Molecular Thumbprints: Biological Signatures That Measure Loss of Identity.

Each life is challenged to adapt to an ever-changing environment with integrity-simply put, to maintain identity. We hypothesize that this mission statement of adaptive homeostasis is particularly poignant in an adaptive response, like inflammation. A maladaptive response of unresolved inflammation can seed chronic disease over a lifetime.

Physiological healing of chronic gastric ulcer is not impaired by the hydrogen sulphide (HS)-releasing derivative of acetylsalicylic acid (ATB-340): functional and proteomic approaches.

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.

Hydrogen Sulfide-Releasing Indomethacin-Derivative (ATB-344) Prevents the Development of Oxidative Gastric Mucosal Injuries.

Hydrogen sulfide (HS) 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.

Potent anti-inflammatory effects of an H S-releasing naproxen (ATB-346) in a human model of inflammation.

ATB-346 is a hydrogen sulfide-releasing non-steroidal anti-inflammatory drug (H S-NSAID) derived from naproxen, which in preclinical studies has been shown to have markedly reduced gastrointestinal adverse effects. However, its anti-inflammatory properties in humans compared to naproxen are yet to be confirmed. To test this, we used a dermal model of acute inflammation in healthy, human volunteers, triggered by ultraviolet-killed Escherichia coli.

Gaseous Mediators as a Key Molecular Targets for the Development of Gastrointestinal-Safe Anti-Inflammatory Pharmacology.

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 (HS) and carbon monoxide (CO) contribute to many physiological processes in the GI tract, including the maintenance of GI mucosal barrier integrity.

Effects of Hydrogen Sulfide on the Microbiome: From Toxicity to Therapy.

Hydrogen sulfide (HS), an important regulator of physiology and health, helps resolve inflammation and promotes tissue repair in the gastrointestinal tract. Gut microbiota live as a multispecies biofilm in close interaction with the upper mucus layer lining the epithelium. The relative abundance, spatial organization, and function of these microorganisms affect a broad range of health outcomes.

Microbiome Profile and Molecular Pathways Alterations in Gastrointestinal Tract by Hydrogen Sulfide-Releasing Nonsteroidal Anti-Inflammatory Drug (ATB-352): Insight into Possible Safer Polypharmacy.

Nonsteroidal anti-inflammatory drugs, including ketoprofen, induce adverse effects within the gastrointestinal (GI)-tract. Hydrogen sulfide (HS) is an antioxidative gaseous mediator contributing to GI-protection. We aimed to evaluate the GI safety of a novel HS-releasing derivative of ketoprofen (ATB-352) classic ketoprofen and the molecular mechanisms of their activity after chronic treatment in experimental animal models.

Gastrointestinal biofilms in health and disease.

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 and in biofilm-dispersed form.

Increased Mucosal Thrombin is Associated with Crohn's Disease and Causes Inflammatory Damage through Protease-activated Receptors Activation.

Background And Aims: Thrombin levels in the colon of Crohn's disease patients have recently been found to be elevated 100-fold compared with 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 tissues from Crohn's disease patients and healthy controls.

Giardia spp. promote the production of antimicrobial peptides and attenuate disease severity induced by attaching and effacing enteropathogens via the induction of the NLRP3 inflammasome.

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.

Enhanced Analgesic Effects and Gastrointestinal Safety of a Novel, Hydrogen Sulfide-Releasing Anti-Inflammatory Drug (ATB-352): A Role for Endogenous Cannabinoids.

The covalent linking of nonsteroidal anti-inflammatory drugs to a hydrogen sulfide (HS)-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 HS-releasing derivative of ketoprofen (ATB-352) would exhibit enhanced efficacy without significant GI damage in a mouse model of allodynia/hyperalgesia. ATB-352 was significantly more potent and effective as an analgesic than ketoprofen and did not elicit GI damage.

Efficacy of a Peruvian Botanical Remedy (Sabell A4+) for Treating Liver Disease and Protecting Gastric Mucosal Integrity.

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 rhizome, flower, and leaf. Individually these plants have been used as traditional remedies for liver disease.

From primordial gas to the medicine cabinet.

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.

Active thrombin produced by the intestinal epithelium controls mucosal biofilms.

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.

Effect of Ketoprofen and ATB-352 on the Immature Human Intestine: Identification of Responders and Non-responders.

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 determined the effects of ketoprofen and ATB-352, a H2S-releasing ketoprofen derivative, on selected metabolic pathways previously identified to be significantly altered by indomethacin in the human immature intestine.

A proof-of-concept, Phase 2 clinical trial of the gastrointestinal safety of a hydrogen sulfide-releasing anti-inflammatory drug.

Background And Purpose: ATB-346 is a hydrogen sulfide (H S)-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 extent as naproxen (550 mg twice daily).

Pathobiont release from dysbiotic gut microbiota biofilms in intestinal inflammatory diseases: a role for iron?

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 aim of the review is to focus on the disruptions of the microbiota biofilm structure and function, the dispersion of commensal bacteria, and the mechanisms whereby these dispersed commensals may become pathobionts.

Nitric oxide in the gastrointestinal tract: opportunities for drug development.

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).

Iron Sequestration in Microbiota Biofilms As A Novel Strategy for Treating Inflammatory Bowel Disease.

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 anaerobic biofilm phenotype.

Eicosanoids in the gastrointestinal tract.

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.

Anti-inflammatory effect of ATB-352, a H2S -releasing ketoprofen derivative, on lipopolysaccharide-induced periodontitis in rats.

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 tissue destruction and bone resorption, a condition associated with a painful state. To do this, the best class of drugs are Non-steroidal anti-inflammatory drugs (NSAIDs), however, the presence of side effects, especially at the gastrointestinal tract, limits their use for long-term therapy.

Hydrogen sulfide: an agent of stability at the microbiome-mucosa interface.

A diverse range of effects of the intestinal microbiota on mucosal defense and injury has become increasingly clear over the past decade. Hydrogen sulfide (HS) has emerged as an important mediator of many physiological functions, including gastrointestinal mucosal defense and repair. Hydrogen sulfide is produced by gastrointestinal tract tissues and by bacteria residing within the gut and can influence the function of a wide range of cells.

Gaseous Mediators in Gastrointestinal Mucosal Defense and Injury.

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 the actions of these gases in modulating mucosal defense and responses to injury, and in some instances they act in a cooperative manner.