Novel Hydrogen Sulfide (H2S)-Releasing BW-HS-101 and Its Non-H2S Releasing Derivative in Modulation of Microscopic and Molecular Parameters of Gastric Mucosal Barrier

Abstract

Hydrogen sulfide (H2S) is an endogenously produced molecule with anti-inflammatory and cytoprotective properties. We aimed to investigate for the first time if a novel, esterase-sensitive H2S-prodrug, BW-HS-101 with the ability to release H2S in a controllable manner, prevents gastric mucosa against acetylsalicylic acid-induced gastropathy on microscopic and molecular levels. Wistar rats were pretreated intragastrically with vehicle, BW-HS-101 (0.5–50 μmol/kg) or its analogue without the ability to release H2S, BW-iHS-101 prior to ASA administration (125 mg/kg, intragastrically). BW-HS-101 was administered alone or in combination with nitroarginine (L-NNA, 20 mg/kg, intraperitoneally) or zinc protoporphyrin IX (10 mg/kg, intraperitoneally). Gastroprotective effects of BW-HS-101 were additionally evaluated against necrotic damage induced by intragastrical administration of 75% ethanol. Gastric mucosal damage was assessed microscopically, and gastric blood flow was determined by laser flowmetry. Gastric mucosal DNA oxidation and PGE2 concentration were assessed by ELISA. Serum and/or gastric protein concentrations of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-13, VEGF, GM-CSF, IFN-γ, TNF-α, and EGF were determined by a microbeads/fluorescent-based multiplex assay. Changes in gastric mucosal iNOS, HMOX-1, SOCS3, IL1-R1, IL1-R2, TNF-R2, COX-1, and COX-2 mRNA were assessed by real-time PCR. BW-HS-101 or BW-iHS-101 applied at a dose of 50 μmol/kg protected gastric mucosa against ASA-induced gastric damage and prevented a decrease in the gastric blood flow level. H2S prodrug decreased DNA oxidation, systemic and gastric mucosal inflammation with accompanied upregulation of SOCS3, and EGF and HMOX-1 expression. Pharmacological inhibition of nitric oxide (NO) synthase but not carbon monoxide (CO)/heme oxygenase (HMOX) activity by L-NNA or ZnPP, respectively, reversed the gastroprotective effect of BW-HS-101. BW-HS-101 also protected against ethanol-induced gastric injury formation. We conclude that BW-HS-101, due to its ability to release H2S in a controllable manner, prevents gastric mucosa against drugs-induced gastropathy, inflammation and DNA oxidation, and upregulate gastric microcirculation. Gastroprotective effects of this H2S prodrug involves endogenous NO but not CO activity and could be mediated by cytoprotective and anti-inflammatory SOCS3 and EGF pathways.

Progress and perspective on hydrogen sulfide donors and their biomedical applications

“…The authors also claimed the application potential of this H 2 S delivery strategy exemplified by the conjugation of donor 45 with an NSAID naproxen. Although most recently, donor 45 proved to markedly assuage drugs‐induced damages on gastric mucosa, 253 cautions should still be taken when using thioacids as H 2 S donors because thioacids are highly reactive species that can easily acylate residues on proteins 254 …”

Oral supramolecular nanovectors for dual natural medicine codelivery to prevent gastric mucosal lesion

“…38 PGE2 can cure gastric ulcers by upregulating vascular endothelial growth factor levels and stimulating angiogenesis by activating prostaglandin receptor 4 receptors. 39…”

“…38 PGE2 can cure gastric ulcers by upregulating vascular endothelial growth factor levels and stimulating angiogenesis by activating prostaglandin receptor 4 receptors. 39 We further investigated the interaction of inhibitors of the nuclear factor (NF)-κB (IκB) related protein IkBβ/NF-κB p65 homodimer complex (chain A: p65 subunit A; chain B: p65 subunit B; chain D: IkBβ) or κB kinase (IκK) and dual drugs or nanovector components by molecular docking (Fig. S19 and 20 †).…”

The mitochondria-targeted sulfide delivery molecule attenuates drugs-induced gastropathy. Involvement of heme oxygenase pathway.

“…Comparatively, separate groups of rats were treated i.g. with vehicle or AP39 (0.02 mg/kg) and after 30 min administered with 1 mL of 75% ethanol to induce necrotic gastric mucosal injuries [ 50 ]. Additional control group (Intact) included rats with healthy gastric mucosa without any lesions (not exposed to the treatments with tested compounds).…”