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OBJECTIVE: To evaluate whether colchicine treatment was associated with the inhibition of NLRP3 inflammasome activation in patients with COVID-19. METHODS: We present a post hoc analysis from a double-blinded placebo-controlled randomized clinical trial (RCT) on the effect of colchicine for the treatment of COVID-19. Serum levels of NOD-like receptor protein 3 (NLRP3) inflammasome products-active caspase-1 (Casp1p20), IL-1ß, and IL-18-were assessed at enrollment and after 48-72 h of treatment in patients receiving standard-of-care (SOC) plus placebo vs. those receiving SOC plus colchicine. The colchicine regimen was 0.5 mg tid for 5 days, followed by 0.5 mg bid for another 5 days. RESULTS: Thirty-six patients received SOC plus colchicine, and thirty-six received SOC plus placebo. Colchicine reduced the need for supplemental oxygen and the length of hospitalization. On Days 2-3, colchicine lowered the serum levels of Casp1p20 and IL-18, but not IL-1ß. CONCLUSION: Treatment with colchicine inhibited the activation of the NLRP3 inflammasome, an event triggering the 'cytokine storm' in COVID-19. TRIAL REGISTRATION NUMBERS: RBR-8jyhxh.
Assuntos
COVID-19 , Inflamassomos , Humanos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Interleucina-18 , Proteínas NLR , Colchicina/uso terapêutico , Interleucina-1beta/metabolismoRESUMO
Osteoclasts play a key role in the regulation of bone mass and are highly active metabolically. Here we show that a metabolic reprogramming toward the hexosamine biosynthetic pathway (HBP) is required not only for osteoclast differentiation but also to determine the bone resorption mode during physiological and pathological bone remodeling. We found that pharmacological inhibition of O-GlcNAc transferase (OGT) significantly reduced protein O-GlcNAcylation and osteoclast differentiation. Accordingly, genetic deletion of OGT also inhibited osteoclast formation and downregulated critical markers related to osteoclasts differentiation and function (NFATc1, αvintegrin, cathepsin K). Indeed, cells treated with OSMI-1, an OGT inhibitor, also reduced nuclear translocation of NFATc1. Furthermore, the addition of exogenous N-acetylglucosamine (GlcNAc) strongly increased osteoclast formation and demineralization ability. Strikingly, our data show for the first time that O-GlcNAcylation facilitates an aggressive trench resorption mode in human cells. The incubation of osteoclasts with exogenous GlcNAc increases the percentage of erosion by trench while having no effect on pit resorption mode. Through time-lapse recording, we documented that osteoclasts making trenches moving across the bone surface are sensitive to GlcNAcylation. Finally, osteoclast-specific Ogt-deficient mice show increased bone density and reduced inflammation-induced bone loss during apical periodontitis model. We show that osteoclast-specific Ogt-deficient mice are less susceptible to develop bacterial-induced periapical lesion. Consistent with this, Ogt-deleted mice showed a decreased number of tartrate-resistant acid phosphatase-positive cells lining the apical periodontitis site. In summary, here we describe a hitherto undiscovered role of the HBP/O-GlcNAcylation axis tuning resorption mode and dictating bone resorption outcome.
Assuntos
Reabsorção Óssea , Periodontite Periapical , Camundongos , Humanos , Animais , Hexosaminas/metabolismo , Vias Biossintéticas , Reabsorção Óssea/metabolismo , Osteoclastos/metabolismo , Fatores de Transcrição/metabolismoRESUMO
We aimed to evaluate whether the administration of riboflavin to septic animals reduces inflammation, oxidative stress, organ dysfunction, and mortality. C57BL/6 mice, 6-8 weeks old, were allocated to the study group (polymicrobial sepsis induced by cecal ligation and puncture (CLP) + antibiotic + iv riboflavin), control (CLP + antibiotic + iv saline), or naïve (non-operated controls). Serum concentrations of alanine aminotransferase (ALT), creatine kinase-MB (CK-MB), urea, and creatinine, and markers of inflammation [interleukin (IL)-6, tumor necrosis factor (TNF)-α, keratinocyte-derived chemokine (KC), and macrophage inflammatory protein (MIP)-2)], and oxidative stress (malondialdehyde (MDA) were measured 12 h after the experiment. Animal survival rates were calculated after 7 days. Means between groups were compared using linear regression models adjusted under the Bayesian approach. No significant difference was observed between control and study groups in serum concentrations of IL-6 (95% credible interval) (-0.35 to 0.44), TNF-α (-15.7 to 99.1), KC (-0.13 to 0.05), MIP-2 (-0.84 to 0.06), MDA (-1.25 to 2.53), or ALT (-6.6 to 11.5). Serum concentrations of CK-MB (-145.1 to -30.1), urea (-114.7 to -15.1), and creatinine (-1.14 to -0.01) were higher in the study group. Survival was similar in both groups (P=0.8). Therefore, the use of riboflavin in mice undergoing sepsis induced by CLP did not reduce inflammation, oxidative stress, organ dysfunction, or mortality compared with placebo.
