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The pathogenesis of Dengue virus (DENV) infection is complex and involves viral replication that may trigger an inflammatory response leading to severe disease. Here, we investigated the correlation between viremia and cytokine levels in the serum of DENV-infected patients. Between 2013 and 2014, 138 patients with a diagnosis of acute-phase DENV infection and 22 patients with a non-dengue acute febrile illness (AFI) were enrolled. Through a focus-forming assay (FFU), we determined the viremia levels in DENV-infected patients and observed a peak in the first two days after the onset of symptoms. A higher level of viremia was observed in primary versus secondary DENV-infected patients. Furthermore, no correlation was observed between viremia and inflammatory cytokine levels in DENV-infected patients. Receiver operating characteristic (ROC) curve analysis revealed that IL-2 has the potential to act as a marker to distinguish dengue from other febrile illnesses and is positively correlated with Th1 cytokines. IFN-α and IFN-γ appear to be potential markers of primary versus secondary infection in DENV-infected patients, respectively. The results also indicate that viremia levels are not the main driving force behind inflammation in dengue and that cytokines could be used as infection biomarkers and for differentiation between primary versus secondary infection.
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The species Euphorbia umbellata has been used to treat inflammatory diseases, cancer, and ulcers. Biological activities reported in the literature, including antiproliferative, cytotoxic and anti-inflammatory, are attributed to the chemical constituents present in its composition as terpenes and polyphenolic compounds. The most recurrently verified metabolites in the Euphorbiaceae family plant species are terpenes, of which euphol is a major constituent with broadly reported cytotoxic, antinociceptive and anti-inflammatory effects; it frequently appears in various extracts obtained from the plant. Euphol has a documented inhibitory effect on neutrophil chemotaxis and can modulate the complement system. Since complement system activation is intimately intertwined with autoimmune and inflammatory diseases, tumor growth promotion and metastasis, plant metabolites from Euphorbia umbellata might influence the outcomes of inflammatory processes. We believe that this is the first review presenting the current knowledge on Euphorbia umbellata secondary metabolites and their biological activities.
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Antineoplásicos , Euphorbia , Euphorbiaceae , Neoplasias , Humanos , Euphorbia/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Lanosterol/farmacología , AntiinflamatoriosRESUMEN
Arctium lappa L., also known as burdock, is an edible wild plant which has the ability to grow in distinct environments and is considered a weed in several parts of the world. This species has great value in the biological and medical fields with its major secondary components being phenolic compounds and terpenes, substances rich in desired biological activities as antioxidant, antimicrobial, antitumor and anti-inflammatory. In addition, burdock leaves extracts have shown a modulatory effect on the complement system, which plays an important role in the development of inflammatory diseases, with an inhibitory effect on all complement pathways. Thus, natural products with those relevant activities are promising agents for healthcare applications. Therefore, the species A.â lappa may represent an interesting asset for researching and developing new therapies for inflammatory afflictions.
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Arctium , Arctium/química , Extractos Vegetales/química , Antioxidantes/química , Antiinflamatorios/farmacología , Antiinflamatorios/metabolismo , Fitoquímicos/farmacología , Fitoquímicos/metabolismoRESUMEN
As the earliest known vertebrate possessing a complete immune system, teleost fish played an important role in the evolution of this system. The complement system is an ancient defense mechanism present in invertebrates and vertebrates. In teleost fish the complement system is formed by more than 35 circulating proteins, or found at the cell surface. This system is activated by three pathways: alternative, classical and lectin, generating functions such as the opsonization, lysis and modulation of the innate and adaptive immune responses. The complement system is an important immunological indicator that can be used to study and monitor the effects of environmental, nutritional, and infectious processes. The Nile tilapia (Oreochromis niloticus) is a teleost fish of great economic interest due to its characteristics of easy cultivation, high growth rates, and tolerance to adverse environmental conditions. In addition, Nile tilapia is an excellent model for ecotoxicological studies, however, there are very few studies reporting the performance of the complement system in this species after exposure to environmental pollutants. The aim of this review is to gather recent studies with to address the molecular and functional characterizations of the complement system in Nile tilapia and provide new insights about this defense mechanism. Looking to the future, we believe that the complement system analysis in Tilapia can be used as a biomarker of water quality and the general health status of fish.
