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Gemcitabine is a standard first-line drug for pancreatic cancer chemotherapy. Nevertheless, gemcitabine resistance is common and significantly limits its therapeutic efficacy, impeding advancements in pancreatic cancer treatment. In this study, through a comprehensive analysis of gemcitabine-resistant cell lines and patient samples, 39 gemcitabine resistance-associated risk genes were identified, and two distinct gemcitabine response-related phenotypes were delineated. Through a combination of bioinformatics analysis and in vivo and in vitro experiments, we identified the C3a/C3aR signaling pathway as a pivotal player in the development of gemcitabine resistance in pancreatic cancer. We found that activation of the C3a/C3aR signaling pathway promoted the proliferation, migration and gemcitabine resistance of pancreatic cancer cells, while the C3aR antagonist SB290157 effectively counteracted these effects by impeding the activation of the C3a/C3aR pathway. Our study reveals the fundamental role of complement C3a in the progression of pancreatic cancer, suggesting that complement C3a may serve as a promising biomarker in pancreatic cancer.
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Milk fat globules (MFGs) are a remarkable example of nature's ingenuity. Human milk (HM) carries contains 3-5% fat, 0.8-0.9% protein, 6.9-7.2% carbohydrate calculated as lactose, and 0.2% mineral constituents. Most of these nutrients are carried in these MFGs, which are composed of an energy-rich triacylglycerol (TAG) core surrounded by a triple membrane structure. The membrane contains polar lipids, specialized proteins, glycoproteins, and cholesterol. Each of these bioactive components serves important nutritional, immunological, neurological, and digestive functions. These MFGs are designed to release energy rapidly in the upper gastrointestinal tract and then persist for some time in the gut lumen so that the protective bioactive molecules are conveyed to the colon. These properties may shape the microbial colonization and innate immune properties of the developing gastrointestinal tract. Milk fat globules in milk from humans and ruminants may resemble in structure but there are considerable differences in size, profile, composition, and specific constituents. There are possibilities to not only enhance the nutritional composition in a goal-oriented fashion to correct specific deficiencies in the infant but also to use these fat globules as a nutraceutical in infants who require specific treatments. To mention a few, there might be possibilities in enhancing neurodevelopment, in defense against gastrointestinal and respiratory tract infections, improving insulin sensitivity, treating chronic inflammation, and altering plasma lipids. This review provides an overview of the composition, structure, and biological activities of the various components of the MFGs. We have assimilated research findings from our own laboratory with an extensive review of the literature utilizing key terms in multiple databases including PubMed, EMBASE, and Science Direct. To avoid bias in the identification of studies, keywords were short-listed a priori from anecdotal experience and PubMed's Medical Subject Heading (MeSH) thesaurus.
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Cognitive impairment is a common issue among human patients undergoing surgery, yet the neural mechanism causing this impairment remains unidentified. Surgical procedures often lead to glial cell activation and neuronal hypoexcitability, both of which are known to contribute to postoperative cognitive dysfunction (POCD). However, the role of neuron-glia crosstalk in the pathology of POCD is still unclear. Through integrated transcriptomics and proteomics analyses, we found that the complement cascades and microglial phagocytotic signaling pathways are activated in a mouse model of POCD. Following surgery, there is a significant increase in the presence of complement C3, but not C1q, in conjunction with presynaptic elements. This triggers a reduction in excitatory synapses, a decline in excitatory synaptic transmission, and subsequent memory deficits in the mouse model. By genetically knockout out C3ar1 or inhibiting p-STAT3 signaling, we successfully prevented neuronal hypoexcitability and alleviated cognitive impairment in the mouse model. Therefore, targeting the C3aR and downstream p-STAT3 signaling pathways could serve as potential therapeutic approaches for mitigating POCD.
