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Background: The Thr92Ala-DIO2 polymorphism has been associated with clinical outcomes in hospitalized patients with COVID-19 and neuropsychiatric diseases. This study examines the impact of the Thr92Ala-DIO2 polymorphism on neuropsychological symptoms, particularly depressive symptoms, in patients who have had moderate to severe SARS-CoV-2 infection and were later discharged. Methods: Our prospective cohort study, conducted from June to August 2020, collected data from 273 patients hospitalized with COVID-19. This included thyroid function tests, inflammatory markers, hematologic indices, and genotyping of the Thr92Ala-DIO2 polymorphism. Post-discharge, we followed up with 68 patients over 30 to 45 days, dividing them into depressive (29 patients) and non-depressive (39 patients) groups based on their Beck Depression Inventory scores. Results: We categorized 68 patients into three groups based on their genotypes: Thr/Thr (22 patients), Thr/Ala (41 patients), and Ala/Ala (5 patients). Depressive symptoms were less frequent in the Thr/Ala group (29.3%) compared to the Thr/Thr (59.1%) and Ala/Ala (60%) groups (p = 0.048). The Thr/Ala heterozygous genotype correlated with a lower risk of post-COVID-19 depression, as shown by univariate and multivariate logistic regression analyses. These analyses, adjusted for various factors, indicated a 70% to 81% reduction in risk. Conclusion: Our findings appear to be the first to show that heterozygosity for Thr92Ala-DIO2 in patients with COVID-19 may protect against post-COVID-19 depression symptoms up to 2 months after the illness.
Assuntos
COVID-19 , Depressão , Alta do Paciente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , COVID-19/genética , COVID-19/psicologia , COVID-19/epidemiologia , COVID-19/complicações , Depressão/genética , Depressão/epidemiologia , Genótipo , Iodeto Peroxidase/genética , Iodotironina Desiodinase Tipo II , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , SARS-CoV-2/genéticaRESUMO
Introduction: The type 2 deiodinase and its Thr92Ala-DIO2 polymorphism have been linked to clinical outcomes in acute lung injury and coronavirus disease 2019 (COVID-19). Objective: The objective was to identify a potential association between Thr92Ala-DIO2 polymorphism and body composition (appendicular muscle mass, myosteatosis, and fat distribution) and to determine whether they reflect the severity or mortality associated with the disease. Methods: In this prospective cohort study (June-August 2020), 181 patients hospitalized with moderate-to-severe COVID-19 underwent a non-contrast-enhanced computed tomography (CT) of the thorax to assess body composition, laboratory tests, and genotyping for the Thr92Ala-DIO2 polymorphism. Results: In total, 181 consecutive patients were stratified into three subgroups according to the genotype: Thr/Thr (n = 64), Thr/Ala (n = 96), and Ala/Ala (n = 21). The prevalence of low muscle area (MA) (< 92 cm²) was 52.5%. Low MA was less frequent in Ala/Thr patients (44.8%) than in Thr/Thr (60.9%) or Ala/Ala patients (61.9%) (P = 0.027). Multivariate logistic regression analysis confirmed that the Thr/Ala allele was associated with a reduced risk of low MA (41% to 69%) and myosteatosis (62% to 72%) compared with Thr/Thr + Ala/Ala (overdominant model). Kaplan-Meier curves showed that patients with low muscle mass and homozygosity had lower survival rates than the other groups. Notably, the heterozygotes with MA ≥92 cm² exhibited the best survival rate. Conclusion: Thr92Ala-DIO2 heterozygosity is associated with increased skeletal MA and less myosteatosis in patients with COVID-19. The protective effect of Thr92Ala-DIO2 heterozygosity on COVID-19 mortality is restricted to patients with reduced MA.
