RETRACTED: Antiulcerogenic Activity of Li‐Zhong Decoction on Duodenal Ulcers Induced by Indomethacin in Rats: Involvement of TLR‐2/MyD88 Signaling Pathway

Abstract

Background. Administration of nonsteroidal anti-inflammatory drugs (NSAIDs) often causes small intestinal ulcers in patients, but few effective drugs are currently available to manage such serious adverse events of NSAIDs. Li-Zhong decoction (LZD), a well-known traditional Chinese medicine (TCM) formula, is commonly prescribed for treatment of gastrointestinal diseases. The present study aimed to investigate the anti-ulcerogenic activity of LZD on indomethacin- (IND-) induced duodenal ulcer in rats. Mechanistic studies of action of LZD were focused on involvement of TLR-2/MyD88 signaling pathway. Methods. Fifty male Sprague-Dawley (SD) rats were randomly and evenly divided into five groups: normal control, ulcer control (IND, 25 mg/kg), IND + esomeprazole (ESO, 4.17 mg/kg), and IND + low and high doses of LZD (3.75 and 7.50 g/kg). Macroscopic and histopathological examinations were performed for evaluation of ulcer index (UI), curative index (CI), and microscopic score (MS). Levels of duodenal inflammatory biomarkers and cytoprotective mediators including interleukin-4 (IL-4), IL-10, tumor necrosis factor-α (TNF-α), and prostaglandin E2 (PGE2) were measured by ELISA. Expression levels of TLR-2 and MyD88 mRNA were assessed by qRT-PCR. The expression and distribution of TLR-2 and MyD88 proteins were analyzed by western blot and immunohistochemistry, respectively. Results. Gross and microscopic examinations of the IND-treated rats revealed severe duodenal hemorrhagic necrosis, inflammatory infiltration, villus destruction, and crypt abscess, while LZD-treated rats manifested these pathological events to a markedly lesser degree. LZD significantly decreased UI and MS, increased CI, preserved the integrity of the villus and crypt, and normalized the tissue architecture of the duodenum of rats. The elevated TNF-α levels in the IND-treated rats were markedly diminished in the LZD-treated rats, while lower levels of IL-4, IL-10, and PGE2 observed in IND-treated rats were significantly increased in LZD-treated rats. Interestingly, improvement of immune function in duodenal mucosa by reduction of mRNA and protein expression levels of TLR-2 and MyD88 was also observed in rats treated with LZD. Consistently, immunohistochemical analyses revealed a lower co-localization of TLR-2 and MyD88 proteins in the duodenal mucosa of LZD-treated rats as compared to the IND-induced rats. Conclusions. Our data demonstrate that LZD protects the duodenal mucosa from IND-caused lesions, which is at least partially attributable to the interaction of its potential cytoprotective and anti-inflammatory mechanisms together with enhancement of the mucosal immunity through TLR-2/MyD88 signaling pathway.

A Comparative Study on the Ameliorative Effects of Aqueous Extract of Two Varieties of Hibiscus on the Intestinal Epithelial Barrier in Bowel Inflammation

“…Morphometric data revealed a significant increase in inflammation grading score, crypts depth and muscle layer thickness when compared with the control group. Similar results were obtained by Song et al, (2020) and Yan et al, (2020) who reported the indomethacin-induced histopathological alterations within duodenal and colonic tissues. Song et al (2020) reported that severe macroscopic and microscopic destructions in the indomethacin treated rats were observed in duodenal tissues which revealed hemorrhagic necrosis, inflammatory infiltration, deformation of duodenal glands, deep ulcerations, submucosal edema , villus destruction, and crypt abscess.…”

“…These results were found to be in an agreement with many authors. Katary and Salahuddin (2017) and Song et al (2020), reported that oral treatment by indomethacin-induced a significant elevation in proinflammatory cytokines TNF-α, IL-6 and MPO while it decreased anti-inflammatory cytokines IL-10, and evidently reduced intestinal mucosal PGE2 contents in albino rats. In our study, indomethacin-induced a significant elevation of serum CRP, these results agreed with those of Abd El-Kareem et al (2006) who observed that patients with ulcerative colitis showed elevated Serum C-reactive protein (CRP) than normal group.…”

“…IL-10 promotes intestinal secretory cell function as it modulates the endoplasmic reticulum (ER) of goblet cells in maintaining the mucus production and MUC2 secretion that aids production of the mucosal barrier (Hasnain et al 2013). Indomethacin causes intestinal damage by suppressing the PGE2 synthesis, reducing mucus production and blood circulation within the mucosa causing tissue damage and ulceration in rodents and humans (Adhikary et al, 2011;and Song et al, 2020). PGE2 is beneficial for duodenal ulcer healing wherein it enhances the release of mucus.…”

“…PGE2 is beneficial for duodenal ulcer healing wherein it enhances the release of mucus. Elevated PGE2 level could lower the permeability of the epithelium (Song et al 2020). Thus, a reduction in goblet cell count and mucin content may have resulted from the reduced PGE2 and IL-10 levels.…”

Interplay of Biochemical, Genetic, and Immunohistochemical Factors in the Etio-Pathogenesis of Gastric Ulcer in Rats: A Comparative Study of the Effect of Pomegranate Loaded Nanoparticles Versus Pomegranate Peel Extract

“…A significant drawback of the extensive use of a common non-steroidal anti-inflammatory drug (Indomethacin) is the development of gastric ulcers ( Song et al, 2020b ). Multiple studies consider IND-induced gastric ulcers in rats as a standard model to investigate the underlying pathophysiological and pharmacological mechanisms ( Liu et al, 2015 ; Gomaa et al, 2018 ).…”