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Complemento C3 , Modelos Animais de Doenças , Transtornos da Memória , Camundongos Knockout , Microglia , Animais , Camundongos , Microglia/metabolismo , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Complemento C3/metabolismo , Complemento C3/genética , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Receptores de Complemento/metabolismo , Receptores de Complemento/genética , Masculino , Complicações Cognitivas Pós-Operatórias/metabolismo , Complicações Cognitivas Pós-Operatórias/etiologia , Sinapses/metabolismo , Sinapses/patologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacosRESUMO
Neuroinflammation and autoimmunity are pivotal in the pathogenesis of neurodegenerative diseases. Complement activation and involvement of astrocyte-neuron C3/C3aR pathway have been observed, yet the mechanisms influencing α-synuclein (α-syn) pathology and neurodegeneration remain unclear. In this study, elevated levels of complement C3 were detected in the plasma of α-syn PFF-induced mice and the substantia nigra of A53T transgenic mice. Colocalization of complement C3 with astrocytes was also observed. Overexpression of complement C3 exacerbated motor dysfunction, dopaminergic neuron loss, and phosphorylated α-syn expression in mice injected with α-syn preformed fibrils (α-syn PFFs). Conversely, downregulation of complement C3 protected α-syn PFF-induced mice. Molecular investigations revealed that inhibition of Toll-like receptor 2 (TLR2) or NF-κB reduced complement C3 expression in primary astrocytes following α-syn PFF treatment. Astrocyte-neuron communication via the C3/C3aR pathway influenced α-syn PFF-induced neuronal apoptosis and α-syn pathology, potentially through modulation of GSK3ß. These findings underscore the critical role of astrocyte-neuron communication via the C3/C3aR pathway in PD pathogenesis, highlighting its potential as a therapeutic target.
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Complement component 3 (C3) deficiency has recently been reported as one of the novel causes of constipation. To identify a unique gene specific to constipation caused by C3 deficiency, the total RNA extracted from the mid colon of C3 knockout (C3 KO) mice was hybridized to oligonucleotide microarrays, and the function of the candidate gene was verified in in vitro and in vivo models. C3 KO mice used for microarrays showed definite phenotypes of constipation. Overall, compared to the wild type (WT), 1237 genes were upregulated, and 1292 genes were downregulated in the C3 KO mice. Of these, the major genes included were lysine (K)-specific demethylase 5D (KDM5D), olfactory receptor 870 (Olfr870), pancreatic lipase (PNLIP), and alkaline phosphatase intestinal (ALPI). Specifically, the ALPI gene was selected as a novel gene candidate based on alterations during loperamide (Lop)-induced constipation and intestinal bowel disease (IBD). The upregulation of ALPI expression treated with acetate recovered the expression level of mucin-related genes in primary epithelial cells of C3 KO mice as well as most phenotypes of constipation in C3 KO mice. These results indicate that ALPI plays an important role as the novel gene associated with C3 deficiency-induced constipation.
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Complemento C3 , Constipação Intestinal , Camundongos Knockout , Animais , Constipação Intestinal/genética , Constipação Intestinal/etiologia , Complemento C3/genética , Complemento C3/deficiência , Complemento C3/metabolismo , Camundongos , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Receptores Odorantes/genética , Receptores Odorantes/deficiência , Modelos Animais de Doenças , Loperamida , Colo/metabolismo , Colo/patologia , Perfilação da Expressão GênicaRESUMO
OBJECTIVES: To study the risk factors and prognostic characteristics of pediatric silent lupus nephritis (SLN) with class â ¢ to V. METHODS: A retrospective study was conducted to collect clinical data from 30 children diagnosed with SLN at the Department of Pediatrics, Second Xiangya Hospital, Central South University, from May 2007 to April 2023. Based on renal pathological classification, the patients were divided into a class â ¡ group (12 cases) and a class â ¢ to â ¤ group (18 cases). The risk factors for the occurrence of class â ¢ to â ¤ SLN were analyzed, and the prognostic characteristics were summarized. RESULTS: Among the 30 SLN patients, the median follow-up time was 61.50 months. There were no statistically significant differences in the proportions of patients who discontinued glucocorticoids or achieved low disease activity status, nor in the annual decline rate of estimated glomerular filtration rate (eGFR) between the class â ¡ and class â ¢ to V groups (P>0.05). However, three patients in the class â ¡ group progressed to stage 1 chronic kidney disease (CKD), while eight patients in the class III to V group reached stage 1 CKD, and four patients reached stage 2 CKD. Among the 26 female SLN patients, serum complement C3 levels in the class III to V group were lower than those in the class â ¡ group (P<0.05). Serum C3 levels in SLN patients, as well as in female SLN patients, were negatively correlated with the fluorescence intensity of IgA, IgG, and C3 immune complexes in the kidneys (P<0.05). Additionally, serum C3 levels in female SLN patients were negatively correlated with the renal pathological activity index (P<0.05). Binary logistic regression analysis indicated that being female and having low serum complement C3 levels were risk factors for the occurrence of class â ¢ to V SLN in children (P<0.05). CONCLUSIONS: Class â ¢ to V SLN is not uncommon among SLN children, and there remains a risk of long-term renal function progression. Being female and having low serum complement C3 levels are identified as risk factors for class â ¢ to V SLN in children.
