5-Amino-2-hydroxybenzoic Acid 4-(5-Thioxo-5<i>H</i>-[1,2]dithiol-3yl)-phenyl Ester (ATB-429), a Hydrogen Sulfide-Releasing Derivative of Mesalamine, Exerts Antinociceptive Effects in a Model of Postinflammatory Hypersensitivity

Distrutti, Eleonora; Sediari, Luca; Mencarelli, Andrea; Renga, Barbara; Orlandi, Stefano; Russo, Giuseppe; Caliendo, Giuseppe; Santagada, Vincenzo; Cirino, Giuseppe; Wallace, John L.; Fiorucci, Stefano

doi:10.1124/jpet.106.106435

Cited by 133 publications

(106 citation statements)

References 40 publications

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“…In contrast, hydrogen sulfide stimulated endothelial cell proliferation in a dose-dependent manner. In contrast to some other activities of S-NSAIDs and dithioles, their antiangiogenic activity is probably independent of H 2 S release (Distrutti et al, 2006;Li et al, 2006).…”

Section: Discussionmentioning

confidence: 82%

Modulation of angiogenesis by dithiolethione‐modified NSAIDs and valproic acid

Isenberg

Jia

Field

et al. 2007

British J Pharmacology

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Background and purpose: Angiogenesis involves multiple signaling pathways that must be considered when developing agents to modulate pathological angiogenesis. Because both cyclooxygenase inhibitors and dithioles have demonstrated antiangiogenic properties, we investigated the activities of a new class of anti-inflammatory drugs containing dithiolethione moieties (S-NSAIDs) and S-valproate. Experimental approach: Anti-angiogenic activities of S-NSAIDS, S-valproate, and the respective parent compounds were assessed using umbilical vein endothelial cells, muscle and tumor tissue explant angiogenesis assays, and developmental angiogenesis in Fli:EGFP transgenic zebrafish embryos. Key results: Dithiolethione derivatives of diclofenac, valproate, and sulindac inhibited endothelial cell proliferation and induced Ser 78 phosphorylation of hsp27, a known molecular target of anti-angiogenic signaling. The parent drugs lacked this activity, but dithiolethiones were active at comparable concentrations. Although dithiolethiones can potentially release hydrogen sulphide, NaSH did not reproduce some activities of the S-NSAIDs, indicating that the dithioles regulate angiogenesis through mechanisms other than release of H 2 S. In contrast to the parent drugs, S-NSAIDs, S-valproate, NaSH, and dithiolethiones were potent inhibitors of angiogenic responses in muscle and HT29 tumor explants assessed by 3-dimensional collagen matrix assays. Dithiolethiones and valproic acid were also potent inhibitors of developmental angiogenesis in zebrafish embryos, but the S-NSAIDs, remarkably, lacked this activity. Conclusions and implication: S-NSAIDs and S-valproate have potent anti-angiogenic activities mediated by their dithiole moieties. The novel properties of S-NSAIDs and S-valproate to inhibit pathological versus developmental angiogenesis suggest that these agents may have a role in cancer treatment.

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Section: Discussionmentioning

confidence: 82%

Modulation of angiogenesis by dithiolethione‐modified NSAIDs and valproic acid

Isenberg

Jia

Field

et al. 2007

British J Pharmacology

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“…However, the documented low-grade inflammation in IBS, the suggestive preliminary data from animal studies (52), and the noticeable paucity of clinical data in this area emphasize the need for further investigation to enable more solid conclusions regarding this treatment option in IBS. Understanding the role of the immune system in IBS pathophysiology may further clarify the potential therapeutic role of targeting the immune system in the treatment of IBS.…”

