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1.
BMC Med ; 21(1): 7, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36600274

RESUMO

BACKGROUND: Perioperative neurocognitive disorders (PND) with a high incidence frequently occur in elderly surgical patients closely associated with prolonged anesthesia-induced neurotoxicity. The neuromorphopathological underpinnings of anesthesia-induced neurotoxicity have remained elusive. METHODS: Prolonged anesthesia with sevoflurane was used to establish the sevoflurane-induced neurotoxicity (SIN) animal model. Morris water maze, elevated plus maze, and open field test were employed to track SIN rats' cognitive behavior and anxiety-like behaviors. We investigated the neuropathological basis of SIN through techniques such as transcriptomic, electrophysiology, molecular biology, scanning electron microscope, Golgi staining, TUNEL assay, and morphological analysis. Our work further clarifies the pathological mechanism of SIN by depleting microglia, inhibiting neuroinflammation, and C1q neutralization. RESULTS: This study shows that prolonged anesthesia triggers activation of the NF-κB inflammatory pathway, neuroinflammation, inhibition of neuronal excitability, cognitive dysfunction, and anxiety-like behaviors. RNA sequencing found that genes of different types of synapses were downregulated after prolonged anesthesia. Microglial migration, activation, and phagocytosis were enhanced. Microglial morphological alterations were also observed. C1qa, the initiator of the complement cascade, and C3 were increased, and C1qa tagging synapses were also elevated. Then, we found that the "Eat Me" complement pathway mediated microglial synaptic engulfment in the hippocampus after prolonged anesthesia. Afterward, synapses were remarkably lost in the hippocampus. Furthermore, dendritic spines were reduced, and their genes were also downregulated. Depleting microglia ameliorated the activation of neuroinflammation and complement and rescued synaptic loss, cognitive dysfunction, and anxiety-like behaviors. When neuroinflammatory inhibition or C1q neutralization occurred, complement was also decreased, and synaptic elimination was interrupted. CONCLUSIONS: These findings illustrated that prolonged anesthesia triggered neuroinflammation and complement-mediated microglial synaptic engulfment that pathologically caused synaptic elimination in SIN. We have demonstrated the neuromorphopathological underpinnings of SIN, which have direct therapeutic relevance for PND patients.


Assuntos
Anestesia , Disfunção Cognitiva , Doenças Neuroinflamatórias , Animais , Ratos , Anestesia/efeitos adversos , Ansiedade/etiologia , Ansiedade/metabolismo , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Complemento C1q/metabolismo , Hipocampo/metabolismo , Microglia/efeitos dos fármacos , Microglia/fisiologia , Doenças Neuroinflamatórias/induzido quimicamente , Doenças Neuroinflamatórias/complicações , Sevoflurano/efeitos adversos , Sevoflurano/metabolismo
2.
World J Surg Oncol ; 20(1): 387, 2022 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-36471393

RESUMO

PURPOSE: Liver cancer is one of the most common tumors with the seventh-highest incidence and the third-highest mortality. Many studies have shown that small extracellular vesicles (sEVs) play an important role in liver cancer. Here, we report comprehensive signatures for sEV proteins from plasma obtained from patients with hepatocellular carcinoma (HCC), which might be valuable for the evaluation and diagnosis of HCC. METHODS: We extracted sEVs from the plasma of controls and patients with HCC. Differentially expressed proteins in the sEVs were analyzed using label-free quantification and bioinformatic analyses. Western blotting (WB) was used to validate the abovementioned sEV proteins. RESULTS: Proteomic analysis was performed for plasma sEVs from 21 patients with HCC and 15 controls. Among the 335 identified proteins in our study, 27 were significantly dysregulated, including 13 upregulated proteins that were involved predominantly in the complement cascade (complement C1Q subcomponent subunit B (C1QB), complement C1Q subcomponent subunit C (C1QC), C4B-binding protein alpha chain (C4BPA), and C4B-binding protein beta chain (C4BPB)) and the coagulation cascade (F13B, fibrinogen alpha chain (FGA), fibrinogen beta chain (FGB), and fibrinogen gamma chain (FGG)). We verified increased levels of the C1QB, C1QC, C4BPA, and C4BPB proteins in the plasma sEVs from patients with HCC in both the discovery cohort and validation cohort. CONCLUSIONS: The complement cascade in sEVs was significantly involved in HCC progression. C1QB, C1QC, C4BPA, and C4BPB were highly abundant in the plasma sEVs from patients with HCC and might represent molecular signatures.