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Complemento C3 , Nefrite Lúpica , Humanos , Feminino , Masculino , Criança , Fatores de Risco , Estudos Retrospectivos , Prognóstico , Complemento C3/análise , Adolescente , Taxa de Filtração Glomerular , Pré-EscolarRESUMO
INTRODUCTION: Acute kidney injury (AKI) is associated with adverse outcomes, including death and dialysis. The goal of this study was to identify prognostic biomarkers of AKI that could be used across multiple phenotypes of AKI and across different species. METHODS: Liquid chromatography/tandem mass spectrometry analysis of urine samples from three species (human, rat, and mouse) and four etiologies of AKI identified five potential biomarkers, of which two were validated, complement C3 and vitamin D-binding protein, in a cohort of 157 patients that developed AKI following cardiothoracic surgery. We studied the relationship between the biomarker's concentration in the urine and the development of a composite primary endpoint (stage 3 AKI within 10 days or death within 30 days). RESULTS: Of the 153 patients who developed AKI following cardiovascular surgery, 17 met the combined primary outcome. The median concentration of urine complement C3 adjusted to urine creatinine had the best predictive value and was significantly higher in the primary outcome group than in the controls. Similarly, the median concentration of vitamin D-binding protein was higher in the primary outcome group. CONCLUSIONS: The studies provide proof in principle that cross-species discovery analyses could be a valuable tool for identifying novel prognostic biomarkers in AKI. Urine complement C3 and vitamin D-binding protein could be promising early predictors of adverse outcomes in patients who develop AKI after cardiac surgery.
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Arteriogenesis is an inflammatory driven mechanism, describing the growth of a natural bypass from pre-existing collateral arteries to compensate for an occluded artery. The complement system component C3 is a potent natural inflammatory activator. Here, we investigated its impact on the process of collateral artery growth using C3-deficient (C3 -/-) and wildtype control mice in a murine hindlimb model of arteriogenesis. Induction of arteriogenesis by unilateral femoral artery ligation resulted in decreased perfusion recovery in C3 -/- mice on day 7 as shown by Laser Doppler imaging. Immunofluorescence staining revealed a reduced vascular cell proliferation in C3 -/- mice. Gene expression analysis displayed a significant reduction in monocyte chemoattractant protein-1 (MCP-1) expression in C3 -/- mice. Interestingly, 3 days after induction of arteriogenesis, the number of macrophages (CD68+) recruited to growing collaterals was not affected by C3 deficiency. However, a significant reduction in inflammatory M1-like polarized macrophages (CD68+/MRC1-) was noted. Forced mast cell activation by Compound 48/80 as well as exogenous MCP-1 application rescued the number of M1-like polarized macrophages along with perfusion recovery in C3 -/- mice. In summary, this study demonstrates that complement C3 influences arteriogenesis by mediating MCP-1 expression, which is essential for the induction and enhancement of sterile inflammation.
