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1.
Int J Mol Sci ; 22(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205507

RESUMO

Complement overactivation has been reported in most patients with Barraquer-Simons syndrome (BSS), a rare form of acquired partial lipodystrophy. Complement Factor D (FD) is a serine protease with a crucial role in the activation of the alternative pathway of the complement system, which is mainly synthesized by adipose tissue. However, its role in the pathogenesis of BSS has not been addressed. In this study, plasma FD concentration was measured in 13 patients with BSS, 20 patients with acquired generalized lipodystrophy, 22 patients with C3 glomerulopathy (C3G), and 50 healthy controls. Gene expression and immunohistochemistry studies were assayed using atrophied adipose tissue from a patient with BSS. We found significantly elevated FD levels in BSS cases compared with the remaining cohorts (p < 0.001). There were no significant differences in FD levels between sexes but FD was strongly and directly associated with age in BSS (r = 0.7593, p = 0.0036). A positive correlation between FD and C3 was seen in patients with C3G, characterized by decreased FD levels due to chronic C3 consumption, but no correlation was detected for BSS. Following mRNA quantification in the patient's adipose tissue, we observed decreased CFD and C3 but elevated C5 transcript levels. In contrast, the increased FD staining detected in the atrophied areas reflects the effects of persistent tissue damage on the adipose tissue, thus providing information on the ongoing pathogenic process. Our results suggest that FD could be a reliable diagnostic biomarker involved in the pathophysiology of BSS by promoting unrestrained local complement system activation in the adipose tissue environment.


Assuntos
Fator D do Complemento/metabolismo , Lipodistrofia/sangue , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
2.
Front Immunol ; 12: 690821, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177949

RESUMO

Complement factor B (FB) mutant variants are associated with excessive complement activation in kidney diseases such as atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy and membranoproliferative glomerulonephritis (MPGN). Patients with aHUS are currently treated with eculizumab while there is no specific treatment for other complement-mediated renal diseases. In this study the phenotype of three FB missense variants, detected in patients with aHUS (D371G and E601K) and MPGN (I242L), was investigated. Patient sera with the D371G and I242L mutations induced hemolysis of sheep erythrocytes. Mutagenesis was performed to study the effect of factor D (FD) inhibition on C3 convertase-induced FB cleavage, complement-mediated hemolysis, and the release of soluble C5b-9 from glomerular endothelial cells. The FD inhibitor danicopan abrogated C3 convertase-associated FB cleavage to the Bb fragment in patient serum, and of the FB constructs, D371G, E601K, I242L, the gain-of-function mutation D279G, and the wild-type construct, in FB-depleted serum. Furthermore, the FD-inhibitor blocked hemolysis induced by the D371G and D279G gain-of-function mutants. In FB-depleted serum the D371G and D279G mutants induced release of C5b-9 from glomerular endothelial cells that was reduced by the FD-inhibitor. These results suggest that FD inhibition can effectively block complement overactivation induced by FB gain-of-function mutations.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/imunologia , Ativação do Complemento , Fator B do Complemento/genética , Fator D do Complemento/antagonistas & inibidores , Glomerulonefrite Membranoproliferativa/imunologia , Animais , Síndrome Hemolítico-Urêmica Atípica/genética , Criança , Convertases de Complemento C3-C5/imunologia , Complemento C3b/imunologia , Fator B do Complemento/imunologia , Fator D do Complemento/imunologia , Células Endoteliais/imunologia , Eritrócitos , Feminino , Glomerulonefrite Membranoproliferativa/genética , Hemólise , Humanos , Lactente , Glomérulos Renais/citologia , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Coelhos , Ovinos
3.
Elife ; 102021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34155972