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Cíclidos , Enfermedades de los Peces , Tilapia , Animales , Proteínas del Sistema Complemento/metabolismo , Proteínas de Peces , Lectinas/metabolismoRESUMEN
ABSTRACT Chagas disease (CD) is a chronic tropical disease caused by Trypanosoma cruzi , affecting about 8 million people in Latin America. The lectin pathway (LP) of the complement system is one of the first lines of host defense in the response against T. cruzi , and can continue to be activated in chronic infection due to the escape of the parasite to its action. Although some components of this pathway have been investigated in CD, there are no reports on its activation in patient serum. In this context, our objective was to evaluate the activation of LP in chronic chagasic patients and controls by the detection of the C4 component, using the direct ELISA assay. For this purpose, serum of 80 patient with chronic CD (clinical forms: asymptomatic n=17; symptomatic n=63; cardiac n=45; cardio digestive n=13; digestive n=5) followed at the Ambulatory of Attention to Chagasic Patients (HC/UFPR) and 80 healthy controls (donors of the Blood Bank of HC) were evaluated regarding the evaluation of the LP. The results showed that LP activation by mannose-binding lectin (MBL) was found reduced while activation by ficolins was increased in patients with CD when compared to controls. The same results were observed when the patients were categorized according to the indeterminate and symptomatic clinical forms. We conclude that the detection of the C4 component by ELISA is an efficient methodology to assess LP activation in serum from patients with chronic CD, enabling to differentiate the activation profile between patients and controls..
RESUMO A doença de Chagas (DC) é uma doença tropical crônica causada pelo Trypanosoma cruzi, atingindo cerca de 8 milhões de pessoas na América Latina. A via das lectinas (VL) do sistema complemento é uma das primeiras linhas de defesa na resposta imunológica contra a infecção pelo T. cruzi, e pode continuar sendo ativada na infecção crônicadevido ao escape do parasito à sua ação. Embora alguns componentes dessa via tenham sido investigados na DC, não existem relatos sobre sua ativação em soro de pacientes. Neste contexto, nosso objetivo foi avaliar a ativação da VL no soro de pacientes com DC crônica e controles pela detecção do componente C4 empregando a técnica de ELISA. Para isso, amostras de soro de 80 pacientes com DC crônica (formas clínicas: indeterminada n=17; sintomática n=63; cardíaca n=45; cardiodigestiva n=13; digestiva n=5) atendidos no Ambulatório de Atenção ao Paciente Chagásico (HC/UFPR) e 80 controles saudáveis (doadores do Banco de Sangue do HC) foram avaliados quanto a ativação da VL. Os resultados demonstraram que a ativação da VL pela lectina ligante de manose (MBL) encontra-se reduzida, enquanto que a ativação pelas ficolinas está aumentada em pacientes com DC quando comparados aos controles. Os mesmos resultados foram observados quando os pacientes foram categorizados quanto às formas clínicas indeterminada e sintomática. Concluímos que a detecção do componente C4 por ELISA é uma metodologia eficiente para avaliar a ativação da VL em soro de pacientes com DC crônica possibilitando diferenciar o perfil de ativação entre pacientes e controles.
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Innate immunity contributes effectively to the development of Alcohol-Associated liver disease (ALD). Particularly, human studies and murine models of ALD have shown that Complement activation plays an important role during the initial and later stages of ALD. The Complement System may contribute to the pathogenesis of this disease since it has been shown that ethanol-derived metabolic products activate the Complement cascade on liver membranes, leading to hepatocellular damage. However, studies evaluating the plasma levels of Complement proteins in ALD patients present contradictory results in some cases, and do not establish a well-marked role for each Complement component. The impairment of leukocyte chemoattractant activity observed in these patients may contribute to the susceptibility to bacterial infections in the latter stages of the disease. On the other hand, murine models of ALD have provided more detailed insights into the mechanisms that link the Complement System to the pathogenesis of the disease. It has been observed that Classical pathway can be activated via C1q binding to apoptotic cells in the liver and contributes to the development of hepatic inflammation. C3 contributes to the accumulation of triglycerides in the liver and in adipose tissue, while C5 seems to be involved with inflammation and liver injury after chronic ethanol consumption. In this review, we present a compendium of studies evaluating the role of Complement in human and murine models of ALD. We also discuss potential therapies to human ALD, highlighting the use of Complement inhibitors.
