RESUMO
The inflammatory response is a common feature of many pathological conditions, and there is urgent necessity for new substances that minimize the harmful effects of inflammation. Chromenes represent a class of compounds with multiple pharmacological actions that have already been described and may be potential candidates for studies of therapeutic action. This study aimed to test novel 4-aryl-4H-chromene-derived molecules in an in vitro model of inflammation using lipopolysaccharide (LPS)-induced Raw 264.7 cells. Seven compounds derived from 4-aryl-4H-chromene were tested on Raw 264.7 cells to evaluate their cytotoxic effects. Next, the effect of the selected compounds on the pro-inflammatory mediators (tumor necrosis factor-alpha [TNF-α], monocyte chemoattractant protein-1 [MCP-1], interleukin [IL]-6) and on the anti-inflammatory mediators (IL-10 and IL-13) was analyzed, and finally, the effect of the compounds on macrophage apoptosis and expression of surface receptors (toll-like receptor 4 [TLR-4] and mannose) was evaluated. The results of this study demonstrated that changes in the molecular structure of 4-aryl-4H-chromene altered its cytotoxic profile. Therefore, derivatives that showed safe results were selected for further analyses (named compounds: 4-6). In these experiments, the compounds were able to decrease nitric oxide (NO) levels and production of MCP-1, IL-6, IL-10, and IL-13. Furthermore, these derivatives were effective in reducing macrophage apoptosis and the expression of surface receptors, as TLR-4/CD284. Moreover, compounds 5 and 6 also were effective in increasing mannose receptor (CD206) expression. The results indicate, for the first time to our knowledge, that the anti-inflammatory effect produced by chromenes is linked to macrophage repolarization (M1 to M2).
Assuntos
Anti-Inflamatórios , Benzopiranos , Macrófagos , Anti-Inflamatórios/farmacologia , Benzopiranos/farmacologia , Inflamação/metabolismo , Interleucina-10/metabolismo , Interleucina-13/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Receptor 4 Toll-Like , Animais , Camundongos , Células RAW 264.7RESUMO
The inflammatory process is a mammalian physiological reaction against infectious agents or injuries. Among the cells involved, the macrophages have a highlighted role during this process. Depending on the inflammatory context, they can polarize into pro- or anti-inflammatory profiles (M1 and M2). In this context, compounds derived from cinnamic acid have demonstrated strong evidence of anti-inflammatory activity; however, the mechanism responsible for this effect remains unclear. In this study, we investigated the anti-inflammatory activity of five cinnamate-derived dienes of synthetic origin. The compounds that did not demonstrate significant cytotoxicity were tested to assess anti-inflammatory activity (NOx ) in RAW 264.7 cells stimulated with LPS. Then, the selected compound (diene 1) was evaluated as to its ability to inhibit the secretion of pro-inflammatory cytokines (IL-1ß, TNF-α, INF-γ, MCP-1, and IL-6) and increase the production of anti-inflammatory cytokines (IL-13, IL-4, and IL-10). Finally, diene 1 was able to reduce the expression of TLR4 and increase the phagocytic activity of the macrophages. Gathering these results together, we conclude that diene 1 showed an important anti-inflammatory effect, and this effect is linked to its immunomodulatory characteristic. Since the M1 markers were reduced at the same time, M2 markers were increased by the treatment of the macrophages with diene 1.
Assuntos
Anti-Inflamatórios , Macrófagos , Animais , Anti-Inflamatórios/farmacologia , Cinamatos/metabolismo , Cinamatos/farmacologia , Citocinas/metabolismo , Lipopolissacarídeos/farmacologia , Mamíferos/metabolismo , Camundongos , Células RAW 264.7RESUMO
Macrophages are critical in both tissue homeostasis and inflammation, and shifts in their polarization have been indicated as pivotal for the resolution of inflammatory processes. Inflammation is a complex and necessary component of the immune response to stimuli that are harmful to host homeostasis and is regulated by cellular and molecular events that remain a source of ongoing investigation. Among the compounds studied that have potential against autoimmune and inflammatory diseases, cannabinoids are currently highlighted. In this work, nineteen aryl-cyclohexanones diesters and their derivatives were synthesized based on the aryl-cyclohexane skeleton of phytocannabinoids, such as cannabidiol (CBD), and were evaluated for their anti-inflammatory and macrophage polarization potential. The results showed that Compound 4 inhibited the production of nitric oxide in RAW 264.7 macrophages. Furthermore, it reduced the levels of pro-inflammatory cytokines IL-12p70, TNF-α, IFN-γ, MCP-1, and IL-6 while, at the same time, was able to increase the production of anti-inflammatory cytokines IL-4, IL-10, and IL-13. Compound 4 also reduced macrophage apoptosis, increased the expression of the CD206 (mannose receptor) and at the same time, decreased the expression of CD284 (TLR-4 receptor) on the surface of these cells. Finally, it increased the phagocytic capacity and inhibited the phosphorylation of the p65 of NF-kß. In conclusion, Compound 4, identified as diethyl-4-hydroxy-2-(4-methoxyphenyl)-4-methyl-6-oxocyclohexane-1-3-dicarboxylate, showed significant anti-inflammatory effect, while demonstrating the ability to transform phenotypically macrophages from the M1 phenotype (pro-inflammatory) to the M2 phenotype (anti-inflammatory). This led us to hypothesize that the main mechanism of anti-inflammatory effect of this molecule is linked to its immune modulation capacity.