RESUMO

Background: Marrow adipose tissue (MAT) has been shown to be vital for regulating metabolism and maintaining skeletal homeostasis in the bone marrow (BM) niche. As a reflection of BM remodeling, MAT is highly responsive to nutrient fluctuations, hormonal changes, and metabolic disturbances such as obesity and diabetes mellitus. Expansion of MAT has also been strongly associated with bone loss in mice and humans. However, the regulation of BM plasticity remains poorly understood, as does the mechanism that links changes in marrow adiposity with bone remodeling. Methods: We studied deletion of Adipsin, and its downstream effector, C3, in C57BL/6 mice as well as the bone-protected PPARγ constitutive deacetylation 2KR mice to assess BM plasticity. The mice were challenged with thiazolidinedione treatment, calorie restriction, or aging to induce bone loss and MAT expansion. Analysis of bone mineral density and marrow adiposity was performed using a µCT scanner and by RNA analysis to assess adipocyte and osteoblast markers. For in vitro studies, primary bone marrow stromal cells were isolated and subjected to osteoblastogenic or adipogenic differentiation or chemical treatment followed by morphological and molecular analyses. Clinical data was obtained from samples of a previous clinical trial of fasting and high-calorie diet in healthy human volunteers. Results: We show that Adipsin is the most upregulated adipokine during MAT expansion in mice and humans in a PPARγ acetylation-dependent manner. Genetic ablation of Adipsin in mice specifically inhibited MAT expansion but not peripheral adipose depots, and improved bone mass during calorie restriction, thiazolidinedione treatment, and aging. These effects were mediated through its downstream effector, complement component C3, to prime common progenitor cells toward adipogenesis rather than osteoblastogenesis through inhibiting Wnt/ß-catenin signaling. Conclusions: Adipsin promotes new adipocyte formation and affects skeletal remodeling in the BM niche. Our study reveals a novel mechanism whereby the BM sustains its own plasticity through paracrine and endocrine actions of a unique adipokine. Funding: This work was supported by the National Institutes of Health T32DK007328 (NA), F31DK124926 (NA), R01DK121140 (JCL), R01AR068970 (BZ), R01AR071463 (BZ), R01DK112943 (LQ), R24DK092759 (CJR), and P01HL087123 (LQ).


Assuntos
Adiposidade , Medula Óssea/metabolismo , Fator D do Complemento/genética , Células-Tronco Mesenquimais/metabolismo , Animais , Fator D do Complemento/metabolismo , Feminino , Humanos , Masculino , Camundongos
4.
Parasit Vectors ; 14(1): 232, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33933138

RESUMO

BACKGROUND: Schistosoma japonicum is a parasitic flatworm that is the aetiological agent of human schistosomiasis, an important cause of hepatic fibrosis. Schistosomiasis-induced hepatic fibrosis is a consequence of the highly fibrogenic nature of egg-induced granulomatous lesions, which are the main pathogenic features of schistosomiasis. Although global awareness of the association between schistosomiasis-induced hepatic fibrosis and S. japonicum infection is increasing, little is known about the molecular differences associated with rapid progression to schistosomiasis in cirrhotic patients. METHODS: We systematically used data-independent acquisition (DIA)-based liquid chromatography-mass spectrometry to identify differentially expressed proteins in serum samples from patients with advanced S. japonicum-induced hepatic fibrosis. RESULTS: Our analysis identified 1144 proteins, among which 66 were differentially expressed between the healthy control group and the group of patients with advanced S. japonicum-induced hepatic fibrosis stage F2 (SHF-F2) and 214 were differentially expressed between the SHF-F2 and SHF-F4 groups (up- or downregulation of at least 1.5-fold in serum samples). The results also indicated that two selected proteins (C1QA and CFD) are potential biomarkers for distinguishing between patients with SHF-F2 and those with SHF-F4 due to S. japonicum infection. CONCLUSIONS: We provide here the first global proteomic profile of serum samples from patients with advanced S. japonicum-induced hepatic fibrosis. The proteins C1QA and CFD are potential diagnostic markers for patients with SHF-F2 and SHF-F4 due to S. japonicum infection, although further large-scale studies are needed. Our DIA-based quantitative proteomic analysis revealed molecular differences among individuals at different stages of advanced S. japonicum-induced hepatic fibrosis and may provide fundamental information for further detailed investigations.


