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Thiazolidine scaffolds have been investigated for decades, due to their wide range of biological activity. In this way, the main objective of this systematic review was to elucidate the anti-inflammatory activity of thiazolidine derivatives against nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. From 9718 identified registers, 13 articles were included, where 11 studies evaluated thiazolidinediones. The summary of relevance demonstrated that seven studies (53.8%) were relevant without restrictions, and 6 (46.2%) were relevant with restrictions. The certainty in cumulative evidence was considered moderate and the six studies included in the meta-analysis demonstrated the positive activity of thiazolidinediones against NO production when compared to the negative LPS control.
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BACKGROUND: Respiratory distress syndrome is a complex inflammatory condition defined by the presence of acute hypoxemia and cellular infiltration with diffuse alveolar injury following a tissue injury, such as acute lung injury. The inflammatory process involved in this pathology is a defense mechanism of the body against infectious agents and/or tissue injuries. However, when the condition is not reversed, it becomes a significant cause of tissue damage, sometimes leading to loss of function of the affected organ. Therefore, it is essential to understand the mechanisms underlying inflammation, as well as the development of new therapeutic agents that reduce inflammatory damage in these cases. Aryl-cyclohexanone derivatives have previously shown significant anti-inflammatory activity linked to an immunomodulatory capacity in vitro and may be good candidates for therapies in which inflammation plays a central role. METHODS: Was evaluated the anti-inflammatory capacity of a synthesized molecule aryl-cyclohexanone in the murine model of lipopolysaccharide (LPS)-induced acute lung injury. The assessment of acute oral toxicity follows the Organization for Economic Co-operation and Development (OECD) guideline 423. RESULTS: The results demonstrated that the studied molecule protects against LPS-induced inflammation. We observed a decrease in the migration of total and differential leukocytes to the bronchoalveolar lavage fluid (BALF), in addition to a reduction in exudation, myeloperoxidase (MPO) activity, nitric oxide metabolites, and the secretion of pro-inflammatory cytokines (alpha tumor necrosis factors [TNF-α], interleukin-6 [IL-6], interferon-gamma [IFN-γ], and monocyte chemoattractant protein-1 [MCP-1]). Finally, aryl cyclohexanone did not show signs of acute oral toxicity (OECD 423). CONCLUSIONS: The results prove our hypothesis that aryl-cyclohexanone is a promising molecule for developing a new, safe anti-inflammatory drug.
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This study investigated the anti-inflammatory effect of hydrophilic and lipophilic extracts from juçara fruits (Euterpe edulis Martius) through measurement of nitric oxide (NOx) and cytokines (IL-12p70, TNF-α, INF-γ, MCP-1, IL-6, and IL-10). J774 macrophages were stimulated with lipopolysaccharides (1 µg/mL) and treated with various concentrations (1-100 µg/mL) of juçara fruits extracts from crude extracts, and hexane, dichloromethane, ethyl acetate, and butanol fractions. Potential relationships between the phenolic composition of the extracts determined by LC-ESI-MS/MS and their anti-inflammatory capacity were also evaluated. Hexane and dichloromethane fractions inhibited NOx and IL-12p70 while increased IL-10. Hexane fractions also decreased IL-6 and IFN-γ production. Hexane and dichloromethane fractions showed a higher number of phenolic compounds (32 and 34, respectively) than the other extracts tested and were also the only ones that presented benzoic acid and pinocembrin. These results suggest juçara fruits compounds as potential anti-inflammatory agents, especially those of a more apolar nature.
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Antiinflamatorios , Frutas , Lipopolisacáridos , Macrófagos , Óxido Nítrico , Extractos Vegetales , Macrófagos/efectos de los fármacos , Frutas/química , Extractos Vegetales/farmacología , Antiinflamatorios/farmacología , Óxido Nítrico/metabolismo , Ratones , Animales , Fenoles/análisis , Fenoles/farmacología , Citocinas/metabolismo , Línea CelularRESUMEN
BACKGROUND: In view of the scientific gap in knowledge of the involvement of the B-cell compartment and clinical prognostic in SARS-CoV-2 infection, this work aims to evaluate the B-cell subsets and the presence of specific IgM and IgG, as well as neutralizing antibodies against SARS-CoV-2, in unvaccinated patients diagnosed with COVID-19. METHODS: This study included 133 patients with COVID-19. Cellular components were assessed by flow cytometry, and immunoglobulin levels and reactivity were measured by indirect enzyme-linked immunosorbent assay. RESULTS: Our results showed no changes in less differentiated B cells. However, non-switched memory B cells (NS-MBCs) and class-switched memory B cells (CS-MBCs) were reduced in the patients with moderate disease. Also, plasmablasts and double-negative (DN) or "atypical" memory B cells were increased in groups of patients with moderate to critical conditions. In addition, the production of IgM, IgG, and neutralizing antibodies against SARS-CoV-2 demonstrated a positive correlation between the positivity of antibodies against SARS-CoV-2 and disease severity. Besides being related to the development of a more severe course of the disease, the increase in DN B-cell count also contributed to a poorer disease outcome in patients with a higher percentage of these cells. On the other hand, we observed an increase in the absolute number of CS-MBCs in patients with greater chances of survival. CONCLUSIONS: This study demonstrates that the B-cell compartment may contribute to the development of clinical symptoms of COVID-19, with changes in B-cell subset counts linked to disease course and patient prognosis.