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Proteínas del Sistema Complemento/inmunología , Proteínas del Sistema Complemento/metabolismo , Susceptibilidad a Enfermedades , Hepatopatías Alcohólicas/etiología , Hepatopatías Alcohólicas/metabolismo , Animales , Biomarcadores , Activación de Complemento/genética , Activación de Complemento/inmunología , Manejo de la Enfermedad , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades/inmunología , Humanos , Inmunomodulación , Hepatopatías Alcohólicas/patología , Hepatopatías Alcohólicas/terapia , Terapia Molecular DirigidaRESUMEN
In the past 20 years, infections caused by coronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2 have posed a threat to public health since they may cause severe acute respiratory syndrome (SARS) in humans. The Complement System is activated during viral infection, being a central protagonist of innate and acquired immunity. Here, we report some interactions between these three coronaviruses and the Complement System, highlighting the central role of C3 with the severity of these infections. Although it can be protective, its role during coronavirus infections seems to be contradictory. For example, during SARS-CoV-2 infection, Complement System can control the viral infection in asymptomatic or mild cases; however, it can also intensify local and systemic damage in some of severe COVID-19 patients, due to its potent proinflammatory effect. In this last condition, the activation of the Complement System also amplifies the cytokine storm and the pathogenicity of coronavirus infection. Experimental treatment with Complement inhibitors has been an enthusiastic field of intense investigation in search of a promising additional therapy in severe COVID-19 patients.
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COVID-19/inmunología , Proteínas del Sistema Complemento/inmunología , SARS-CoV-2/inmunología , Animales , COVID-19/complicaciones , COVID-19/patología , Activación de Complemento/efectos de los fármacos , Complemento C3/inmunología , Inactivadores del Complemento/farmacología , Inactivadores del Complemento/uso terapéutico , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Síndrome de Liberación de Citoquinas/complicaciones , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/patología , Humanos , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Coronavirus del Síndrome Respiratorio de Oriente Medio/inmunología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/inmunología , Síndrome Respiratorio Agudo Grave/complicaciones , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Síndrome Respiratorio Agudo Grave/inmunología , Síndrome Respiratorio Agudo Grave/patología , Tratamiento Farmacológico de COVID-19RESUMEN
Rheumatic fever (RF) and chronic rheumatic heart disease (RHD) are complications of oropharyngeal infection caused by Streptococcus pyogenes. Despite the importance of the complement system against infections and autoimmunity diseases, studies on the role of the lectin pathway in RF and RHD are scarce. Thus, our aim was to evaluate the association of ficolin-3 serum levels, FCN3 polymorphisms and haplotypes with the susceptibility to RF and RHD. We investigated 179 patients with a history of RF (126 RHD and 53 RF only) and 170 healthy blood donors as control group. Ficolin-3 serum concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Three FCN3 single nucleotide polymorphisms (SNPs rs532781899, rs28362807 and rs4494157) were genotyped through the sequence-specific PCR method. Lower ficolin-3 serum levels were observed in RF patients when compared to controls (12.81 µg/mL vs. 18.14 µg/mL respectively, p < 0.0001, OR 1.22 [1.12-1.34]), and in RHD in comparison to RF only (RFo) (12.72 µg/mL vs. 14.29 µg/mL respectively, p = 0.016, OR 1.38 [1.06-1.80]). Low ficolin-3 levels (<10.7 µg/mL) were more common in patients (39.5 %, 30/76) than controls (20.6 %, 13/63, p = 0.018, OR = 2.51 [1.14-5.31]), and in RHD (44.4 %, 28/63) than RFo (15.4 %, 2/13, p = 0.007, OR = 3.08 [1.43-6.79]). On the other hand, FCN3 polymorphism/haplotypes were not associated with ficolin-3 serum levels or the disease. Low ficolin-3 levels might be associated with RF, being a potential marker of disease progression.
