Secretion Of Chemical Mediators Research Articles

Tagetes erecta L.: A traditional medicine effective in inflammatory process treatment

Ethnopharmacological relevanceTagetes erecta L. (Asteraceae), popularly known as Aztec Marigold, is used in folk medicine to treat several ailments including inflammatory processes. Despite its historical use, the specific mechanisms through which it may modulate inflammation, particularly its effects on neutrophils and macrophages activation, have not yet been completely investigated. Aim of the studyThis study aimed to elucidate the anti-inflammatory mechanism of the hydroalcoholic extract obtained from T. erecta flowers, focusing on its role in the regulation of neutrophil and macrophage functions. Material and methodsThe production of TNF, IL-6, CXCL-1, IL-1β, IL-10 (ELISA) and NO (Griess reaction), adhesion molecule expression (CD62L, CD49d and CD18, flow cytometry), and chemotaxis were analyzed in vitro using oyster glycogen-recruited peritoneal neutrophils or macrophages (RAW 264.7) stimulated with lipopolysaccharide (LPS) and treated with the extract (1, 10 or 100 μg/mL). The resolution of inflammation was accessed by efferocytosis assay. The in vivo anti-inflammatory activity was investigated using carrageenan-induced inflammation in the subcutaneous tissue of male Swiss mice orally treated with the T. erecta extract (30, 100 or 300 mg/kg). The leukocyte influx (optical microscopy), secretion of chemical mediators (TNF, IL-6 and IL-1β, ELISA) and protein exudation (Bradford reaction) were quantified in the inflamed exudate. ResultsIn vitro studies demonstrated that the extract inhibited neutrophil chemotaxis and reduced the production and/or release of cytokines (TNF, IL-1β, CXCL1, and IL-6) as well as nitric oxide (NO) by neutrophils and macrophages when stimulated with LPS. Neutrophils treated with LPS and incubated with the extract showed an increase in CD62L expression, which leads to the impairment of neutrophil adhesion. The extract also enhanced efferocytosis of apoptotic neutrophils by macrophages, which was accompanied by increased IL-10 secretion and decreased TNF levels. In vivo studies yielded similar results, showing reduction in neutrophil migration, protein exudation, and cytokine release (TNF, IL-6, and IL-1β). ConclusionsTogether, the data herein obtained shows that T. erecta flower extract has anti-inflammatory effects by regulating inflammatory mediators, limiting neutrophil migration, and promoting efferocytosis. The in vivo results suggest that an herbal medicine made with T. erecta could represent an interesting pharmacological tool for the treatment of acute inflammatory condition.

Sambucus nigra: A traditional medicine effective in reducing inflammation in mice

