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Based on the present study, it was concluded that Holothuria arenicola extract (HaE) may be a potential alternative for the treatment of gastric ulceration-induced by administration of indomethacin with cold stress. Moreover, the present results confirmed that HaE decreased lipid peroxidation, improved antioxidant status, activation of free radical scavenging enzymes, and restoration of the stomach architecture, thereby could be a good new treatment for gastric ulcer. The study also demonstrated that the combination of HaE and ranitidine (especially in the pre-treated group) compared to an individual use of HaE or ranitidine has more potent therapeutics effect.Moreover, the present study showed a high effective free radical scavenging activity of HaE in the DPPH (1, 1-Diphenyl-2-picryl hydrazyl) assay. Therefore, the current study suggested that HaE is a powerful free radical quencher and its use as a complementary drug with the recommended anti-ulcer drugs may offer attractive strategy for healing gastric ulcer in human.