Search

Gastric ulcers affect approx. 10% of population. Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid (ASA) predispose to or impair the physiologically complex healing of pre-existing ulcers. Since H 2 S is an endogenous cytoprotective molecule, we hypothesized that new H 2 S-releasing ASA-derivative (ATB-340) could overcome pathological impact of NSAIDs on GI regeneration.Clinically translational gastric ulcers were induced in Wistar rats using state-of-the-art microsurgical model employing serosal application of acetic acid. This was followed by 9 days long i.g. daily treatment with vehicle, ATB-340 (6-24 mg/kg) or equimolar ASA doses (4-14 mg/kg). Ulcer area was assessed macro- and microscopically. Prostaglandin (PG)E2  levels, indicating pharmacological activity of NSAIDs and 8-hydroxyguanozine content, reflecting nucleic acids oxidation in serum/gastric mucosa, were determined by ELISA. Qualitative and/or quantitative pathway-specific alterations at the ulcer margin were evaluated using real-time PCR and mass spectrometry-based proteomics.ASA, unlike ATB-340, dose-dependently delayed/impaired gastric tissue recovery, deregulating 310 proteins at the ulcer margin, including Ras signalling, wound healing or apoptosis regulators. ATB-340 maintained NSAIDs-specific cyclooxygenase-inhibiting capacity on systemic and GI level but in time-dependent manner. High dose of ATB-340 (24 mg/kg daily), but not ASA, decreased nucleic acids oxidation and upregulated anti-oxidative/anti-inflammatory heme oxygenase-1, 24-dehydrocholesterol reductase or suppressor of cytokine signalling (SOCS3) at the ulcer margin.Thus, ASA impairs the physiological healing of pre-existing gastric ulcers, inducing the extensive molecularly functional and proteomic alterations at the wound margin. H 2 S-releasing ATB-340 maintains the target activity of NSAIDs with limited impact on gastric PGE2 signalling and physiological GI regeneration, enhancing anti-inflammatory and anti-oxidative response, and providing the pharmacological advantage., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Hydrogen sulfide (H 2 S) emerged recently as an anti-oxidative signaling molecule that contributes to gastrointestinal (GI) mucosal defense and repair. Indomethacin belongs to the class of non-steroidal anti-inflammatory drugs (NSAIDs) and is used as an effective intervention in the treatment of gout- or osteoarthritis-related inflammation. However, its clinical use is strongly limited since indomethacin inhibits gastric mucosal prostaglandin (PG) biosynthesis, predisposing to or even inducing ulcerogenesis. The H 2 S moiety was shown to decrease the GI toxicity of some NSAIDs. However, the GI safety and anti-oxidative effect of a novel H 2 S-releasing indomethacin derivative (ATB-344) remain unexplored. Thus, we aimed here to compare the impact of ATB-344 and classic indomethacin on gastric mucosal integrity and their ability to counteract the development of oxidative gastric mucosal injuries. Wistar rats were pretreated intragastrically (i.g.) with vehicle, ATB-344 (7-28 mg/kg i.g.), or indomethacin (5-20 mg/kg i.g.). Next, animals were exposed to microsurgical gastric ischemia-reperfusion (I/R). Gastric damage was assessed micro- and macroscopically. The volatile H 2 S level was assessed in the gastric mucosa using the modified methylene blue method. Serum and gastric mucosal PGE 2 and 8-hydroxyguanozine (8-OHG) concentrations were evaluated by ELISA. Molecular alterations for gastric mucosal barrier-specific targets such as cyclooxygenase-1 (COX)-1, COX-2, heme oxygenase-1 (HMOX)-1, HMOX-2, superoxide dismutase-1 (SOD)-1, SOD-2, hypoxia inducible factor (HIF)-1α, xanthine oxidase (XDH), suppressor of cytokine signaling 3 (SOCS3), CCAAT enhancer binding protein (C/EBP), annexin A1 (ANXA1), interleukin 1 beta (IL-1β), interleukin 1 receptor type I (IL-1R1), interleukin 1 receptor type II (IL-1R2), inducible nitric oxide synthase (iNOS), tumor necrosis factor receptor 2 (TNFR2), or H 2 S-producing enzymes, cystathionine γ-lyase (CTH), cystathionine β-synthase (CBS), or 3-mercaptopyruvate sulfur transferase (MPST), were assessed at the mRNA level by real-time PCR. ATB-344 (7 mg/kg i.g.) reduced the area of gastric I/R injuries in contrast to an equimolar dose of indomethacin. ATB-344 increased gastric H 2 S production, did not affect gastric mucosal PGE 2 content, prevented RNA oxidation, and maintained or enhanced the expression of oxidation-sensitive HMOX-1 and SOD-2 in line with decreased IL-1β and XDH. We conclude that due to the H 2 S-releasing ability, i.g., treatment with ATB-344 not only exerts dose-dependent GI safety but even enhances gastric mucosal barrier capacity to counteract acute oxidative injury development when applied at a low dose of 7 mg/kg, in contrast to classic indomethacin. ATB-344 (7 mg/kg) inhibited COX activity on a systemic level but did not affect cytoprotective PGE 2 content in the gastric mucosa and, as a result, evoked gastroprotection against oxidative damage.

