geranylgeranylacetone and Intestinal-Diseases

We aimed to explore the effect of geranylgeranylacetone on small-intestinal mucosal injuries induced by diclofenac sodium in patients with rheumatic diseases.. The patients were randomly divided into two groups in our prospective study. The patients in the geranylgeranylacetone group received diclofenac sodium plus geranylgeranylacetone, and those in the control group received only diclofenac sodium for 12 weeks. We examined small-intestinal mucosal injuries using capsule endoscopy before and after treatment.. There were no significant differences between geranylgeranylacetone (n = 21, male: 42.9%; age: 31.0 ± 9.0 year) and control (n = 19, male: 68.4%; age: 31.0 ± 11.0 year) groups in terms of the numbers of patients with petechiae/red spots, denuded areas and mucosal breaks at baseline capsule endoscopy. After treatment, the numbers of patients with denuded areas (χ(2) = 0.000, P = 1.000) and mucosal breaks (χ(2) = 1.750, P = 0.186) did not increase in the geranylgeranylacetone group. However, the numbers of patients with petechiae/red spots (χ(2) = 5.216, P = 0.022), denuded areas (χ(2) = 8.686, P = 0.003) and mucosal breaks (χ(2) = 7.795, P = 0.005) increased after treatment in the control groups. Geranylgeranylacetone improved both the Lewis score (Z = -2.459, P = 0.017) and degree (χ(2) = 5.414, P = 0.020) on capsule endoscopy 12 weeks later.. In patients with rheumatic diseases, geranylgeranylacetone is effective for protecting against small-intestinal mucosal injuries induced by diclofenac sodium.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Capsule Endoscopy; Diclofenac; Diterpenes; Female; Follow-Up Studies; Humans; Intestinal Diseases; Intestinal Mucosa; Intestine, Small; Male; Prospective Studies; Rheumatic Diseases

The intestinal epithelial barrier plays an important role in the pathogenesis of non-steroidal anti-inflammatory drug-induced enteropathy, and its disruption is often associated with increased cell shedding. The purpose of this report is to observe the gap density in indomethacin-induced small intestinal damage by confocal laser endomicroscopy (CLE) and to investigate the mechanisms involved in this process and how mucosal protectants improve intestinal epithelial barrier dysfunction. CLE is expected to provide a new way for evaluating non-steroidal anti-inflammatory drugs-induced enteropathy in humans and assessing drug efficacy.. Using the new technique of CLE, we established a method to evaluate, in real time, intestinal damage after the administration of indomethacin in Wistar rats by investigating the gap density in the small intestine. The mucosal protectant teprenone and acid-suppressant rabeprazole were then given by gavage before and after the administration of indomethacin, and the mechanisms affecting the intestinal epithelial barrier were investigated.. Using CLE, gaps could be clearly observed and easily distinguished from goblet cells. Gap density was increased after the administration of indomethacin. During this process, the expression of tumor necrosis factor-α, nuclear factor-κB, and caspase-3 was up-regulated and the expression of tight junctions was down-regulated, which led to the damage of the epithelial barrier. Teprenone and rabeprazole could intervene in this pathway and protect the integrity of the epithelial barrier.. CLE can be objective, accurate, and real time in investigating gap density. Teprenone and rabeprazole can prevent indomethacin-induced intestinal lesions and protect the epithelial barrier by intervening in the tumor necrosis factor-α pathway. Gap density was expected to be an indicator of evaluating intestinal inflammation and drug efficacy.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Biomarkers; Blotting, Western; Diterpenes; Enzyme-Linked Immunosorbent Assay; Goblet Cells; Indomethacin; Intestinal Diseases; Intestinal Mucosa; Jejunum; Male; Microscopy, Confocal; Rabeprazole; Random Allocation; Rats; Rats, Wistar; Tight Junctions; Treatment Outcome

It is well known that heat shock proteins (HSPs) are induced by various stressors in order to confer protection against such stressors. Since stressor-induced tissue damage is involved in various diseases, especially gastrointestinal diseases, such as gastric ulcer, it has been thought that HSPs are protective against these diseases. Indirect lines of evidence, such as identification of geranylgeranylacetone (GGA, a leading anti-ulcer drug in Japanese market) as non-toxic HSP-inducer, suggest that HSPs provide a major protective mechanism against irritant-induced gastric lesions. However, no direct evidences that support this notion exits. Furthermore, because GGA has other gastroprotective effects, it was not clear whether HSP-induction by GGA is the main mechanism for its anti-ulcer effect. In this article, I review our recent work on protective roles of HSPs against gastrointestinal diseases, using transgenic mice. We obtained genetic evidence showing not only that HSPs are protective against irritant-induced gastric lesions but also that GGA achieves its anti-ulcer effect through induction of HSPs. We also obtained genetic evidence that HSPs are protective against inflammatory bowel disease (IBD)-related colitis and lesions of small intestine. Furthermore, we found that GGA is effective against these diseases. Based on these observations, we propose that non-toxic HSP-inducers, such as GGA are therapeutically beneficial for these diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Diterpenes; Drug Evaluation, Preclinical; Gastrointestinal Tract; Heat-Shock Proteins; Inflammatory Bowel Diseases; Intestinal Diseases; Intestine, Small; Irritants; Mice; Mice, Transgenic; Protective Agents; Stomach Ulcer