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Circulação Colateral , Complemento C3 , Inflamação , Animais , Inflamação/patologia , Camundongos , Complemento C3/metabolismo , Complemento C3/genética , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Macrófagos/metabolismo , Neovascularização Fisiológica/genética , Camundongos Endogâmicos C57BL , Membro Posterior/irrigação sanguínea , Camundongos Knockout , Artéria Femoral/patologia , Artérias/crescimento & desenvolvimento , Artérias/metabolismo , Masculino , Proliferação de Células , Mastócitos/metabolismoRESUMO
Complement C3 (C3) is usually deposited spontaneously on the surfaces of invading bacteria prior to internalization, but the impact of C3 coating on cellular responses is largely unknown. Staphylococcus aureus (S. aureus) is a facultative intracellular pathogen that subverts autophagy and replicates in both phagocytic and nonphagocytic cells. In the present study, we deposited C3 components on the surface of S. aureus by complement opsonization before cell infection and confirmed that C3-coatings remained on the surface of the bacteria after they have invaded the cells, suggesting S. aureus cannot escape or degrade C3 labeling. We found that the C3 deposition on S. aureus notably enhanced cellular autophagic responses, and distinguished these responses as xenophagy, in contrast to LC3-associated phagocytosis (LAP). Furthermore, this upregulation was due to the recruitment of and direct interaction with autophagy-related 16-like 1 (ATG16L1), thereby resulting in autophagy-dependent resistance to bacterial growth within cells. Interestingly, this autophagic effect occurred only after C3 activation by enzymatic cleavage because full-length C3 without cleavage of the complement cascade reaction, although capable of binding to ATG16L1, failed to promote autophagy. These findings demonstrate the biological function of intracellular C3 upon bacterial infection in enhancing autophagy against internalized S. aureus.
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Autofagia , Complemento C3 , Fagocitose , Infecções Estafilocócicas , Staphylococcus aureus , Staphylococcus aureus/imunologia , Staphylococcus aureus/fisiologia , Complemento C3/metabolismo , Humanos , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/metabolismo , Proteínas Relacionadas à Autofagia/metabolismo , Proteínas Relacionadas à Autofagia/genética , Animais , Interações Hospedeiro-Patógeno , Camundongos , Opsonização , Ativação do ComplementoRESUMO
BACKGROUND: Sudden sensorineural hearing loss (SSNHL) is characterized by rapid, unexplained loss of hearing within a 72-hour period and exhibits a high incidence globally. Despite this, the outcomes of therapeutic interventions remain largely unpredictable, especially for those with profound hearing loss. Extracellular vesicles (EVs), nano-sized entities containing biological materials, are implicated in the development of numerous diseases. The specific relationship between EVs and both the severity and treatment effectiveness of SSNHL, however, is not well understood. METHODS: This study involved the analysis of medical records from the Department of Otolaryngology (September 1, 2020 - December 31, 2022) of patients diagnosed with SSNHL according to the 2015 Guidelines for Diagnosis and Treatment of Sudden Deafness in China. Peripheral blood samples from patients with various types of SSNHL before and after treatment were collected, alongside samples from healthy volunteers serving as controls. Plasma EVs were isolated using gel rejection chromatography and analyzed for concentration, marker presence, and morphology using Nanosight, Western blot, and transmission electron microscopy (TEM), respectively. Proteomics and miRNA assessments were conducted to identify differentially expressed proteins and miRNAs in the plasma EVs of SSNHL patients and healthy volunteers. Key proteins were further validated through Western blot analysis. Enzyme-linked immunosorbent assay (ELISA) was utilized to determine the levels of complement C3 in plasma EVs, and correlation analyses were performed with audiological data pre- and post-treatment. RESULTS: Plasma from SSNHL patients of varying types was collected and their EVs were successfully isolated and characterized. Proteomic analysis revealed that complement C3 levels in the plasma EVs of patients with profound SSNHL were significantly higher compared to healthy controls. Differential expression of miRNAs in plasma EVs and their related functions were also identified. The study found that the level of complement C3 in plasma EVs, but not the total plasma complement C3, positively correlated with the severity of SSNHL in patients exhibiting positive therapeutic responses, particularly in those with initially lower levels of EV-associated complement C3. After treatment, complement C3 level was decreased in patients with initially higher levels of EV-associated complement C3. No significant correlation was observed between changes in plasma EV-derived complement C3 levels and the degree of hearing loss in either responders or non-responders among patients with profound SSNHL. CONCLUSION: Differential profiles of proteins and miRNAs were identified in patients with profound SSNHL. Notably, plasma EV-derived complement C3 was linked to both the severity and early treatment effectiveness of patients with profound SSNHL.