Assuntos
Carcinoma Hepatocelular , Vesículas Extracelulares , Neoplasias Hepáticas , Humanos , Proteína de Ligação ao Complemento C4b/análise , Proteômica , Complemento C1q , Fibrinogênio
3.
Sci Adv ; 8(48): eabq0898, 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36459558

RESUMO

C1q/tumor necrosis factor-related protein 9 (CTRP9) is an adipokine and has high potential as a therapeutic target. However, the role of CTRP9 in cardiovascular disease pathogenesis remains unclear. We found CTRP9 to induce HDAC7 and p38 MAPK phosphorylation via tight regulation of AMPK in vascular endothelial cells, leading to angiogenesis through increased MEF2 activity. The expression of CTRP9 and atheroprotective MEF2 was decreased in plaque tissue of atherosclerotic patients and the ventricle of post-infarction mice. CTRP9 treatment inhibited the formation of atherosclerotic plaques in ApoE KO and CTRP9 KO mice. In addition, CTRP9 induced significant ischemic injury prevention in the post-MI mice. Clinically, serum CTRP9 levels were reduced in patients with MI compared with healthy controls. In summary, CTRP9 induces a vasoprotective response via the AMPK/HDAC7/p38 MAPK pathway in vascular endothelial cells, whereas its absence can contribute to atherosclerosis and MI. Hence, CTRP9 may represent a valuable therapeutic target and biomarker in cardiovascular diseases.


Assuntos
Aterosclerose , Infarto do Miocárdio , Animais , Camundongos , Proteínas Angiogênicas , Adipocinas , Complemento C1q , Células Endoteliais , Proteínas Quinases Ativadas por AMP , Histona Desacetilases/genética , Proteínas Quinases p38 Ativadas por Mitógeno , Glicoproteínas , Adiponectina/genética
4.
Zhen Ci Yan Jiu ; 47(12): 1041-7, 2022 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-36571217

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture (EA) of "Xiusanzhen" ï¼»bilateral "Yingxiang"(LI20)+"Yintang"(GV24+)ï¼½ on synaptophysin (SYN), postsynaptic density protein-95 (PSD-95), Iba-1+ CD68+ microglia and complement C related protein expression of hippocampus in Parkinson's disease dementia (PDD) mice, so as to explore its mechanism in improving memory impairment of PDD. METHODS: Male C57BL/6 mice were randomly divided into control, sham operation, model and EA groups, with 10 mice in each group. The PDD model was established by injecting 6-OHDA into the medial forebrain tract. EA (2 Hz, 1 mA) was applied to unilateral LI20 and GV29 for 20 min once daily for consecutive 14 days. Morris water maze and new object recognition test were used to evaluate the learning and memory ability. Western blot was used to detect the expression of SYN and PSD-95 proteins in hippocampus. Immunofluorescence was used to label Iba-1+ CD68+ microglia and C1q positive cells in hippocampal CA1 region. The content of C3 protein in hippocampus was detected by ELISA. RESULTS: Compared with the control group, there was no statistical significance in all the observed indexes in the sham operation group. Compared with the sham operation group, the average escape latency (AEL) prolonged significantly (P<0.01), the target platform crossing times (TPCT) and new object recognition index (NORI) decreased remarkably (P<0.01); the expressions of SYN and PSD-95 proteins in hippocampal CA1 region were significantly decreased (P<0.01); the rate of Iba-1+CD68+ microglia, the rate of C1q positive cells and the content of C3 protein were significantly increased (P<0.01) in the model group. In comparison with the model group, the AEL was shortened (P<0.01), the TPCT and NORI were increased (P<0.05) remarkably; the expressions of SYN and PSD-95 proteins in hippocampal CA1 region were increased (P<0.01, P<0.05); the rate of Iba-1+ CD68+ microglia, the rate of C1q positive cells and the content of C3 protein were significantly decreased (P<0.01) in the EA group. CONCLUSION: "Xiusanzhen" can alleviate the learning and memory impairment of PDD model mice, and improve the synaptic plasticity of hippocampal CA1 area. The mechanism may be related to the reduction of C1q and C3 deposition in hippocampal CA1 region and the reduction of microglia phagocytosis.


Assuntos
Doença de Alzheimer , Demência , Eletroacupuntura , Doença de Parkinson , Animais , Masculino , Camundongos , Ratos , Complemento C1q , Hipocampo , Camundongos Endogâmicos C57BL , Plasticidade Neuronal , Doença de Parkinson/genética , Doença de Parkinson/terapia , Ratos Sprague-Dawley
5.
J Immunol Res ; 2022: 7263740, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36573216