Metal-based carbon monoxide (CO)-releasing molecules have been shown to exert anti-inflammatory and anti-oxidative properties maintaining gastric mucosal integrity. We are interested in further development of metal-free CO-based therapeutics for oral administration. Thus, we examine the protective effect of representative CO prodrug, BW-CO-111, in rat models of gastric damage induced by necrotic ethanol or aspirin, a representative non-steroidal anti-inflammatory drug. Treatment effectiveness was assessed by measuring the microscopic/macroscopic gastric damage area and gastric blood flow by laser flowmetry. Gastric mucosal mRNA and/or protein expressions of HMOX1, HMOX2, nuclear factor erythroid 2-related factor 2, COX1, COX2, iNos , Anxa1 and serum contents of TGFB1, TGFB2, IL1B, IL2, IL4, IL5, IL6, IL10, IL12, tumor necrosis factor α , interferon γ , and GM-CSF were determined. CO content in gastric mucosa was assessed by gas chromatography. Pretreatment with BW-CO-111 (0.1 mg/kg, i.g.) increased gastric mucosal content of CO and reduced gastric lesions area in both models followed by increased GBF. These protective effects of the CO prodrug were supported by changes in expressions of molecular biomarkers. However, because the pathomechanisms of gastric damage differ between topical administration of ethanol and aspirin, the possible protective and anti-inflammatory mechanisms of BW-CO-111 may be somewhat different in these models., (© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Endogenous gaseous mediators, such as nitric oxide, hydrogen sulfide or carbon monoxide (CO) are known to exert anti-inflammatory and anti-oxidative activity due to modulation of various molecular pahtways. Therefore, we aimed to investigate if CO released from tricarbonyldichlororuthenium (II) dimer (CORM-2) prevents gastric mucosa against ischemia/reperfusion (I/R)-induced injury in male Wistar rats. Animals were pretreated i.g. With vehicle (DMSO and saline, 1:10), CORM-2 (1, 5 or 10 mg/kg) or zinc protoporphyrin IX (ZnPP, 10 mg/kg i.p.), the HMOXs inhibitor. In separate series, rats were pretreated with CORM-2 (5 mg/kg) applied in combination with glibenclamide (10 mg/kg i.g.), N G -nitro-l-arginine (L-NNA, 20 mg/kg i.p.), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 mg/kg i.p.) or indomethacin (5 mg/kg i.p.). I/R-injuries were induced by clamping celiac artery for 30 min (I) followed by removal of the clamp to obtain R for 3 h. The macroscopic and microscopic area of gastric damage, mucus production and protein expression for HMOX-1/Nrf-2 was determined by planimetry, histology and immunohistochemistry, respectively. Gastric mucosal HMOX-1, HMOX-2, COX-1, COX-2, Kir6.1, Sur2, sGC-α1, sGC-α2, iNOS and eNOS mRNA expression was assessed by real-time PCR. COHb in blood and gastric mucosal CO concentration was analyzed by gas chromatography. Serum content of TGF-β1, TGF-β2, TGF-β3, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, TNF-α, IFN-γ, GM-CSF was evaluated using Luminex platform. PGE 2 concentration and 8-hydroxyguanozine (8-OHG) concentration in gastric mucosa was determined by ELISA. Exposure to I/R induced extensive hemorrhagic erosions in gastric mucosa pretreated with vehicle as compared with intact rats and the area of this gastric damage was reduced by pretreatment with CORM-2 (5 mg/kg i.g.). This effect of CO donor was accompanied by the increased PGE 2 content and a significant decrease in 8-OHG and expression of pro- and anti-inflammatory markers mRNA and proteins. Concurrent treatment of CORM-2 with glibenclamide, L-NNA, ODQ but not with indomethacin significantly increased the area of I/R-induced injury and significantly decreased GBF as compared with the group treated with CORM-2 alone. We conclude that CO releasing CORM-2 prevents gastric mucosal oxidative damage induced