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Complemento C3 , Vesículas Extracelulares , Perda Auditiva Neurossensorial , Perda Auditiva Súbita , Humanos , Complemento C3/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Vesículas Extracelulares/metabolismo , Adulto , Perda Auditiva Neurossensorial/sangue , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Súbita/sangue , Perda Auditiva Súbita/terapia , Índice de Gravidade de Doença , Resultado do Tratamento , MicroRNAs/sangue , Idoso , Adulto Jovem , Biomarcadores/sangue , ProteômicaRESUMO
Ginsenoside Rb1, known as gypenoside III, exerts antidepressant-like effects in previous studies. It has also been indicated that ginsenoside Rb1 regulated neuroinflammation via inhibiting NF-κB signaling. According to the evidence that astrocytes can regulate microglia and neuroinflammation by secreting complement C3, the present study aimed to demonstrate the molecular mechanisms underlying ginsenoside Rb1-induced antidepressant-like effects from the astrocytic and microglial complement C3 pathway. The complement C3 mediated mechanism of ginsenoside Rb1 was investigated in mice exposed to chronic restraint stress (CRS). The results showed that ginsenoside Rb1 reversed the depressive-like behaviors in CRS. Treatment with ginsenoside Rb1 reduced both the number of astrocytes and microglia. In addition, ginsenoside Rb1 suppressed TLR4/NF-κB/C3 signaling in the astrocytes of the hippocampus. Furthermore, ginsenoside Rb1 attenuated the contents of synaptic protein including synaptophysin and PSD95 in microglia, suggesting the inhibition of microglia-mediated synaptic elimination caused by CRS. Importantly, ginsenoside Rb1 also maintained the dendritic spines in mice. In conclusion, our results demonstrate that ginsenoside Rb1 produces the antidepressant-like effects by inhibiting astrocyte TLR4/NF-κB/C3 signaling to covert microglia from a pro-inflammatory phenotype (amoeboid) towards an anti-inflammatory phenotype (ramified), which inhibit the synaptic pruning in the hippocampus.
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Astrócitos , Complemento C3 , Depressão , Ginsenosídeos , Microglia , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Camundongos , Depressão/tratamento farmacológico , Depressão/metabolismo , Masculino , Complemento C3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Camundongos Endogâmicos C57BL , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Receptor 4 Toll-Like/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/tratamento farmacológico , NF-kappa B/metabolismoRESUMO
IgA nephropathy (IgAN) is still one of the leading causes of end-stage kidney disease (ESRD), and complement system activation is a key to the pathogenesis of IgAN. The role of complement C3a/C3aR and C5a/C5aR in late stage of IgAN remains unknown. Renal specimens of 75 IgAN patients at the stage 4 CKD were stained using immunofluorescence and immunohistochemistry. The primary outcome was a composite of end-stage renal disease (ESRD) and death. Associations of complement components with baseline clinicopathological characteristics and outcomes were assessed using multivariable Cox regression and Spearman analyses. During a median follow-up of 15.0 months, 27 patients progressed to ESRD and none died. Lower eGFR [hazards ratio (HR), 0.827, 95% confidence interval (CI), 0.732-0.935; P = 0.002] and glomerular C3 deposition (HR, 3.179, 95% CI, 1.079-9.363; P = 0.036) were predictive of time to ESRD in stage 4 CKD IgAN. Higher expression of C3a (P = 0.010), C3aR (P = 0.005), C5a (P = 0.015), and C5aR (P < 0.001) was identified in ESRD group than in non-ESRD group. Glomerular C3a/C3aR and C5a/C5aR deposits were both correlated with a lower baseline eGFR, higher baseline 24 h-urinary protein (24 h-UP) and faster decline of eGFR. Besides, C3a and C5a deposits were found in patients with high S (S1) and T (T1/2) scores, respectively. Complement C3a/C3aR and C5a/C5aR in IgAN patients with stage 4 CKD may portend a faster deterioration of kidney function.
