RESUMO
Malva parviflora has shown anti-inflammatory, antihypertensive, antihyperlipidemic, and hypoglycemic effects. This study is aimed to evaluate the anti-adipogenic effect of M. parviflora on 3T3-L1 adipocytes. Fibroblast differentiation was induced either in the absence or presence of M. parviflora fractions (F3, F4, F7, F12, F13, F17, F18 and F19) for 4 days; F17 and 18 were the most effective fractions in reducing intracellular lipid accumulation (by 25.6% and 23.1%, respectively). EC50 of F17 and F18 (14 µg/mL and 17 µg/mL, respectively) were used to evaluate their anti adipogenic effect. After 10 days of inducing differentiation in the absence or presence of the extracts at the EC50 of F17 and F18, lipid accumulation, the concentration of interleukin 6 (IL-6) were measured in the culture medium; the presence of PPAR-γ, AKT, and p-AKT was also determined. In differentiated adipocytes (C2), F17 maintained intracellular lipid concentration at levels comparable to metformin, while decreasing PPAR-γ and increasing p-AKT presence; it also prevented IL-6 expression. F17 consists of alanine, valine, phenylalanine, and proline. On the other hand, F18 reduced intracellular lipid concentrations, prevented the increase of PPAR-γ and p-AKT, and maintained IL-6 expression at similar levels as metformin. F18 is mainly constituted by alanine, valine, proline, and sucrose. In conclusion, M. parviflora fractions (F17 and F18) control the process of adipogenesis, lipogenesis, and cellular dysfunction.
Assuntos
Células 3T3-L1 , Adipócitos , Adipogenia , PPAR gama , Extratos Vegetais , Animais , Camundongos , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipócitos/citologia , Adipogenia/efeitos dos fármacos , Extratos Vegetais/farmacologia , PPAR gama/metabolismo , Interleucina-6/metabolismo , Diferenciação Celular/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Fatty liver is a multifactorial disease characterized by excessive accumulation of lipids in hepatocytes (steatosis), insulin resistance, oxidative stress, and inflammation. This disease has a major public health impact because it is the first stage of a chronic and degenerative process in the liver that can lead to steatohepatitis, cirrhosis, and liver cancer. Although this disease is mainly diagnosed in patients with obesity, type 2 diabetes mellitus, and dyslipidemia, recent evidence indicates that vasoactive hormones such as angiotensin II (ANGII) not only promote endothelial dysfunction (ED) and hypertension, but also cause fatty liver, increase adipose tissue, and develop a pro-steatotic environment characterized by a low-grade systemic pro-inflammatory and pro-oxidant state, with elevated blood lipid levels. The role of ANGII in lipid accumulation has been little studied, so this review aims to summarize existing reports on the possible mechanism of action of ANGII in inducing lipid accumulation in hepatocytes.
Assuntos
Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Humanos , Angiotensina II , Diabetes Mellitus Tipo 2/complicações , Lipídeos , Fígado , Hepatopatia Gordurosa não Alcoólica/etiologiaRESUMO
Steatosis is characterized by fat accumulation and insulin resistance (IR) in hepatocytes, which triggers a pro-oxidant, pro-inflammatory environment that may eventually lead to cirrhosis or liver carcinoma. This work was aimed to assess the effect of Sechium edule root hydroalcoholic extract (rSe-HA) (rich in cinnamic and coumaric acid, among other phenolic compounds) on triglyceride esterification, lipid degradation, AMPK expression, and the phosphorylation of insulin receptor in a Ser312 residue, as well as on the redox status, malondialdehyde (MDA) production, and the production of proinflammatory cytokines in an in vitro model of steatosis induced by oleic acid, to help develop a phytomedicine that could reverse this pathology. rSe-HA reduced triglyceride levels in hepatocyte lysates, increased lipolysis by activating AMPK at Thr172, and improved the redox status, as evidenced by the concentration of glycerol and formazan, respectively. It also prevented insulin resistance (IR), as measured by glucose consumption and the phosphorylation of the insulin receptor at Ser312. It also prevented TNFα and IL6 production and decreased the levels of MDA and nitric oxide (ON). Our results indicate that rSe-HA reversed steatosis and controlled the proinflammatory and prooxidant environment in oleic acid-induced dysfunctional HepG2 hepatocytes, supporting its potential use to control this disorder.