Ethnopharmacological relevanceSambucus nigra L. is a plant of European origin and popularly known as elder, elderberry, black elder, European elder, European elderberry, and European black elderberry, being described in pharmacopoeia of several countries. Its flowers and berries have been used in folk medicine to treat feverish conditions, coughing, nasal congestion, and influenza besides its popular use as anti-inflammatory, analgesic, and diuretic agent. Aim of the studyThe aim of this investigation was to elucidate the anti-inflammatory and the relaxant effect of the lyophilized aqueous extract obtained from S. nigra's flowers on in vivo and in vitro inflammation assays and on the isolated rat vascular and airway smooth muscle tissue. Material and methodsThe anti-inflammatory activity of the extract was investigated using carrageenan-induced inflammation model in the subcutaneous tissue of male Swiss mice orally treated with S. nigra extract (30, 100, 300 or 600 mg/kg). Leukocyte influx and the secretion of chemical mediators were quantified in the inflamed exudate. Additionally, histological analysis of the pouches was performed. N-Formyl-methionine-leucine-phenylalanine-induced chemotaxis, lipopolysaccharide-induced TNF, IL-6, IL-1β, IL-10 and NO production, and adhesion molecule expression (CD62L, CD49d and CD18, flow cytometry) were analyzed in vitro using oyster glycogen-recruited peritoneal neutrophils or macrophages (RAW 264.7) stimulated with LPS and treated with the extract (1, 10 or 100 μg/mL). The resolution of inflammation was accessed by efferocytosis assay, and the antinociceptive activity was investigated using carrageenan-induced mechanical hypersensitivity. Finally, the effect of the extract was evaluated in isolated rat aorta and trachea rings. ResultsThe oral treatment with S. nigra promoted reduction in the neutrophil migration as well as the decrease of TNF, IL-1β and IL-6 levels in the inflamed exudate. In vitro treatment with S. nigra decreased NO2−, TNF, IL-1β and IL-6 and promoted increase of IL-10 in LPS-stimulated neutrophils. Similarly, the extract reduced the NO2−, TNF and IL-6 in LPS-stimulated macrophages. Rutin, the major constituent of S. nigra extract reduced NO2−, TNF, IL-1β, and IL-6 and promoted the increase of IL-10 in LPS-stimulated neutrophils supernatant. The extract also shed CD62L and CD18 expressions. The extract was able to increase the efferocytosis of apoptotic neutrophils by increasing the IL-10 and decreasing the TNF levels. Additionally, the extract reduced the hypersensitivity induced by carrageenan and promoted a relaxant effect in isolated vascular and non-vascular rat tissue. ConclusionsS. nigra flowers extract presents anti-inflammatory effect by modulating macrophage and neutrophil functions including the production of inflammatory mediators and cell migration, by promoting efferocytosis and consequently the resolution of acute inflammation, besides exerting antinociceptive effects, scientifically proving its popular use as medicinal plant. Allied to the relaxant effect in both vascular and non-vascular smooth muscle tissue, S. nigra extract represents an important tool for the management of acute inflammation.

Molecular pathways underlying tissue injuries in the bladder with ketamine cystitis.

Ketamine cystitis (KC) is a chronic bladder inflammation leading to urinary urgency, frequency, and pain. The pathogenesis of KC is complicated and involves multiple tissue injuries in the bladder. Recent studies indicated that urothelium disruption, lamina propria fibrosis and inflammation, microvascular injury, neuropathological alterations, and bladder smooth muscle (BSM) abnormalities all contribute to the pathogenesis of KC. Ketamine has been shown to induce these tissue injuries by regulating different signaling pathways. Ketamine can stimulate antiproliferative factor, adenosine triphosphate, and oxidative stress to disrupt urothelium. Lamina propria fibrosis and inflammation are associated with the activation of cyclooxygenase-2, nitric oxide synthase, immunoglobulin E, and transforming growth factor β1. Ketamine contributes to microvascular injury via the N-methyl-D aspartic receptor (NMDAR), and multiple inflammatory and angiogenic factors such as tumor necrosis factor α and vascular endothelial growth factor. For BSM abnormalities, ketamine can depress the protein kinase B, extracellular signal-regulated kinase, Cav1.2, and muscarinic receptor signaling. Elevated purinergic signaling also plays a role in BSM abnormalities. In addition, ketamine affects neuropathological alterations in the bladder by regulating NMDAR- and brain-derived neurotrophic factor-dependent signaling. Inflammatory cells also contribute to neuropathological changes via the secretion of chemical mediators. Clarifying the role and function of these signaling underlying tissue injuries in the bladder with KC can contribute to a better understanding of the pathophysiology of this disease and to the design of effective treatments for KC.