RESUMO

Background: The ability of vaccine-induced antibodies to bind C1q could affect pathogen neutralization. In this study, we investigated C1q binding and subsequent complement activation by anti-spike (S) protein receptor-binding domain (RBD) specific antibodies produced following vaccination with either the mRNA vaccine BNT162b2 or the inactivated vaccine BBIBP-CorV. Methods: Serum samples were collected in the period of July 2021-March 2022. Participants' demographic data, type of vaccine, date of vaccination, as well as adverse effects of the vaccine were recorded. The serum samples were incubated with S protein RBD-coated plates. Levels of human IgG, IgA, IgM, C1q, and mannose-binding lectin (MBL) that were bound to the plate, as well as formed C3d, and C5b-9 were compared between different groups of participants. Results: A total of 151 samples were collected from vaccinated (n = 116) and nonvaccinated (n = 35) participants. Participants who received either one or two doses of BNT162b2 formed higher levels of anti-RBD IgG and IgA than participants who received BBIBP-CorV. The anti-RBD IgG formed following either vaccine bound C1q, but significantly more C1q binding was observed in participants who received BNT162b2. Subsequently, C5b-9 formation was significantly higher in participants who received BNT162b2, while no significant difference in C5b-9 formation was found between the nonvaccinated and BBIBP-CorV groups. The formation of C5b-9 was strongly correlated to C1q binding and not to MBL binding, additionally, the ratio of formed C5b-9/bound C1q was significantly higher in the BNT162b2 group. Conclusion: Anti-RBD IgG formed following vaccination can bind C1q with subsequent complement activation, and the degree of terminal complement pathway activation differed between vaccines, which could play a role in the protection offered by COVID-19 vaccines. Further investigation into the correlation between vaccine protection and vaccine-induced antibodies' ability to activate complement is required.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Humanos , Complexo de Ataque à Membrana do Sistema Complemento , Vacina BNT162 , Complemento C1q , COVID-19/prevenção & controle , Proteínas do Sistema Complemento , Vacinação , Anticorpos Antivirais , Imunoglobulina A
6.
Diab Vasc Dis Res ; 19(6): 14791641221137355, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36409464

RESUMO

BACKGROUND: Collateral growth plays an important role in the recovery of acute myocardial infarction. C1q/TNF-related protein-2 (CTRP2), a CTRP family member, showed some protective effects on cell survival. In this study, the relationship between CTRP2 and collateral growth was examined. METHODS: C57BL/6 mice were subjected to myocardial ischaemia/reperfusion (I/R), and the expression of CTRP2 and the effect of CTRP2 on infarction size, cardiac function and angiogenesis were examined. The ischaemic hindlimb model was also used to examine the effect of CTRP2. In vitro, CTRP2-mediated regulation of angiogenesis, AKT activation and VEGFR2 expression in endothelial cells was examined. The CTRP2 level associated with good collateral growth was observed in a cohort. RESULTS: I/R reduced CTRP2 expression, and intraperitoneal injection of recombinant CTRP2 protein improved infarction size, cardiac function and angiogenesis. Overexpression of CTRP2 promoted blood refusion and collateral growth in ischaemic hindlimb mice. In vitro, CTRP2 enhanced tube formation and migration in a dose-dependent manner, while CTRP2 increased AKT phosphorylation and VEGFR2 expression. In an observational clinical cohort, CTRP2 levels were significantly increased in patients with good collateral growth, and CTRP2 was negatively associated with poor collateral growth in patients. CONCLUSION: CTRP2 improved cardiac function by promoting collateral growth by promoting AKT-VEGFR2.


Assuntos
Complemento C1q , Infarto do Miocárdio , Animais , Camundongos , Células Endoteliais/metabolismo , Isquemia , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/prevenção & controle , Neovascularização Patológica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Reperfusão
7.
Mol Immunol ; 152: 172-182, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36371813

RESUMO

Antibody-dependent enhancement (ADE) has been associated with severe disease outcomes in several viral infections, including respiratory infections. In vitro and in vivo studies showed that antibody-response to SARS-CoV and MERS-CoV could exacerbate infection via ADE. Recently in SARS CoV-2, the in vitro studies and structural analysis shows a risk of disease severity via ADE. This phenomenon is partially attributed to non-neutralizing antibodies or antibodies at sub-neutralizing levels. These antibodies result in antigen-antibody complexes' deposition and propagation of a chronic inflammatory process that destroys affected tissues. Further, antigen-antibody complexes may enhance the internalization of the virus into cells through the Fc gamma receptor (FcγR) and lead to further virus replication. Thus, ADE occur via two mechanisms; 1. Antibody mediated replication and 2. Enhanced immune activation. Antibody-mediated effector functions are mainly driven by complement activation, and the first complement in the cascade is complement 1q (C1q) which binds to the virus-antibody complex. Reports say that deficiency in circulating plasma levels of C1q, an independent predictor of mortality in high-risk patients, including diabetes, is associated with severe viral infections. Complement mediated ADE is reported in several viral infections such as dengue, West Nile virus, measles, RSV, Human immunodeficiency virus (HIV), and Ebola virus. This review discusses ADE in viral infections and the in vitro evidence of ADE in coronaviruses. We outline the mechanisms of ADE, emphasizing the role of complements, especially C1q in the outcome of the enhanced disease.