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OBJECTIVES: This study aimed to investigate disparities in clinical profiles and autoantibody patterns between patients with and without neuropsychiatric systemic lupus erythematosus (NPSLE) in a cohort and to identify risk factors associated with NPSLE in the Chinese population. METHODS: SLE patients were retrospectively reviewed from two tertiary hospitals. The relationships between NPSLE and immunological biomarkers were explored. RESULTS: Among the 945 SLE patients, 75 (7.94%) were diagnosed with NPSLE. The most prevalent NP manifestations involved cognitive disorder (30.67%), headache (26.67%), seizure disorder (26.67%), and psychosis (26.67%).We observed significant associations between psychosis and anti-ß2GPI antibodies (F = 6.092, p = 0.015), polyneuropathy and anti-Scl70 antibodies (F = 20.161, p < 0.001), demyelinating syndrome and anti-cardiolipin antibodies (F = 6.637, p = 0.011), myasthenia gravis and anti-RNP (F = 5.864, p = 0.017), and anti-Smith antibodies (F = 5.096, p = 0.026). Multivariate logistics analysis showed that anti-prothrombin (aPT) IgM antibodies (OR = 10.985, CI 1.279-94.343, p = 0.029), age (OR = 1.169, CI 1.032-1.325, p = 0.014), and serum creatinine (SCr) (OR = 1.014, CI 1.003-1.025, p = 0.009) were independent risk factors of NPSLE, while anti-Sjogren syndrome antigen B (SSB) antibodies (OR 0.023, CI 0.002-0.622, p = 0.023) and high complement C3 (OR = 0.001, CI 0-0.045, p < 0.001) indicated reduced risk of NPSLE. CONCLUSION: Various neuropsychiatric manifestations in SLE were found to be correlated with specific autoantibodies. Independent risk factors for NPSLE included aPT IgM antibodies, age, and elevated serum creatinine, while the absence of anti-SSB antibodies and low complement C3 levels were associated with increased risk. KEY POINTS: â¢Significant associations were found between specific autoantibodies and neuropsychiatric symptoms, shedding light on potential biomarkers for predicting and understanding NPSLE. â¢The study identifies independent risk factors for NPSLE in the Chinese population, including the presence of anti-prothrombin IgM antibodies, older age, elevated serum creatinine, and lower complement C3 levels.
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Autoanticorpos , Biomarcadores , Vasculite Associada ao Lúpus do Sistema Nervoso Central , Humanos , Feminino , Masculino , Estudos Retrospectivos , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/sangue , Adulto , Biomarcadores/sangue , Autoanticorpos/sangue , Autoanticorpos/imunologia , Pessoa de Meia-Idade , China , Fatores de Risco , Adulto Jovem , Complemento C3/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Protrombina/imunologiaRESUMO
Background: This study aims to investigate the association between nine tag single nucleotide polymorphisms (SNPs) in the C3 gene locus and the risk of coronary artery disease (CAD) as well as lipid levels in the Chinese population, and to further explore the interactions between SNPs and environmental factors that may be associated with CAD risk. Methods: A case-control study was conducted to investigate the association between CAD and C3 gene polymorphisms in a hospital setting. The study consisted of 944 CAD patients with a mean age of 55.97 ± 10.182 years and 897 non-CAD controls with a mean age of 55.94 ± 9.162 years. There were 565 males and 288 females in the CAD group and 583 males and 314 females in the control group. TagSNPs in the C3 gene were identified by employing the improved multiplex ligation detection reaction (iMLDR) technique, and multifactor dimensionality reduction (MDR) analysis was utilized to investigate the C3 gene-environment and gene-gene interactions in relation to the risk of CAD. Results: Results of the polymorphism study indicated that the CC genotype of rs7257062 was more frequent in the CAD group compared to the control group (10.9% vs 7.7%), with a statistically significant difference (p = 0.009). Moreover, the TT and CC + CT genotype groups of rs7257062 in the CAD subgroup showed a significant difference in terms of serum triglyceride levels (2.326 ± 1.889 vs 2.059 ± 1.447, p = 0.019). Analysis of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A (ApoA), and apolipoprotein B (ApoB) levels revealed no significant differences between the TT and CC + CT genotypes. Furthermore, no significant differences in serum lipid levels were observed between genotypes of the other SNPs. Multivariable logistic analysis, controlling for gender, age, body mass index (BMI), triglycerides (TG), TC, HDL-C, LDL-C, ApoA and ApoB, demonstrated that rs7257062 was still an independent risk factor of CAD (OR = 1.499, 95% CI: 1.036-2.168, p = 0.032). MDR analysis revealed that the rs7257062 interacted significantly with environmental factors such as smoking, diabetes, hypertension, BMI, and TG (p < 0.05). Conclusions: The rs7257062 variation of the C3 gene could be linked to both lipid balance and the risk of CAD. It is conceivable that the interplay between C3 polymorphisms and environmental elements could account for the etiology of CAD.
