaminase(AST),and gamma-glutamyl transpeptidase(GGT).IgG positively correlated with IgM,IgA,ALT,and AST,while it negatively correlated with C3 and C4.Multivariable analysis indicated that age,DC status,and GGT were independent risk factors for HCC development.CONCLUSION The predictive value of TH,Ig,and complements for HCC development is suboptimal.Age,DC,and GGT emerge as more significant factors during HCC surveillance in hepatitis B virus-related LC.
文摘Antibody-mediated rejection(AMR)represents a major challenge in kidney transplantation,significantly contributing to tissue injury and graft failure.AMR is primarily driven by donor-specific alloantibodies(DSAs),which recognize and bind to specific target antigens present within the transplanted kidney tissue.Upon binding,these DSAs commonly initiate activation of the complement system within the graft.The activation of the complement cascade sets off a powerful inflammatory response characterized by the recruitment and activation of immune cells,endothelial damage,and subsequent tissue injury.This inflammation underlies many clinical and histological manifestations of AMR,making complement activation a critical player in the disease process.Advancements in our understanding of how complement pathways contribute to kidney graft injury have opened new avenues for therapeutic intervention.Recent research has facilitated the development and application of novel therapies specifically designed to inhibit complement activation.Such targeted complement-inhibitory strategies have shown promise in improving graft outcomes by inhibiting complement-mediated damage and extending graft survival.This review comprehensively discusses the critical role of complement activation in inducing kidney graft injury with a focus on its role in AMR.By elucidating the detailed mechanisms and contributions of complement pathways,the review seeks to enhance the understanding necessary for developing targeted therapeutic interventions to prevent or treat AMR effectively.
基金Supported by the National Natural Science Foundation of China(Grant No.12026411)。
文摘We deal with the properties of incompressible and pairwise incompressible surfaces in knot complements through the application of relevant properties of almost simple topological graphs.We analyze the topological graph invariants associated with surfaces embedded in the complements of alternating and almost alternating knots.Specifically,we prove that the characteristic numbers of these graphs remain invariant under two fundamental transformations(R-move and S^(2)-move).Leveraging the interplay between characteristic numbers and Euler characteristics,and further connecting Euler characteristics to surface genus,we derive novel results regarding the genus of incompressible pairwise incompressible surfaces.Additionally,we establish a discriminant criterion to determine when such surfaces in knot complements admit genus zero.
文摘Objectives:Colorectal cancer(CRC)remains a major contributor to global cancer mortality,ranking second worldwide for cancer-related deaths in 2022,and is characterized by marked heterogeneity in prognosis and therapeutic response.We sought to construct a machine-learning prognosticmodel based on a complement-related risk signature(CRRS)and to situate this signature within the CRC immune microenvironment.Methods:Transcriptomic profiles with matched clinical annotations from TCGA and GEO CRC cohorts were analyzed.Prognostic CRRS genes were screened using Cox proportional hazards modeling alongside machine-learning procedures.A random survival forest(RSF)predictor was trained and externally validated.Comparisons of immune infiltration,mutational burden,pathway enrichment,and drug sensitivity were made between risk groups.The function of FAM84A,a key model gene,was examined in CRC cell lines.Results:The six-gene CRRS model accurately stratified patients by survival outcomes.Low-risk patients exhibited greater immune cell infiltration and higher predicted response to immunotherapy and chemotherapy,while high-risk patients showed enrichment of complement activation and matrix remodeling pathways.FAM84A was shown to promote CRC cell proliferation,migration,and epithelial–mesenchymal transition.Conclusion:CRRS is a critical modulator of the CRC immune microenvironment.The developed model enables precise risk prediction and supports individualized therapeutic decisions in CRC.
文摘目的探究血清网膜素-1(Omentin-1)、补体/C1q肿瘤坏死因子相关蛋白9(CTRP-9)水平与急性脑梗死(ACI)神经功能康复的相关性。方法选取2022年11月至2024年2月于该院治疗的ACI患者106例作为研究组,其中包括ACI神经功能康复良好患者62例(良好组)和康复不良患者44例(不良组)。采用酶联免疫吸附试验检测所有研究对象的血清Omentin-1、CTRP-9水平;采用Spearman相关性分析血清Omentin-1、CTRP-9水平与ACI患者入院时的美国国立卫生研究院卒中量表(NIHSS)评分及脑梗死体积的相关性;采用多因素Logistic回归分析ACI患者神经功能康复不良的影响因素;采用受试者工作特征(ROC)曲线分析血清Omentin-1、CTRP-9水平对ACI患者神经功能康复不良的诊断价值。结果良好组血清Omentin-1、CTRP-9水平明显高于不良组(P<0.05),入院时NIHSS评分、脑梗死面积和发病90 d时改良Rankin量表(mRS)评分明显低于不良组(P<0.05);Spearman相关性分析显示,血清Omentin-1、CTRP-9水平与90 d mRS评分呈负相关(r=-0.648,-0.573,均P<0.001);多因素Logistic回归分析结果显示,90 d mRS评分是ACI患者神经功能康复不良的危险因素(P<0.05),血清Omentin-1、CTRP-9水平是ACI患者神经功能康复不良的保护因素(P<0.05);ROC曲线分析结果显示,血清Omentin-1、CTRP-9水平诊断ACI患者神经功能康复不良的曲线下面积(AUC)为0.843、0.828,二者联合诊断的AUC为0.937,明显大于二者单独诊断(Z_(二者联合-Omentin-1)=2.321,P=0.020;Z_(二者联合-CTRP-9)=2.532,P=0.011)。结论ACI神经功能康复不良患者血清Omentin-1、CTRP-9水平明显降低,且Omentin-1、CTRP-9水平与90 d mRS评分呈负相关,与神经功能康复情况密切相关。