Assuntos
COVID-19 , Síndrome Respiratória Aguda Grave , Humanos , Anticorpos Facilitadores , Complemento C1q , Complexo Antígeno-Anticorpo , Anticorpos Antivirais
8.
Cell Rep ; 41(8): 111673, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36417869

RESUMO

In North America, the Lyme disease agent, Borrelia burgdorferi, is commonly transmitted by the black-legged tick, Ixodes scapularis. Tick saliva facilitates blood feeding and enhances pathogen survival and transmission. Here, we demonstrate that I. scapularis complement C1q-like protein 3 (IsC1ql3), a tick salivary protein, directly interacts with B. burgdorferi and is important during the initial stage of spirochetal infection of mice. Mice fed upon by B. burgdorferi-infected IsC1ql3-silenced ticks, or IsC1ql3-immunized mice fed upon by B. burgdorferi-infected ticks, have a lower spirochete burden during the early phase of infection compared with control animals. Mechanically, IsC1ql3 interacts with the globular C1q receptor present on the surface of CD4+ and CD8+ T cells, resulting in decreased production of interferon γ. IsC1ql3 is a C1q-domain-containing protein identified in arthropod vectors and has an important role in B. burgdorferi infectivity as the spirochete transitions from the tick to vertebrate host.


Assuntos
Ixodes , Doença de Lyme , Camundongos , Animais , Interferon gama , Linfócitos T CD8-Positivos , Complemento C1q
9.
BMC Psychiatry ; 22(1): 741, 2022 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-36447174

RESUMO

BACKGROUND: Dysregulated complement system is linked to pathophysiology of major depressive disorder (MDD). Childhood trauma has been associated with an increased incidence of adult depression via a putative mechanism of immune activation. This study aimed to measure and compare peripheral levels of complement C3, C3a, C1q and C-reactive protein (CRP) in MDD patients and healthy controls and explore the relationship between these molecule levels and childhood trauma history in the participants. METHODS: The participants were 49 medication-free MDD patients and 45 healthy controls. All participants were asked to finish the Childhood Trauma Questionnaire, followed by blood sampling for measurement of plasma complement C3, C3a, C1q and CRP by means of enzyme-linked immunosorbent assay. RESULTS: Peripheral plasma concentration of C3 and C3a in medication-free MDD group was significantly higher than that in the healthy controls; whereas the concentration of plasma C1q and CRP in depressed patients was comparable to that in healthy controls. All these inflammatory factors were not associated to childhood trauma experience in patients with MDD. CONCLUSION: Our data suggest that complement C3 and C3a may be implicated in the pathophysiology of MDD, although traumatic childhood experiences were not associated with the circulating levels of complement C3, C3a, C1q and CRP.


Assuntos
Experiências Adversas da Infância , Transtorno Depressivo Maior , Adulto , Humanos , Complemento C3 , Complemento C1q , Proteína C-Reativa
10.
Sci Rep ; 12(1): 20640, 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36450921

RESUMO

There is a need for rapid non-sputum-based tests to identify and treat patients infected with Mycobacterium tuberculosis (Mtb). The overall objective of this study was to measure and compare the expression of a selected panel of human plasma proteins in patients with active pulmonary tuberculosis (ATB) throughout anti-TB treatment (from baseline to the end of treatment), in Mtb-infected individuals (TBI) and healthy donors (HD) to identify a putative host-protein signature useful for both TB diagnosis and treatment monitoring. A panel of seven human host proteins CLEC3B, SELL, IGFBP3, IP10, CD14, ECM1 and C1Q were measured in the plasma isolated from an HIV-negative prospective cohort of 37 ATB, 24 TBI and 23 HD. The protein signatures were assessed using a Luminex xMAP® to quantify the plasmatic levels in unstimulated blood of the different clinical group as well as the protein levels at baseline and at three timepoints during the 6-months ATB treatment, to compare the plasma protein levels between culture slow and fast converters that may contribute to monitor the TB treatment outcome. Protein signatures were defined using the CombiROC algorithm and multivariate models. The studied plasma host proteins showed different levels between the clinical groups and during the TB treatment. Six of the plasma proteins (CLEC3B, SELL, IGFBP3, IP10, CD14 and C1Q) showed significant differences in normalised median fluorescence intensities when comparing ATB vs HD or TBI groups while ECM1 revealed a significant difference between fast and slow sputum culture converters after 2 months following treatment (p = 0.006). The expression of a four-host protein markers (CLEC3B-ECM1-IP10-SELL) was significantly different between ATB from HD or TBI groups (respectively, p < 0.05). The expression of the same signature was significantly different between the slow vs the fast sputum culture converters after 2 months of treatment (p < 0.05). The results suggest a promising 4 host-plasma marker signature that would be associated with both TB diagnostic and treatment monitoring.


Assuntos
Mycobacterium tuberculosis , Tuberculose dos Linfonodos , Humanos , Quimiocina CXCL10 , Complemento C1q , Estudos Prospectivos , Antituberculosos/uso terapêutico , Proteínas Sanguíneas , Proteínas da Matriz Extracelular
11.
BMC Med Imaging ; 22(1): 210, 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36451131