Assuntos
Cicloexanonas , Macrófagos , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Cicloexanonas/metabolismo , Cicloexanonas/farmacologia , Citocinas/metabolismo , Humanos , Inflamação/metabolismo , Macrófagos/metabolismoRESUMO
INTRODUCTION: Although both pro- and anti-inflammatory circulating cytokines are known to be elevated in liver cirrhosis, its clinical significance is not completely recognized. Our aim was to evaluate the prognostic significance of circulating cytokines interleukin (IL)-6, IL-17 and IL-10 in different stages of cirrhosis. METHODS: This prospective study included two cohorts: (1) stable cirrhosis attended in the Outpatient Clinic (n=118), and (2) subjects hospitalized for acute decompensation (AD) (n=130). Thirty healthy subjects served as control group. RESULTS: Patients with cirrhosis exhibited higher levels of cytokines as compared to controls. In stable cirrhosis, during a median follow-up of 17months, liver-related events occurred in 26 patients. Higher IL-10 levels and Child-Pugh B/C were independently associated with reduced event-free survival. In AD cohort, death after 90days of follow-up occurred in 39 patients and was independently associated with ascites, higher IL-6 and model for end-stage liver disease. IL-6 levels also showed higher AUROC than CRP for predicting bacterial infection in the AD cohort (0.831±0.043vs. 0.763±0.048, respectively). IL-17 decreased at third day of hospitalization only in patients who progressed to death. Higher IL-6 levels were observed in acute-on-chronic liver failure (ACLF) patients even in the absence of bacterial infection whereas IL-10 was higher only in subjects with infection-related ACLF. Higher IL-10 and IL-17 levels were associated with progression to death in ACLF. CONCLUSIONS: The pattern of immune response seems to vary according to the phase of cirrhosis and is related to prognosis, from stable disease to ACLF.
Assuntos
Insuficiência Hepática Crônica Agudizada/sangue , Citocinas/sangue , Cirrose Hepática/sangue , Insuficiência Hepática Crônica Agudizada/diagnóstico , Adulto , Idoso , Humanos , Cirrose Hepática/diagnóstico , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND: Studies have shown that prebiotics and synbiotics modulate the intestinal microbiota and may have beneficial effects on the immune response and anthropometric indices; however, the impact of the use of these supplements after bariatric surgery is not yet known. GOALS: This study investigated the effects of prebiotic and synbiotic supplementation on inflammatory markers and anthropometric indices in individuals undergoing open Roux-en-Y gastric bypass (RYGB). STUDY: In this randomized, controlled, and triple-blind trial conducted as a pilot study, individuals undergoing RYGB (n=9) and healthy individuals (n=9) were supplemented with 6 g/d of placebo (maltodextrin), prebiotic (fructo-oligosaccharide, FOS), or synbiotic (FOS+Lactobacillus and Bifidobacteria strains) for 15 days. RESULTS: Interleukin-1ß, interleukin-6, tumor necrosis factor-α, C-reactive protein, albumin, and the C-reactive protein/albumin ratio showed no significant changes on comparison between groups after supplementation. The reduction in the body weight of patients undergoing RYGB was 53.8% higher in the prebiotic group compared with the placebo group (-0.7 kg, P=0.001), whereas the reduction in the BMI and the increase in the percentage of excess weight loss were higher in the placebo and the prebiotic groups compared with the synbiotic group (P<0.05). CONCLUSIONS: Supplementation of FOS increased weight loss, whereas both prebiotics and synbiotics were not able to promote significant changes in inflammatory markers, although in most analyses, there was a reduction in their absolute values. The use of FOS may represent a potential adjunct in the treatment of obesity.