Complement-dependent neuroinflammation in spinal cord injury:from pathology to therapeutic implications

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.

Repetitive traumatic brain injury–induced complement C1–related inflammation impairs long-term hippocampal neurogenesis

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.

Overview of hydro–wind–solar power complementation development in China

1Introduction Hydropower generation in China started over a century ago, greatly contributing to their economic and social development. Wind power and photovoltaic (PV) power generation began on a large scale in the 21st century.

Peak shaving operation optimization of high proportion new energypower generation considering wind-solar complementationand source-load coupling

To optimize peaking operation when high proportion new energy accesses to power grid,evaluation indexes are proposed which simultaneously consider wind-solar complementation and source-load coupling.A typical wind-solar power output scene model based on peaking demand is established which has anti-peaking characteristic.This model uses balancing scenes and key scenes with probability distribution based on improved Latin hypercube sampling(LHS)algorithm and scene reduction technology to illustrate the influence of wind-solar on peaking demand.Based on this,a peak shaving operation optimization model of high proportion new energy power generation is established.The various operating indexes after optimization in multi-scene peaking are calculated,and the ability of power grid peaking operation is compared whth that considering wind-solar complementation and source-load coupling.Finally,a case of high proportion new energy verifies the feasibility and validity of the proposed operation strategy.

Emodin regulating excision repair cross-complementation group 1 through fibroblast growth factor receptor 2 signaling

AIM: To investigate the molecular mechanisms underlying the reversal effect of emodin on platinum resistance in hepatocellular carcinoma. METHODS: After the addition of 10 μmol/L emodin to HepG2/oxaliplatin (OXA) cells, the inhibition rate (IR), 50% inhibitory concentration (IC 50 ) and reversal index (IC 50 in experimental group/IC 50 in control group) were calculated. For HepG2, HepG2/OXA, HepG2/OXA/T, each cell line was divided into a control group, OXA group, OXA + fibroblast growth factor 7 (FGF7) group and OXA + emodin group, and the final concentrations of FGF7, emodin and OXA in each group were 5 ng/mL, 10 μg/mL and 10 μmol/L, respectively. Single-cell gel electrophoresis was conducted to detect DNA damage, and the fibroblast growth factor receptor 2 (FGFR2), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) and excision repair cross-complementing gene 1 (ERCC1) protein expression levels in each group were examined by Western blotting. RESULTS: Compared with the IC50 of 120.78 μmol/L in HepG2/OXA cells, the IC 50 decreased to 39.65 μmol/L after treatment with 10 μmol/L emodin; thus, the reversal index was 3.05. Compared with the control group, the tail length and Olive tail length in the OXA group, OXA + FGF7 group and OXA + emodin group were significantly increased, and the differences were statistically significant (P < 0.01). The tail length and Olive tail length were lower in the OXA + FGF7 group than in the OXA group, and this difference was also statistically significant. Compared with the OXA + FGF7 group, the tail extent, the Olive tail moment and the percentage of tail DNA were significantly increased in the OXA + emodin group, and these differences were statistically significant (P < 0.01). In comparison with its parental cell line HepG2, the HepG2/OXA cells demonstrated significantly increased FGFR2, p-ERK1/2 and ERCC1 expression levels, whereas the expression of all three molecules was significantly inhibited in HepG2/ OXA/T cells, in which FGFR2 was silenced by FGFR2 shRNA. In the examined HepG2 cells, the FGFR2, p-ERK1/2 and ERCC1 expression levels demonstrated increasing trends in the OXA group and OXA + FGF7 group. Compared with the OXA group and OXA + FGF7 group, the FGFR2, p-ERK1/2, and ERCC1 expression levels were significantly lower in the OXA + emodin group, and these differences were statistically significant. In the HepG2/OXA/T cell line that was transfected with FGFR2 shRNA, the FGFR2, p-ERK1/2 and ERCC1 expression levels were significantly inhibited, but there were no significant differences in these expression levels among the OXA, OXA + FGF7 and OXA + emodin groups. CONCLUSION: Emodin markedly reversed OXA resistance by enhancing OXA DNA damage in HepG2/OXA cells, and the molecular mechanism was related to the inhibitory effect on ERCC1 expression being mediated by the FGFR2/ERK1/2 signaling pathway.