RESUMO

OBJECTIVES: To investigate the correlation between the histopathology of the kidney and clinical indicators in patients with lupus nephritis (LN) using magnetic resonance imaging (MRI). METHODS: A total 50 female participants were enrolled in the study. Thirty patients with LN were divided into types 2, 3, 4, and 5, according to their pathological features. The control group consisted of 20 healthy female volunteers. Serum creatinine, C3, C1q, and anti-ds-DNA were measured. Conventional MRI, DTI, DWI, and BOLD scanning was performed to obtain the FA, ADC, and R2* values for the kidney. RESULTS: Compared with the control group, FA and the ADC were decreased in patients with LN, while the R2* value was increased (P < 0.05). The overall comparison of the SLEDAI (Activity index of systemic lupus erythematosus) score, total pathological score, AI, and serum creatinine C3 showed that these were significantly different between the two groups (P < 0.05). FA and the ADC were negatively correlated with urinary, blood ds-DNA, and serum creatinine and positively correlated with C1q (P < 0.05). The R2* value was positively correlated with urinary NGAL, blood ds-DNA, and serum creatinine (P < 0.05). FA and the ADC were negatively correlated with the SLEDAI score, total pathological score, AI, CI, nephridial tissue C3, and C1q. The R2* value was positively correlated with the SLEDAI score, total pathological score, AI, CI, nephridial tissue C3, and C1q (P < 0.05). CONCLUSIONS: MRI examination in female patients with LN was correlated with pathologic test results, which may have clinical significance in determining the disease's severity, treatment, and outcome.


Assuntos
Nefrite Lúpica , Humanos , Feminino , Nefrite Lúpica/diagnóstico por imagem , Creatinina , Complemento C1q , Rim , Imageamento por Ressonância Magnética , Hematúria
12.
Front Immunol ; 13: 1037191, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36439146

RESUMO

C1q, the recognition molecule of the classical pathway of the complement system, plays a central role in pregnancy. Lack of C1q is characterized by poor trophoblast invasion and pregnancy failure. C1q can be the target of an antibody response: anti-C1q autoantibodies (anti-C1q) are present in several infectious and autoimmune diseases. The presence of these autoantibodies has been detected also in 2-8% of the general population. Recent evidence indicates that women who undergo assisted reproductive technology (ART) have an increased risk of developing pre-eclampsia (PE), particularly oocyte donation (OD) pregnancies. The aim of this study was to characterize the levels of C1q and anti-C1q in PE gestations, in healthy spontaneous, homologous and heterologous ART pregnancies. Serum of the following four groups of women, who were followed throughout two or three trimesters, were collected: PE, patients diagnosed with PE; OD, oocyte donation recipients; HOM, homologous ART women; Sp, spontaneous physiological pregnancy. Our results indicate that PE patients have lower levels of anti-C1q. In ART pregnant women, the trend of C1q and anti-C1q levels were similar to PE patients, even though these women did not develop PE-like symptoms during pregnancy. This finding suggests an immunological dysfunction at the foetal-maternal interface in ART pregnancies, a hypothesis confirmed by the observation of C1q deposition in placentae derived from OD, comparable to PE. Since significantly lower levels of anti-C1q were detected in PE compared to healthy control sera, we hypothesize the possible binding on placental syncytiotrophoblast microvesicles (STBM), which are increased in the circulation of PE mothers. Furthermore, the characterization of the binding-epitope of anti-C1q revealed that "physiological" autoantibodies were mainly directed against C1q globular domain. We concluded that anti-C1q could have a physiological role in pregnancy: during the healthy spontaneous pregnancy the raised levels of these autoantibodies can be important for the clearance of STBM. In PE and in pathological pregnancies (but also in OD pregnancies), the increase in syncytiotrophoblast apoptosis and consequent increase of the circulating STMB levels lead to a consumption of C1q and anti-C1q.


Assuntos
Pré-Eclâmpsia , Feminino , Humanos , Gravidez , Autoanticorpos , Complemento C1q , Estudos Longitudinais , Placenta/metabolismo
13.
J Transl Med ; 20(1): 449, 2022 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-36195912

RESUMO

BACKGROUND: C1q/tumor necrosis factor-related protein 1 (CTRP1) is an adipokine secreted by adipose tissue, related to chondrocyte proliferation, inflammation, and glucose homeostasis. However, the therapeutic effects on metabolic disorders and the underlying mechanism were unclear. Here, we investigated the functions and mechanisms of CTRP1 in treating obesity and diabetes. METHODS: The plasmid containing human CTRP1 was delivered to mice by hydrodynamic injection, which sustained expression of CTRP1 in the liver and high protein level in the blood. High-fat diet (HFD) fed mice and STZ-induced diabetes model were used to study the effects of CTRP1 on obesity, glucose homeostasis, insulin resistance, and hepatic lipid accumulation. The lipid accumulation in liver and adipose tissue, glucose tolerance, insulin sensitivity, food intake, and energy expenditure were detected by H&E staining, Oil-Red O staining, glucose tolerance test, insulin tolerance test, and metabolic cage, respectively. The metabolic-related genes and signal pathways were determined using qPCR and western blotting. RESULTS: With high blood circulation, CTRP1 prevented obesity, hyperglycemia, insulin resistance, and fatty liver in HFD-fed mice. CTRP1 also improved glucose metabolism and insulin resistance in obese and STZ-induced diabetic mice. The metabolic cage study revealed that CTRP1 reduced food intake and enhanced energy expenditure. The mechanistic study demonstrated that CTRP1 upregulated the protein level of leptin in blood, thermogenic gene expression in brown adipose tissue, and the gene expression responsible for lipolysis and glycolysis in white adipose tissue (WAT). CTRP1 also downregulated the expression of inflammatory genes in WAT. Overexpression of CTRP1 activated AMPK and PI3K/Akt signaling pathways and inhibited ERK signaling pathway. CONCLUSION: These results demonstrate that CTRP1 could improve glucose homeostasis and prevent HFD-induced obesity and fatty liver through upregulating the energy expenditure and reducing food intake, suggesting CTRP1 may serve as a promising target for treating metabolic diseases.