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Background and Aim: Osteoarthritis (OA) stands as the prevailing degenerative joint condition, and although it is widely observed, its precise causes are not fully understood. The main focus of the study was to assess the role of Complement C3 and Cathepsin D in the development of knee osteoarthritis (OA), which is the most prevalent degenerative joint disease. Materials and Methods: The study was carried out in 20 patients with knee OA and 20 healthy control group. OA knee (Grade II/III, Radiological Kellgren and Lawrence (K/L) classification), aged between 40 and 65 years were able to walk with a painful knee. The study also included healthy age-matched controls. The concentration of Complement C3 and Cathepsin D in serum was determined. Results: The results of the present study demonstrated significantly (P < 0.001) higher concentrations of C3 and Cathepsin D in OA patients in comparison to that of the healthy aged matched control group. Conclusions: The analysis showed that inflammatory markers, Complement C3 as well as Cathepsin D may be used as diagnostic markers of knee OA. The observations suggest that the activation of the complement system mainly affects processes within the joints, while C3 appears to play a central role in generating a systemic inflammatory response.
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OBJECTIVE: The aim of this study was to investigate the potential importance of complement system activation, with particular emphasis on the complement alternative pathway (AP), in the pathogenesis of hypertensive renal damage. METHODS: Serum complement C3, complement Factor H (CFH) and AP activation were assessed in 66 participants with established essential hypertension with renal damage (RD). Fifty-nine patients with age- and sex-matched essential hypertension without renal damage (NRD) and 58 healthy participants (normal) were selected. RESULTS: Our study revealed that C3 and AP50 continuously increased from normal to NRD to RD (p < 0.05, respectively), while CFH was significantly lower than that in NRD and healthy participants (p < 0.05, respectively). After multifactorial logistic regression analysis corrected for confounders, elevated serum C3 (p = 0.001) and decreased CFH (p < 0.001) were found to be independent risk factors for hypertension in healthy participants; elevated serum C3 (p = 0.034), elevated AP50 (p < 0.001), decreased CFH (p < 0.001), increased age (p = 0.011) and increased BMI (p = 0.013) were found to be independent risk factors for the progression of hypertension to hypertensive renal damage; elevated serum C3 (p = 0.017), elevated AP50 (p = 0.023), decreased CFH (p = 0.005) and increased age (p = 0.041) were found to be independent risk factors for the development of hypertensive renal damage in healthy participants. CONCLUSION: Abnormal activation of complement, particularly complement AP, may be a risk factor for the development and progression of hypertensive renal damage.