Complement activation targeted inhibitor C2-FH ameliorates acetaminophen-induced liver injury in mice

BACKGROUND Complement activation is recognized as an important factor in the progression of liver damage caused by acetaminophen(APAP).However,the role of the complement inhibitor C2-FH in APAP-induced liver injury remains unclear.AIM To explore C2-FH in protecting against APAP-induced liver injury by inhibiting complement activation.METHODS A model of APAP-induced liver injury was used to study the protective effect of C2-FH on liver injury.C2-FH was administered through intraperitoneal injection 30 minutes after APAP treatment.We detected the effects of C2-FH on liver function,inflammatory response and complement activation.Additionally,RNA-sequencing(RNA-Seq)analysis was conducted to understand the mechanism through which C2-FH provides protection against APAP-induced liver injury.RESULTS C2-FH inhibited the increase in serum alanine aminotransferase activity,aspartate aminotransferase activity and lactate dehydrogenase,and reduced liver tissue necrosis caused by APAP.Moreover,it attenuated the inflammatory response and inhibited complement activation in APAP-induced liver injury.RNA-Seq analysis provided additional explanations for the protective role of C2-FH against APAP-induced liver injury.CONCLUSION C2-FH attenuates APAP-induced liver injury by inhibiting complement activation.

Boundedness of Complements for Log Calabi-Yau Threefolds

In this paper,we study the theory of complements,introduced by Shokurov,for Calabi-Yau type varieties with the coefficient set[0,1].We show that there exists afinite set of positive integers N,such that if a threefold pair(X/Z∋z,B)has an R-complement which is klt over a neighborhood of z,then it has an n-complement for some n∈N.We also show the boundedness of complements for R-complementary surface pairs.

Antibodies elicited by Newcastle disease virus-vectored H7N9 avian influenza vaccine are functional in activating the complement system

H7N9 subtype avian influenza virus poses a great challenge for poultry industry.Newcastle disease virus(NDV)-vectored H7N9 avian influenza vaccines(NDV_(vec)H7N9)are effective in disease control because they are protective and allow mass administration.Of note,these vaccines elicit undetectable H7N9-specific hemagglutination-inhibition(HI)but high IgG antibodies in chickens.However,the molecular basis and protective mechanism underlying this particular antibody immunity remain unclear.Herein,immunization with an NDV_(vec)H7N9 induced low anti-H7N9 HI and virus neutralization titers but high levels of hemagglutinin(HA)-binding IgG antibodies in chickens.Three residues(S150,G151 and S152)in HA of H7N9 virus were identified as the dominant epitopes recognized by the NDV_(vec)H7N9 immune serum.Passively transferred NDV_(vec)H7N9 immune serum conferred complete protection against H7N9 virus infection in chickens.The NDV_(vec)H7N9 immune serum can mediate a potent lysis of HA-expressing and H7N9 virus-infected cells and significantly suppress H7N9 virus infectivity.These activities of the serum were significantly impaired after heat-inactivation or treatment with complement inhibitor,suggesting the engagement of the complement system.Moreover,mutations in the 150-SGS-152 sites in HA resulted in significant reductions in cell lysis and virus neutralization mediated by the NDV_(vec)H7N9 immune serum,indicating the requirement of antibody-antigen binding for complement activity.Therefore,antibodies induced by the NDV_(vec)H7N9 can activate antibody-dependent complement-mediated lysis of H7N9 virus-infected cells and complement-mediated neutralization of H7N9 virus.Our findings unveiled a novel role of the complement in protection conferred by the NDV_(vec)H7N9,highlighting a potential benefit of engaging the complement system in H7N9 vaccine design.

Association of complement components with risk of colorectal cancer:A systematic review and meta-analysis

BACKGROUND Complement components could contribute to the tumor microenvironment and the systemic immune response.Nevertheless,their role in colorectal cancer(CRC)remains a contentious subject.AIM To elucidate the relationship between complement components and CRC risk and clinical characteristics.METHODS Searches were conducted in PubMed,the Cochrane Library,and the China National Knowledge Infrastructure database until June 1,2023.We included cohort studies encompassing participants aged≥18 years,investigating the association between complement components and CRC.The studies were of moderate quality or above,as determined by the Agency for Healthcare Research and Quality.The meta-analysis employed fixed-effects or random-effects models based on the I^(2)test,utilizing risk ratio(RR)and their corresponding 95%confidence interval(CI)for outcomes.Sensitivity and subgroup analyses were performed to validate the robustness of the collective estimates and identify the source of heterogeneity.RESULTS Data from 15 studies,comprising 1631 participants that met the inclusion criteria,were included in the meta-analysis.Our findings indicated that protein levels of cluster of differentiation 46(CD46)(RR=3.66,95%CI:1.75-7.64,P<0.001),CD59(RR=2.86,95%CI:1.36-6.01,P=0.005),and component 1(C1)(RR=5.88,95%CI:1.75-19.73,P=0.004)and serum levels of C3(standardized mean difference=1.82,95%CI:0.06-3.58,P=0.040)were significantly elevated in patients with CRC compared to healthy controls.Strong expression of CD55 or CD59 was associated with a higher incidence of lymph node metastasis,whereas strong CD46 expression correlated with a higher incidence of tumor differentiation compared to low CD46 expression(P<0.05 for all).Although specific pooled results demonstrated notable heterogeneity,subgroup analyses pointed to regional differences as the primary source of inconsistency among the studies.CONCLUSION Our analysis underscores that increased levels of specific complement components are associated with a heightened risk of CRC,emphasizing the potential significance of monitoring elevated complement component levels.