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Susceptibilidad a Enfermedades , Lectinas/genética , Fiebre Reumática/etiología , Fiebre Reumática/metabolismo , Cardiopatía Reumática/etiología , Adulto , Alelos , Biomarcadores , Femenino , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Humanos , Lectinas/sangre , Lectinas/metabolismo , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Pronóstico , Fiebre Reumática/diagnóstico , Cardiopatía Reumática/diagnóstico , Cardiopatía Reumática/metabolismoRESUMEN
Leishmania (Viannia) braziliensis is the main agent of mucocutaneous Leishmaniasis, a neglected tropical disease that affects thousands of people in Brazil. It has been shown that complement plays a critical role at early stages of Leishmania infection and that is involved in the invasion of macrophages by the promastigotes. Ficolins and collectins are soluble pattern recognition and triggering molecules of the lectin complement pathway. We investigated here whether lectin pathway activators ficolin-1, ficolin-2, ficolin-3 and CL-11 bind to live L. braziliensis promastigotes in vitro. Promastigote forms in the stationary growth phase were incubated with normal human serum (NHS) or recombinant ficolins 1, 2 and 3, MBL and CL-11, and protein binding was evaluated by confocal microscopy and flow cytometry. Ficolins 1, 2 and 3, MBL and CL-11 were able to bind to the surface of live promastigotes after incubation with either NHS or recombinant proteins. A partial inhibition by N-acetyl-d-glucosamine characterizing the participation of acetylated groups in the deposition of ficolins and CL-11 to glycoconjugates on the surface of L. braziliensis was observed. These evidences highlight a role for the lectin pathway in the innate response to L. braziliensis.
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Colectinas/fisiología , Lectinas/fisiología , Leishmania braziliensis/inmunología , Proteínas del Sistema Complemento/fisiología , Humanos , Inmunidad Innata , FicolinasRESUMEN
Rheumatoid arthritis (RA) is an autoimmune disease, which compromises the synovial membrane resulting in chronic inflammation. Ficolins are key proteins of the lectin pathway of complement able to recognize pathogen-associated molecular patterns, apoptotic cells, and cellular debris mediating the clearance by phagocytes. High ficolin-1 and ficolin-3 levels have been observed in RA patients, however, the influence of polymorphisms in the FCN1 gene in RA is not completely established, while no study evaluated FCN3 gene polymorphisms in RA to date. We investigated the influence of FCN1 and FCN3 gene polymorphisms in the susceptibility and clinical presentation of RA. A total of 148 patients with RA and up to 160 controls from Southern Brazil were genotyped by sequence-specific PCR (PCR-SSP) for five FCN1 promoter polymorphisms (rs2989727, rs10120023, rs17039495, rs10117466, and rs10858293) and three FCN3 gene variants (rs532781899, rs28362807, and rs4494157). The FCN1 g.-542GG (rs10120023) genotype and g.-542G allele, were associated with increased susceptibility to RA (p = .025, OR = 1.69 [1.07-2.69]; p = .041, OR = 1.47 [1.02-2.12], respectively) and related to decreased FCN1 gene expression in whole blood (p < .00001), according to gene expression databases. In addition, the FCN1 AAGAG haplotype was more prevalent in rheumatoid factor seronegative in comparison to seropositive patients (p = .006, OR = 0.042 [0.002-0.80]). There was no association of FCN3 polymorphisms with the susceptibility or clinical characteristics of RA. Our results indicate that the FCN1 rs10120023 [g.-542G>A] polymorphism in the promoter region might contribute to RA susceptibility, probably by impacting FCN1 gene expression.
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Artritis Reumatoide/etiología , Predisposición Genética a la Enfermedad , Lectinas/genética , Polimorfismo de Nucleótido Simple , Alelos , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/metabolismo , Brasil , Proteínas del Sistema Complemento/inmunología , Expresión Génica , Estudios de Asociación Genética , Genotipo , Haplotipos , Humanos , Regiones Promotoras Genéticas , FicolinasRESUMEN
Social and epidemiological aspects of dengue were evaluated in an important metropolitan area in southern Brazil, from August 2012 to September 2014. Demographic, clinical, serological data were collected from patients with acute dengue symptoms treated at public health system units (HSUs). A systematic approach to analyze the spatial and temporal distribution of cases was developed, considering the temporal cross-correlation between dengue and weather, and the spatial correlation between dengue and income over the city's census tracts. From the 878 patients with suggestive symptoms, 249 were diagnosed as positive dengue infection (28%). Considering the most statistically significant census tracts, a negative correlation was found between mean income and dengue (r = -0.65; p = 0.02; 95% CI: -0.03 to -0.91). The occurrence of dengue followed a seasonal distribution, and it was found to be three and four months delayed in relation to precipitation and temperature, respectively. Unexpectedly, the occurrence of symptomatic patients without dengue infection followed the same seasonal distribution, however its spatial distribution did not correlate with income. Through this methodology, we have found evidence that suggests a relation between dengue and poverty, which enriches the debate in the literature and sheds light on an extremely relevant socioeconomic and public health issue.
