John L Wallace

The University of Calgary · Department of Physiology and Pharmacology

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 H2S is an endogenous cytoprotective molecule, we hypothesized that new H2S-releasing ASA-derivative (ATB-340) could overcome p...

Hydrogen sulfide (H2S) 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,...

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 c...

The recent report by Fan et al . alleged that the ProPerDP method is inadequate for the detection of protein persulfidation. Upon careful evaluation of their work, we conclude that the claim made by Fan et al . is not supported by their data, rather founded in methodological shortcomings. It is understood that the ProPerDP method generates a mixtur...

Significance: Hydrogen sulfide (H2S), an important regulator of physiology and health, helps resolve inflammation and promotes tissue repair in the gastrointestinal tract. Recent advances: Gut microbiota live as a multispecies biofilm in close interaction with the upper mucus layer lining the epithelium. The relative abundance, spatial organisatio...

Aims: Nonsteroidal anti-inflammatory drugs, including ketoprofen, induce adverse effects within the gastrointestinal (GI)-tract. Hydrogen sulfide (H2S) is an antioxidative gaseous mediator contributing to GI-protection. We aimed to evaluate the GI safety of a novel H2S-releasing derivative of ketoprofen (ATB-352) versus classic ketoprofen and the m...

Microorganisms colonize various ecological niches in the human habitat, as they do in nature. Predominant forms of multicellular communities called biofilms colonize human tissue surfaces. The gastrointestinal tract is home to a profusion of microorganisms with intertwined, but not identical, lifestyles: as isolated planktonic cells, as biofilms an...

Background and Aims: Thrombin levels in the colon of Crohn’s disease patients have recently been found to be elevated 100-fold compared to healthy controls. Our aim was to determine whether and how dysregulated thrombin activity could contribute to local tissue malfunctions associated with Crohn’s disease.Methods: Thrombin activity was studied in t...

Following a request from the European Commission, the EFSA Panel on Additives and products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of BioWorma® (Duddingtonia flagrans NCIMB 30336) when used as a zootechnical feed additive for all grazing animals. Duddingtonia flagrans belongs t...

Silicosis is an occupational disease triggered by the inhalation of fine particles of crystalline silica and characterized by inflammation and scarring in the form of nodular lesions in the lungs. In spite of the therapeutic arsenal currently available, there is no specific treatment for the disease. Flunisolide is a potent corticosteroid shown to...

Remodeling of adipocytes in mesentery (AM) associated with nutritional overload from high fructose diet (HFD) is a source of several comorbidities. However, its pathogenesis is still unclear and there are no specific effective drugs for AM remodeling. Recently hydrogen sulfide (H2S) demonstrated potent cytoprotective actions. The purpose of this st...

Remodeling of adipocytes in mesentery (AM) associated with nutritional overload from high fructose diet (HFD) is a source of several comorbidities. However, its pathogenesis is still unclear and there are no specific effective drugs for AM remodeling. Recently hydrogen sulfide (H2S) demonstrated potent cytoprotective actions. The purpose of this st...

Polymicrobial infections of the gastro-intestinal tract are common in areas with poor sanitation. Disease outcome is the result of complex interactions between the host and pathogens. Such interactions lie at the core of future management strategies of enteric diseases. In developed countries of the world, Giardia duodenalis is a common cause of di...

LINKED ARTICLES This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc

Aims: The covalent linking of nonsteroidal anti-inflammatory drugs to a hydrogen sulfide (H2S)-releasing moiety has been shown to dramatically reduce gastrointestinal (GI) damage and bleeding, as well as increase anti-inflammatory and analgesic potency. We have tested the hypothesis that an H2S-releasing derivative of ketoprofen (ATB-352) would exh...

Gut microbiota interacting with an intact mucosal surface are key to the maintenance of homeostasis and health. This review discusses the current state of knowledge of the biofilm mode of growth of these microbiota communities, and how in turn their disruptions may cause disease. Beyond alterations of relative microbial abundance and diversity, the...

The purpose of this study was to determine the efficacy of a Peruvian botanical formulation for treating disorders of hepatic function and gastric mucosal integrity. The formulation A4+ (Sabell Corporation) contains extracts of Curcuma longa rhizome, Cordia lutea flower, and Annona muricata leaf. Individually these plants have been used as traditio...

Proteolytic homeostasis is important at mucosal surfaces, but its actors and their precise role in physiology are poorly understood. Here we report that healthy human and mouse colon epithelia are a major source of active thrombin. We show that mucosal thrombin is directly regulated by the presence of commensal microbiota. Specific inhibition of lu...