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Anticuerpos Neutralizantes , Anticuerpos Antivirales , Biomarcadores , COVID-19 , Inmunoglobulina G , Inmunoglobulina M , SARS-CoV-2 , Humanos , COVID-19/inmunología , COVID-19/sangre , COVID-19/diagnóstico , COVID-19/mortalidad , COVID-19/virología , Masculino , Femenino , Persona de Mediana Edad , Pronóstico , SARS-CoV-2/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina M/sangre , Biomarcadores/sangre , Adulto , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Anciano , Subgrupos de Linfocitos B/inmunología , Índice de Severidad de la EnfermedadRESUMEN
Traditionally, the treatment of inflammatory conditions has focused on the inhibition of inflammatory mediator production; however, many conditions are refractory to this classical approach. Recently, an alternative has been presented by researchers to solve this problem: The immunomodulation of cells closely related to inflammation. Hence, macrophages, a critical key in both innate and acquired immunity, have been presented as an alternative target for the development of new medicines. In this work, we tested the fluorophenyl-imidazole for its anti-inflammatory activity and possible immunomodulatory effect on RAW 264.7 macrophages. We also evaluated the anti-inflammatory effect of the compound, and the macrophage repolarization to M2 was confirmed by the ability of the compound to reduce the M1 markers TNF-α, IL-6, MCP-1, IL-12p70, IFN-γ, and TLR4, the high levels of p65 phosphorylated, iNOS and COX-2 mRNA expression, and the fact that the compound was not able to induce the production of M1 markers when used in macrophages without lipopolysaccharide (LPS) stimulation. Moreover, fluorophenyl-imidazole had the ability to increase the M2 markers IL-4, IL-13, CD206, apoptosis and phagocytosis levels, arginase-1, and FIZZ-1 mRNA expression before LPS stimulation. Similarly, it was also able to induce the production of these same M2 markers in macrophages without being induced with LPS. These results reinforce the affirmation that the fluorophenyl-imidazole has an important anti-inflammatory effect and demonstrates that this effect is due to immunomodulatory activity, having the ability to trigger a repolarization of macrophages from M1 to M2a. These facts suggest that this molecule could be used as an alternative scaffold for the development of a new medicine to treat inflammatory conditions, where the anti-inflammatory and proregenerative properties of M2a macrophages are desired.
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Lipopolisacáridos , Macrófagos , Lipopolisacáridos/metabolismo , Macrófagos/metabolismo , Interleucina-12/metabolismo , Imidazoles/farmacología , Imidazoles/metabolismo , ARN Mensajero/metabolismoRESUMEN
INTRODUCTION: Inflammation is a physiological event that protects the organism against different factors that lead to loss of tissue homeostasis. Dihydropyridine (DHP) derivatives are heterocyclic compounds known for their different biological activities, including anti-inflammatory activities. OBJECTIVE: To evaluate the anti-inflammatory activity of 1,4-dihydropyridine (1,4-DHP) derivatives using anti-inflammatory models in vitro, in RAW264.7 cells induced by lipopolysaccharide (LPS) and in vivo using the acute lung injury (ALI) model in mice. RESULTS: Fifteen compounds derived from 1,4-DHP were tested in RAW264.7 cells for their cytotoxic effect and cell viability. Thereafter, only the six compounds that showed the highest cell viability were tested for the production or inhibition of the pro-inflammatory cytokine interleukin 6 (IL-6). The best compound (compound 4) was tested for its anti-inflammatory effects in vitro and in vivo, showing inhibition of nitric oxide (NO), pro-inflammatory cytokines, increased phagocytic activity, and an increase in IL-10 in vitro. In in vivo tests, compound 4 also reduces the levels of NO, myeloperoxidase (MPO) activity, leukocyte migration, and exudation, as well as reducing the levels of tumor necrosis factor-alpha (TNF-α) and IL-6 and preventing the loss in the lung architecture. CONCLUSION: This compound showed important anti-inflammatory activity, with a significant ability to reduce the production of pro-inflammatory mediators and increase the phagocytic activity of macrophages and anti-inflammatory mediator secretion (IL-10). These findings led us to hypothesize that this compound can repolarize the macrophage response to an anti-inflammatory profile (M2). Moreover, it was also able to maintain its anti-inflammatory activity in vivo experiments.
