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
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
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
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
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
Synaptic pruning is a crucial process in synaptic refinement,eliminating unstable synaptic connections in neural circuits.This process is triggered and regulated primarily by spontaneous neural activity and experience...Synaptic pruning is a crucial process in synaptic refinement,eliminating unstable synaptic connections in neural circuits.This process is triggered and regulated primarily by spontaneous neural activity and experience-dependent mechanisms.The pruning process involves multiple molecular signals and a series of regulatory activities governing the“eat me”and“don't eat me”states.Under physiological conditions,the interaction between glial cells and neurons results in the clearance of unnecessary synapses,maintaining normal neural circuit functionality via synaptic pruning.Alterations in genetic and environmental factors can lead to imbalanced synaptic pruning,thus promoting the occurrence and development of autism spectrum disorder,schizophrenia,Alzheimer's disease,and other neurological disorders.In this review,we investigated the molecular mechanisms responsible for synaptic pruning during neural development.We focus on how synaptic pruning can regulate neural circuits and its association with neurological disorders.Furthermore,we discuss the application of emerging optical and imaging technologies to observe synaptic structure and function,as well as their potential for clinical translation.Our aim was to enhance our understanding of synaptic pruning during neural development,including the molecular basis underlying the regulation of synaptic function and the dynamic changes in synaptic density,and to investigate the potential role of these mechanisms in the pathophysiology of neurological diseases,thus providing a theoretical foundation for the treatment of neurological disorders.展开更多
Myasthenia gravis is a chronic autoimmune disorder that affects the neuromuscular junction leading to fluctuating skeletal muscle fatigability. The majority of myasthenia gravis patients have detectable antibodies in ...Myasthenia gravis is a chronic autoimmune disorder that affects the neuromuscular junction leading to fluctuating skeletal muscle fatigability. The majority of myasthenia gravis patients have detectable antibodies in their serum, targeting acetylcholine receptor, muscle-specific kinase, or related proteins. Current treatment for myasthenia gravis involves symptomatic therapy, immunosuppressive drugs such as corticosteroids, azathioprine, and mycophenolate mofetil, and thymectomy, which is primarily indicated in patients with thymoma or thymic hyperplasia. However, this condition continues to pose significant challenges including an unpredictable and variable disease progression, differing response to individual therapies, and substantial longterm side effects associated with standard treatments(including an increased risk of infections, osteoporosis, and diabetes), underscoring the necessity for a more personalized approach to treatment. Furthermore, about fifteen percent of patients, called “refractory myasthenia gravis patients”, do not respond adequately to standard therapies. In this context, the introduction of molecular therapies has marked a significant advance in myasthenia gravis management. Advances in understanding myasthenia gravis pathogenesis, especially the role of pathogenic antibodies, have driven the development of these biological drugs, which offer more selective, rapid, and safer alternatives to traditional immunosuppressants. This review aims to provide a comprehensive overview of emerging therapeutic strategies targeting specific immune pathways in myasthenia gravis, with a particular focus on preclinical evidence, therapeutic rationale, and clinical translation of B-cell depletion therapies, neonatal Fc receptor inhibitors, and complement inhibitors.展开更多
The complement system plays a crucial role in the innate defense against common pathogens. Activation of complement leads to robust and efficient proteolytic cascades, which terminate in opsonization and lysis of the ...The complement system plays a crucial role in the innate defense against common pathogens. Activation of complement leads to robust and efficient proteolytic cascades, which terminate in opsonization and lysis of the pathogen as well as in the generation of the classical inflammatory response through the production of potent proinflammatory molecules. More recently, however, the role of complement in the immune response has been expanded due to observations that link complement activation to adaptive immune responses. It is now appreciated that complement is a functional bridge between innate and adaptive immune responses that allows an integrated host defense to pathogenic challenges. As such, a study of its functions allows insight into the molecular underpinnings of host-pathogen interactions as well as the organization and orchestration of the host immune response. This review attempts to summarize the roles that complement plays in both innate and adaptive immune responses and the consequences of these interactions on host defense.展开更多
