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The actions of hydrogen sulfide in human physiology have been extensively studied and, although it is an essential mediator of many biological functions, the underlying molecular mechanisms of its actions are ill-defined. To elucidate the roles of sulfide in inflammation, we have investigated its interactions with human myeloperoxidase (MPO), a major contributor to inflammatory oxidative stress.The interactions of sulfide and MPO were investigated using electron paramagnetic resonance, electronic circular dichroism, UV-vis and stopped-flow spectroscopies.We found favourable reactions between sulfide and the native-ferric enzyme as well as the MPO redox intermediates, ferrous MPO, compound I and compound II. Sulfide was a potent reversible inhibitor of MPO enzymic activity with an IC50 of 1 µM. In addition, the measured second-order rate constants for the reactions of sulfide with compound I [k = (1.1 ± 0.06) × 10(6) M(-1) s(-1)] and compound II [k = (2.0 ± 0.03) × 10(5) M(-1) s(-1)] suggest that sulfide is a potential substrate for MPO in vivo.Endogenous levels of sulfide are likely to inhibit the activity of circulating and endothelium-bound MPO. The fully reversible inhibition suggests a mediatory role of sulfide on the oxidant-producing function of the enzyme. Furthermore, the efficient HOCl oxidation of sulfide to give polysulfides (recently recognized as important components of sulfide biology) together with MPO-catalysed sulfide oxidation and the lack of interaction between MPO and sulfide oxidation products, predict a modulatory role of MPO in sulfide signalling.

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Naproxen belongs to commonly used NSAIDs associated with less cardiovascular toxicity than selective COX-2 inhibitors and other NSAIDs but its use is limited due to serious gastrointestinal (GI)-tract adverse effects. Novel H2S-releasing derivative of naproxen (ATB-346) was shown to inhibit COX-1 and prostaglandins (PGs) generation without causing mucosal damage unlike parent drug but whether ATB-346 can affect stress-induced gastric damage remains unknown. We compared ATB-346 vs naproxen and celecoxib and determined the role of reactive oxygen species and cytokines in the action of these NSAIDs against water immersion restraint stress (WRS)-induced gastric lesions in rats. WRS exposed animals were pretreated with (1) naproxen, (2) ATB-346 (0.5–40 m/kg i.g.), and (3) celecoxib (10 mg/kg i.g.) with or without ODQ (5 mg/kg i.p.), selective guanylate cyclase inhibitor or BCA (10 mg/kg i.p.), the inhibitor of H2S-synthesizing enzyme CSE. The number of gastric lesions was assessed by planimetry, the gastric blood flow (GBF) by H2-gas clearance technique, the malonyldialdehyde (MDA) concentration, MPO and PGE2 generation, the plasma level of IL-1beta and TNF-alpha and the expression of SOD and glutathione peroxidase (GPx) were determined by ELISA and RT-PCR. Pretreatment with ATB-346 dose-dependently reduced WRS-induced gastric lesions; the dose inhibiting these lesions by 50% being 29 mg/kg, caused significant rise in GBF and fall in MPO and MDA content. These effects of ATB-346 were reversed by cotreatment with ODQ but not BCA (p

H 2 S is an endogenous gasotransmitter which exerts vasodilatatory, neuromodulatory and anti-inflammatory activities but little is known whether this gaseous mediator affects ischemia–reperfusion (I/R)-induced gastric erosions. We studied the effect of H 2 S precursor, l -cysteine and H 2 S-donor, NaHS on I/R lesions induced by 30 min of I followed by 3 h of R and their progression into chronic gastric ulcers at 12–72 h after the end of I. Rats exposed to I/R received once daily (1) l -cysteine (2–40 mg/kg) and (2) NaHS (0.1–10 mg/kg i.g.) combined or not with the inhibitor of CSE, d , l -propargylglycine (PAG 30 mg/kg i.g.); (3) the non-selective (indomethacin; 5 mg/kg i.p.) or selective COX-1 (SC-560, 5 mg/kg i.p.) and COX-2 inhibitors (celecoxib 30 mg/kg i.g.); (4) blockade of sensory nerves by capsaicin (125 mg/kg s.c.) and the inhibition of vanilloid receptor (VR-1) by capsazepine (10 mg/kg i.g.). The number of gastric lesions was measured by planimetry, the gastric blood flow (GBF) determined by H 2 -gas clearance technique, the mucosal concentration of H 2 S was determined spectrophotometrically, the plasma IL-1beta and TNF-alpha were determined by ELISA and mRNA expressions for CSE, COX-1-, COX-2-, CGRP, IL-1beta-, and TNF-alpha were assessed by RT-PCR. I/R-induced gastric mucosal lesions progressed into gastric ulcers at 72 h following the end of I. The significant fall in the H 2 S concentration and GBF were observed in gastric mucosa of I/R and these effects persisted up to 72 h upon standard I/R. NaHS (5 mg/kg i.g.) and l -cysteine (20 mg/kg i.g.) which significantly increased H 2 S content in the gastric mucosa and GBF, significantly reduced I/R-induced gastric lesions area at 24 h and 72 h following end of I. Capsaicin denervation, capsazepine and treatment with COXs inhibitors exacerbated I/R injury and significantly reduced the GBF and these effects were reversed by co-treatment with CGRP (10 μg/kg s.c.) or dimethyl PGE 2 (5 μg/kg i.g.) in the presence of NaHS and cysteine in capsaicin-denervated or COX-1- and COX-2-inhibited animals. The mRNA expression for CSE and CBS was increased in I/R gastric mucosa and this was inhibited by NaHS and cysteine. We conclude that (1) pathogenesis of I/R injury involves the fall in the generation of H 2 S and (2) NaHS and cysteine protect the gastric mucosa against I/R lesions and accelerate the healing of these lesions progressing into gastric ulcers via an increase in GBF mediated by endogenous H 2 S, PG pathway and CGRP.

rary endoscopic hemostasis followed by high-dose PPI infusion, although most rebleeding occurs within the first 72 hours, a significant proportion of patients experience a later rebleed. Data are too few and heterogeneous to confidently identify predictors of delayed rebleeding. These require further characterization and may justify a more tailored approach to using second-look endoscopy, while justifying the need for future studies that assess the duration of post-hemostasis profound acid suppression.

G A A b st ra ct s of the oxyntic mucosa, increased apoptosis, oxidative stress, and surface layer erosion. Inflammation was also observed in the mucosa as shown by the activation of the NFkB pathway and increases in TFF1, TIMP1 and Cox-2 expression. The pit region of the mucosa was affected by changes in cell interactions due to changes in beta-catenin and E-cadherin expression, loss of interaction in adherent junctions and activation of the beta-catenin pathway. Many of these changes, already detectable in 20-day-old fetuses, were specific of the offspring and were not observed in dams. All pups were refed a normal diet after weaning. We evaluated the persistence of stomach changes by comparing adult rats with MMD during gestation and suckling period and normal diet thereafter with control rats. The gastric mucosa thickness remained smaller in than that of control rats. SOD expression, NFkB activity, and apoptotic cell loss remained increased. CONCLUSIONS: These results indicate that the deleterious effects of MDD during gestation and lactation were accompanied by inflammatory and ulcerative states that were not reversed by the ingestion of a normal diet after weaning.