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Dihidropiridinas , Interleucina-10 , Interleucina-6 , Ratones , Animales , Citocinas , Antiinflamatorios/farmacología , Factor de Necrosis Tumoral alfa , Lipopolisacáridos/farmacología , Óxido NítricoRESUMEN
Coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). An adequate T cell response is essential not only for fighting disease but also for the creation of immune memory. Thus, the present study aims to evaluate the T cells of patients with moderate, severe and critical COVID-19 not only at the time of illness but also 2 months after diagnosis to observe whether changes in this compartment persist. In this study, 166 COVID-19 patients were stratified into moderate/severe and critical disease categories. The maturation and activation of T cells were evaluated through flow cytometry. In addition, Treg cells were analysed. Until 15 days after diagnosis, patients presented a reduction in absolute and relative T lymphocyte counts. After 2 months, in moderate/severe patients, the counts returned to a similar level as that of the control group. In convalescent patients who had a critical illness, absolute T lymphocyte values increased considerably. Patients with active disease did not show differentiation of T cells. Nonetheless, after 2 months, patients with critical COVID-19 showed a significant increase in CD4+ EMRA (CD45RA+ effector memory) T lymphocytes. Furthermore, COVID-19 patients showed delayed T cell activation and reduced CD8+ suppressor T cells even 2 months after diagnosis. A reduction in CD4+ Treg cells was also observed, and their numbers returned to a similar level as that of healthy controls in convalescent patients. The results demonstrate that COVID-19 patients have a delayed activation and differentiation of T cells. In addition, these patients have a great reduction of T cells with a suppressor phenotype.
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COVID-19 , Humanos , SARS-CoV-2 , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Diferenciación CelularRESUMEN
Nowadays, macrophages are recognized as key cells involved in chronic inflammatory conditions, and play central roles in all inflammatory diseases and cancer. Due to their extensive involvement in the pathogenesis of inflammatory diseases, they are now considered a relevant therapeutic target in the development of new therapeutic strategies. 2-Iminothiazolidines are associated with important anti-inflammatory activity and represent a rich source for the development of new drugs and treatments. Our research focuses on evaluating the anti-inflammatory capacity of these compounds and their relationship with M1/M2 macrophage polarization. The results demonstrate that 2-iminothiazolidines have the capacity to decrease the levels of anti-inflammatory biomarkers, such as cytokines (IL-1ß, TNF-α, and IL-6), nitric oxide synthase (with impact on NOx production), and COX-2, following a significant decline in NF-kB activation. We also observed an increase in levels of anti-inflammatory cytokines (IL-4 and IL-13) in the in vitro model of RAW 264.7 macrophages induced by LPS. Moreover, this is the first report, suggesting that the anti-inflammatory activity of 2-iminothiazolidines is associated with the ability to enhance phagocytosis, increase Arginase-1 and CD206 expression, and increase the secretion of IL-10. Furthermore, an in vivo study using the acute lung injury model induced by LPS proved the anti-inflammatory activity of a selected 2-iminothiazolidine, named methyl 2-(benzoylimino)-3-methyl-4-(4-nitrobenzyl)-1,3-thiazolidine-4-carboxylate. All these results, taken together, lead us to hypothesize that the mechanism of anti-inflammatory effect observed with this compound is closely related to the ability of this compound to produce macrophage repolarization, from the M1 to the M2 phenotype.
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Lipopolisacáridos , Macrófagos , Lipopolisacáridos/farmacología , Activación de Macrófagos , Antiinflamatorios/farmacología , Antiinflamatorios/metabolismo , Citocinas/metabolismoRESUMEN
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.
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Antiinflamatorios , Macrófagos , Animales , Antiinflamatorios/farmacología , Cinamatos/metabolismo , Cinamatos/farmacología , Citocinas/metabolismo , Lipopolisacáridos/farmacología , Mamíferos/metabolismo , Ratones , Células RAW 264.7RESUMEN
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.