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Dengue/epidemiología , Adulto , Brasil/epidemiología , Clima , Estudios Epidemiológicos , Femenino , Humanos , Incidencia , Masculino , Pobreza , Salud Pública , Factores Socioeconómicos , Tiempo (Meteorología)RESUMEN
CONTEXT: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of fractures. No study has evaluated the correlation of bone histomorphometry (BH) parameters with glycemic control and presence of chronic complications (CCs) in premenopausal women with T2DM. OBJECTIVES: To evaluate BH and correlate them with the degree of glycemic control and presence of CCs. DESIGN, SETTINGS, AND PATIENTS: This was a cross-sectional study conducted at a tertiary medical center. Twenty-six premenopausal women with T2DM were divided into groups with glycated hemoglobin HbA1c < 7% (good control, GC; n = 10) and HbA1c > 7% (poor control, PC; n = 16), and further subdivided into groups with (n = 9) and without (n = 17) CCs. BH parameters (bone volume [bone volume per total volume, BV/TV], trabecular thickness [Tb.Th], trabecular number [Tb.N], trabecular separation [Tb.Sp], osteoid thickness [O.Th], osteoid surface [osteoid surface per bone surface, OS/BS]), mineralizing surface [MS/BS], bone formation rate [BFR]), mineral apposition rate [MAR]) as well as serum pentosidine (PEN) and insulin-like growth factor (IGF)-1 were measured. The BH data were compared among the groups and with a BH control group (control group, CG, n = 15) matched by age, sex, and race. RESULTS: BV/TV was increased in GC (P < .001) and PC (P = .05) groups and O.th (P = .03) was smaller in the PC group than in the CG. A comparison of the groups with and without CCs with the CG showed in the group with CCs, O.Th was smaller(P = .01) and BV/TV similar to the CG (P = .11). HbA1c correlated negatively with O.Th (P = .02) and OS/BS (P = .01). There was no correlation of BH to PEN and IGF-1. CONCLUSION: BH in premenopausal patients with T2DM is affected by disease control and chronic complications.
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Desarrollo Óseo , Enfermedades Óseas/etiología , Diabetes Mellitus Tipo 2/fisiopatología , Adulto , Arginina/análogos & derivados , Arginina/sangre , Glucemia/análisis , Hueso Esponjoso/fisiopatología , Enfermedad Crónica , Estudios Transversales , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Hemoglobina Glucada/análisis , Humanos , Factor I del Crecimiento Similar a la Insulina/análisis , Lisina/análogos & derivados , Lisina/sangre , MasculinoRESUMEN
Leptospirosis is considered a neglected disease with an estimated more than one million cases every year. Since rodents are at the same time the main reservoir and generally asymptomatic to Leptospira infection, understanding why some animal species are resistant and others are susceptible to this infection would shed some light in how to control this important zoonosis. The innate immune response against Leptospira is mainly dependent on phagocytosis and activation of the Complement System. In this context, cytokines may drive the early control of infection and the adaptive response. Since the Complement System is important to eliminate leptospires in vivo, we investigated if Complement C5 in A/J mice would modulate the cytokine production during infection by Leptospira interrogans serovar Kennewicki type Pomona Fromm (LPF). Thus, our aim was to investigate the systemic levels of pro- and anti-inflammatory cytokines during Leptospira infection in the blood, liver, lung, and kidney on the third and sixth days of infection in A/J C5+/+ and A/J C5-/- mice. Blood levels of TNF-α, IL-6, IFN-γ, and MCP-1 reached a peak on the third day. Although both mouse strains developed splenomegaly, similar histopathological alterations in the liver and the lung, levels of pro- and anti-inflammatory cytokines were different. A/J C5+/+ mice had higher levels of liver IL-10, IL-1ß, IL-12p40, and IL-12p70 and kidney IL-1ß, IL-12p40, and IL-12p70 on the sixth day of infection when compared to A/J C5-/- mice. Our results showed that in A/J genetic background, the Complement component C5 modulates a cytokine profile in the liver and kidney of infected mice, which may play a role in the control of disease progression.