Assuntos
COVID-19 , Músculo Esquelético , SARS-CoV-2 , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Composição Corporal/genética , COVID-19/genética , COVID-19/diagnóstico por imagem , Genótipo , Heterozigoto , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Estudos Prospectivos , Tomografia Computadorizada por Raios XRESUMO
p-Cymene (p-C) and rosmarinic acid (RA) are secondary metabolites that are present in medicinal herbs and Mediterranean spices that have promising anti-inflammatory properties. This study aimed to evaluate their intestinal anti-inflammatory activity in the trinitrobenzene sulphonic acid (TNBS)-induced colitis model in rats. p-C and RA (25-200 mg/kg) oral administration reduced the macroscopic lesion score, ulcerative area, intestinal weight/length ratio, and diarrheal index in TNBS-treated animals. Both compounds (200 mg/kg) decreased malondialdehyde (MDA) and myeloperoxidase (MPO), restored glutathione (GSH) levels, and enhanced fluorescence intensity of superoxide dismutase (SOD). They also decreased interleukin (IL)-1ß and tumor necrosis factor (TNF)-α, and maintained IL-10 basal levels. Furthermore, they modulated T cell populations (cluster of differentiation (CD)4+, CD8+, or CD3+CD4+CD25+) analyzed from the spleen, mesenteric lymph nodes, and colon samples, and also decreased cyclooxigenase 2 (COX-2), interferon (IFN)-γ, inducible nitric oxide synthase (iNOS), and nuclear transcription factor kappa B subunit p65 (NFκB-p65) mRNA transcription, but only p-C interfered in the suppressor of cytokine signaling 3 (SOCS3) expression in inflamed colons. An increase in gene expression and positive cells immunostained for mucin type 2 (MUC-2) and zonula occludens 1 (ZO-1) was observed. Altogether, these results indicate intestinal anti-inflammatory activity of p-C and RA involving the cytoprotection of the intestinal barrier, maintaining the mucus layer, and preserving communicating junctions, as well as through modulation of the antioxidant and immunomodulatory systems.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Cinamatos/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Cimenos/uso terapêutico , Depsídeos/uso terapêutico , Mucina-2/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Cinamatos/farmacologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Cimenos/farmacologia , Depsídeos/farmacologia , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Interferon gama/genética , Interferon gama/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucina-2/genética , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Wistar , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteína da Zônula de Oclusão-1/genética , Ácido RosmarínicoRESUMO
Rosmarinic acid (RA) is a secondary metabolite present in several plant species that has already demonstrated antioxidant, antiallergic, anticancer, antimicrobial, neuroprotective, and hepatoprotective effects experimentally. Due to the promising pharmacological properties found previously, this study aimed to assess the oral acute toxicity and the gastroprotective effect of RA using animal models. Acute toxicity was assessed according to OECD guide 423. Ethanol, stress, NSAIDs, and pylorus ligature-induced gastric ulcer models were used to investigate antiulcer properties. The related mechanisms of action were also evaluated from ethanol-induced gastric lesions protocol. RA (300 and 2000 mg/kg) showed no changes in behavioral, water and food intake, body and organs weight parameters with LD50 set around 2500 mg/kg. RA presented gastroprotective activity in all assessed doses (25, 50, 100, and 200 mg/kg) using different animal models. Besides, it was observed that this effect is not related to the modulation of gastric juice parameters (pH, volume, and [H+]), the participation of nitric oxide, mucus, and prostaglandins. However, increased sulfhydryl groups, GSH and IL-10 levels as well as reduced of proinflammatory cytokine (TNF-α and IL-1ß) levels were found for RA-treated groups. RA presents low acute toxicity and gastroprotective activity, preventing ulcer formation via cytoprotective, antioxidant, and anti-inflammatory mechanisms. Graphical abstract.
Assuntos
Antiulcerosos/administração & dosagem , Antioxidantes/administração & dosagem , Cinamatos/administração & dosagem , Depsídeos/administração & dosagem , Fatores Imunológicos/administração & dosagem , Úlcera Gástrica/prevenção & controle , Compostos de Sulfidrila/administração & dosagem , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/imunologia , Mucosa Gástrica/metabolismo , Masculino , Camundongos , Ratos , Ratos Wistar , Úlcera Gástrica/imunologia , Úlcera Gástrica/metabolismo , Ácido RosmarínicoRESUMO
Cancer is one of the most urgent problems in medicine. In recent years, cancer is the second leading cause of death globally. In search for more effective and less toxic treatment against cancer, natural products are used as prototypes in the synthesis of new anticancer drugs. The aim of this study was to investigate the in vivo toxicity and the mechanism of antitumor action of 7-isopentenyloxycoumarin (UMB-07), a coumarin derivative with antitumor activity. The toxicity was evaluated in vitro (hemolysis assay), and in vivo (micronucleus and acute toxicity assays). Ehrlich ascites carcinoma model was used to evaluate in vivo antitumor activity of UMB-07 (12.5, 25, or 50 mg/kg, intraperitoneally, i.p.), after 9 days of treatment, as well as toxicity. UMB-07 (2000 µg/mL) induced only 0.8% of hemolysis in peripheral blood erythrocytes of mice. On acute toxicity assay, LD50 (50% lethal dose) was estimated at around 1000 mg/kg (i.p.), and no micronucleated erythrocytes were recorded after UMB-07 (300 mg/kg, i.p.) treatment. UMB-07 (25 and 50 mg/kg) reduced tumor volume and total viable cancer cells. In the mechanism action investigation, no changes were observed on the cell cycle analysis; however, UMB-07 reduced peritumoral microvessels density and CCL2 chemokine levels. In addition, UMB-07 showed weak toxicity on biochemical, hematological, and histological parameters after 9 days of antitumor treatment. The current findings suggest that UMB-07 has low toxicity and exerts antitumor effect by inhibit angiogenesis via CCL2 chemokine decrease.