RESUMO
The extract, fractions, and compounds of the Bouvardia ternifolia root were evaluated as an antiarthritic using a complete Freund's adjuvant (CFA) model in mice and NF-κB inhibition in RAW 264.7 macrophages. Four active compounds, including two new compounds, ternifoliol and ternifolial, were isolated by open column chromatography and identified by spectroscopic and spectrometric techniques, resulting in benzochromone-like structures with aromatic rings and hydroxyl groups, which could be responsible for the anti-inflammatory activity and inhibitory NF-κB. Changes in the joint cytokine profile monitored the antiarthritic effect. A decrement was observed in the local concentration of the following cytokines with different treatments: IL-17 by 64% and 70.3% with the aqueous extract (BtAq), ethyl acetate extract (BtAcOEt), and M3 fraction; interleukin-1 beta (IL-1ß) by 10.2% and 15.7% with BtAq and the M4 fraction, respectively; IL-6 with M1, M2, M3, and M4 between 42% and 64%; necrosis factor-alpha (TNF-α) by 60.9% with M4. Conversely, the anti-inflammatory cytokine interleukin-10 (IL-10) increased between 94% and 99% with M1, M2, M3, and M4. Kidney IL-6 decreased with BtAq, M1, M2, M3, and M4 between 68.9% and 85.8%. TNF-α decreased with BtAcOEt, BtAq, M1, M2, and M4 between 34% and 80.2%. The NF-κB pathway was inhibited with BtAcOEt (90.1%), M1 (85%), M2 (93.5%), M3 (84.5%), M4 (90.3%), ternifoliol (75.6%), bouvardin (20.4%), and scopoletin (89%). We conclude that B. ternifolia modulated the inflammatory response at the joint and kidney levels and the NF-κB pathway.
RESUMO
Endothelial dysfunction (ED) is a key factor for the development of cardiovascular diseases. Due to its chronic, life-threatening nature, ED only can be studied experimentally in animal models. Therefore, this work was aimed to characterize a murine model of ED induced by a daily intraperitoneal administration of angiotensin II (AGII) for 10 weeks. Oxidative stress, inflammation, vascular remodeling, hypertension, and damage to various target organs were evaluated in treated animals. The results indicated that a chronic intraperitoneal administration of AGII increases the production of systemic soluble VCAM, ROS and ICAM-1 expression, and the production of TNFα, IL1ß, IL17A, IL4, TGFß, and IL10 in the kidney, as well as blood pressure levels; it also promotes vascular remodeling and induces non-alcoholic fatty liver disease, glomerulosclerosis, and proliferative retinopathy. Therefore, the model herein proposed can be a representative model for ED; additionally, it is easy to implement, safe, rapid, and inexpensive.
Assuntos
Angiotensina II/administração & dosagem , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Doenças Vasculares/metabolismo , Angiotensina II/toxicidade , Animais , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Infusões Parenterais , Molécula 1 de Adesão Intercelular/metabolismo , Interleucinas/metabolismo , Rim/metabolismo , Rim/patologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Doenças Vasculares/etiologia , Doenças Vasculares/patologia , Remodelação VascularRESUMO
Rheumatoid arthritis (RA) is an autoimmune disease that causes physical disability in people worldwide. Despite progress made in RA treatment in the past decade, new drugs with high efficacy but few long-term adverse effects are still needed. This study focused on evaluating the therapeutic potential of α-mangostin on established collagen-induced arthritis (CIA) in DBA/1J mice. Arthritic DBA/1J mice were orally administered with two doses of α-mangostin (10 and 40â¯mg/kg) daily, for 33 days. Alpha-mangostin significantly decreased the clinical score in the short term at both doses and decreased the histopathological score at the higher dose. This improvement was accompanied by a reduction on serum levels of anti-collagen IgG2a autoantibodies and of the production of LIX/CXCL5, IP-10/CXCL10, MIG/CXCL9, RANTES/CCL5, IL-6 and IL-33 in the joints of CIA mice. Alpha-mangostin also exhibited an anti-oxidant effect decreasing the NADPH oxidase activity and lipid peroxidation and preserving the levels of reduced glutathione in the arthritic joints. In vitro this xanthone demonstrated modulatory properties on LPS-activated dendritic cells, although in Th1 and Th17-polarized lymphocytes promotes a pro-apoptotic phenotype. Altogether this study illustrates the capacity of α-mangostin to ameliorate the early clinical and histological signs of established CIA by reducing the inflammatory and oxidative responses.
Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Xantonas/uso terapêutico , Animais , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/isolamento & purificação , Apoptose/efeitos dos fármacos , Artrite Experimental/induzido quimicamente , Artrite Reumatoide/induzido quimicamente , Colágeno/imunologia , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Garcinia mangostana/química , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Inflamação/tratamento farmacológico , Articulação do Joelho/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Estresse Oxidativo/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Xantonas/isolamento & purificaçãoRESUMO
Neonates have an increased susceptibility to infections, particularly those caused by intracellular pathogens, leading to high morbidity and mortality rates. This is partly because of a poor response of neonatal CD4+ T cells, leading to deficient antibody production and a low production of IFN-γ, resulting in deficient elimination of intracellular pathogens. The poor memory response of human neonates has underpinned the need for improving vaccine formulations. Molecular adjuvants that improve the response of neonatal lymphocytes, such as the ligands of toll-like receptors (TLRs), are attractive candidates. Among them, flagellin, the TLR5 ligand, is effective at very low doses; prior immunity to flagellin does not impair its adjuvant activity. Human CD4+ and CD8+ T cells express TLR5. We found that flagellin induces the expression of IFN-γ, IL-1ß and IL-12 in mononuclear cells from human neonate and adult donors. When human naïve CD4+ T cells were activated in the presence of flagellin, there was high level of expression of IFN-γ in both neonates and adults. Furthermore, flagellin induced IFN-γ production in Th1 cells obtained from adult donors; in the Th2 population, it inhibited IL-4 cytokine production. Flagellin also promoted expression of the IFN-γ receptor in naive CD4+ T cells from neonates and adults. To test the adjuvant capacity of flagellin in vivo, we used a murine neonate vaccination model for infection with rotavirus, a pathogen responsible for severe diarrhea in young infants. Using the conserved VP6 antigen, we observed an 80% protection against rotavirus infection in the presence of flagellin, but only in those mice previously primed in the neonatal period. Our data suggest that flagellin could be an attractive adjuvant for achieving a Th1 response.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Flagelina/administração & dosagem , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus/administração & dosagem , Vacinas contra Rotavirus/imunologia , Rotavirus/imunologia , Células Th1/imunologia , Adulto , Animais , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Recém-Nascido , Camundongos Endogâmicos BALB CRESUMO
Inflammation and oxidative stress play major roles in endothelial dysfunction, and are key factors in the progression of cardiovascular diseases. The aim of this study was to evaluate in vitro the effect of three subfractions (SFs) from the Cucumis sativus aqueous fraction to reduce inflammatory factors and oxidative stress induced by angiotensin II (Ang II) in human microvascular endothelial cells-1 (HMEC-1) cells. The cells were cultured with different concentrations of Ang II and 0.08 or 10 µg/mL of SF1, SF2, or SF3, or 10 µmol of losartan as a control. IL-6 (Interleukin 6) concentration was quantified. To identify the most effective SF combinations, HMEC-1 cells were cultured as described above in the presence of four combinations of SF1 and SF3. Then, the effects of the most effective combination on the expression of adhesion molecules, the production of reactive oxygen species (ROS), and the bioavailability of nitric oxide (NO) were evaluated. Finally, a mass spectrometry analysis was performed. Both SF1 and SF3 subfractions decreased the induction of IL-6 by Ang II, and C4 (SF1 and SF3, 10 µg/mL each) was the most effective combination to inhibit the production of IL-6. Additionally, C4 prevented the expression of adhesion molecules, reduced the production of ROS, and increased the bioavailability of NO. Glycine, arginine, asparagine, lysine, and aspartic acid were the main components of both subfractions. These results demonstrate that C4 has anti-inflammatory and antioxidant effects.
