Over the past few years, the role of intestinal alkaline phosphatase (IAP) as a crucial mucosal defence factor essential for maintaining gut homeostasis has been established. IAP is an important ...apical brush border enzyme expressed throughout the gastrointestinal tract and secreted both into the intestinal lumen and into the bloodstream. IAP exerts its effects through dephosphorylation of proinflammatory molecules including lipopolysaccharide (LPS), flagellin, and adenosine triphosphate (ATP) released from cells during stressful events. Diminished activity of IAP could increase the risk of disease through changes in the microbiome, intestinal inflammation, and intestinal permeability. Exogenous IAP exerts a protective effect against intestinal and systemic inflammation in a variety of diseases and represents a potential therapeutic agent in diseases driven by gut barrier dysfunction such as IBD. The intestinal protective mechanisms are impaired in IBD patients due to lower synthesis and activity of endogenous IAP, but the pathomechanism of this enzyme deficiency remains unclear. IAP has been safely administered to humans and the human recombinant form of IAP has been developed. This review was designed to provide an update in recent research on the involvement of IAP in intestinal inflammatory processes with focus on IBD in experimental animal models and human patients.
Nitric oxide (NO) and hydrogen sulfide (H2S) are known as biological messengers; they play an important role in human organism and contribute to many physiological and pathophysiological processes. ...NO is produced from l-arginine by constitutive NO synthase (NOS) and inducible NOS enzymatic pathways. This gaseous mediator inhibits platelet aggregation, leukocyte adhesion and contributes to the vessel homeostasis. NO is known as a vasodilatory molecule involved in control of the gastric blood flow (GBF) and the maintenance of gastric mucosal barrier integrity in either healthy gastric mucosa or that damaged by strong irritants. Biosynthesis of H2S in mammals depends upon two enzymes cystathionine-β-synthase and cystathionine γ-lyase. This gaseous mediator, similarly to NO and carbon monoxide, is involved in neuromodulation, vascular contractility and anti-inflammatory activities. For decades, H2S has been known to inhibit cytochrome c oxidase and reduce cell energy production. Nowadays it is generally considered to act through vascular smooth muscle ATP-dependent K+ channels, interacting with intracellular transcription factors and promote sulfhydration of protein cysteine moieties within the cell, but the mechanism of potential gastroprotective and ulcer healing properties of H2S has not been fully explained. The aim of this review is to compare current results of the studies concerning the role of H2S and NO in gastric mucosa protection and outline areas that may pose new opportunities for further development of novel therapeutic targets.
Background: Stress of different origin is known to alter so called "braingut axis" and contributes to a broad array of gastrointestinal disorders including
inflammatory bowel disease (IBD), irritable ...bowel syndrome (IBS) and other
functional gastrointestinal diseases. The stressful situations and various stressors
including psychosocial events, heat, hypo- and hyperthermia may worsen the course
of IBD via unknown mechanism. The aims of this paper were to provide an overview
of experimental and clinical evidences that stress activates the brain-gut axis which
results in a mucosal mast cells activation and an increase in the production of
proinflammatory cytokines and other endocrine and humoral mediators.
Methods: Research and online content related to effects of stress on lower bowel
disorders are reviewed and most important mechanisms are delineated.
Results: Brain conveys the neural, endocrine and circulatory messages to the gut via brain-gut axis
reflecting changes in corticotrophin releasing hormone, mast cells activity, neurotransmission at the
autonomic nerves system and intestinal barrier function all affecting the pathogenesis of animal colitis
and human IBD. Stress triggers the hypothalamus-pituitary axis and the activation of the autonomic
nervous system, an increase in cortisol levels and proinflammatory cytokines such as tumor necrosis
factor-alpha, interleukin-8, interleukin-1beta and interleukin-6.
Conclusion: The acute or chronic stress enhances the intestinal permeability weakening of the tight
junctions and increasing bacterial translocation into the intestinal wall. An increased microbial load in the
colonic tissue, excessive cytokine release and a partially blunted immune reactivity in response to stress
result in its negative impact on IBD.
Recently discovered irisin, a member of the myokines family, is a potential mediator of exercise-induced energy metabolism and a factor promoting browning of the white adipose tissue. Recent evidence ...indicates that this myokine, released from contracting muscles, can mediate the beneficial effects of exercise on health. Irisin may be a potential therapeutic agent against obesity and has been shown to play an important role in the protection of various cells, tissues, and organs due to its anti-inflammatory, antioxidative, and anti-cancer properties. Our aim was to review the recent experimental and clinical studies on irisin and its expression, release into the bloodstream, tissue targets, and potential contribution to the protective effects of exercise in the gastrointestinal tract. Particular emphasis was placed on inflammatory bowel disease, intestinal ischemia/reperfusion injury, periodontitis, and other digestive tract disorders, including carcinogenesis. Overall, irisin holds significant potential as a novel target molecule, offering a safe and therapeutic approach to treating various gastrointestinal diseases.
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Hydrogen sulfide (H2S) and carbon monoxide (CO) exert gastroprotection against acute gastric lesions. We determined the cross-talk between H2S and CO in gastric ulcer healing process ...and regulation of gastric blood flow (GBF) at ulcer margin.