Assuntos
Biomarcadores/sangue , Cirrose Hepática , Esquistossomose Japônica , Idoso , Idoso de 80 Anos ou mais , Animais , Cromatografia Líquida , Complemento C1q/metabolismo , Fator D do Complemento/metabolismo , Feminino , Humanos , Fatores Imunológicos/metabolismo , Fígado/parasitologia , Fígado/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/metabolismo , Cirrose Hepática/parasitologia , Masculino , Espectrometria de Massas , Proteômica , Schistosoma japonicum
6.
Arch Gynecol Obstet ; 304(6): 1467-1473, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33881585

RESUMO

OBJECTIVE: In preeclampsia, there are excessive complement components expressed due to increased complement activation; therefore, this study investigated the concentration of adipsin and C9 in HIV-associated preeclampsia. METHOD: The study population (n = 76) was stratified by pregnancy type (normotensive pregnant and preeclampsia) and by HIV status. Serum was assayed for the concentration of adipsin and C9 using a Bioplex immunoassay procedure. RESULTS: Maternal weight did not differ (p = 0.1196) across the study groups. The concentration of adipsin was statistically different between the PE vs normotensive pregnant groups, irrespective of HIV status (p = 0.0439). There was no significant difference in adipsin concentration between HIV-negative vs HIV-positive groups, irrespective of pregnancy type (p = 0.6290). Additionally, there was a significant difference in adipsin concentration between HIV-negative normotensive vs HIV-negative preeclampsia (p < 0.05), as well as a difference between HIV-negative preeclampsia vs HIV-positive preeclampsia (p < 0.05). C9 protein expression was not statistically different between the normotensive and PE groups, regardless of HIV status (p = 0.5365). No statistical significance in C9 expression was found between HIV-positive vs HIV-negative groups, regardless of pregnancy type (p = 0.3166). Similarly, no statistical significance was noted across all study groups (p = 0.0774). CONCLUSION: This study demonstrates that there is a strong correlation between the up-regulation of adipsin and PE and that adipsin is a promising biomarker to use as a diagnostic tool for PE.


Assuntos
Fator D do Complemento/metabolismo , Infecções por HIV/complicações , Placenta/metabolismo , Pré-Eclâmpsia/diagnóstico , Complicações Infecciosas na Gravidez/virologia , Adulto , Biomarcadores/sangue , Pressão Sanguínea , Complemento C9/genética , Complemento C9/metabolismo , Feminino , Humanos , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/metabolismo , Gravidez , Estudos Prospectivos
7.
BMC Gastroenterol ; 21(1): 131, 2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33743586

RESUMO

BACKGROUND: As a secreted adipokine, adipsin has been recently shown to play a pivotal role in metabolic disorders. However, information regarding the association of circulating adipsin with non-alcoholic fatty liver disease (NAFLD) in humans is scant. METHODS: We recruited 1163 obese adult subjects with waist circumference at least 90 cm in men and 80 cm in women from the community. Circulating adipsin levels were measured by enzyme-linked immunosorbent assay. RESULTS: Circulating adipsin levels of NAFLD subjects was decreased compared to those in non-NAFLD (p < 0.05). The prevalence of NAFLD with lower levels of serum adipsin was significantly higher than those with higher values (57.6% vs. 50.9%, p < 0.05). Circulating adipsin levels were significantly associated with decreasing levels of fasting glucose and postprandial glucose (both p < 0.001 for interaction) in NAFLD subjects but not in non-NAFLD subjects. The risk of NAFLD was significantly decreased by 21.7% [OR (95% CI): 0.783 (0.679-0.902), p < 0.001], adjusting for age, gender, current smoking, alcohol consumption, physical activity, BMI, systolic BP, fasting glucose, total cholesterol, HDL-c, HOMA-IR, and body fat mass. Importantly, subjects in the lowest quartile of circulating adipsin were 1.88 times more likely to have NAFLD than those in the highest quartile in multivariable logistic regression analyses. However, such associations with circulating adipsin were not noted for metabolic syndrome, abnormal liver enzyme and significant liver fibrosis. CONCLUSIONS: These results demonstrate that circulating adipsin levels in Chinese obese adults are negatively associated with risk of NAFLD, implying that serum adipsin levels may be a potential protective factor in NAFLD.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Adulto , Índice de Massa Corporal , Fator D do Complemento , Estudos Transversais , Feminino , Humanos , Masculino , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Fatores de Risco , Circunferência da Cintura
8.
Eur J Nutr ; 60(4): 1935-1944, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32930848