Abstract l‐Arginine is an amino acid that is conditionally essential for mammalian neonates, some strict carnivores, birds and fish. The subject of this opinion is a request for renewal of authorisation of l‐arginine produced by a strain of Corynebacterium glutamicum. The strain designation has changed to its new deposition number, NITE SD 00285, b...

Background Hydrogen sulfide (H2S) is a naturally occurring gaseous mediator produced by intestinal bacteria and various eukaryotic cells. H2S exerts anti-inflammatory, pro-resolution and cytoprotective effects in vivo. ATB-346 is an H2S-releasing derivative of naproxen, which in animals was shown to produce negligible gastrointestinal (GI) damage a...

Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on l-tryptophan produced by fermentation with Escherichia coli CGMCC 11674 when used as a nutritional additive in feed and water for drinking for all animal species and categories...

Background Hydrogen sulfide (H2S) is a naturally occurring mediator produced by intestinal bacteria and various eukaryotic cells, which can exert protective and analgesic effects. ATB-346 is a H2S-releasing derivative of naproxen. In animals, ATB-346 produces negligible gastrointestinal (GI) damage and bleeding. In humans, ATB-346 was found to be m...

The product subject of this assessment is l-valine produced by fermentation with a strain of Corynebacterium glutamicum (CGMCC 11675). It is intended to be used in feed and water for drinking for all animal species and categories. Owing to the uncertainties regarding the possible genetic modification of the original production strain, the FEEDAP Pa...

Background and Purpose ATB‐346 is a hydrogen sulfide (H2S)‐releasing anti‐inflammatory and analgesic drug. Animal studies demonstrated negligible gastrointestinal (GI) damage despite marked inhibition of COX activity and significant analgesic and anti‐inflammatory effects. In humans, ATB‐346 (250 mg once daily) was found to inhibit COX to the same...

Background and objective: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a broad spectrum of life-threatening adverse effects on the immature gastrointestinal tract. NSAID derivatives exploiting the beneficial effects of biologically active gases, such as hydrogen sulfide (H2S), have been developed. Herein, we determin...

Nitric oxide (NO) plays important roles in gastrointestinal mucosal defence, as well as in the pathogenesis of several gastrointestinal diseases (e.g. irritable bowel syndrome and inflammatory bowel disease). The potent cytoprotective effects of NO have been demonstrated in a range of animal models. However, in some disease states, inhibition of NO...

High molecular weight cell-free DNA (hmw cfDNA) found in biological fluid, such as blood, is a promising biomarker for cancer detection. Due to the abundance of background apoptotic cell-free DNA in blood, quantifying the native concentration of hmw cfDNA using existing methods is technically challenging, time consuming, and expensive. We have deve...

Significant alterations of intestinal microbiota and anemia are hallmarks of inflammatory bowel disease (IBD). It is widely accepted that iron is a key nutrient for pathogenic bacteria, but little is known about its impact on microbiota associated with IBD. We used a model device to grow human mucosa-associated microbiota in its physiological anaer...

Introduction. The mesentery is one of the recently described separate organs, whose functions and ability to protect itself from injuries are still unclear. Adipocytes are a part of the mesentery (MAC); however, little is known about their age-related changes, responses at times of damage induced by hyperglycemia, stress, and their interaction. Hyd...

Introduction. Sulfite oxidase (SO) is one of mitochondrial enzymes involved in H2S-pathway and multiple physiological processes, including oxidative stress. The dominant sulfide oxidation products vary in a tissue-specific manner, whatever SO/oxidative stress involved in gastric mucosa (GM) injury is unclear. Our labs has shown potent cytoprotectiv...

Background The use of nonsteroidal anti-inflammatory drugs (NSAIDs) among neonates is associated with a broad spectrum of life-threatening adverse effects on the gastrointestinal tract. Indeed, we have previously demonstrated that NSAIDs, such as indomethacin (INDO), induce damaging effects on the immature intestine (Perron et al. Genomics, 2013)....

Background Infectious diarrheal disease represents a critical concern for child health in developing countries. Recent findings indicate that in such environments, infection with Giardia intestinalis may protect against bacterial driven diarrhea via mechanisms that remain unknown. Aims We hypothesized that cysteine protease(s) released by Giardia...

Eicosanoids play important roles in modulating inflammation throughout the body. The gastrointestinal (GI) tract, in part because of its intimate relationship with the gut microbiota, is in a constant state of low‐grade inflammation. Eicosanoids like PGs, lipoxins and leukotrienes play essential roles in maintenance of mucosal integrity. On the oth...