Male Wistar rats with acetic acid-induced gastric ulcers were treated i.g. throughout 9 days with vehicle (control), NaHS (0.1–10 mg/kg) +/− zinc protoporphyrin (ZnPP, 10 mg/kg), d,l-propargylglycine (PAG, 30 mg/kg), CO-releasing CORM-2 (2.5 mg/kg) +/− PAG. GBF was assessed by laser flowmetry, ulcer area was determined by planimetry/histology. Gastric mucosal H2S production was analysed spectrophotometrically. Protein and/or mRNA expression at ulcer margin for vascular endothelial growth factor (VEGF)A, epidermal growth factor receptor (EGFr), cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3-MST), heme oxygenases (HOs), nuclear factor (erythroid-derived 2)-like 2 (Nrf-2), cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), IL-1β, TNF-α and hypoxia inducible factor (HIF)-1α were determined by real-time PCR or western blot. IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IFN-γ, TNF-α, GM-CSF plasma concentration was assessed using Luminex platform.
NaHS dose-dependently decreased ulcer area and increased GBF but ZnPP attenuated these effects. PAG decreased H2S production but failed to affect CORM-2-mediated ulcer healing and vasodilation. NaHS increased Nrf-2, EGFr, VEGFA and decreased pro-inflammatory markers expression and IL-1β, IL-2, IL-13, TNF-α, GM-CSF plasma concentration. CORM-2 decreased IL-1β and GM-CSF plasma levels.
We conclude that NaHS accelerates gastric ulcer healing increasing microcirculation and Nrf-2, EGFr, VEGFA expression. H2S-mediated ulcer healing involves endogenous CO activity while CO does not require H2S. NaHS decreases systemic inflammation more effectively than CORM-2.
Turmeric obtained from the rhizomes of Curcuma longa has been used in the prevention and treatment of many diseases since the ancient times. Curcumin is the principal polyphenol isolated from ...turmeric, which exhibits anti-inflammatory, antioxidant, antiapoptotic, antitumor, and antimetastatic activities. The existing evidence indicates that curcumin can exert a wide range of beneficial pleiotropic properties in the gastrointestinal tract, such as protection against reflux esophagitis, Barrett's esophagus, and gastric mucosal damage induced by nonsteroidal anti-inflammatory drugs (NSAIDs) and necrotizing agents. The role of curcumin as an adjuvant in the treatment of a
infection in experimental animals and humans has recently been proposed. The evidence that this turmeric derivative inhibits the invasion and proliferation of gastric cancer cells is encouraging and warrants further experimental and clinical studies with newer formulations to support the inclusion of curcumin in cancer therapy regimens. This review was designed to analyze the existing data from in vitro and in vivo animal and human studies in order to highlight the mechanisms of therapeutic efficacy of curcumin in the protection and ulcer healing of the upper gastrointestinal tract, with a major focus on addressing the protection of the esophagus and stomach by this emerging compound.
Background
Aspirin exerts side effects within the gastrointestinal tract. Hydrogen sulfide (H
2
S) and carbon monoxide (CO) have been implicated in gastroprotection but the mechanism of beneficial ...action of these gaseous mediators against aspirin-induced damage has not been fully studied. We determined the involvement of afferent sensory neurons, calcitonin-gene-related peptide (CGRP), lipid peroxidation, and nitric oxide (NO) biosynthesis in gastroprotection of H
2
S-releasing NaHS and CO-releasing tricarbonyldichlororuthenium(II) dimer (CORM-2) against aspirin-induced injury.
Methods
Wistar rats with or without capsaicin-induced denervation of sensory neurons were pretreated with vehicle, CORM-2 (5 mg/kg intragastrically), or NaHS (5 mg/kg intragastrically) with or without capsazepine (5 mg/kg intragastrically) or
N
G
-nitro-
l
-arginine (
l
-NNA, 20 mg/kg intraperitoneally). The areas of aspirin-induced lesions and gastric blood flow (GBF) were assessed by planimetry and laser flowmetry respectively. Gastric mucosal messenger RNA and/or protein expression of CGRP, heme oxygenase 1, inducible nitric oxide synthase, cyclooxygenase 2, interleukin-1β, glutathione peroxidase 1 (GPx-1), and superoxide dismutase was determined by real-time PCR or Western blot. Malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) content was determined by colorimetric assay.
Results
Aspirin caused gastric lesions, decreased GBF, and raised MDA content, but pretreatment with NaHS and CORM-2 reduced these effects. Capsaicin-induced denervation or co-treatment with capsazepine reversed the gastroprotective and vasodilatory effects of NaHS but not those of CORM-2.
l
-NNA reversed NaHS-induced gastroprotection and partly reduced CORM-2-induced gastroprotection. NaHS and CORM-2 decreased MDA and 4-HNE content, restoring GPx-1 protein expression.
Conclusions
We conclude that H
2
S- but not CO-mediated gastroprotection against aspirin-induced injury involves afferent sensory nerves and partly NO activity. NaHS and CORM-2 prevented aspirin-induced gastric mucosal lipid peroxidation via restoration of microcirculation and antioxidative GPx-1 protein expression.
Non-steroidal anti-inflammatory drugs (NSAIDs) represent one of the most widely used classes of drugs and play a pivotal role in the therapy of numerous inflammatory diseases. However, the adverse ...effects of these drugs, especially when applied chronically, frequently affect gastrointestinal (GI) tract, resulting in ulceration and bleeding, which constitutes a significant limitation in clinical practice. On the other hand, it has been recently discovered that gaseous mediators nitric oxide (NO), hydrogen sulfide (H
S) and carbon monoxide (CO) contribute to many physiological processes in the GI tract, including the maintenance of GI mucosal barrier integrity. Therefore, based on the possible therapeutic properties of NO, H
S and CO, a novel NSAIDs with ability to release one or more of those gaseous messengers have been synthesized. Until now, both preclinical and clinical studies have shown promising effects with respect to the anti-inflammatory potency as well as GI-safety of these novel NSAIDs. This review provides an overview of the gaseous mediators-based NSAIDs along with their mechanisms of action, with special emphasis on possible implications for GI mucosal defense mechanisms.
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