Complement factor Ⅰ knockdown inhibits colon cancer development by affecting Wnt/β-catenin/c-Myc signaling pathway and glycolysis

BACKGROUND Colon cancer(CC)occurrence and progression are considerably influenced by the tumor microenvironment.However,the exact underlying regulatory mechanisms remain unclear.AIM To investigate immune infiltration-related differentially expressed genes(DEGs)in CC and specifically explored the role and potential molecular mechanisms of complement factor I(CFI).METHODS Immune infiltration-associated DEGs were screened for CC using bioinformatics.Quantitative reverse transcription polymerase chain reaction was used to examine hub DEGs expression in the CC cell lines.Stable CFI-knockdown HT29 and HCT116 cell lines were constructed,and the diverse roles of CFI in vitro were assessed using CCK-8,5-ethynyl-2’-deoxyuridine,wound healing,and transwell assays.Hematoxylin and eosin staining and immunohistochemistry staining were employed to evaluate the influence of CFI on the tumorigenesis of CC xenograft models constructed using BALB/c male nude mice.Key proteins associated with glycolysis and the Wnt pathway were measured using western blotting.RESULTS Six key immune infiltration-related DEGs were screened,among which the expression of CFI,complement factor B,lymphoid enhancer binding factor 1,and SRY-related high-mobility-group box 4 was upregulated,whereas that of fatty acid-binding protein 1,and bone morphogenic protein-2 was downregulated.Furthermore,CFI could be used as a diagnostic biomarker for CC.Functionally,CFI silencing inhibited CC cell proliferation,migration,invasion,and tumor growth.Mechanistically,CFI knockdown downregulated the expression of key glycolysis-related proteins(glucose transporter type 1,hexokinase 2,lactate dehydrogenase A,and pyruvate kinase M2)and the Wnt pathway-related proteins(β-catenin and c-Myc).Further investigation indicated that CFI knockdown inhibited glycolysis in CC by blocking the Wnt/β-catenin/c-Myc pathway.CONCLUSION The findings of the present study demonstrate that CFI plays a crucial role in CC development by influencing glycolysis and the Wnt/β-catenin/c-Myc pathway,indicating that it could serve as a promising target for therapeutic intervention in CC.

Interleukin-1 receptor associated kinase 2 is a functional downstream regulator of complement factor D that controls mitochondrial fitness in diabetic cardiomyopathy

Diabetic cardiomyopathy is a disorder of the cardiac muscle that affects patients with diabetes.The exact mechanisms underlying diabetic cardiomyopathy are mostly unknown,but several factors have been implicated in the pathogenesis of the disease and its progression towards heart failure,including endothelial dysfunction,autonomic neuropathy,metabolic alterations,oxidative stress,and alterations in ion homeostasis,especially calcium transients[1].In Military Medical Research,Jiang et al.[2]sought to determine the functional role of complement factor D(Adipsin)in the pathophysiology of diabetic cardiomyopathy.

Tumor-related factor complement Clq/TNF-related protein 6 affects the development of digestive system tumors through the phosphatidylinositol 3-kinase pathway

In this editorial,we review the work of Razali et al published in World J Gas-troenterology,with a particular focus on the effect of rs10889677 variation in the phosphatidylinositol 3-kinase(PI3K)pathway and buparlisib on colitis-associated cancer.The role of PI3K in promoting cancer progression has been widely recognized,as it is involved in regulating the survival,differentiation,and prolif-eration of cancer cells.The complement Clq/TNF-related protein 6(CTRP6)is a newer tumor-associated factor.Recent studies have revealed the pro-tumor effect of CTRP6 in gastric cancer,hepatocellular carcinoma,colorectal cancer,and other gastrointestinal tumors through the PI3K pathway.This article attempts to reveal the mechanism through which the CTRP6 affects the development of digestive system tumors through the PI3K pathway by summarizing recent research.