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Citocinas/sangre , Leptospira interrogans , Leptospirosis/sangre , Leptospirosis/microbiología , Animales , Biomarcadores , Biopsia , Citocinas/metabolismo , Modelos Animales de Enfermedad , Interacciones Huésped-Patógeno , Leptospirosis/metabolismo , Leptospirosis/patología , Recuento de Leucocitos , Hígado/metabolismo , Hígado/microbiología , Hígado/patología , Ratones , Especificidad de Órganos , Factores de TiempoRESUMEN
The complement system participates in host defense by eliminating microorganisms and triggering inflammation. However, insufficient control or exacerbated complement activation contributes to inflammatory diseases. Since promising antioxidant and anti-inflammatory activities have been identified in Arctium lappa L. extracts, this study aims to explore the effect of A. lappa extracts on the lectin pathway (LP) of complement activation. Four extracts were obtained by supercritical extraction using scCO2 with or without ethanol as co-solvent, at different temperatures and pressures (E1: 2.2â mg/mL, E2: 2.6â mg/mL and E3: 2.0â mg/mL, E4: 1.5â mg/mL). To evaluate the effect of A. lappa extracts on the LP activation, an ELISA assay using mannose binding lectin pathway of complement was carried out with C4 detection. All extracts showed a concentration-dependent inhibitory effect on the activation of complement by the LP. The following IC50 were observed for E1, E2, E3 and E4: 179.4â µg/mL, 74.69â µg/mL, 119.1â µg/mL and 72.19â µg/mL, respectively. Our results suggest that A. lappa extracts are potential candidates for the treatment of inflammatory disorders that are complement-related.
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Arctium/química , Cromatografía con Fluido Supercrítico/métodos , Proteínas del Sistema Complemento/metabolismo , Lectinas/metabolismo , Extractos Vegetales/química , Arctium/metabolismo , Dióxido de Carbono/química , Proteínas del Sistema Complemento/agonistas , Lectinas/antagonistas & inhibidores , Hojas de la Planta/química , Hojas de la Planta/metabolismo , TemperaturaRESUMEN
Carlos Chagas discovered American trypanosomiasis, also named Chagas disease (CD) in his honor, just over a century ago. He described the clinical aspects of the disease, characterized by its etiological agent (Trypanosoma cruzi) and identified its insect vector. Initially, CD occurred only in Latin America and was considered a silent and poorly visible disease. More recently, CD became a neglected worldwide disease with a high morbimortality rate and substantial social impact, emerging as a significant public health threat. In this context, it is crucial to better understand better the epidemiological scenarios of CD and its transmission dynamics, involving people infected and at risk of infection, diversity of the parasite, vector species, and T. cruzi reservoirs. Although efforts have been made by endemic and non-endemic countries to control, treat, and interrupt disease transmission, the cure or complete eradication of CD are still topics of great concern and require global attention. Considering the current scenario of CD, also affecting non-endemic places such as Canada, USA, Europe, Australia, and Japan, in this review we aim to describe the spread of CD cases worldwide since its discovery until it has become a global public health concern.
RESUMEN
Chagas disease (CD), a neglected tropical disease caused by the protozoan Trypanosoma cruzi, affects around six million individuals in Latin America. Currently, CD occurs worldwide, becoming a significant public health concern due to its silent aspect and high morbimortality rate. T. cruzi presents different escape strategies which allow its evasion from the host immune system, enabling its persistence and the establishment of chronic infection which leads to the development of chronic Chagas cardiomyopathy (CCC). The potent immune stimuli generated by T. cruzi persistence may result in tissue damage and inflammatory response. In addition, molecular mimicry between parasites molecules and host proteins may result in cross-reaction with self-molecules and consequently in autoimmune features including autoantibodies and autoreactive cells. Although controversial, there is evidence demonstrating a role for autoimmunity in the clinical progression of CCC. Nevertheless, the exact mechanism underlying the generation of an autoimmune response in human CD progression is unknown. In this review, we summarize the recent findings and hypotheses related to the autoimmune mechanisms involved in the development and progression of CCC.