RESUMO

BACKGROUND: Epidemiological studies have suggested that adipsin and visfatin are associated with the development of type 2 diabetes. This is the first study to investigate the effects of supplementation with purified anthocyanins on serum adipsin and visfatin in patients with prediabetes or newly diagnosed diabetes. METHODS: A total of 160 participants with prediabetes or newly diagnosed diabetes (40-75 years old) were given 320 mg anthocyanins or placebo daily for 12 weeks in a randomized trial. Serum adipsin, serum visfatin, lipids and glycated hemoglobin A1c (HbA1c) were measured. The areas under the curve (AUCs) for glucose, insulin and C-peptide were determined before-and after-treatment by a standard 3-h 75 g oral glucose tolerance test (OGTT). RESULTS: Relatively significant increases in serum adipsin (net change 0.15 µg/mL [0.03, 0.27], p = 0.018) and decreases in visfatin (-3.5 ng/mL [-6.69, -0.31], p = 0.032) were observed between the anthocyanins and placebo groups. We also observed significant improvements in HbA1c (-0.11% [-0.22, -0.11], p = 0.033), apolipoprotein A-1 (apo A-1) (0.12 g/L [0.03, 0.21], p = 0.012) and apolipoprotein B (apo B) (-0.07 g/L [-0.14, -0.01], p = 0.033) in response to the anthocyanins intervention. CONCLUSION: Purified anthocyanins supplementation for 12 weeks increased serum adipsin and decreased serum visfatin in patients with prediabetes or newly diagnosed diabetes. Trial registration ClinicalTrials.gov, identifier: NCT02689765.


Assuntos
Diabetes Mellitus Tipo 2 , Estado Pré-Diabético , Adulto , Idoso , Antocianinas , Glicemia , Fator D do Complemento , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobina A Glicada , Humanos , Pessoa de Meia-Idade , Nicotinamida Fosforribosiltransferase , Estado Pré-Diabético/diagnóstico , Estado Pré-Diabético/tratamento farmacológico
9.
Am J Physiol Endocrinol Metab ; 320(1): E87-E92, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33135458

RESUMO

Obesity is a potent risk factor for atherosclerotic morbidity and mortality. Cytokines secreted from adipose tissue, namely, adipokines, have been suggested to be actively involved in atherosclerosis. One of the most abundant adipokines, adipsin, is downregulated in obesity. It catalyzes the rate-limiting step of alternative complement activation, which is one of the three complement pathways potentially involved in inflammation in atherosclerosis. Interestingly, adipsin has been identified as a novel biomarker in human coronary artery disease. However, its role in the development of atherosclerosis remains unexplored. We crossed adipsin-/- mice onto an Ldlr-/- background [double-knockout (DKO) mice] and induced atherogenesis by high-fat and high-cholesterol feeding. Metabolic profiles were systemically characterized, and atherosclerotic plaques were measured at both aortic root and arch regions. Western blotting was conducted to assess adipsin level and complement activity. The DKO mice exhibited similar sizes of atherosclerotic lesions as Ldlr-/- control mice at both the aortic root and arch regions. Accordingly, they displayed comparable metabolic parameters, including body weight, insulin sensitivity, and lipid profiles, along with compensated complement activity. Adipsin deficiency does not impact the development of atherosclerosis in Ldlr-/- mice despite its crucial function in alternative complement activation. Therefore, it is unlikely to play an important role in mediating the risk of atherosclerotic complications in obesity.NEW & NOTEWORTHY Adipsin deficiency does not impact the development of atherosclerosis in Ldlr-/- mice despite its crucial function in alternative complement activation. Therefore, it is unlikely to play an important role in mediating the risk of atherosclerotic complications in obesity.


Assuntos
Aterosclerose/genética , Aterosclerose/metabolismo , Receptores de LDL/deficiência , Receptores de LDL/genética , Adipocinas/genética , Adipocinas/fisiologia , Animais , Aorta/patologia , Peso Corporal , Colesterol na Dieta/farmacologia , Fator D do Complemento/deficiência , Fator D do Complemento/genética , Proteínas do Sistema Complemento/metabolismo , Dieta Hiperlipídica , Resistência à Insulina/genética , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica/patologia
10.
Hepatology ; 73(3): 983-997, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32557728