The northem pig-tailed macaque （NPM, Macaca leonina） has become a widely used animal model in biomedical research. In this study, we measured serum immunoglobulin IgG, IgM, IgA, complement C3, C4 and CRP levels in 3...The northem pig-tailed macaque （NPM, Macaca leonina） has become a widely used animal model in biomedical research. In this study, we measured serum immunoglobulin IgG, IgM, IgA, complement C3, C4 and CRP levels in 3-11 year old captive northem pig-tailed macaques using HITACHI 7600-20 automated chemistry analyzer in order to determine the influences of age and gender on these items. The results showed that serum IgA, IgM, C3 and C4 levels were not correlated with age （P〉0.05）, while serum IgG levels increased progressively with age （r=0.202; P=0.045）. Serum IgG, IgA, IgM and C3 levels were higher in females than in males （P〈0.05）. Moreover, serum C3 concentration was both positively and strongly correlated with that of C4 （r=0.700; P〈0.0001）. This study provides basic serum immunoglobulin and complement data of captive northem pig-tailed macaques, which may prove useful for future breeding efforts and biomedical research.展开更多
AIM： To investigate the effect of IL-4 on the altered expression of complement activation regulators in pancreas and pancreatic necrosis during experimental severe acute pancreatitis （SAP）. METHODS： SAP model of r...AIM： To investigate the effect of IL-4 on the altered expression of complement activation regulators in pancreas and pancreatic necrosis during experimental severe acute pancreatitis （SAP）. METHODS： SAP model of rats was established by retrograde injection of 5% sodium taurocholate （1 mL/kg） into the pancreatic duct. We immunohistochemically assayed the expression of three complement activation regulators： decay accelerating factor （DAF; CD55）, 20 ku homologous restriction factor （HRF20; CD59） and membrane cofactor protein （MCP; CEH6）, in the pancreatic acinar cells of rats at 0, 3, 6, 12, and 24 h after the induction of SAP model. Meanwhile the levels of amylase and lipase were determined, and morphological examination was performed. Then, 61 rats were randomly divided into three groups. Group A （n = 21） received no treatment after the SAP model was established; group B （n = 20） was given IL-4 （8 IJg/animal） intraperitoneally 0.5 h before the SAP model was established; group C （n = 20） was given IL-4 （8 μg/animal） intraperitoneaUy 0.5 h after the SAP model was established. Plasma amylase and lipase, extent of pancreatic necrosis and expression of complement activation regulators were investigated 6 h after the induction of SAP model. RESULTS： Three complement activation regulators were all expressed in pancreatic acinar cells. MCP was not found on the basolateral surface as reported. Contrary to the gradually increasing plasma level of amylase and lipase, expression of complement activation regulators decreased after SAP model was set up. At the same time, the severity of pancreatic necrosis was enhanced. A strong negative correlation was found between the expression of MCP, DAF, CD59 in pancreatic acinar cells and the severity of pancreatic necrosis （r = -0.748, -0.827, -0.723; P〈0.01）. In the second series of experiments, no matter when the treatment of IL-4 was given （before or after the induction of SAP model）, the serum level of amylase or lipase was decreased and the extent of pancreatic necrosis was ameliorated significantly. Compared to SAP control group, the expression of DAF and CD59 in pancreas was reinforced when IL-4 was given before the induction of SAP model （P〈0.01, P〈0.05）, but the expression of MCP was not influenced （P〉0.05）. The expression of DAF was enhanced, when IL-4 was given after the induction of SAP model （P〈0.05）, but the expression of CD59 and MCP did not change （P〉0.05）. CONCLUSION： Complement activation regulators may participate in the pathogenesis of pancreatic inflammation. Downregulation of complement activation regulators expression may be one of the causes of pancreatic necrosis. IL-4 treatment may control SAP aggravation by enhancing expression of DAF and CD59 in pancreas and decreasing pancreatic necrosis. Moreover, DAF and CD59 may play an important role in the regulation of complement activation regulators during SAP.展开更多