Section: Discussionmentioning

confidence: 99%

Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome

Ringel

Maharshak

2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Ringel Y, Maharshak N.Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 305: G529-G541, 2013. First published July 25, 2013; doi:10.1152/ajpgi.00207.2012.-The pathophysiology of irritable bowel syndrome (IBS) is believed to involve alterations in the brain-gut axis; however, the etiological triggers and mechanisms by which these changes lead to symptoms of IBS remain poorly understood. Although IBS is often considered a condition without an identified "organic" etiology, emerging evidence suggests that alterations in the gastrointestinal microbiota and altered immune function may play a role in the pathogenesis of the disorder. These recent data suggest a plausible model in which changes in the intestinal microbiota and activation of the enteric immune system may impinge upon the brain-gut axis, causing the alterations in gastrointestinal function and the clinical symptoms observed in patients with IBS. This review summarizes the current evidence for altered intestinal microbiota and immune function in IBS. It discusses the potential etiological role of these factors, suggests an updated conceptual model for the pathogenesis of the disorder, and identifies areas for future research.inflammation; gastrointestinal; microbiota IRRITABLE BOWEL SYNDROME (IBS) is the most common and best studied condition of a larger group of functional gastrointestinal (GI) disorders. Functional GI disorders refer to the presence of a variable combination of chronic or recurrent GI symptoms not explained by structural or biochemical abnormalities (130,159). IBS is characterized by chronic or recurring abdominal pain or discomfort that is associated with altered bowel habits (53, 99). The condition is often associated with other GI symptoms (e.g., bloating, distention, and gas), other functional GI disorders (e.g., functional dyspepsia), other non-GI disorders (e.g., fibromyalgia, interstitial cystitis, migraine headache), and psychological disorders (e.g., depression, anxiety, somatization) (96,146,167). Traditionally, IBS has been subtyped on the basis of the patient's predominant symptom/stool pattern (99). These subtypes include diarrhea predominant (IBS-D), constipation predominant (IBS-C), and mixed type (IBS-M), in which patients experience alternating periods of diarrhea and constipation. Unlike other conditions that can be associated with abdominal pain and abnormal bowel patterns such as inflammatory bowel diseases (IBD), IBS is not associated with any overt histopathology, structural, or biochemical abnormalities. IBS has been generally considered to be caused by alterations in the brain-gut axis (the bidirectional communication network involving the enteric nervous system, the autonomic nervous system, and the central nervous system) (60,108,125), and the pathophysiological mechanisms behind this condition remain unclear. Traditionally, IBS is considered to be a multifactorial condition in which multiple environmental, genetic, physiological, ...

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“…This appears to contribute significantly to protection and repair of tissue injury. H 2 S has been shown to exert anti-nociceptive effects in some (15,18,19,62), but not all (37) visceral pain studies. The discrepancies may be related to the different methods for measuring pain or to different doses or routes of administration of the H 2 S-releasing agents.…”

Section: H 2 S and Inflammationmentioning

confidence: 99%

Hydrogen Sulfide: An Endogenous Mediator of Resolution of Inflammation and Injury

Wallace

Ferraz

Muscará

2012

Antioxidants & Redox Signaling

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203

148

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Significance: Hydrogen sulfide is emerging as an important mediator of many aspects of inflammation, and perhaps most importantly as a factor promoting the resolution of inflammation and repair of injury. Recent Advances: In the gastrointestinal tract, H 2 S has been shown to promote healing of ulcers and the resolution of mucosal inflammation. On the other hand, suppression of endogenous H 2 S synthesis impairs mucosal defense and leads to increased granulocyte infiltration. H 2 S has been exploited in the design of more effective and safe anti-inflammatory drugs. Critical Issues: Enteric bacteria can be a significant source of H 2 S, which could affect mucosal integrity; indeed, luminal H 2 S can serve as an alternative to oxygen as a metabolic substrate for mitochondrial respiration in epithelial cells. Enterocytes and colonocytes thereby represent a ''metabolic barrier'' to the diffusion of bacteria-derived H 2 S into the subepithelial space. A compromise of this barrier could result in modulation of mucosal function and integrity by bacterial H 2 S. Future Directions: Improvements in methods for measurement of H 2 S and development of more selective inhibitors are crucial for gaining a better understanding of the pathophysiological importance of this mediator. Results from animal studies suggest that H 2 S-releasing agents are promising therapeutic agents for many indications, but these compounds need to be assessed in a clinical setting. Antioxid. Redox Signal. 17, 58-67.

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5-Amino-2-hydroxybenzoic Acid 4-(5-Thioxo-5H-[1,2]dithiol-3yl)-phenyl Ester (ATB-429), a Hydrogen Sulfide-Releasing Derivative of Mesalamine, Exerts Antinociceptive Effects in a Model of Postinflammatory Hypersensitivity

Cited by 133 publications

References 40 publications

Modulation of angiogenesis by dithiolethione‐modified NSAIDs and valproic acid

Modulation of angiogenesis by dithiolethione‐modified NSAIDs and valproic acid

Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome

Hydrogen Sulfide: An Endogenous Mediator of Resolution of Inflammation and Injury

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