Periodontal disease is the most common cause of tooth loss in humans, is an inflammatory disease initiated by oral microbial biofilm. Given the involvement of the inflammatory pathway in this type of pathology, the main pharmacological strategy for the treatment of periodontitis, is the inhibition of the inflammatory process in order to prevent tis...

Clinical use of non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin or naproxen is limited due to the gastrotoxicity evoked by these compounds. Endogenous hydrogen sulfide (H2S) and delivered via an H2S donor have been shown to play important role in the maintenance of gastric mucosal integrity. This study aimed to compare the effects o...

Of the numerous gaseous substances that can act as signaling molecules, the best characterized are nitric oxide, carbon monoxide and hydrogen sulfide. Contributions of each of these low molecular weight substances, alone or in combination, to maintenance of gastrointestinal mucosal integrity have been established. There is considerable overlap in t...

The metabolic relationship between H2S and NO in gastric mucosa in norm and pathology is still poorly studied. Aim of this study was to determine mechanisms of interaction between NO and H2S generating systems under conditions of the combined actions of NSAIDs and stress. Water restraint stress (WRS) was used to induce peptic lessions in rats; napr...

Our understanding of polymicrobial gastrointestinal infections and their effects on host biology remains incompletely understood. Giardia duodenalis is an ubiquitous intestinal protozoan parasite infecting animals and humans. Concomitant infections with Giardia and other gastrointestinal pathogens commonly occur. In countries with poor sanitation,...

Giardia inhibits C. rodentium translocation to the liver. Male C57/Bl6 mice (7–8 week old) were infected with G. muris and C. rodentium (C.r.) separately and in co-infection. On 14th day post-infection, liver samples were plated on lysogeny broth (LB) agar to reveal and count translocated bacteria. All data are representative of n = 5–10/group and...

Giardia co-infection attenuates microscopic damage in the colon of mice infected with C. rodentium. Male C57/Bl6 mice (7–8 week old) were infected with G. muris and C. rodentium (C.r.) separately and in co-infection. On 14th day post-infection, colonic samples were collected and stained. (A-D) Hematoxylin eosin (H&E) staining of colon tissues, repr...

Giardia prevents C. rodentium attachment, and invasion through the colonic epithelium. Male C57/Bl6 mice (7–8 week old) were infected with G. muris and C. rodentium (C.r.) separately and in co-infection. Colonic samples were collected and analyzed on 14th day post-infection. Anti-GFP-C. rodentium staining represents C. rodentium burden of colon (at...

Giardia co-infection with EPEC activates AMPs production in Caco-2 cells in a cathepsin B-like -dependent manner. G. duodenalis co-infection with EPEC increased mRNA expression of HBD-2. Cells were incubated with G. duodenalis for 3 hours and co-incubated with EPEC for 2 hours. (A) mRNA level of HBD-2. (B) IF staining for HBD-2. (C) mRNA level of T...

Primers sequences for PCR. (DOCX)

Recent data of study H2S in gastrointestinal tract has proven its potent cytoprotection on mucosal defense among acid-related diseases in the gut. The aim was to evaluate the effects of H2S-releasing aspirin derivative (ATB-340) on esophageal and gastric mucosa compromised by stress injury. Rats were treated with vehicle (control), aspirin (10 mg/k...

Significance: Shortly after the discovery of the role of hydrogen sulfide in many physiological and pathological processes, attempts were made to develop novel pharmaceuticals that may be of benefit for treatment or prevention of a wide range of disorders. The promise of hydrogen sulfide (H2S)-based therapeutics is now being demonstrated in clinic...

Giardia duodenalis is a prevalent cause of acute diarrheal disease worldwide. However, recent outbreaks in Italy and Norway have revealed a link between giardiasis and the subsequent development of chronic post-infectious irritable bowel syndrome (PI-IBS). While the mechanisms underlying the causation of PI-IBS remain obscure, recent findings sugge...

Recent data of study H2S in gastrointestinal tract has proven its potent cytoprotection on mucosal defense. Among acid-related diseases in the gut esophagitis, Barrett esophagus, gastritis are prevalent and characterized by low-grade inflammation, which is a pre-malignant condition. Aspirin is one of the most widely prescribed nonsteroid anti-infla...

Objective — to compare effects of acetylsalicylic acid (ASA) and hydrogen sulphide-releasing aspirin (H2S-ASA) on the esophageal mucosa (EM), compromised by stress injury. Materials and methods. The rodents were injected either placebo (control), ASA (10 mg/kg) or H2S-ASA (ATB-340, 17.5 mg/kg) as a single injection and injections over 9 days with i...

