Ethacrynic acid decreases expression of proinflammatory intestinal wall cytokines and ameliorates gastrointestinal stasis in murine postoperative ileus

OBJECTIVES: Several compounds characterized by an olefin linkage conjugated to a carbonyl group have anti-inflammatory properties. The diuretic ethacrynic acid (EA) is a compound of this type. Herein, we tested the hypothesis that ethacrynic acid can modulate the development of ileus after bowel manipulation. METHODS: Groups (n=9) of male C57Bl/6 mice underwent surgical manipulation of the small intestine using a pair of cotton-tipped applicators (MAN). Control animals (CONT) did not undergo any surgical intervention or receive treatment. MAN mice were pre- and post-treated with four intraperitoneal doses of phosphate buffered saline (PBS), EA1 (1mg/kg per dose), or EA10 (10mg/kg per dose). Gastrointestinal transit of non-absorbable FITC-labeled dextran was assessed by gavaging the mice with the tracer 24h after operation and assessing FD70 concentration 120 min later in the bowel contents from the stomach, 10 equally long segments of small intestine, cecum, and two equally long segments of colon. The geometric center for the tracer was calculated for each animal. Expression of interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS) transcripts in the ileal muscularis propria was assessed using semiquantitative reverse transcriptase-polymerase chain reaction. RESULTS: In control animals, the mean (±SE) geometric center for the transit marker was 9.89±0.47, whereas it was 4.59±0.59 for PBS-treated animals (p<0.05 vs CONT). The geometric center for pre- post treatment with low (1mg/kg) and high (10mg/kg) doses of ethacrynic acid were 7.23±0.97 and 5.15±0.57, respectively. Compared to PBS, treatment with ethacrynic acid (1mg/kg) significantly decreased manipulation-induced IL-6 and iNOS mRNA expression in the wall of the small bowel. CONCLUSIONS: Pre- and post-treatment with ethacrynic acid ameliorates ileus and modulates inflammation in the gut wall induced by bowel manipulation.

Inhibitory effects on the production of inflammatory mediators and reactive oxygen species by Mori folium in lipopolysaccharide-stimulated macrophages and zebrafish

ABSTRACT Mori folium, the leaf of Morus alba L. (Moraceae), has been traditionally used for various medicinal purposes from ancient times to the present. In this study, we examined the effects of water extract of Mori folium (WEMF) on the production of inflammatory mediators, such as nitric oxide (NO) and prostaglandin E2 (PGE2), and reactive oxygen species (ROS) in lipopolysaccharide (LPS)-stimulated murine RAW 264.7 macrophages. Our data indicated that WEMF significantly suppressed the secretion of NO and PGE2 in RAW 264.7 macrophages without any significant cytotoxicity. The protective effects were accompanied by a marked reduction in their regulatory gene expression at the transcription level. WEMF attenuated LPS-induced intracellular ROS production in RAW 264.7 macrophages. It inhibited the nuclear translocation of the nuclear factor-kappa B p65 subunit and the activation of mitogen-activated protein kinases in LPS-treated RAW 264.7 macrophages. Furthermore, WEMF reduced LPS-induced NO production and ROS accumulation in zebrafish. Although more efforts are needed to fully understand the critical role of WEMF in the inhibition of inflammation, the findings of the present study may provide insights into the approaches for Mori folium as a potential therapeutic agent for inflammatory and antioxidant disorders.

Diabetic retinopathy: could the alpha-1 antitrypsin be a therapeutic option?

Diabetic retinopathy is one of the most important causes of blindness. The underlying mechanisms of this disease include inflammatory changes and remodeling processes of the extracellular-matrix (ECM) leading to pericyte and vascular endothelial cell damage that affects the retinal circulation. In turn, this causes hypoxia leading to release of vascular endothelial growth factor (VEGF) to induce the angiogenesis process. Alpha-1 antitrypsin (AAT) is the most important circulating inhibitor of serine proteases (SERPIN). Its targets include elastase, plasmin, thrombin, trypsin, chymotrypsin, proteinase 3 (PR-3) and plasminogen activator (PAI). AAT modulates the effect of protease-activated receptors (PARs) during inflammatory responses. Plasma levels of AAT can increase 4-fold during acute inflammation then is so-called acute phase protein (APPs). Individuals with low serum levels of AAT could develop disease in lung, liver and pancreas. AAT is involved in extracellular matrix remodeling and inflammation, particularly migration and chemotaxis of neutrophils. It can also suppress nitric oxide (NO) by nitric oxide sintase (NOS) inhibition. AAT binds their targets in an irreversible way resulting in product degradation. The aim of this review is to focus on the points of contact between multiple factors involved in diabetic retinopathy and AAT resembling pleiotropic effects that might be beneficial.

Modulation of host cell signaling pathways as a therapeutic approach in periodontal disease

Recently, new treatment approaches have been developed to target the host component of periodontal disease. This review aims at providing updated information on host-modulating therapies, focusing on treatment strategies for inhibiting signal transduction pathways involved in inflammation. Pharmacological inhibitors of MAPK, NFκB and JAK/STAT pathways are being developed to manage rheumatoid arthritis, periodontal disease and other inflammatory diseases. Through these agents, inflammatory mediators can be inhibited at cell signaling level, interfering on transcription factors activation and inflammatory gene expression. Although these drugs offer great potential to modulate host response, their main limitations are lack of specificity and developments of side effects. After overcoming these limitations, adjunctive host modulating drugs will provide new therapeutic strategies for periodontal treatment.

Efeitos do óxido nítrico e das fibras nervosas sensitivas sensíveis à capsaicina na modulãção da inflamação crônica de visas aéreas em cobaias / Effects of nitric oxide and sensitive nervous fibers sensitive to capsaicin im modulation of chronic airway inflammation in guinea pigs

O óxido nítrico (NO) parece modeular diferentes aspectos da fisiopatogenia da asma. Resultados prévios sugerem possíveis interações entre os mediadores do sistema não-adrenérgico não colinérgico excitatíró (neuropeptídios) e inibitório (NO) / The nitric oxide (NO) seems tod modulate different aspects of the asthma the mediators of the excitatory (beuropepitides) and inhibitory (NO) non adrenergic non-cholinergic system...

Role of mast cells in gastrointestinal mucosal defense

The purpose of this review, based on studies from our laboratory as well as from others, is to summarize salient features of mast cell immunobiology and to describe their associations with gastrointestinal mucosal defense. Gastrointestinal mast cells are involved in many pathologic effects, such as food hypersensitivity. On the other hand, they also play a protective role in defense against parasitic and microbial infections. Thus, they have both positive and negative effects, but presently the mechanisms that control the balance of these various effects are poorly known. It has been suggested that stabilization of mast cells may be a key mechanism to protect the gastrointestinal tract from injury. Few molecules are known to possess both mast cell stabilizing and gastrointestinal cytoprotective activity. These include zinc compounds, sodium cromoglycate, FPL 52694, ketotifen, aloe vera, certain flavonoids such as quercetin, some sulfated proteoglycans such as chondroitin sulfate and dehydroleucodine. Dehydroleucodine, a sesquiterpene lactone isolated from Artemisia douglasiana Besser, exhibits anti-inflammatory and gastrointestinal cytoprotective action. The lactone stimulates mucus production, and inhibits histamine and serotonin release from intestinal mast cells. The lactone could act as a selective mast cell stabilizer by releasing cytoprotective factors and inhibiting pro-inflammatory mast cell mediators.