Toxicological and anti-inflammatory profile of Synadenium grantii Hook. f. in mice

Ethnopharmacological relevanceSynadenium grantii Hook. f., popularly known as “janaúba” or “leiterinha”, is used in the folk medicine to treat gastric disorders, some types of neoplasias and inflammatory diseases. Aim of the studyThe aim of this study was to show the anti-inflammatory activity of the methanol extract obtained from S. grantii stems and also certify the safety of the extract performing toxicological analysis. Material and methodsThe anti-inflammatory activity was investigated using carrageenan-induced inflammation in the subcutaneous tissue of male Swiss mice orally pre-treated with the S. grantii extract (1, 3 or 10 mg/kg). The leukocyte influx (optical microscopy) and secretion of chemical mediators (TNF, IL-6 and IL-1β, by enzyme-linked immunosorbent assay) were quantified in the inflamed exudate. The toxicity was investigated using the dose-fixed procedure (acute toxicity) and repeated dose 28-day (subacute toxicity) in mice orally treated with S. grantii extract. The open field and rota-rod test were used to evaluate possible interference of adverse effect of S. grantii on motor coordination, locomotor and exploratory activity. ResultsThe analysis of the inflammatory exudate of S. grantii-treated mice demonstrated reduction in the polymorphonuclear cells (PMN) migration to the inflamed tissue, as well as the reduction of the pro-inflammatory cytokines TNF and IL-1β. Furthermore, the acute and sub-acute toxicity studies did not show significant changes in body weight, general behaviour, biochemical parameters, organ weight and liver and kidney histopathological analysis. However, animals acutely treated with S. grantii presented reduction in the number of crosses in relation to the vehicle group, without significant difference in the number of elevations and latency time between the groups in rota-rod test. The obtained results allow to set the NOAEL (Non-observed-adverse-effect level) in 100 mg/kg for this specie of rodent. ConclusionsTogether, the results herein obtained show that S. grantii extract presented anti-inflammatory activity by decreasing the influx of PMN to the inflamed tissue, as well as the cytokines TNF and IL-1β levels. In addition, S. grantii extract seemed not to present significant acute or subacute toxicity when administered to mice, demonstrating for the first time the safety of this extract, when orally administered.

Effects of Eugenia umbelliflora O. Berg (Myrtaceae)-leaf extract on inflammation and hypersensitivity

Ethnopharmacological relevanceThe leaves of Eugenia species are widely used in popular medicine to treat several diseases, such as arthritis, rheumatism and diabetes. Eugenia umbelliflora O. Berg is popularly known in Brazil as “baguaçu", name also conferred to Eugenia jambolana probably due to their apparent similarity. Although the popular use scientifically proved of E. jambolana as anti-diabetes and also as anti-inflammatory, there are only two scientific studies demonstrating anti-ulcer and bactericide activities of E. umbelliflora leaves extract, without reference to its possible anti-inflammatory activity. Aim of the studyThe aim of this study was to show the anti-oxidant and anti-inflammatory activity of the methanol extract obtained from E. umbelliflora leaves (EuL) using in vitro and in vivo protocols. Materials and methodsThe total phenolic content was evaluated using the folin-Ciocalteu colorimetric method and phloroglucinols content by HPLC. The anti-oxidant activity was evaluated by ORAC, ABTS•+, DPPH, and metal chelation methods. The anti-inflammatory activity was investigated using carrageenan-induced inflammation in the subcutaneous tissue of male Swiss mice orally pre-treated with the EuL (0.3, 1 or 3 mg/kg). The leukocyte influx (optical microscopy) and secretion of chemical mediators (TNF, IL-6, IL-1β and CXCL1, by enzyme-linked immunosorbent assay) were quantified in the inflamed exudate. Histological analysis of the pouches was also performed. The anti-hypersensitive activity was investigated using carrageenan-induced mechanical hypersensitivity and mice were then evaluated using the von Frey filaments. The Open Field test was used to evaluate possible interference of adverse effect of EuL on locomotor activity that could lead to misinterpretation of the hypersensitivity evaluation. ResultsThe EuL demonstrated important and moderate reducing capacity on ABTS•+ and DPPH assays, respectively, but with slight activity in ORAC test. It reflects low protection against cell damage. The EuL also presented 30% of phenolic compounds. The phloroglucinols content of EuL was 25.9 mg/g, 18.4 mg/g and 16.6 mg/g of eugenial C, eugenial D and eugenial E, respectively. The in vivo analysis of the inflammatory exudate of EuL-treated mice demonstrated reduction in the polymorphonuclear cells (PMN) migration to the inflamed tissue, as well as the reduction of the pro-inflammatory cytokine IL-1β. Histologically, it was observed evident decrease in the oedema, formed essentially by non-haemorrhagic fibrin exudate, as well as PMN infiltrate, when compared with control mice injected with carrageenan. Furthermore, the extract also presented effective reduction of the mechanical hypersensitivity induced by carrageenan without any interference in animal's locomotor and exploratory activity. ConclusionsTogether, the results herein obtained show that EuL presented anti-inflammatory activity by decreasing the influx of PMN to the inflamed tissue, as well as the cytokine IL-1β level. This anti-inflammatory activity was also accompanied by significant anti-hypersensitive effect. The effects presented by EuL seem not to be correlated with an antioxidant activity. However other extract chemical compounds could be responsible for its important anti-inflammatory effects.