RESUMO

BACKGROUND AND AIMS: Given the lack of effective therapies and high mortality in acute alcohol-associated hepatitis (AH), it is important to develop rationally designed biomarkers for effective disease management. Complement, a critical component of the innate immune system, contributes to uncontrolled inflammatory responses leading to liver injury, but is also involved in hepatic regeneration. Here, we investigated whether a panel of complement proteins and activation products would provide useful biomarkers for severity of AH and aid in predicting 90-day mortality. APPROACH AND RESULTS: Plasma samples collected at time of diagnosis from 254 patients with moderate and severe AH recruited from four medical centers and 31 healthy persons were used to quantify complement proteins by enzyme-linked immunosorbent assay and Luminex arrays. Components of the classical and lectin pathways, including complement factors C2, C4b, and C4d, as well as complement factor I (CFI) and C5, were reduced in AH patients compared to healthy persons. In contrast, components of the alternative pathway, including complement factor Ba (CFBa) and factor D (CFD), were increased. Markers of complement activation were also differentially evident, with C5a increased and the soluble terminal complement complex (sC5b9) decreased in AH. Mannose-binding lectin, C4b, CFI, C5, and sC5b9 were negatively correlated with Model for End-Stage Liver Disease score, whereas CFBa and CFD were positively associated with disease severity. Lower CFI and sC5b9 were associated with increased 90-day mortality in AH. CONCLUSIONS: Taken together, these data indicate that AH is associated with a profound disruption of complement. Inclusion of complement, especially CFI and sC5b9, along with other laboratory indicators, could improve diagnostic and prognostic indications of disease severity and risk of mortality for AH patients.


Assuntos
Hepatite Alcoólica/diagnóstico , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Complemento C2/análise , Complemento C3/análise , Complemento C4/análise , Complemento C5/análise , Fator B do Complemento/análise , Fator D do Complemento/análise , Proteínas do Sistema Complemento/análise , Feminino , Hepatite Alcoólica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
11.
Nutr Hosp ; 38(1): 121-127, 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33319583

RESUMO

Introduction: Background: açaí is the fruit of the palm tree Euterpe oleracea Martius, which is native to the Amazon region. This fruit has been extensively studied due to its potential effects on human health. Studies have also evaluated the potential effect of açaí on the inflammatory response, but there are still few studies that have assessed this property in humans. Objective: in this study we aimed to evaluate the effects of 200 g of açaí pulp consumption per day during four weeks on a rich panel of inflammatory biomarkers. Methods: a prospective nutritional intervention study was conducted on forty apparently healthy women who consumed 200 g of açaí pulp per day for four weeks. A panel of serum inflammatory markers were evaluated before and after the nutritional intervention, namely, cell adhesion molecules (ICAM-1, IVAM-1, P-selectin, MCP-1, and fractalkine), interleukins (IL-1ß, IL-6, IL-8, IL-10, and IL-17) and adipokines (adiponectin, leptin, visfatin, and adipsin). The data were analyzed using paired Student's t-test to evaluate the effect of the intervention using PASW Statistics, version 17.0, and a p-value of < 0.05 was considered significant. Results: four weeks of açaí pulp consumption decreased p-selectin, leptin, and visfatin concentrations in the serum of the participating women. Conclusion: these results show that consumption of açaí pulp was able to modulate important biomarkers of the inflammatory process in apparently healthy women.


Assuntos
Citocinas/sangue , Euterpe , Frutas , Leptina/sangue , Nicotinamida Fosforribosiltransferase/sangue , Selectina-P/sangue , Adiponectina/sangue , Biomarcadores/sangue , Moléculas de Adesão Celular/sangue , Fator D do Complemento/análise , Feminino , Humanos , Interleucinas/sangue , Estudos Prospectivos
12.
Biomed Pharmacother ; 132: 110875, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33254428