Assuntos
Diabetes Mellitus Experimental , Fígado Gorduroso , Resistência à Insulina , Insulinas , Proteínas Quinases Ativadas por AMP/metabolismo , Adipocinas , Tecido Adiposo Marrom , Animais , Complemento C1q/metabolismo , Complemento C1q/uso terapêutico , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica , Glucose/metabolismo , Homeostase , Humanos , Insulinas/metabolismo , Insulinas/uso terapêutico , Leptina , Lipídeos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Necrose Tumoral/metabolismo
14.
Front Immunol ; 13: 1010893, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36248824

RESUMO

Cellular death, aging, and tissue damage trigger inflammation that leads to enzymatic and non-enzymatic lipid peroxidation of polyunsaturated fatty acids present on cellular membranes and lipoproteins. This results in the generation of highly reactive degradation products, such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), that covalently modify free amino groups of proteins and lipids in their vicinity. These newly generated neoepitopes represent a unique set of damage-associated molecular patterns (DAMPs) associated with oxidative stress termed oxidation-specific epitopes (OSEs). OSEs are enriched on oxidized lipoproteins, microvesicles, and dying cells, and can trigger sterile inflammation. Therefore, prompt recognition and removal of OSEs is required to maintain the homeostatic balance. This is partially achieved by various humoral components of the innate immune system, such as natural IgM antibodies, pentraxins and complement components that not only bind OSEs but in some cases modulate their pro-inflammatory potential. Natural IgM antibodies are potent complement activators, and 30% of them recognize OSEs such as oxidized phosphocholine (OxPC-), 4-HNE-, and MDA-epitopes. Furthermore, OxPC-epitopes can bind the complement-activating pentraxin C-reactive protein, while MDA-epitopes are bound by C1q, C3a, complement factor H (CFH), and complement factor H-related proteins 1, 3, 5 (FHR-1, FHR-3, FHR-5). In addition, CFH and FHR-3 are recruited to 2-(ω-carboxyethyl)pyrrole (CEP), and full-length CFH also possesses the ability to attenuate 4-HNE-induced oxidative stress. Consequently, alterations in the innate humoral defense against OSEs predispose to the development of diseases associated with oxidative stress, as shown for the prototypical OSE, MDA-epitopes. In this mini-review, we focus on the mechanisms of the accumulation of OSEs, the pathophysiological consequences, and the interactions between different OSEs and complement components. Additionally, we will discuss the clinical potential of genetic variants in OSE-recognizing complement proteins - the OSE complotype - in the risk estimation of diseases associated with oxidative stress.


Assuntos
Proteína C-Reativa , Fator H do Complemento , Complemento C1q , Epitopos , Humanos , Imunoglobulina M , Fatores Imunológicos , Inflamação , Lipídeos , Malondialdeído , Fosforilcolina
15.
Front Immunol ; 13: 969984, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36248871

RESUMO

Background: Inflammation increases the risk of thrombosis in coronary artery disease (CAD) patients and affects the antiplatelet efficacy of clopidogrel. C1q interacts with platelets to activate platelets and induce thrombosis by participating in and regulating the inflammatory response. Whether C1q affects adenosine diphosphate (ADP)-induced platelet reactivity during clopidogrel therapy was unclear and our study aimed to explore the issue. Method: We enrolled 1,334 CAD patients receiving clopidogrel therapy and evaluated the association between C1q level and high residual platelet reactivity (HRPR) using logistic regression and restricted cubic spline (RCS). HRPR was defined as ADP-induced maximum amplitude (MAADP) > 47 mm plus ADP-induced platelet aggregation (ADPi) < 50%. Results: A total of 516 patients (38.7%) performed HRPR. The frequency of HRPR increases with the increase in C1q level (26.3%, 38.4%, 43.2%, and 46.7% for the 1st to 4th quartile of C1q). The result of multivariate logistic regression demonstrated elevated C1q as an independent predictor for HRPR (2nd quartile: OR = 1.722, 95% CI 1.215-2.440; 3rd quartile: OR = 2.015, 95% CI 1.413-2.874; 4th quartile: OR = 2.362, 95% CI 1.631-3.421, compared to the 1st quartile). RCS depicted the nonlinear relationship between C1q and HRPR risk (p for non-linear < 0.05). Conclusion: The current research is the first to explore the association of C1q and ADP-induced platelet reactivity and to demonstrate elevated C1q as an independent risk factor for HRPR in CAD patients during clopidogrel therapy.