英藏“补语”比较及Complement一词藏译略考

在汉语基础薄弱的偏远藏族农牧区的英文教学中,进行英藏语法直接的比较,对该地区英语教学效果的提高具有积极意义。本文以英文语法教学为主体,旨在通过对英藏基础句法中"Complement"一词的直接对比和语法术语的藏译探讨,望能帮助解决农牧区藏族学生英文教学中对该语法盲点的理解困扰。

“On complemented subgroups of finite groups”一文的注记

“给出文Oncomplementedsubgroupsoffinitegroups,Chin .Ann .OfMath .,2 2B :2 (2 0 0 0 ) ,2 4 9- 2 5 4”中主要定理 (定理 2 )的一个较简洁的证明 ,且此定理也被推广至区系 (formation) .

中外学习者使役结构使用对比研究——以“make+object+complement”结构为例

中国大学英语学习者在表达使役关系的时候多倾向于使用"make+object+complement"结构,但对中国学生在使用这一结构和本族语者使用这一结构存在哪些差异及其原因的研究却不多。利用WordNeighbors数据库对本族语者使用这一结构的情况进行了调查研究,结果显示:就使用频率而言,本族语者也比较频繁地使用这一结构,但在具体用法上与汉语存在两点不同之处。究其原因,主要是受母语负迁移的影响。研究表明,输入的匮乏是造成中国学习者过度依赖母语的一个原因。

Complements are involved in alcoholic fatty liver disease, hepatitis and fibrosis

The complement system is a key component of the body's immune system. When abnormally activated, this system can induce inflammation and damage to normal tissues and participate in the development and progression of a variety of diseases. In the past, many scholars believed that alcoholic liver disease(ALD) is induced by the stress of ethanol on liver cells, including oxidative stress and dysfunction of mitochondria and protease bodies, causing hepatocyte injury and apoptosis. Recent studies have shown that complement activation is also involved in the genesis and development of ALD. This review focuses on the roles of complement activation in ALD and of therapeutic intervention in complement-activation pathways. We intend to provide new ideas on the diagnosis and treatment of ALD.

Complement and its role in innate and adaptive immune responses

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.

Analysis of immunoglobulin, complements and CRP levels in serum of captive northern pig-tailed macaques （Macaca leonina）

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.

Complement activation in the context of stem cells and tissue repair

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.

Complement factors C1q, C3 and C5b-9 in the posterior sclera of guinea pigs with negative lens-defocused myopia

· AIM: To investigate the expression of complement factors in the posterior scleral fibroblasts of guinea pigs with negative lens-defocused myopia.· METHODS: Eighteen guinea pigs were assigned randomly to two groups: the negative lens-defocused group(NLD group, n =9) and the normal control without treatment group(NC group, n =9). The effect of myopic induction was compared in three subgroups: eyes treated with a-10.00 D negative lens in the NLD group(NL group), eyes treated with a plano(0 D) lens in the NLD group(PL group), and untreated right eyes in the NC group(NC group). The following analyses were conducted at four weeks: examination of the refractive error via retinoscopy, assessment of complement C5b-9expression in the posterior scleral fibroblasts using immunohistochemistry, and measurements of complement C1 q and C3 protein levels in the posterior sclera by Western blot.·RESULTS: After an induction period of four weeks, a significant myopic shift was detected in the eyes of the NL group, relative to that of the PL and NC groups(P 【0.05). Data analysis showed a significant increase in the percentage of C5b-9 immunopositive fibroblasts in the posterior sclera of the NL group eyes, compared to the PL group(q =11.50, P 【0.001). Significantly higher levels of C1q(q =4.94, P =0.01) and C3(q =4.07, P =0.03)protein were detected in the posterior sclera of NL group eyes, compared to the PL group. There were no significant difference between the PL and NC groups for C5b-9(q =2.44, P =0.10), C1q(q =1.55, P =0.53) and C3(q =0.98, P =0.77) in the posterior sclera.·CONCLUSION: The data from present study provide evidence of the up-regulation of C5b-9, C1 q and C3 in the posterior scleral fibroblasts in a NLD myopic animal model. The results suggest that the complement system may be involved in the development of myopia.