RESUMO

OBJECTIVE: The relationships between body fat distribution, the adipokine adipsin and metabolic risks were assessed in patients with adult growth hormone deficiency (AGHD) before and after growth hormone (GH) treatment. METHODS: Sixty newly diagnosed AGHD patients were included in our study, 24 of whom were evaluated after at least one year of GH treatment. Anthropometric parameters, glucolipid metabolism and the adipokine adipsin were measured. Visceral adipose tissue (VAT) and body composition were evaluated using a dual-energy X-ray-absorptiometry (DXA) scanner. RESULTS: At baseline, the higher VAT group had worse glucolipid metabolism parameters. Basal GH was negatively associated with VAT (r=-0.277, p = 0.045), while minimal correlations were found with fat mass depots, such as limbs and trunk fat (all p > 0.05). Adipsin was correlated with total body fat (r = 0.543, p < 0.001), VAT (r = 0.563, p < 0.001) and insulin resistance (r = 0.353, p = 0.006). The effect of GH administration on fat distribution was mainly reflected in the reduction in VAT. Partial improvements were found in lipid profiles, including increased high-density lipoprotein (HDL) and decreases in triglycerides (TGs) and lipoprotein(a), while glucose metabolism showed little change. The adipsin level also decreased significantly. The best predictors of VAT at baseline were trunk fat and IGF-I, and after treatment, VAT was predicted by decreased adipsin and an increase in lean mass. CONCLUSIONS: (1) VAT is an important metabolic risk factor for AGHD patients. (2) GH treatment decreased body fat predominantly in the visceral and central fat depots. (3) The lipid profiles partially improved after treatment, while glucose metabolism showed little change.


Assuntos
Distribuição da Gordura Corporal/tendências , Fator D do Complemento/metabolismo , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/deficiência , Gordura Intra-Abdominal/metabolismo , Adulto , Idoso , Biomarcadores/sangue , Estudos de Coortes , Feminino , Hormônio do Crescimento Humano/administração & dosagem , Humanos , Gordura Intra-Abdominal/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
13.
Sci Rep ; 10(1): 17593, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33067533

RESUMO

Excessive intake of fat causes accumulation of fat in liver, leading to non-alcoholic fatty liver disease (NAFLD). High-fat diet (HFD) upregulates the expression of Factor D, a complement pathway component, in the liver of mice. However, the functions of Factor D in liver are not well known. Therefore, the current study investigated the relationship between Factor D and hepatic lipid accumulation using CRISPR/Cas9-mediated Factor D knockout (FD-KO) mice. Factor D deficiency downregulated expression of genes related to fatty acid uptake and de novo lipogenesis in the liver. Furthermore, Factor D deficiency reduced the expression of inflammatory factors (Tnf and Ccl2) and fibrosis markers and decreased accumulation of F4/80-positive macrophages. These data suggest that the Factor D deficiency improved hepatic lipid accumulation and hepatic inflammation in HFD-fed mice.


Assuntos
Fator D do Complemento/deficiência , Fator D do Complemento/metabolismo , Doenças da Deficiência Hereditária de Complemento/fisiopatologia , Metabolismo dos Lipídeos/fisiologia , Animais , Quimiocina CCL2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Doenças da Deficiência Hereditária de Complemento/metabolismo , Inflamação/metabolismo , Resistência à Insulina/genética , Lipídeos/fisiologia , Lipogênese/fisiologia , Fígado/metabolismo , Fígado/patologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
14.
Physiol Res ; 69(Suppl 2): S339-S349, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-33094632

RESUMO

Peripheral insulin resistance is associated with decreasing adiponectin and increasing leptin plasma levels, and also with cognitive decline. The effects of adipokines on brain function have been published from both animal and human studies. In particular, the influence of leptin and adiponectin on the development of Alzheimer's disease (AD) has been extensively investigated. However, the association between adipsin and AD is as yet unknown. In 37 patients with AD and 65 controls that followed the same study protocol, we tested whether adiponectin, leptin, and adipsin could be used as biomarkers in the early stages of AD. In contrast with conclusions of cognition studies in insulin resistant states, our study found a correlation of impaired neuropsychological performance with increasing adiponectin and decreasing leptin in AD patients. Nevertheless, no significant differences between patients and controls were found. AD women had significantly increased adipsin compared to controls, and there was a positive correlation of adipsin with age and disease duration. Although adipokines do not appear to be suitable biomarkers for early AD diagnosis, they certainly play a role in the pathogenesis of AD. Further studies will be needed to explain the cause of the adipokine "breaking point" that leads to the pathogenesis of overt AD.