by I/R improving GBF, decreasing DNA oxidation and inflammatory response on systemic level. This CO-gastroprotection is mediated by the activity of sGC, NOS and K-ATP channels. CO delivered from its donor maintained physiological gastric mucosal PGE 2 concentration but the involvement of endogenous COX in beneficial activity of this gaseous mediator at least in this model is questionable., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: We aimed to evaluate the effects of unilateral vagotomy (right-VR or left-VL) on the severity of caerulein-induced acute pancreatitis (AP)., Material and Methods: VR or VL was done in Wistar rats 4 days before AP, except in control, sham operated group. Following 5 h administration of subcutaneous injections of caerulein, the pancreatic blood flow (PBF), serum lipase and IL-10 in caval blood samples were measured. The pancreatic specimens were taken from sacrificed rats for the assessment of MDA-4-HNE and morphology., Results: PBF decreased from 310 ± 20 ml/min/100 g of tissue in control rats to 130 ± 12 units in AP (p < 0.01). VR and VL alleviated this effect to 234 ± 22 and 229 ± 26 units, respectively, (p < 0.01). There was an immense increase of serum lipase in AP, from 100 ± 7 U/L up to 5220 ± 210 U/L (p < 0.01). Only VL limited this increase to 3469 ± 300 U/L (p < 0.01). Serum IL-10 increased uniformly in AP, without any effect of preceding VR or VL. VL performed in rats subjected subsequently to AP resulted in stronger reduction of histological changes, such as pancreatic edema and leukocyte infiltration, than the above parameters in AP rats with VR. MDA+4-HNE increased from 7.5 ± 0.1 pmol/g of tissue in control group to 30.6 ± 3 units in AP group (p < 0.01). Concentration of MDA+4-HNE in pancreatic tissue achieved 16.48 ± 3 pmol/g after VR and 13.84 ± 4 pmol/g following VL., Conclusion: Our observation might suggest that protective effect of VL could be stronger than VR in the protection on AP. However changes of PBF seem to be similar in both groups of rats., (Copyright © 2019 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

Nonsteroidal anti-inflammatory drugs (NSAIDs), especially acetylsalicylic acid (ASA), are commonly used in the therapy of various diseases. However, the serious side effects of these drugs, such as bleedings, acute lesions, gastric ulcers, and even intestinal perforations, are widely recognized. NSAIDs inhibit cyclooxygenase (COX) activity resulting in the suppression of mucosal generation of gastroprotective prostaglandins (PGs) derived from a constitutive isoform, COX-1, as well as an inducible isoform, COX-2. COX-1-derived PGs are responsible for gastroprotection, while PGs generated via COX-2 activity also play an important role in gastroprotection and ulcer healing. Recently, a new class of NSAIDs has been developed by adding NO moiety to conventional NSAIDs. In contrast to native NSAIDs, their NO-releasing derivatives such as NO-ASA were found to exhibit lower gastric toxicity despite inhibiting both COX-1 and COX-2 activity in the gastric mucosa. Similar limited gastrointestinal toxicity and protective actions were observed with a new class of hydrogen sulfide (H₂S)-releasing NSAIDs, such as H₂S-releasing naproxen (ATB-346). Dual antiplatelet therapy with ASA and clopidogrel increases the risk of gastrointestinal bleeding in patients with acute coronary syndrome in whom concomitant treatment with a proton-pump inhibitor (PPI) was less effective owing to the interaction of clopidogrel and PPI with the same hepatic cytochrome P-450. In conclusion, new derivatives of NSAIDs releasing vasoactive gaseous mediators NO or H₂S are associated with fewer gastrointestinal adverse effects, suggesting that, in the future, they may be used as a safer alternative in everyday clinical practice and antithrombotic therapy.