Background Infectious diarrheal disease represents a critical concern for child health in developing countries, and often occurs in the context of polymicrobial infections. Mechanisms whereby concurrent infections may alter clinical disease outcome remain obscure. Recent findings indicate that giardiasis could protect against pediatric diarrhea, bu...

Inflammation plays a key role in tumor promotion and development. Indeed, cyclooxygenase-2 (COX-2) expression is strongly associated with different types of cancer. An emerging class of compounds with significant anti-inflammatory properties is the hydrogen sulfide-releasing non-steroidal anti-inflammatory drugs (H2S-NSAIDs). They consist of a trad...

The aim of review. To assess protective mechanisms and efficacy of gaseous mediators based antiinflammatory therapy. Key points. Nowadays there are no reasonable and effective methods of prevention and treatment of NSAID-induced intestinal lesions. The discovery of powerful anti-inflammatory and cytoprotective effects of endogenous gaseous mediator...

Background Rebamipide is a gastroprotective agent with promising results against gastric damage induced by non-steroidal anti-inflammatory drugs. The present study evaluated if rebamipide protects against naproxen-induced gastric damage in healthy volunteers. Changes in gastric PGE2 tissue concentration were also evaluated. Methods After a prelimin...

Aspirin is one of the widely prescribed antiplatelet and anti-inflammatory drugs and last data expanded its role into complex biological processes such as cancerogenesis, tissue repair, and aging, despite that well know its effects for peptic ulcer or gastrointestinal (GI) bleeding which can develop even in an achlorhydric environment. Recent exten...

Glyprolines have been reported to exert protective effects in the stomach. In this study, we examined the potential effects of intranasal administration of Pro-Gly-Pro (PGP) and N-acetyl-Pro-Gly-Pro (AcPGP) on experimental gastric ulcer formation and healing. We also studied gastric release of the cytokine GRO/CINC-1, and its potential role in ulce...

Aspirin is one of the widely prescribed antiplatelet and anti‐inflammatory drugs and last data expanded its role into complex biological processes such as cancerogenesis, tissue repair, and aging, despite that well know its effects for peptic ulcer or gastrointestinal (GI) bleeding which can develop even in an achlorhydric environment. Recent exten...

Background Polymicrobial gastrointestinal (GI) infections are common in individuals living in areas with poor sanitation. In areas where Giardia sp. infections are found in association with enteropathogens causing diarrhea via gut inflammation, Giardia sp. appears to protect against diarrhea via mechanisms that remain unlcear. Intestinal epithelial...

Nonsteroidal anti-inflammatory drugs have been shown to reduce the incidence of gastrointestinal cancers, but the propensity of these drugs to cause ulcers and bleeding limits their use. H2S has been shown to be a powerful cytoprotective and anti-inflammatory substance in the digestive system. This study explored the possibility that a H2S-releasin...

Significance Nonsteroidal antiinflammatory drugs (NSAIDs) work by inhibiting cyclooxygenase-2 (COX-2) induced at sites of inflammation. They are among the most widely used drugs worldwide, but their cardiovascular side effects are a major concern for patients, regulators, and industry. NSAID side effects are mediated by inhibition of constitutively...

Introduction. Aspirin is one of the widely prescribed antiplatelet and anti-inflammatory drugs and last data expanded its role into complex biological processes such as cancerogenesis, despite the fact that its effects for peptic ulcer or gastrointestinal (GI) bleeding, which can develop even in an achlorhydric environment, are well known. Recent e...

GIARDIA MURIS INCREASES INTESTINAL CASPASE-1 AND CASPASE-11 AND REDUCES THE SEVERITY OF CITROBACTER RODENTIUM-INDUCED COLITIS. Anna Manko1,2, Jean-Paul Motta2, James Cotton2, Bruce A. Vallance3, John L. Wallace1, Andre G. Buret 1,2 1- Department of Physiology & Pharmacology, University of Calgary, AB, Canada 2- Department of Biological Sciences, H...

Opinion statement: Despite the introduction 20-30 years ago of potent inhibitors of gastric acid secretion and anti-inflammatory drugs that preferentially inhibit cyclo-oxygenase (COX)-2, the GI adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) remain a significant clinical concern and a considerable economic burden. Inhibitors of a...

Among the most commonly used drugs, nonsteroidal anti-inflammatory drugs (NSAIDs) remain problematic because of their propensity to cause serious adverse events, principally affecting the gastrointestinal tract. In recent years, the discovery of potent anti-inflammatory and cytoprotective effects of endogenous gaseous mediators (nitric oxide, hydro...

Hydrogen sulfide has potent anti-inflammatory and cytoprotective properties. In the gastrointestinal tract, hydrogen sulfide contributes significantly to mucosal defence and responses to injury. This includes promotion of resolution of inflammation and healing. Inhibition of hydrogen sulfide synthesis increases the susceptibility of the gastrointes...

