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Abstract The present study evaluated the gastroprotective effect of individual and combined use of vitamin D, simvastatin and α-lipoic acid against indomethacin-induced gastric ulcer in adult male rats. The protective effect of these drugs was evaluated by checking the stomach of rats both macroscopically and microscopically. Furthermore, the levels of some biochemical markers of oxidative stress, inflammation and gene expression of angiogenic and anti-apoptotic factors were assessed. The main results and conclusions are summarized and outlined below: 1. The oral administration of indomethacin induced multiple ulcers in gastric mucosa. Indomethacin-induced gastric ulcer was associated with increased levels of inflammatory markers (increased serum CRP, gastric mucosal TNF-α, and TGF-β1) and augmentation of gastric mucosal oxidative stress (increased MDA and nitic oxide and decreased GSH levels, SOD and catalase activities). On the other hand, the gene expression of VEGF (angiogenic factor) and miR-21 and mir-210 (anti-apoptotic regulatory microRNA) were increased in the gastric mucosa as indicies of endogenous repair. <2. The administration of vitamin D orally for 6 days, prior to the induction of gastric ulcer by indomethacin, partially reduced the incidence and severity (ulcer index) of indomethacin-induced gastric ulcer. The anti-ulcerogenic action of vitamin D could be attributed to its anti-inflammatory action manifested as reduced serum CRP and mucosal TNF-α and TGF-β1. This is in addition to its well-known antioxidant effect manifested as decreased gastric MDA, nitric oxide and increased the levels of GSH, SOD and catalase activities. <3. Administration of simvastatin for 6 days, prior to the induction of gastric ulcer by indomethacin, partially ameliorated the ulcerogenic action of indomethacin and showed ulcer index equivalent to that of vitamin D. Nonetheless, the anti-inflammatory and antioxidant effects of simvastatin were superior to that of vitamin D. Notably, unlike vitamin D, simvastatin increased the gene expression of VEGF and mir-21. <99< 4. Alpha-lipoic acid administration for 6 days, prior to the induction of gastric ulcer by indomethacin, partially reduced indomethacin-induced gastric lesions via reduction of inflammatory markers as well as oxidative stress. <However, the reducion in gastric ulcer index was significantly less than that induced by vitamin D or simvastatin. Although α- lipoic acid was able to restore normal mir-21 and mir-210 (even in presence of evident ulceration in the stomach), the gene expression of VEGF gene expression was increased tremendously possibly to increase blood flow to accelerate healing in absence of the ability of α-lipoic acid to increase the gene expression of anti-apoptotic regulatory genes as mir-21 and mir-210. <5. Morphologically as represented by the ulcer index, combined treatment with vitamin D and simvastatin did not revealed a better protective effect on indomethacininduced ulcer compared to groups treated with vitamin D or simvastatin alone. Nonetheless, this combination showed significantly more anti-inflammatory and antioxidative action compared to its individual drugs. < Notably, this combination showed the least nitrate/nitrite content in the gastric mucosa indicating the lowest production in nitric oxide in the mucosal tissue. < Also, this combination showed a universal heightened increase in the gene expression of the cellular proliferative markers assessed in this work (VEGF, mir-21 and mir-210), which dictate caution in dealing with simvastatin and vitamin D combination and warrant further research. <6. Combined treatment with vitamin D and α-lipoic acid showed a greater protective effect on indomethacin-induced ulcer compared to groups treated with α-lipoic acid alone. This combination showed a better anti-inflammatory and antioxidant effects compared to the individual drugs. Interesting, this combination showed the greatest capacity in restoring the level of GSH to near normal levels compared to all other tested individual drugs or combinations. The increase in GSH can explain the ability of vitamin D to mitigate the increased in VEGF gene expression induced by α-lipoic acid. <7. Clinically, it is crucial to identify the molecular mechanisms involved in gastric ulcer to design new strategies for gastric ulcer treatment. <The use of vitamin D, simvastatin, α-lipoic acid, or their combinations in the current study plays an important role in protection against gastric ulcer and could clarify the contribution of oxidative stress and inflammation as well as angiogenic and anti-apoptotic factors in modulating gastric ulcer course. Subsequently, the present data emphasizes on the prospective drug interactions revealed upon using novel therapy of drug combinations in gastric ulcer treatment, which necessitates further studies prior to implementing new combined treatment. |