Assuntos
Adiponectina/sangue , Doença de Alzheimer/patologia , Biomarcadores/sangue , Fator D do Complemento/análise , Leptina/sangue , Doença de Alzheimer/sangue , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
15.
Haematologica ; Online ahead of print2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-33121236

RESUMO

Paroxysmal nocturnal hemoglobinuria (PNH) is characterised by complement-mediated intravascular hemolysis (IVH) due to absence of complement regulators CD55 and CD59 on affected erythrocytes. Danicopan is a first-in-class oral proximal, complement alternative pathway factor D (FD) inhibitor. Therapeutic FD inhibition was designed to control IVH and prevent C3-mediated extravascular hemolysis (EVH). In this open-label, phase 2, dose-finding trial, 10 untreated hemolytic PNH patients received danicopan monotherapy (100-200 mg thrice daily). Endpoints included change in lactate dehydrogenase (LDH) at day 28 (primary) and day 84 and hemoglobin. Safety, pharmacokinetics/pharmacodynamics, and patient-reported outcomes were measured. Ten patients reached the primary endpoint; two later discontinued: one for a serious adverse event (elevated aspartate aminotransferase/alanine aminotransferase coincident with breakthrough hemolysis, resolving without sequelae) and one for personal reasons unrelated to safety. Eight patients completed treatment. IVH was inhibited, demonstrated by mean decreased LDH (5.7 times upper limit of normal [ULN] at baseline vs 1.8 times ULN [day 28] and 2.2 times ULN [day 84]; both p.


Assuntos
Fator D do Complemento , Hemoglobinúria Paroxística , Anticorpos Monoclonais Humanizados , Complemento C3 , Inativadores do Complemento , Proteínas do Sistema Complemento , Eritrócitos , Hemoglobinúria Paroxística/tratamento farmacológico , Hemólise , Humanos
17.
Artigo em Inglês | MEDLINE | ID: mdl-32982987

RESUMO

Background: Back pain is the leading cause of disability worldwide and is associated with obesity and chronic low-grade inflammation. Alterations in intestinal microbiota may contribute to the pathogenesis of back pain through metabolites affecting immune and inflammatory responses. Aims and Methods: We compared the gut microbiota composition in a cohort of 36 overweight or obese individuals with or without self-reported back pain in the preceding month. Participants were characterized for anthropometry; bone health; metabolic health; inflammation; dietary intake; and physical activity. Results: Demographic, clinical, biochemical characteristics, diet and physical activity were similar between participants with (n = 14) or without (n = 22) back pain. Individuals with back pain had a higher abundance of the genera Adlercreutzia (p = 0.0008; FDR = 0.027), Roseburia (p = 0.0098; FDR = 0.17), and Uncl. Christensenellaceae (p = 0.02; FDR = 0.27) than those without back pain. Adlercreutzia abundance remained higher in individuals with back pain in the past 2 weeks, 6 months, and 1 year. Adlercreutzia was positively correlated with BMI (rho = 0.35, p = 0.03), serum adipsin (rho = 0.33, p = 0.047), and serum leptin (rho = 0.38, p = 0.02). Conclusions: Our findings suggest that back pain is associated with altered gut microbiota composition, possibly through increased inflammation. Further studies delineating the underlying mechanisms may identify strategies for lowering Adlercreutzia abundance to treat back pain.


Assuntos
Dor nas Costas/microbiologia , Microbioma Gastrointestinal/fisiologia , Obesidade/microbiologia , Sobrepeso/microbiologia , Adulto , Dor nas Costas/sangue , Dor nas Costas/complicações , Índice de Massa Corporal , Fator D do Complemento/metabolismo , Estudos Transversais , Feminino , Humanos , Leptina/sangue , Masculino , Obesidade/sangue , Obesidade/complicações , Sobrepeso/sangue , Sobrepeso/complicações
18.
Blood ; 136(18): 2080-2089, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-32877502