Previous studies have reported age-specific pathological and functional outcomes in young and aged patients suffering spinal cord injury,but the mechanisms remain poorly understood. In this study, we examined mice wit...Previous studies have reported age-specific pathological and functional outcomes in young and aged patients suffering spinal cord injury,but the mechanisms remain poorly understood. In this study, we examined mice with spinal cord injury. Gene expression profiles from the Gene Expression Omnibus database （accession number GSE93561） were used, including spinal cord samples from 3 young injured mice （2–3-months old, induced by Impactor at Th9 level） and 3 control mice （2–3-months old, no treatment）, as well as 2 aged injured mice （15–18-months old, induced by Impactor at Th9 level） and 2 control mice （15–18-months old, no treatment）. Differentially expressed genes （DEGs） in spinal cord tissue from injured and control mice were identified using the Linear Models for Microarray data method,with a threshold of adjusted P 〈 0.05 and ｜logFC（fold change）｜ 〉 1.5. Protein–protein interaction networks were constructed using data from the STRING database, followed by module analysis by Cytoscape software to screen crucial genes. Kyoto encyclopedia of genes and genomes pathway and Gene Ontology enrichment analyses were performed to investigate the underlying functions of DEGs using Database for Annotation, Visualization and Integrated Discovery. Consequently, 1,604 and 1,153 DEGs were identified between injured and normal control mice in spinal cord tissue of aged and young mice, respectively. Furthermore, a Venn diagram showed that 960 DEGs were shared among aged and young mice, while 644 and 193 DEGs were specific to aged and young mice, respectively. Functional enrichment indicates that shared DEGs are involved in osteoclast differentiation, extracellular matrix–receptor interaction, nuclear factor-kappa B signaling pathway, and focal adhesion. Unique genes for aged and young injured groups were involved in the cell cycle （upregulation of PLK1） and complement （upregulation of C3） activation, respectively. These findings were confirmed by functional analysis of genes in modules （common, 4; aged, 2; young, 1） screened from protein–protein interaction networks. Accordingly, cell cycle and complement inhibitors may be specific treatments for spinal cord injury in aged and young mice, respectively.展开更多
The complement pathway is best known for its role in immune surveillance and inflammation. However,its ability of opsonizing and removing not only pathogens,but also necrotic and apoptotic cells,is a phylogenetically ...The complement pathway is best known for its role in immune surveillance and inflammation. However,its ability of opsonizing and removing not only pathogens,but also necrotic and apoptotic cells,is a phylogenetically ancient means of initiating tissue repair. The means and mechanisms of complement-mediated tissue repair are discussed in this review. There is increasing evidence that complement activation contributes to tissue repair at several levels. These range from the chemo-attraction of stem and progenitor cells to areas of complement activation,to increased survival of various cell types in the presence of split products of complement,and to the production of trophic factors by cells activated by the anaphylatoxins C3 a and C5 a. This repair aspect of complement biology has not found sufficient appreciation until recently. The following will examine this aspect of complement biology with an emphasis on the anaphylatoxins C3 a and C5 a.展开更多
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.
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 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.
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.
基金supported by the National Natural Science Foundation of China,No.31760290,82160688the Key Development Areas Project of Ganzhou Science and Technology,No.2022B-SF9554(all to XL)。
文摘Synaptic pruning is a crucial process in synaptic refinement,eliminating unstable synaptic connections in neural circuits.This process is triggered and regulated primarily by spontaneous neural activity and experience-dependent mechanisms.The pruning process involves multiple molecular signals and a series of regulatory activities governing the“eat me”and“don't eat me”states.Under physiological conditions,the interaction between glial cells and neurons results in the clearance of unnecessary synapses,maintaining normal neural circuit functionality via synaptic pruning.Alterations in genetic and environmental factors can lead to imbalanced synaptic pruning,thus promoting the occurrence and development of autism spectrum disorder,schizophrenia,Alzheimer's disease,and other neurological disorders.In this review,we investigated the molecular mechanisms responsible for synaptic pruning during neural development.We focus on how synaptic pruning can regulate neural circuits and its association with neurological disorders.Furthermore,we discuss the application of emerging optical and imaging technologies to observe synaptic structure and function,as well as their potential for clinical translation.Our aim was to enhance our understanding of synaptic pruning during neural development,including the molecular basis underlying the regulation of synaptic function and the dynamic changes in synaptic density,and to investigate the potential role of these mechanisms in the pathophysiology of neurological diseases,thus providing a theoretical foundation for the treatment of neurological disorders.