The small intestine is a significant site of ulceration and bleeding induced by nonsteroidal anti-inflammatory drugs (NSAIDs). The pathogenesis is poorly understood. The present study explored the roles of bile, bacteria and enterohepatic circulation to NSAID-enteropathy, using both a conventional NSAID (naproxen) and a gastrointestinal-safe naprox...

Hydrogen sulfide (H2S) has become recognized as an important signalling molecule throughout the body, contributing to many physiological and pathological processes. In recent years, improved methods for measuring H2S levels and the availability of a wider range of H2S donors and more selective inhibitors of H2S synthesis have helped to more accurat...

Hydrogen sulfide (H2S) plays an important role in human physiology, exerting vasodilatory, neuromodulatory and anti-inflammatory effects. H2S has been implicated in the mechanism of gastrointestinal integrity but whether this gaseous mediator can affect hemorrhagic lesions induced by stress has been little elucidated. We studied the effect of the H...

Hydrogen sulfide is an endogenous gaseous mediator that plays important roles in many physiological processes in microbes, plants, and animals. This chapter focuses on the important roles of hydrogen sulfide in protecting tissues against injury, promoting the repair of damage, and downregulating the inflammatory responses. The chapter focuses large...

Microbiota dysbiosis and impaired barrier function are among the most prominent features of inflammatory bowel disease. In the gastrointestinal tract, hydrogen sulfide (H2S) is an important regulator of mucosal homeostasis. We hypothesized that H2S promotes resolution of colonic inflammation through actions on microbiota biofilm and the mucus barri...

BACKGROUND: In experimental periodontitis, non-steroidal antiinflammatory drugs (NSAIDs) effectively inhibit the resultant alveolar bone loss. However, their deleterious gastric effects, observed in both animals and humans, dramatically limit their long-term use. It has been proven that the addition of a hydrogen sulfide (H2S)-releasing moiety to c...

The non-steroid anti-inflammatory drugs (NSAIDs) are among the drugs that can commonly cause injury in the esophagus, such as non-reflux oesophagitis, with important clinical consequences. This injury may be 'silent' and therefore often overlooked. Recently, we established that hydrogen sulfide (H2S) is a critical mediator of esophageal mucosal pro...

The clinical significance of small intestinal damage caused by nonsteroidal anti-inflammatory drugs (NSAIDs) remains under-appreciated. It occurs with greater frequency than the damage caused by these drugs in the upper gastrointestinal tract, but is much more difficult to diagnose and treat. Although the pathogenesis of NSAID enteropathy remains i...

During a course of colitis, production of the gaseous mediator hydrogen sulfide (H2S) is markedly up-regulated at sites of mucosal damage and contributes significantly to healing and resolution of inflammation. The signaling mechanisms through which H2S promotes resolution of colitis are unknown. We hypothesized that the beneficial effects of H2S i...

Background Traumatic brain injury (TBI) induces secondary injury mechanisms, including dynamic interplay between ischemic, inflammatory and cytotoxic processes. We recently reported that administration of ATB-346 (2-(6-methoxynapthalen- 2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester), a hydrogen sulfide-releasing cyclooxygenase inhibitor, showed...

Non-erosive esophagitis is a chronic inflammatory condition of the esophagus and is a form of gastroesophageal reflux disease. There are limited treatment options for non-erosive esophagitis, and it often progresses to Barrett's esophagus and esophageal carcinoma. Hydrogen sulfide has been demonstrated to be a critical mediator of gastric and intes...

Background and purpose: Hydrogen sulphide is an important mediator of gastrointestinal mucosal defence. The use of non-steroidal anti-inflammatory drugs (NSAIDs) is significantly limited by their toxicity in the gastrointestinal tract. Particularly concerning is the lack of effective preventative or curative treatments for NSAID-induced intestinal...

Abstract Mechanisms of gastric defence under conditions of combined influence of acute stress and nonsteroidal anti-inflammatory drugs (NSAIDs) are still poorly studied. The aim of this study was to explore the effects of different types of NSAIDs (naproxen, celecoxib, and ATB-346) in producing experimental gastric lesions (induced by water restrai...

Significance Inflammatory bowel diseases (IBDs) are debilitating conditions with no known cure. Recent evidence suggests that elevated intestinal hydrogen sulfide (H 2 S) synthesis promotes healing and reduces inflammation. H 2 S is synthesized from cysteine largely via vitamin B 6 -dependent enzymes. People with IBD are also at increased risk of h...