Assuntos
Inibidores da Angiogênese/farmacologia , Carcinoma de Ehrlich/tratamento farmacológico , Quimiocina CCL2/metabolismo , Cumarínicos/farmacologia , Neovascularização Patológica , Animais , Carcinoma de Ehrlich/metabolismo , Carcinoma de Ehrlich/patologia , Regulação para Baixo , Feminino , Camundongos , Densidade Microvascular/efeitos dos fármacos , Transdução de Sinais , Microambiente TumoralRESUMO
MHTP [2-methoxy-4-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl) phenol], a synthetic isoquinolinic alkaloid, presented anti-inflammatory activity in several experimental models of acute inflammation as lipopolysaccharide (LPS)-induced acute lung injury and phlogistic agent-induced edema and presented low preclinical toxicity. The aim of this study was to determine the MHTP effect on ovalbumin (OVA)-induced pulmonary allergic inflammation. In other to realize this study, female BALFB/c mice were sensitized and challenged with OVA (OVA group) and treated with MHTP (MHTP group) by nasal instillation. Inflammatory, allergic, and immunomodulatory parameters such as migration of inflammatory cells to the lung tissue, pulmonary histological analysis, serum level of IgE-allergen specific, cytokine secretion, and lung T cell population characterization were analyzed and the data were considered statistically significant with p < 0.05. OVA-sensitized and OVA-challenged and MHTP (5.0 mg/kg)-treated mice presented reduction on total leukocyte migration into the bronchoalveolar lavage (BALF) dependent of lymphocyte and eosinophil migration (p < 0.001 and p < 0.01) as compared with the OVA group. Flow cytometric analysis showed that MHTP treatment decreased the percentage of granulocytes (p < 0.001) into the BALF and lung tissue histological analyzes demonstrated that the MHTP treatment decreased leukocyte migration and mucus production. In addition, treatment with MHTP decreased the number of CD3+CD4+ T cells independently of CD8+ T cell reduction into the BALF. The treatment also reduced significantly (p < 0.05) the serum level of IgE-OVA specific followed by reduction of IL-4, IL-13, and IL-17 production. Surprisingly, the MHTP treatment increased significantly (p < 0.05) the IFN-γ production in the BALF of these animals. Therefore, the results presented here showed that MHTP treatment, by nasal instillation, in a mouse model of OVA-induced pulmonary allergy has anti-allergic and immunomodulatory effects dependent on a Th1-skewed cytokine production that ameliorate the pulmonary allergic inflammation.
Assuntos
Asma/metabolismo , Interferon gama/biossíntese , Tetra-Hidroisoquinolinas/farmacologia , Animais , Asma/tratamento farmacológico , Asma/patologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/efeitos dos fármacos , Feminino , Granulócitos/citologia , Granulócitos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Interferon gama/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Células Th1/imunologiaRESUMO
Asthma is a heterogeneous disease of the airways characterized by chronic inflammation associated with bronchial and smooth muscle hyperresponsiveness. Currently, different murine models for the study of asthma show poor bronchial hyperresponsiveness due to a scarcity of smooth muscle and large airways, resulting in a failure to reproduce smooth muscle hyperreactivity. Thus, we aimed to standardize a guinea pig model of chronic allergic lung inflammation mimicking airway smooth muscle hyperreactivity observed in asthmatics (Asth). Animals were randomly divided into a control group (Ctrl), which received saline (0.9% NaCl), and the Asth group, subjected to in vivo sensitization with ovalbumin (OVA) nebulization. Morphological analysis was performed by hematoxylin-eosin staining. Bronchial hyperresponsiveness was evaluated by nebulization time in the fifth, sixth, and seventh inhalations (NT5-7) and tracheal isometric contractions were assessed by force transducer. Total antioxidant capacity was measured by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method and protein expression by Western blot. Histologically, the Asth group developed peribronchial cellular infiltrate, epithelial hyperplasia and smooth muscle thickening. After the fourth nebulization, the Asth group developed bronchial hyperreactivity. The trachea from the Asth group contracted after in vitro stimulation with OVA, differing from the Ctrl group, which showed no response. Additionally, airway smooth muscle hyperreactivity to carbachol and histamine was observed in the Asth group only in intact epithelium preparations, but not to KCl, and this effect was associated with an augmented production of reactive oxygen species. Moreover, lung inflammation impaired the relaxant potency of isoproterenol only in intact epithelium preparations, without interfering with nifedipine, and it was found to be produced by transforming growth factor-ß negative modulation of ß adrenergic receptors and, furthermore, big-conductance Ca2+-sensitive K+ channels. These effects were also associated with increased levels of phosphatidylinositol 3-kinases but not extracellular signal-regulated kinases 1/2 or phosphorylation, and augmented α-actin content as well, explaining the increased smooth muscle mass. Furthermore, pulmonary antioxidant capacity was impaired in the Asth group. Therefore, we developed a standardized and easy-to-use, reproducible guinea pig model of lung inflammation that mimics airway smooth muscle hypercontractility, facilitating the investigation of the mechanisms of bronchial hyperresponsiveness in asthma and new therapeutic alternatives.