Inflammation and Cancer: Critical View

Inflammation is the physiological response to an injury, it could be chemical, thermal, physical and infectious for reparative activity to injury. Recent data suggest that chronic inflammation leads to cancer development. Inflammatory mediators released to surrounding environment due to inflammation by inflammatory cells acts as a defensive or offensive depends on secretion of chemical mediators of inflammation such as growth factors, cytokines activating various transcriptional pathways bring about cell proliferation, angiogenesis further leads to tumor growth. This article describe the role of inflammatory cells and its mediators to development of cancer, various underlying unanswered future challenge questions in association with inflammation and cancer.

Sphingosine 1‐phosphate as an intracellular messenger and extracellular mediator in immunity

The omnific mediator system composed of sphingosine 1-phosphate (S1P) and its five G-protein-coupled receptors, designated S1P(1)-S1P(5), affects diverse cellular functions in the nervous, endocrine, cardiovascular and immune systems. The many activities of the S1P-S1P(1) axis, which predominates in the cardiovascular and immune systems, have previously been classified according to their relationship with the distinct functional roles of each type of cell or according to their most frequently used signalling pathways. In the immune system, cell surface S1P(1) receptors transduce the rapid, transient effects of extracellular S1P on T- and B-lymphocyte trafficking in the lymphoid system, lymphocyte migration in non-immune tissues and cytokine generation. After immune stimulation of T- and B-lymphocytes, S1P(1) receptors translocate from the cell surface to endosomal and nuclear compartments. The present hypothesis is that nuclear S1P(1) receptors represent distinct signalling complexes that, through a series of transcriptional events, transduce the sustained effects of intracellular S1P on survival and proliferation of T-lymphocytes. It is postulated that similar types of sustained signalling from nuclear S1P receptors in other types of cells affect proliferation, survival and specific effector functional activities. Effective pharmacological approaches to intracellular, as well as cell surface, S1P-S1P receptor axes will thus require the bioaccessibility of agonists and antagonists to the nuclear domain of relevant target cells. Most investigations of the effects of the S1P-S1P(1) axis in immunity have focused primarily on rapid, transient alterations in lymphocyte migration and trafficking, and on mast cell migration and secretion of chemical mediators. The discovery of functional S1P(1)-G protein signalling complexes in the nuclear membranes of activated lymphocytes, that are coupled to the transduction of prolonged inhibition of proliferative responses by intracellular S1P, adds a new dimension to the role of the S1P-S1P(1) axis in immunity. Recruitment of this novel, potentially immunosuppressive, function of S1P(1) may be beneficial in some autoimmune diseases and will require application of cell membrane-permeant S1P(1)-specific drugs.

Macrophage functional heterogeneity.

Macrophages are ubiquitous in mammalian tissues where they participate in such vital processes as homeostasis (1,2), the secretion of chemical mediators (3), the development of immune competence (4,5), the regulation of immune induction (6), and as effector cells in certain expressions of efferent immunity (7). It is now evident that macrophages are not uniformly capable of all these functions; indeed, evidence accumulated over the past several years shows that populations of macrophages, like populations of lymphocytes, are functionally heterogeneous.