Assuntos
Antioxidantes , Sepse , Animais , Antibacterianos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Teorema de Bayes , Quimiocinas , Creatinina , Inflamação/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Modelos Teóricos , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Riboflavina/uso terapêutico , Sepse/tratamento farmacológico , Sepse/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , UreiaRESUMO
Purpose: To investigate the anti-inflammatory and antioxidant activities of N-salicyloyltryptamine (NST) in experimental models of carrageenan (Cg)-induced peritonitis in mice, and evaluation of the effects of NST on Cg-induced joint disability in rats. Methods: Female Swiss mice were submitted to Cg-induced peritonitis in mice or Cg-induced joint disability in rats after intraperitoneal injection of NST (100 or 200 mg/kg). Total leukocyte count, total protein concentration, myeloperoxidase (MPO) and catalase (CAT) activities, and nitrite (NO2 -) and thiobarbituric acid reactive species (TBARS) levels were determined. Results: NST significantly decrease the migration of leukocytes to peritoneal exudate. Cg induces inflammatory responses mediated by expression of reactive oxygen species (ROS). The results further showed that NST significantly decreased MPO and CAT activities, as well as reduced NO2 - and TBARS levels, compared with the vehicle group. Animals treated with NST significantly reduced paw elevation time (PET) on the first hour after induction of joint injury, and this effect was sustained throughout the analysis. Conclusion: NST presented anti-inflammatory and antioxidant effects in experimental models of carrageenan-induced peritonitis and joint disability in mice and rats, respectively, which may be related to the modulation of neutrophils migration as well as the involvement of antioxidant mechanisms.
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A canine patient, 13-year-old mixed breed male, 24kg, was seen at a private clinic in the city of Guayaquil, Ecuador. The main reason for consultation was the evaluation of a mass in the right knee and neck that had previously been cytologically diagnosed of neoplastic origin by another team of veterinarians through fine needle puncture and cytology. The contacts were asymptomatic. At the time of the consultation, a detailed exploration and complementary methods were performed that included hematological and urinary exams, mass cytology, serological test, chest radiography and biopsy for further histopathological study. The final diagnosis was a cutaneous granuloma due to microfilariae of Acanthocheilonema spp. and its subsequent surgical and medical treatment with excellent results. The canine heartworm is a cosmopolitan disease caused by nematodes of the genus Dirofilaria, with D. immitis being the best-known species. Less frequently, the species Acanthocheilonema spp., found in this patient, is also reported in Americas, with little knowledge about it. This is the first report of its kind hoping that it will serve as a basis for future studies.
Foi atendido, em uma clínica particular, na cidade de Guaiaquil, Equador, um paciente canino, sem raça definida, de 13 anos de idade, macho, não castrado, de 24kg. O motivo da consulta foi a avaliação de uma massa em região de articulação de joelho direito e de pescoço, que havia sido previamente diagnosticada como de origem neoplásica por outra equipe de médicos veterinários, mediante punção por agulha fina e citologia. Os contactantes eram assintomáticos. No momento da consulta, realizaram-se detalhadas avaliações clínica e complementar, que incluíram exames hematológicos, urinálise, citologia da massa, teste sorológico, radiografia torácica e biopsia para posterior estudo histopatológico. O diagnóstico final foi granuloma cutâneo por microfilária de Acanthocheilonema spp., para o qual os tratamentos clínico e cirúrgico apresentaram excelentes resultados. A dirofilariose é uma enfermidade cosmopolita causada por nematódeos do gênero Dirofilaria, sendo a espécie D. immitis a mais conhecida. Em menor frequência, a espécie Acanthocheilonema spp. encontrada neste paciente é também relatada na América, existindo pouco conhecimento a seu respeito. Este é o primeiro relato de caso sobre este tema e espera-se que sirva como base para futuros estudos.
Assuntos
Animais , Cães , Dirofilariose/cirurgia , Dirofilariose/diagnóstico , Dirofilariose/tratamento farmacológico , Doenças do Cão/parasitologia , Acanthocheilonema/isolamento & purificação , Granuloma/etiologia , Equador , MicrofiláriasRESUMO
This study identified the risk factors associated with parasite infestation in tambaqui fingerlings Colossoma macropomum from São Francisco region SE/AL. The fingerlings fish farms were and characterized about water quality, handling, feeding management and sanitary aspects. Parasitological indexes (prevalence, mean intensity and abundance) were obtained from 380 fish and correlated to the aspects of fish farms as well as biotic and abiotic factors to determine the risk factors. The fish rearing in earthen ponds increased the parasite infestations in tambaqui fingerlings, and the mainly parasites founded were monogenean, Myxobolus sp., Ichthyophthirius multifiliis and digenean metacercaria. The main risk factors identified were associated to irregular water supply and consequently low water quality (total ammonia); lack of biometric procedure which promoted an inadequate feeding rate; and absence of disinfection of tools and ponds. Thus, improvements on these specific aspects in fish farms from São Francisco region must be carried out to avoid disease outbreaks, dissemination, mortalities and economic losses.