Assuntos
Aminoácidos/farmacologia , Angiotensina II/toxicidade , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Cucumis sativus , Células Endoteliais/efeitos dos fármacos , Inflamação/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Aminoácidos/isolamento & purificação , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/isolamento & purificação , Moléculas de Adesão Celular/metabolismo , Linhagem Celular , Cucumis sativus/química , Relação Dose-Resposta a Droga , Células Endoteliais/metabolismo , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-6/metabolismo , Óxido Nítrico/metabolismo , Fitoterapia , Extratos Vegetais/isolamento & purificação , Plantas Medicinais , Espécies Reativas de Oxigênio/metabolismoRESUMO
Sechium edule is traditionally used in Mexico as a therapeutic resource against renal diseases and to control high blood pressure. The purpose of this work is to evaluate the antihypertensive effect of the hydroalcoholic extract obtained from the roots of this plant, including its fractions and subfractions, on different hypertension models induced with angiotensin II (AG II). The hydroalcoholic extract was tested on an in vitro study of isolated aorta rings denuded of endothelial cells, using AG II as the agonist; this assay proved the vasorelaxant effect of this extract. Vagotomized rats were administered different doses of AG II as well as the Hydroalcoholic extract, which reduced blood pressure in 30 mmHg approximately; subsequently this extract was separated into two fractions (acetone and methanol) which were evaluated in the acute hypertension mouse model induced with AG II, where the acetone fraction was identified as the most effective one and was subsequently subfractioned using an open chromatographic column packed with silica gel. The subfractions were also evaluated in the acute hypertension model. Finally, the extract, fraction, and active subfraction were analyzed by MS-PDA-HPLC, identifying cinnamic derivative compounds like cinnamic acid methyl ester.
RESUMO
BACKGROUND: The activation and effector phenotype of T cells depend on the strength of the interaction of the TcR with its cognate antigen and additional signals provided by cytokines and by co-receptors. Lymphocytes sense both the presence of an antigen and also clues from antigen-presenting cells, which dictate the requisite response. CD43 is one of the most abundant molecules on the surface of T cells; it mediates its own signalling events and cooperates with those mediated by the T cell receptor in T cell priming. We have examined the role of CD43 signals on the effector phenotype of adult CD4+ and CD8+ human T cells, both alone and in the presence of signals from the TcR. RESULTS: CD43 signals direct the expression of IFNgamma in human T cells. In freshly isolated CD4+ T cells, CD43 signals potentiated expression of the IFNgamma gene induced by TcR activation; this was not seen in CD8+ T cells. In effector cells, CD43 signals alone induced the expression of the IFNgamma gene in CD4+ T cells and to a lesser extent in CD8+ cells. The combined signals from CD43 and the TcR increased the transcription of the T-bet gene in CD4+ T cells and inhibited the transcription of the GATA-3 gene in both populations of T cells, thus predisposing CD4+ T cells to commitment to the T1 lineage. In support of this, CD43 signals induced a transient membrane expression of the high-affinity chains of the receptors for IL-12 and IFNgamma in CD4+ T cells. CD43 and TcR signals also cooperated with those of IL-12 in the induction of IFNgamma expression. Moreover, CD43 signals induced the co-clustering of IFNgammaR and the TcR and cooperated with TcR and IL-12 signals, triggering a co-capping of both receptors in CD4+ populations, a phenomenon that has been associated with a T1 commitment. CONCLUSION: Our results suggest a key role for CD43 signals in the differentiation of human CD4+ T cells into a T1 pattern.