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Milonine is an alkaloid of Cissampelos sympodialis Eichl. (Menispermaceae), a plant used in the northeast of Brazil to treat allergies such as asthma, rhinitis, and other conditions. Previously, several alkaloids were isolated from its roots and leaves with pharmacological properties in asthma and acute inflammation models. Therefore, the aim of this study was to evaluate the milonine effect on mast cells degranulation in vivo and in vitro. Swiss mice (n = 8) were used in models of paw edema induced by carrageenan, compound 48/80, or histamine. One hour before challenge, the animals were treated with milonine (at different doses) or standard drugs and, at different time points, the edema formation was measured. In addition, other different methods, such as anaphylactic shock reaction and scratching behavior models both induced by compound 48/80, a mast cell degranulator, were used to assess milonine effect histamine release in vivo. Moreover, milonine effect on mast cell degranulation in vitro was also carried out. Firstly, it was observed that milonine significantly decreased the carrageenan edema formation only at the beginning of the reaction (i.e., up to 2 h after challenge). Furthermore, this alkaloid decreased the edema induced by compound 48/80, maintained the paw tissue integrity, without modulating histamine-induced paw edema. In anaphylactic shock reaction, milonine increased the time of animal survival when compared with compound 48/80 group. Milonine also significantly decreased the scratching behavior induced by compound 48/80 with decreasing of mast cell degranulation in vitro. Therefore, these data indicated that milonine presents anti-allergic properties by decreasing mast cell degranulation rather than acting on histamine effect.
Assuntos
Antialérgicos/farmacologia , Liberação de Histamina/efeitos dos fármacos , Mastócitos/metabolismo , Morfinanos/farmacologia , Alcaloides/farmacologia , Anafilaxia/tratamento farmacológico , Anafilaxia/prevenção & controle , Animais , Cissampelos/química , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/prevenção & controle , Camundongos , Morfinanos/uso terapêutico , Prurido/tratamento farmacológico , Prurido/prevenção & controleRESUMO
BACKGROUND: Cissampelos sympodialis Eichl. (Menispermaceae) is a plant found in Northeastern and Southeast of Brazil and hot water infusion of C. sympodialis root bark is largely used in the indigenous and folk medicine to treat several inflammatory disorders, including asthma. Asthma is a chronic inflammatory allergic disease characterized by airway hyperreactivity (AHR), eosinophil tissue infiltration and lung remodeling. The aim of this study was to evaluate the therapeutic effect of C. sympodialis and its isolated alkaloid warifteine on allergen triggered airway hyperreactivity (AHR) and lung remodeling in murine model of asthma. METHODOLOGY/PRINCIPAL FINDINGS: The oral pre-treatment with C. sympodialis or warifteine inhibited allergen-induced AHR to inhaled methacholine and IL-13 levels in the bronchoalveolar lavage (BAL). In order to investigate the therapeutic potential of C. sympodialis and warifteine, animals were treated 1h after the last ovalbumin (OVA) challenge in sensitized animals. Similarly to the pre-treatment, post-treatment with warifteine was effective to inhibit significantly AHR to inhaled methacholine and to reduce IL-13 levels in the BAL. In addition, oral pre- or post-treatments with C. sympodialis or warifteine reduced OVA-induced eosinophil tissue infiltration, mucus production and subepithelial fibrosis to values similar to nonallergic controls. CONCLUSIONS: Our data show the anti-allergic and immunoregulatory properties of C. sympodialis, acting mostly through the active compound warifteine, to inhibit the airway hyperreactivity and lung remodeling through a mechanism at least partially dependent of IL-13 and eosinophil inhibition. Therefore placing warifteine as an interesting therapeutic candidate in allergic inflammation and corroborating the folk medicine use of C. sympodialis as anti-allergic plant.