文摘Myasthenia gravis is a chronic autoimmune disorder that affects the neuromuscular junction leading to fluctuating skeletal muscle fatigability. The majority of myasthenia gravis patients have detectable antibodies in their serum, targeting acetylcholine receptor, muscle-specific kinase, or related proteins. Current treatment for myasthenia gravis involves symptomatic therapy, immunosuppressive drugs such as corticosteroids, azathioprine, and mycophenolate mofetil, and thymectomy, which is primarily indicated in patients with thymoma or thymic hyperplasia. However, this condition continues to pose significant challenges including an unpredictable and variable disease progression, differing response to individual therapies, and substantial longterm side effects associated with standard treatments(including an increased risk of infections, osteoporosis, and diabetes), underscoring the necessity for a more personalized approach to treatment. Furthermore, about fifteen percent of patients, called “refractory myasthenia gravis patients”, do not respond adequately to standard therapies. In this context, the introduction of molecular therapies has marked a significant advance in myasthenia gravis management. Advances in understanding myasthenia gravis pathogenesis, especially the role of pathogenic antibodies, have driven the development of these biological drugs, which offer more selective, rapid, and safer alternatives to traditional immunosuppressants. This review aims to provide a comprehensive overview of emerging therapeutic strategies targeting specific immune pathways in myasthenia gravis, with a particular focus on preclinical evidence, therapeutic rationale, and clinical translation of B-cell depletion therapies, neonatal Fc receptor inhibitors, and complement inhibitors.
文摘The complement system plays a crucial role in the innate defense against common pathogens. Activation of complement leads to robust and efficient proteolytic cascades, which terminate in opsonization and lysis of the pathogen as well as in the generation of the classical inflammatory response through the production of potent proinflammatory molecules. More recently, however, the role of complement in the immune response has been expanded due to observations that link complement activation to adaptive immune responses. It is now appreciated that complement is a functional bridge between innate and adaptive immune responses that allows an integrated host defense to pathogenic challenges. As such, a study of its functions allows insight into the molecular underpinnings of host-pathogen interactions as well as the organization and orchestration of the host immune response. This review attempts to summarize the roles that complement plays in both innate and adaptive immune responses and the consequences of these interactions on host defense.
基金Foundation items： This work was supported by the National Natural Science Foundation of China （81172876, U0832601, 81273251, U1202228） the National Special Science Research Program of China （2012CBA01305） the National Science and Technology Major Project （2013ZX10001-002, 2012ZX10001-007） and the Knowledge Innovation Program of CAS （KSCX2-EW-R-13）.
文摘The northem pig-tailed macaque （NPM, Macaca leonina） has become a widely used animal model in biomedical research. In this study, we measured serum immunoglobulin IgG, IgM, IgA, complement C3, C4 and CRP levels in 3-11 year old captive northem pig-tailed macaques using HITACHI 7600-20 automated chemistry analyzer in order to determine the influences of age and gender on these items. The results showed that serum IgA, IgM, C3 and C4 levels were not correlated with age （P〉0.05）, while serum IgG levels increased progressively with age （r=0.202; P=0.045）. Serum IgG, IgA, IgM and C3 levels were higher in females than in males （P〈0.05）. Moreover, serum C3 concentration was both positively and strongly correlated with that of C4 （r=0.700; P〈0.0001）. This study provides basic serum immunoglobulin and complement data of captive northem pig-tailed macaques, which may prove useful for future breeding efforts and biomedical research.
基金Supported by the Research Program of Science and Technology Technology Commission Foundation of Liaoning Province, No. 2001225001-17
文摘AIM： To investigate the effect of IL-4 on the altered expression of complement activation regulators in pancreas and pancreatic necrosis during experimental severe acute pancreatitis （SAP）. METHODS： SAP model of rats was established by retrograde injection of 5% sodium taurocholate （1 mL/kg） into the pancreatic duct. We immunohistochemically assayed the expression of three complement activation regulators： decay accelerating factor （DAF; CD55）, 20 ku homologous restriction factor （HRF20; CD59） and membrane cofactor protein （MCP; CEH6）, in the pancreatic acinar cells of rats at 0, 3, 6, 12, and 24 h after the induction of SAP model. Meanwhile the levels of amylase and lipase were determined, and morphological examination was performed. Then, 61 rats were randomly divided into three groups. Group A （n = 21） received no treatment after the SAP model was established; group B （n = 20） was given IL-4 （8 IJg/animal） intraperitoneally 0.5 h before the SAP model was established; group