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious respiratory virus that can lead to venous/arterial thrombosis, stroke, renal failure, myocardial infarction, thrombocytopenia, and other end-organ damage. Animal models demonstrating end-organ protection in C3-deficient mice and evidence of complement activation in humans have led to the hypothesis that SARS-CoV-2 triggers complement-mediated endothelial damage, but the mechanism is unclear. Here, we demonstrate that the SARS-CoV-2 spike protein (subunit 1 and 2), but not the N protein, directly activates the alternative pathway of complement (APC). Complement-dependent killing using the modified Ham test is blocked by either C5 or factor D inhibition. C3 fragments and C5b-9 are deposited on TF1PIGAnull target cells, and complement factor Bb is increased in the supernatant from spike protein-treated cells. C5 inhibition prevents the accumulation of C5b-9 on cells, but not C3c; however, factor D inhibition prevents both C3c and C5b-9 accumulation. Addition of factor H mitigates the complement attack. In conclusion, SARS-CoV-2 spike proteins convert nonactivator surfaces to activator surfaces by preventing the inactivation of the cell-surface APC convertase. APC activation may explain many of the clinical manifestations (microangiopathy, thrombocytopenia, renal injury, and thrombophilia) of COVID-19 that are also observed in other complement-driven diseases such as atypical hemolytic uremic syndrome and catastrophic antiphospholipid antibody syndrome. C5 inhibition prevents accumulation of C5b-9 in vitro but does not prevent upstream complement activation in response to SARS-CoV-2 spike proteins.


Assuntos
Betacoronavirus , Fator D do Complemento/antagonistas & inibidores , Inativadores do Complemento/farmacologia , Via Alternativa do Complemento/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/farmacologia , Linhagem Celular , Ativação do Complemento/efeitos dos fármacos , Complemento C3/metabolismo , Complemento C5/antagonistas & inibidores , Fator H do Complemento/metabolismo , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Humanos , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/fisiologia
19.
Commun Biol ; 3(1): 483, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879431

RESUMO

The expansion of Enterobacteriaceae, such as E. coli is a main characteristic of gut inflammation and is related to multiple human diseases. However, how to control these E. coli overgrowth is not well understood. Here, we demonstrate that gut complement factor D (CFD) plays an important role in eliminating E. coli. Increased E. coli, which could stimulate inflammatory macrophages to induce colitis, were found in the gut of CFD deficient mice. We also showed that gut Reg4, which is expressed in gut epithelial cells, stimulated complement-mediated attack complexes to eliminate E. coli. Reg4 deficient mice also had increased E. coli. The dominant E. coli were isolated from colitis tissues of mice and found to be sensitive to both CFD- and Reg4-mediated attack complexes. Thus, gut Reg4- and CFD-mediated membrane attack complexes may maintain gut homeostasis by killing inflammatory E. coli.


Assuntos
Fator D do Complemento/metabolismo , Escherichia coli/crescimento & desenvolvimento , Microbioma Gastrointestinal , Trato Gastrointestinal/microbiologia , Animais , Colite/patologia , Colo/patologia , Fator D do Complemento/deficiência , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Proteínas do Sistema Complemento/metabolismo , Sulfato de Dextrana , Feminino , Trato Gastrointestinal/patologia , Inflamação/patologia , Integrases/metabolismo , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Microfilamentos/metabolismo , Proteínas Associadas a Pancreatite/deficiência , Proteínas Associadas a Pancreatite/metabolismo
20.
JCI Insight ; 5(9)2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32376801

RESUMO

Therapeutic complement inhibition is a major focus for novel drug development. Of upstream targets, factor D (FD) is appealing because it circulates in plasma at low concentrations and has a single function: to cleave factor B to generate C3 convertase of the alternative pathway (AP). Mice with a targeted deletion of factor H (FH; Cfh-/- mice) develop C3 glomerulopathy (C3G) due to uncontrolled AP activity. To assess the impact of FD inhibition, we studied Cfh-/- Cfd-/- mice. We show that C3G in Cfh-/- mice is not rescued by removing FD. We used serum from Cfh-/- Cfd-/- mice to demonstrate that residual AP function occurs even when both FD and FH are missing and that hemolytic activity is present due to the action of C3(H2O). We propose that uncontrolled tick-over leads to slow activation of the AP in Cfh-/- Cfd-/- mice and that a minimal threshold of FH is necessary if tissue deposition of C3 is to be prevented. The FD/FH ratio dictates serum C3 level and renal C3b deposition. In C3G patients with chronic renal disease, the FD/FH ratio correlates inversely with C3 and C5 serum levels, suggesting that continuous AP control may be difficult to achieve by targeting FD.


Assuntos
Complemento C3/imunologia , Fator H do Complemento/imunologia , Via Alternativa do Complemento , Doenças da Deficiência Hereditária de Complemento/imunologia , Nefropatias/imunologia , Animais , Complemento C5/imunologia , Fator D do Complemento/imunologia , Humanos , Rim/imunologia , Rim/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
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