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
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
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
The rapid development of information technology and accelerated digitalization have led to an explosive growth of data across various fields.As a key technology for knowledge representation and sharing,knowledge graph...The rapid development of information technology and accelerated digitalization have led to an explosive growth of data across various fields.As a key technology for knowledge representation and sharing,knowledge graphs play a crucial role by constructing structured networks of relationships among entities.However,data sparsity and numerous unexplored implicit relations result in the widespread incompleteness of knowledge graphs.In static knowledge graph completion,most existing methods rely on linear operations or simple interaction mechanisms for triple encoding,making it difficult to fully capture the deep semantic associations between entities and relations.Moreover,many methods focus only on the local information of individual triples,ignoring the rich semantic dependencies embedded in the neighboring nodes of entities within the graph structure,which leads to incomplete embedding representations.To address these challenges,we propose Two-Stage Mixer Embedding(TSMixerE),a static knowledge graph completion method based on entity context.In the unit semantic extraction stage,TSMixerE leveragesmulti-scale circular convolution to capture local features atmultiple granularities,enhancing the flexibility and robustness of feature interactions.A channel attention mechanism amplifies key channel responses to suppress noise and irrelevant information,thereby improving the discriminative power and semantic depth of feature representations.For contextual information fusion,a multi-layer self-attentionmechanism enables deep interactions among contextual cues,effectively integrating local details with global context.Simultaneously,type embeddings clarify the semantic identities and roles of each component,enhancing the model’s sensitivity and fusion capabilities for diverse information sources.Furthermore,TSMixerE constructs contextual unit sequences for entities,fully exploring neighborhood information within the graph structure to model complex semantic dependencies,thus improving the completeness and generalization of embedding representations.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
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
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
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
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。
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.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.
基金supported by the National Natural Science Foundation of China(No.62267005)the Chinese Guangxi Natural Science Foundation(No.2023GXNSFAA026493)+1 种基金Guangxi Collaborative Innovation Center ofMulti-Source Information Integration and Intelligent ProcessingGuangxi Academy of Artificial Intelligence.
文摘The rapid development of information technology and accelerated digitalization have led to an explosive growth of data across various fields.As a key technology for knowledge representation and sharing,knowledge graphs play a crucial role by constructing structured networks of relationships among entities.However,data sparsity and numerous unexplored implicit relations result in the widespread incompleteness of knowledge graphs.In static knowledge graph completion,most existing methods rely on linear operations or simple interaction mechanisms for triple encoding,making it difficult to fully capture the deep semantic associations between entities and relations.Moreover,many methods focus only on the local information of individual triples,ignoring the rich semantic dependencies embedded in the neighboring nodes of entities within the graph structure,which leads to incomplete embedding representations.To address these challenges,we propose Two-Stage Mixer Embedding(TSMixerE),a static knowledge graph completion method based on entity context.In the unit semantic extraction stage,TSMixerE leveragesmulti-scale circular convolution to capture local features atmultiple granularities,enhancing the flexibility and robustness of feature interactions.A channel attention mechanism amplifies key channel responses to suppress noise and irrelevant information,thereby improving the discriminative power and semantic depth of feature representations.For contextual information fusion,a multi-layer self-attentionmechanism enables deep interactions among contextual cues,effectively integrating local details with global context.Simultaneously,type embeddings clarify the semantic identities and roles of each component,enhancing the model’s sensitivity and fusion capabilities for diverse information sources.Furthermore,TSMixerE constructs contextual unit sequences for entities,fully exploring neighborhood information within the graph structure to model complex semantic dependencies,thus improving the completeness and generalization of embedding representations.
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.
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 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.