C （n = 20） was given IL-4 （8 μg/animal） intraperitoneaUy 0.5 h after the SAP model was established. Plasma amylase and lipase, extent of pancreatic necrosis and expression of complement activation regulators were investigated 6 h after the induction of SAP model. RESULTS： Three complement activation regulators were all expressed in pancreatic acinar cells. MCP was not found on the basolateral surface as reported. Contrary to the gradually increasing plasma level of amylase and lipase, expression of complement activation regulators decreased after SAP model was set up. At the same time, the severity of pancreatic necrosis was enhanced. A strong negative correlation was found between the expression of MCP, DAF, CD59 in pancreatic acinar cells and the severity of pancreatic necrosis （r = -0.748, -0.827, -0.723; P〈0.01）. In the second series of experiments, no matter when the treatment of IL-4 was given （before or after the induction of SAP model）, the serum level of amylase or lipase was decreased and the extent of pancreatic necrosis was ameliorated significantly. Compared to SAP control group, the expression of DAF and CD59 in pancreas was reinforced when IL-4 was given before the induction of SAP model （P〈0.01, P〈0.05）, but the expression of MCP was not influenced （P〉0.05）. The expression of DAF was enhanced, when IL-4 was given after the induction of SAP model （P〈0.05）, but the expression of CD59 and MCP did not change （P〉0.05）. CONCLUSION： Complement activation regulators may participate in the pathogenesis of pancreatic inflammation. Downregulation of complement activation regulators expression may be one of the causes of pancreatic necrosis. IL-4 treatment may control SAP aggravation by enhancing expression of DAF and CD59 in pancreas and decreasing pancreatic necrosis. Moreover, DAF and CD59 may play an important role in the regulation of complement activation regulators during SAP.
基金supported by the National Science Fund for Distinguished Young Scientists of China,No.81601052
文摘Previous studies have reported age-specific pathological and functional outcomes in young and aged patients suffering spinal cord injury,but the mechanisms remain poorly understood. In this study, we examined mice with spinal cord injury. Gene expression profiles from the Gene Expression Omnibus database （accession number GSE93561） were used, including spinal cord samples from 3 young injured mice （2–3-months old, induced by Impactor at Th9 level） and 3 control mice （2–3-months old, no treatment）, as well as 2 aged injured mice （15–18-months old, induced by Impactor at Th9 level） and 2 control mice （15–18-months old, no treatment）. Differentially expressed genes （DEGs） in spinal cord tissue from injured and control mice were identified using the Linear Models for Microarray data method,with a threshold of adjusted P 〈 0.05 and ｜logFC（fold change）｜ 〉 1.5. Protein–protein interaction networks were constructed using data from the STRING database, followed by module analysis by Cytoscape software to screen crucial genes. Kyoto encyclopedia of genes and genomes pathway and Gene Ontology enrichment analyses were performed to investigate the underlying functions of DEGs using Database for Annotation, Visualization and Integrated Discovery. Consequently, 1,604 and 1,153 DEGs were identified between injured and normal control mice in spinal cord tissue of aged and young mice, respectively. Furthermore, a Venn diagram showed that 960 DEGs were shared among aged and young mice, while 644 and 193 DEGs were specific to aged and young mice, respectively. Functional enrichment indicates that shared DEGs are involved in osteoclast differentiation, extracellular matrix–receptor interaction, nuclear factor-kappa B signaling pathway, and focal adhesion. Unique genes for aged and young injured groups were involved in the cell cycle （upregulation of PLK1） and complement （upregulation of C3） activation, respectively. These findings were confirmed by functional analysis of genes in modules （common, 4; aged, 2; young, 1） screened from protein–protein interaction networks. Accordingly, cell cycle and complement inhibitors may be specific treatments for spinal cord injury in aged and young mice, respectively.
基金Supported by The grants R21 HL094878 and R21AI10950 to IUS and RGD
文摘The complement pathway is best known for its role in immune surveillance and inflammation. However,its ability of opsonizing and removing not only pathogens,but also necrotic and apoptotic cells,is a phylogenetically ancient means of initiating tissue repair. The means and mechanisms of complement-mediated tissue repair are discussed in this review. There is increasing evidence that complement activation contributes to tissue repair at several levels. These range from the chemo-attraction of stem and progenitor cells to areas of complement activation,to increased survival of various cell types in the presence of split products of complement,and to the production of trophic factors by cells activated by the anaphylatoxins C3 a and C5 a. This repair aspect of complement biology has not found sufficient appreciation until recently. The following will examine this aspect of complement biology with an emphasis on the anaphylatoxins C3 a and C5 a.