Assuntos
Doença da Artéria Coronariana , Intervenção Coronária Percutânea , Trombose , Adenosina , Difosfato de Adenosina , Clopidogrel/uso terapêutico , Complemento C1q , Doença da Artéria Coronariana/tratamento farmacológico , Humanos , Inibidores da Agregação Plaquetária/uso terapêutico , Ticagrelor , Ticlopidina/uso terapêutico
16.
Front Immunol ; 13: 1015128, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36275687

RESUMO

The molecules of the complement system connect the effectors of innate and adaptive immunity and play critical roles in maintaining homeostasis. Among them, the C1 complex, composed of C1q, C1r, and C1s (C1qr2s2), is the initiator of the classical complement activation pathway. While deficiency of C1s is associated with early-onset systemic lupus erythematosus and increased susceptibility to bacteria infections, the gain-of- function variants of C1r and C1s may lead to periodontal Ehlers Danlos syndrome. As C1s is activated under various pathological conditions and associated with inflammation, autoimmunity, and cancer development, it is becoming an informative biomarker for the diagnosis and treatment of a variety of diseases. Thus, more sensitive and convenient methods for assessing the level as well as activity of C1s in clinic samples are highly desirable. Meanwhile, a number of small molecules, peptides, and monoclonal antibodies targeting C1s have been developed. Some of them are being evaluated in clinical trials and one of the antibodies has been approved by US FDA for the treatment of cold agglutinin disease, an autoimmune hemolytic anemia. In this review, we will summarize the biological properties of C1s, its association with development and diagnosis of diseases, and recent progress in developing drugs targeting C1s. These progress illustrate that the C1s molecule is an effective biomarker and promising drug target.


Assuntos
Complemento C1r , Complemento C1s , Complemento C1s/metabolismo , Complemento C1q/metabolismo , Ativação do Complemento/fisiologia , Peptídeos , Anticorpos Monoclonais
17.
Front Immunol ; 13: 953674, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36211440

RESUMO

Hidradenitis suppurativa (HS) is a chronic auto-inflammatory skin disease with a complex and multifactorial pathogenesis involving both the innate and adaptive immune system. Despite limited evidence for local complement activation, conflicting results have been published on the role of systemic complement activation in HS. It was hypothesized that complement was consumed in highly inflamed HS skin, trapping complement from the circulation. Therefore, the aim of this study was to evaluate this local complement deposition in HS skin lesions using routine and commonly used complement antibodies.Direct immunofluorescence for C1q, C3c, C4d, C5b-9, and properdin was performed on frozen tissue sections of 19 HS patients and 6 controls. C5a receptor 1 (C5aR1) was visualized using immunohistochemistry. Overall, we found no significant local complement deposition in HS patients versus controls regarding C1q, C3c, C4d, C5b-9, or properdin on either vessels or immune cells. C5aR1 expression was exclusively found on immune cells, predominantly neutrophilic granulocytes, but not significantly different relatively to the total infiltrate in HS lesions compared with controls. In conclusion, despite not being able to confirm local complement depositions of C1q, C3c, C4d, or properdin using highly sensitive and widely accepted techniques, the increased presence of C5aR1 positive immune cells in HS suggests the importance of complement in the pathogenesis of HS and supports emerging therapies targeting this pathway.


Assuntos
Hidradenite Supurativa , Ativação do Complemento , Complemento C1q , Complexo de Ataque à Membrana do Sistema Complemento , Humanos , Inflamação , Properdina , Receptor da Anafilatoxina C5a
18.
Hepatol Commun ; 6(12): 3515-3527, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36199236

RESUMO

Complement complex 1 subunit q (C1q) has multiple functions, including cell migration, in addition to its traditional complement-activating effect. Research shows C1q is a ligand for frizzled receptors (FZDs). FZD-induced yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) alternate Wnt signaling activation induces connective tissue growth factor (CTGF) production and hepatic stellate cell (HSC) activation. However, no study exists in which C1q directly induces CTGF in HSCs. Here, we investigated the role of C1q in HSC activation. Human HSCs (LX2) were incubated with C1q to assess HSC activation. C1q and fibrotic markers were assessed using immunohistochemistry, immunoblotting, and quantitative reverse-transcription polymerase chain reaction in cirrhotic rats administered CCl4 for 21 weeks. Serum C1q, liver function, and fibrosis score were measured in 91 patients with chronic liver disease. The correlations between serum C1q and liver function, fibrosis score, and survival prognosis were examined. C1q-activated LX2s showed morphologic changes, up-regulation of CTGF, tissue inhibitors of metalloproteinases (TIMP-1), and alternate Wnt signal genes FZD2, TAZ, and cysteine-rich angiogenic inducer 61 (Cyr61). Cirrhotic rat liver C1q expression correlated with the Azan-positive area and expression of CTGF, TIMP-1, hyaluronan synthase (HAS)1, HAS3, and CD44. Expression of C1q protein and C1q, CTGF, and TIMP-1 genes were higher in deceased cirrhotic rat livers compared to surviving rats. Human serum C1q levels increased in liver cirrhosis compared to chronic hepatitis and correlated with liver fibrosis and functional markers. Ten patients suffered liver-related death over a 66-month observation period. The C1q cut-off value (11 mg/dl) showed patients with serum values < 11 mg/dl had longer rates of survival compared to C1q ≥ 11 mg/dl. Conclusion: C1q-mediated HSC activation in liver fibrosis is associated with CTGF elevation. Additionally, serum C1q may be diagnostic for survival in human chronic liver diseases.