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Autoinmunidad , Enfermedad de Chagas/inmunología , Interacciones Huésped-Patógeno/inmunología , Animales , Autoanticuerpos/inmunología , Cardiomiopatía Chagásica/etiología , Enfermedad de Chagas/complicaciones , Enfermedad de Chagas/metabolismo , Enfermedad de Chagas/parasitología , Proteínas del Sistema Complemento/inmunología , Proteínas del Sistema Complemento/metabolismo , Reacciones Cruzadas , Humanos , Proteínas Protozoarias/inmunología , Transducción de Señal , Trypanosoma cruzi/inmunologíaRESUMEN
BACKGROUND: Acute myocardial infarction (AMI) is a potentially fatal condition, being a major cause of death worldwide. Ischemia suffered during AMI causes tissue damage, leading to an inflammatory process. Moreover, myocardial injury can generate damage-associated molecular patterns that activate pattern recognition molecules including some complement proteins. METHODS: Here we investigated products of complement activation, C3d and soluble C5b9 (sC5b9), as potential biomarkers for myocardial injury and inflammation, as well as serum cytokines (IL-6 and TNF-alpha), alpha-1-acid glycoprotein (AGP), and classical markers of myocardial necrosis (creatine kinase, creatine kinase-MB isoform, myoglobin and troponin-I) in a longitudinal study of patients with AMI (from admission, 6â¯h and 12â¯h post admission, and at discharge from hospital). Individuals undergoing cardiac catheterization (CC) with normal coronary arteries and asymptomatics with no history of cardiovascular disease or invasive procedures were included as controls. RESULTS: Plasma C3d was higher in AMI at admission, 6â¯h, 12â¯h, and discharge vs CC (pâ¯<â¯0.0001; pâ¯=â¯0.0061; pâ¯=â¯0.0081; pâ¯=â¯0.044) and asymptomatic (pâ¯=â¯0.0001 for admission, 6â¯h and 12â¯h; pâ¯=â¯0.0002 for discharge). Moreover, sC5b9 was higher only at admission and 6â¯h vs asymptomatic (pâ¯=â¯0.0031 and pâ¯=â¯0.0019). Additionally, AGP levels were elevated at admission, 6â¯h, 12â¯h, and discharge vs asymptomatic (pâ¯=â¯0.0003; pâ¯=â¯0.0289; pâ¯=â¯0.0009, pâ¯=â¯0.0017). IL-6 concentration was low at admission and 6â¯h and reached a peak at 12â¯h (pâ¯<â¯0.0001 for all groups). All classical markers of myocardial necrosis presented higher concentration at 6â¯h. CONCLUSIONS: Our results showed that complement activation is an early event in AMI occurring before the elevation of classical markers of myocardial necrosis such as creatine kinase, creatine kinase-MB isoform, myoglobin and troponin-I. These findings indicated C3d and sC5b9 as possible biomarkers for inflammation and tissue damage in AMI.
Asunto(s)
Activación de Complemento/inmunología , Proteínas del Sistema Complemento/inmunología , Proteínas del Sistema Complemento/metabolismo , Infarto del Miocardio/etiología , Infarto del Miocardio/metabolismo , Adulto , Anciano , Biomarcadores , Estudios de Casos y Controles , Complemento C3d/inmunología , Complemento C3d/metabolismo , Complejo de Ataque a Membrana del Sistema Complemento/inmunología , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo , Femenino , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Modelos Biológicos , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/terapia , Factores de Tiempo , Troponina I/sangreRESUMEN
Leptospirosis is considered one of the most important zoonosis worldwide. The activation of the Complement System is important to control dissemination of several pathogens in the host. Only a few studies have employed murine models to investigate leptospiral infection and our aim in this work was to investigate the role of murine C5 during in vivo infection, comparing wild type C57BL/6 (B6 C5+/+) and congenic C57BL/6 (B6 C5-/-, C5 deficient) mice during the first days of infection. All animals from both groups survived for at least 8 days post-infection with pathogenic Leptospira interrogans serovar Kennewicki strain Fromm (LPF). At the third day of infection, we observed greater numbers of LPF in the liver of B6 C5-/- mice when compared to B6 C5+/+ mice. Later, on the sixth day of infection, the LPF population fell to undetectable levels in the livers of both groups of mice. On the third day, the inflammatory score was higher in the liver of B6 C5+/+ mice than in B6 C5-/- mice, and returned to normal on the sixth day of infection in both groups. No significant histopathological differences were observed in the lung, kidney and spleen from both infected B6 C5+/+ than B6 C5-/- mice. Likewise, the total number of circulating leukocytes was not affected by the absence of C5. The liver levels of IL-10 on the sixth day of infection was lower in the absence of C5 when compared to wild type mice. No significant differences were observed in the levels of several inflammatory cytokines when B6 C5+/+ and B6 C5-/- were compared. In conclusion, C5 may contribute to the direct killing of LPF in the first days of infection in C57BL/6 mice. On the other hand, other effector immune mechanisms probably compensate Complement impairment since the mice survival was not affected by the absence of C5 and its activated fragments, at least in the early stage of this infection.