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Complemento C3 , Fator H do Complemento , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos de Casos e Controles , Complemento C3/metabolismo , Complemento C3/análise , Fatores de Risco , Idoso , Adulto , Hipertensão/complicações , Hipertensão/sangue , Ativação do Complemento , Hipertensão Essencial/sangue , Hipertensão Essencial/complicações , Hipertensão Essencial/fisiopatologia , Modelos Logísticos , Via Alternativa do Complemento , Progressão da DoençaRESUMO
Purpose: The purpose of the present study was to identify predictors of severe white matter hyperintensity (WMH) with obesity (SWO), and to build a prediction model for screening obese people with severe WMH without Nuclear Magnetic Resonance Imaging (MRI) examination. Patients subjects and methods: From September 2020 to October 2021, 650 patients with WMH were recruited consecutively. The subjects were divided into two groups, SWO group and non-SWO group. Univariate and Logistic regression analysis were was applied to explore the potential predictors of SWO. The Youden index method was adopted to determine the best cut-off value in the establishment of the prediction model of SWO. Each parameter had two options, low and high. The score table of the prediction model and nomogram based on the logistic regression were constructed. Of the 650 subjects, 487 subjects (75%) were randomly assigned to the training group and 163 subjects (25%) to the validation group. By resampling the area under the curve (AUC) of the subject's operating characteristics and calibration curves 1,000 times, nomogram performance was verified. A decision curve analysis (DCA) was used to evaluate the nomogram's clinical usefulness. By resampling the area under the curve (AUC) of the subject's operating characteristics and calibration curves 1,000 times, nomogram performance was verified. A decision curve analysis (DCA) was used to evaluate the nomogram's clinical usefulness. Results: Logistic regression demonstrated that hypertension, uric acid (UA), complement 3 (C3) and Interleukin 8 (IL-8) were independent risk factors for SWO. Hypertension, UA, C3, IL-8, folic acid (FA), fasting C-peptide (FCP) and eosinophil could be used to predict the occurrence of SWO in the prediction models, with a good diagnostic performance, Areas Under Curves (AUC) of Total score was 0.823 (95% CI: 0.760-0.885, p < 0.001), sensitivity of 60.0%, specificity of 91.4%. In the development group, the nomogram's AUC (C statistic) was 0.829 (95% CI: 0.760-0.899), while in the validation group, it was 0.835 (95% CI: 0.696, 0.975). In both the development and validation groups, the calibration curves following 1,000 bootstraps showed a satisfactory fit between the observed and predicted probabilities. DCA showed that the nomogram had great clinical utility. Conclusion: Hypertension, UA, C3, IL-8, FA, FCP and eosinophil models had the potential to predict the incidence of SWO. When the total score of the model exceeded 9 points, the risk of SWO would increase significantly, and the nomogram enabled visualization of the patient's WMH risk. The application prospect of our models mainly lied in the convenient screening of SWO without MRI examination in order to detect SWO and control the WMH hazards early.
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Hematoma clearance is critical for mitigating intracerebral hemorrhage (ICH)-induced brain injury. Multinucleated giant cells (MGCs), a type of phagocyte, and the complement system may play a pivotal role in hematoma resolution, but whether the complement system regulates MGC formation after ICH remains unclear. The current study investigated the following: (1) the characteristics of MGC formation after ICH, (2) whether it was impacted by complement C3 deficiency in mice and (3) whether it also influenced hematoma degradation (hemosiderin formation). Young and aged male mice, young female mice and C3-deficient and -sufficient mice received a 30 µL injection of autologous whole blood into the right basal ganglia. Brain histology and immunohistochemistry were used to examine MGC formation on days 3 and 7. Hemosiderin deposition was examined by autofluorescence on day 28. Following ICH, MGCs were predominantly located in the peri-hematoma region exhibiting multiple nuclei and containing red blood cells or their metabolites. Aging was associated with a decrease in MGC formation after ICH, while sex showed no discernible effect. C3 deficiency reduced MGC formation and reduced hemosiderin formation. Peri-hematomal MGCs may play an important role in hematoma resolution. Understanding how aging and complement C3 impact MGCs may provide important insights into how to regulate hematoma resolution.
RESUMO
Multiple myeloma (MM) is a plasma cell malignancy belonging to the class of monoclonal gammopathies that leads to end-organ damage myeloma events that encompass anemia, the presence of lytic bone lesions, hypercalcemia, and renal insufficiency. However, there are very few reported cases of patients with low complements in the context of MM and renal failure. Traditionally, low complements in glomerular disease are associated with conditions such as membranoproliferative glomerulonephritis, cryoglobulinemia, systemic lupus erythematous, and post-infectious glomerulonephritis. Despite its rarity, physicians should maintain a high degree of suspicion and consider MM as a potential cause of low complements in patients with renal injury. In this case report, we present a patient with a history of MM associated with acute kidney injury with hypocomplementemia, an atypical presentation of myeloma in MM.