Assuntos
Fator de Crescimento do Tecido Conjuntivo , Hepatopatias , Humanos , Ratos , Animais , Fator de Crescimento do Tecido Conjuntivo/genética , Células Estreladas do Fígado , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Prognóstico , Complemento C1q/metabolismo , Cirrose Hepática/diagnóstico , Hepatopatias/metabolismo
19.
Ann Clin Lab Sci ; 52(4): 634-641, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36197773

RESUMO

OBJECTIVE: Pneumococcal meningitis is a common and serious infectious disease that threatens human health worldwide. Recent studies have shown that various regulatory proteins of the immune system may be potential targets for adjuvant therapy. The aim of this study was to investigate CD93 expression and potential signaling pathways in rat models of pneumococcal meningitis. METHODS: The levels of sCD93 (soluble CD93), IL-6 (Interleukin-6) and TNF-α (tumor necrosis factor-α) in cerebrospinal fluid were assessed by ELISA, and the levels of iNOS (inducible nitric oxide synthase), CD93, complement C1q, and GIPC (C-terminal of the regulator of G protein signaling-G alpha interacting protein) in the brain tissue were evaluated by Western Blotting. The interaction between CD93 and complement C1q was investigated by co-immunoprecipitation, and the interaction between CD93 and GIPC was detected by immunofluorescence colocalization. RESULTS: Our results showed a significant increase in the levels of IL-6, TNF-α, sCD93, CD93, complement C1q, GIPC, and iNOS in the Streptococcus pneumoniae infection group. CD93 interacted with complement C1q, and CD93 and GIPC colocalized on the cell membrane of the cerebral cortex. CONCLUSIONS: This study suggests that CD93 may be a new inflammatory factor in pneumococcal meningitis. C1q and GIPC may mediate downstream signaling pathways of CD93 in pneumococcal meningitis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Glicoproteínas de Membrana/metabolismo , Meningite Pneumocócica , Receptores de Complemento/metabolismo , Animais , Complemento C1q/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Humanos , Inflamação , Interleucina-6/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Fator de Necrose Tumoral alfa/metabolismo
20.
Int J Mol Sci ; 23(20)2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36293087

RESUMO

Complement pathway proteins are reported to be increased in polycystic ovary syndrome (PCOS) and may be affected by obesity and insulin resistance. To investigate this, a proteomic analysis of the complement system was undertaken, including inhibitory proteins. In this cohort study, plasma was collected from 234 women (137 with PCOS and 97 controls). SOMALogic proteomic analysis was undertaken for the following complement system proteins: C1q, C1r, C2, C3, C3a, iC3b, C3b, C3d, C3adesArg, C4, C4a, C4b, C5, C5a, C5b-6 complex, C8, properdin, factor B, factor D, factor H, factor I, mannose-binding protein C (MBL), complement decay-accelerating factor (DAF) and complement factor H-related protein 5 (CFHR5). The alternative pathway of the complement system was primarily overexpressed in PCOS, with increased C3 (p < 0.05), properdin and factor B (p < 0.01). In addition, inhibition of this pathway was also seen in PCOS, with an increase in CFHR5, factor H and factor I (p < 0.01). Downstream complement factors iC3b and C3d, associated with an enhanced B cell response, and C5a, associated with an inflammatory cytokine release, were increased (p < 0.01). Hyperandrogenemia correlated positively with properdin and iC3b, whilst insulin resistance (HOMA-IR) correlated with iC3b and factor H (p < 0.05) in PCOS. BMI correlated positively with C3d, factor B, factor D, factor I, CFHR5 and C5a (p < 0.05). This comprehensive evaluation of the complement system in PCOS revealed the upregulation of components of the complement system, which appears to be offset by the concurrent upregulation of its inhibitors, with these changes accounted for in part by BMI, hyperandrogenemia and insulin resistance.


Assuntos
Resistência à Insulina , Lectina de Ligação a Manose , Síndrome do Ovário Policístico , Feminino , Humanos , Properdina/metabolismo , Fator H do Complemento , Fator B do Complemento/metabolismo , Antígenos CD55 , Fator D do Complemento , Estudos de Coortes , Proteômica , Complemento C1q , Complemento C3b , Fibrinogênio , Citocinas
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