Este estudo identificou os fatores de risco associados à ocorrência de parasitas em alevinos de tambaqui Colossoma macropomum da região do baixo São Francisco, SE/AL. As pisciculturas foram caracterizadas segundo parâmetros de qualidade da água, manejo, alimentação e dos aspectos sanitários. Os índices parasitológicos (prevalência, intensidade média e abundância) foram obtidos mediante a análise de 380 peixes e correlacionados com as características das pisciculturas, bem como com os fatores bióticos e abióticos, a fim de determinar os fatores de risco. A fase de crescimento dos alevinos realizada em tanques de terra aumentou as infestações de parasitas, e os principais parasitas encontrados foram monogenéticos, Myxobolus sp., Ichthyophthirius multifiliis e metacercária de digenético. Os principais fatores de risco identificados foram: abastecimento irregular de água e consequente baixa qualidade da água (amônia total); falta de procedimento biométrico, que promoveu uma taxa de alimentação inadequada; e ausência de desinfecção dos tanques e das ferramentas. Pelo exposto, melhorias, especificamente nesses aspectos, nas pisciculturas de alevinos da região do São Francisco, devem ser realizadas para evitar surtos e disseminação de doenças, assim como mortalidades e perdas econômicas.
Assuntos
Animais , Doenças Parasitárias em Animais/prevenção & controle , Doenças Parasitárias em Animais/epidemiologia , Caraciformes/parasitologia , Infecções por Mesomycetozoea , Myxobolus , Metacercárias , PesqueirosRESUMO
We aimed to evaluate whether the administration of riboflavin to septic animals reduces inflammation, oxidative stress, organ dysfunction, and mortality. C57BL/6 mice, 6-8 weeks old, were allocated to the study group (polymicrobial sepsis induced by cecal ligation and puncture (CLP) + antibiotic + iv riboflavin), control (CLP + antibiotic + iv saline), or naïve (non-operated controls). Serum concentrations of alanine aminotransferase (ALT), creatine kinase-MB (CK-MB), urea, and creatinine, and markers of inflammation [interleukin (IL)-6, tumor necrosis factor (TNF)-α, keratinocyte-derived chemokine (KC), and macrophage inflammatory protein (MIP)-2)], and oxidative stress (malondialdehyde (MDA) were measured 12 h after the experiment. Animal survival rates were calculated after 7 days. Means between groups were compared using linear regression models adjusted under the Bayesian approach. No significant difference was observed between control and study groups in serum concentrations of IL-6 (95% credible interval) (-0.35 to 0.44), TNF-α (-15.7 to 99.1), KC (-0.13 to 0.05), MIP-2 (-0.84 to 0.06), MDA (-1.25 to 2.53), or ALT (-6.6 to 11.5). Serum concentrations of CK-MB (-145.1 to -30.1), urea (-114.7 to -15.1), and creatinine (-1.14 to -0.01) were higher in the study group. Survival was similar in both groups (P=0.8). Therefore, the use of riboflavin in mice undergoing sepsis induced by CLP did not reduce inflammation, oxidative stress, organ dysfunction, or mortality compared with placebo.
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While Treg cells are responsible for self-tolerance and immune homeostasis, pathogenic autoreactive Th17 cells produce pro-inflammatory cytokines that lead to tissue damage associated with autoimmunity, as observed in multiple sclerosis. Therefore, the immunological balance between Th17 and Treg cells may represent a promising option for immune therapy. Statin drugs are used to treat dyslipidemia; however, besides their effects on preventing cardiovascular diseases, statins also have anti-inflammatory effects. Here, we investigated the role of pitavastatin on experimental autoimmune encephalomyelitis (EAE) and the differentiation of Treg and Th17 cells. EAE was induced by immunizing C57BL/6 mice with MOG35-55. EAE severity was determined by analyzing the clinical score and inflammatory parameters in the spinal cord. Naive CD4 T cells were cultured under Treg and Th17-skewing conditions in vitro in the presence of pitavastatin. We found that pitavastatin decreased EAE development, which was accompanied by a reduction of all parameters investigated. Pitavastatin also reduced the expression of IBA1 and pSTAT3 (Y705 and S727) in the spinal cords of EAE mice. Interestingly, the reduction of Th17 cell frequency in the draining lymph nodes of EAE mice treated with pitavastatin was followed by an increase of Treg cells. Indeed, pitavastatin directly affects T cell differentiation in vitro by decreasing Th17 and increasing Treg cell differentiation. Mechanistically, pitavastatin effects are dependent on mevalonate synthesis. Thus, our data show the potential anti-inflammatory effect of pitavastatin on the pathogenesis of the experimental neuroinflammation by modulating the Th17/Treg axis.