Asunto(s)
Complemento C5/inmunología , Complemento C5/fisiología , Leptospira interrogans/inmunología , Leptospira interrogans/patogenicidad , Leptospirosis/inmunología , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Inflamación/inmunología , Interleucina-10 , Riñón/inmunología , Riñón/patología , Leptospirosis/sangre , Leptospirosis/patología , Leucocitos , Hígado/inmunología , Hígado/patología , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Bazo/inmunología , Bazo/patología , Análisis de SupervivenciaRESUMEN
Trypanosoma cruzi is a protozoan parasite known to cause Chagas disease (CD), a neglected sickness that affects around 6-8 million people worldwide. Originally, CD was mainly found in Latin America but more recently, it has been spread to countries in North America, Asia, and Europe due the international migration from endemic areas. Thus, at present CD represents an important concern of global public health. Most of individuals that are infected by T. cruzi may remain in asymptomatic form all lifelong, but up to 40% of them will develop cardiomyopathy, digestive mega syndromes, or both. The interaction between the T. cruzi infective forms and host-related immune factors represents a key point for a better understanding of the physiopathology of CD. In this context, the complement, as one of the first line of host defense against infection was shown to play an important role in recognizing T. cruzi metacyclic trypomastigotes and in controlling parasite invasion. The complement consists of at least 35 or more plasma proteins and cell surface receptors/regulators, which can be activated by three pathways: classical (CP), lectin (LP), and alternative (AP). The CP and LP are mainly initiated by immune complexes or pathogen-associated molecular patterns (PAMPs), respectively, whereas AP is spontaneously activated by hydrolysis of C3. Once activated, several relevant complement functions are generated which include opsonization and phagocytosis of particles or microorganisms and cell lysis. An important step during T. cruzi infection is when intracellular trypomastigotes are release to bloodstream where they may be target by complement. Nevertheless, the parasite uses a sequence of events in order to escape from complement-mediated lysis. In fact, several T. cruzi molecules are known to interfere in the initiation of all three pathways and in the assembly of C3 convertase, a key step in the activation of complement. Moreover, T. cruzi promotes secretion of plasma membrane-derived vesicles from host cells, which prevent the activity of C3 convertase C4b2a and thereby may hinder complement. In this review, we aim to present an overview on the strategies used by T. cruzi in order to circumvent the activation of complement and, consequently, its biological effects.
RESUMEN
BACKGROUND: We report the isolation and characterization of dengue virus (DENV) serotype 4 from a resident of Santa Fé, state of Paraná, South Brazil, in March 2013. This patient presented with hemorrhagic manifestations, high viral load and, interestingly, a mixed Th1/Th17 cytokine profile. CASE PRESENTATION: The patient presented with classical dengue symptoms, such as fever, rash, myalgia, arthralgia, and hemorrhagic manifestations including petechiae, gum bleeding and a positive tourniquet test result. A serum sample obtained 1 day after the initial appearance of clinical symptoms was positive for NS1 viral antigen, but this sample was negative for both IgM and IgG against DENV. Dengue virus infection was confirmed by isolation of the virus from C6/36 cells, and dengue virus serotyping was performed via one-step RT-PCR. The infection was confirmed to be caused by a serotype 4 dengue virus. Additionally, based on multiple alignment and phylogeny analyses of its complete genome sequence, the viral strain was classified as genotype II (termed LRV13/422). Moreover, a mixed Th1/Th17 cytokine profile was detected in the patient's serum, and this result demonstrated significant inflammation. Biological characterization of the virus via in vitro assays comparing LRV13/422 with a laboratory-adapted reference strain of dengue virus serotype 4 (TVP/360) showed that LRV13/422 infects both vertebrate and invertebrate cell lines more efficiently than TVP/360. However, LRV13/422 was unable to inhibit type I interferon responses, as suggested by the results obtained for other dengue virus strains. Furthermore, LRV13/422 is the first completely sequenced serotype 4 dengue virus isolated in South Brazil. CONCLUSION: The high viral load and mixed Th1/Th17 cytokine profile observed in the patient's serum could have implications for the development of the hemorrhagic signs observed, and these potential relationships can now be further studied using suitable animal models and/or in vitro systems.