ABSTRACT
In patients with high-level radiation exposure, gastrointestinal injury is the main cause of death. Despite the severity of damage to the gastrointestinal tract, no specific therapeutic option is available. Tauroursodeoxycholic acid (TUDCA) is a conjugated form of ursodeoxycholic acid that suppresses endoplasmic reticulum (ER) stress and regulates various cell-signaling pathways. We investigated the effect of TUDCA premedication in alleviating intestinal damage and enhancing the survival of C57BL/6 mice administered a lethal dose (15Gy) of focal abdominal irradiation. TUDCA was administered to mice 1 h before radiation exposure, and reduced apoptosis of the jejunal crypts 12 h after irradiation. At later timepoint (3.5 days), irradiated mice manifested intestinal morphological changes that were detected via histological examination. TUDCA decreased the inflammatory cytokine levels and attenuated the decrease in serum citrulline levels after radiation exposure. Although radiation induced ER stress, TUDCA pretreatment decreased ER stress in the irradiated intestinal cells. The effect of TUDCA indicates the possibility of radiation therapy for cancer in tumor cells. TUDCA did not affect cell proliferation and apoptosis in the intestinal epithelium. TUDCA decreased the invasive ability of the CT26 metastatic colon cancer cell line. Reduced invasion after TUDCA treatment was associated with decreased matrix metalloproteinase (MMP)-7 and MMP-13 expression, which play important roles in invasion and metastasis. This study shows a potential role of TUDCA in protecting against radiation-induced intestinal damage and inhibiting tumor cell migration without any radiation and radiation therapy effect.
ABSTRACT
Soshiho-tang (Xiao-chai-hu-tang in Chinese and Sho-saiko-to in Japanese) has been widely used for its various pharmacological effects, which include anti-inflammatory, antioxidant, antihepatic fibrosis, and antitumor properties. To evaluate the safety of Soshiho-tang water extract (SST), we tested its subchronic toxicity in male and female Crl:CD (SD) rats. Rats were orally treated with four different doses (0, 500, 1000, and 2000 mg/kg/day) of SST administered for 13 weeks. Mortality, clinical signs, body weight changes, food and water consumption changes, ophthalmology, urinalysis, hematological and biochemical parameters, gross findings, organ weights, and histological markers were monitored during the study. The SST treatment did not result in any toxicologically significant changes in mortality, clinical signs, body weights, food and water consumption, ophthalmoscopy, urinalysis, hematological and serum biochemical parameters, gross findings, organ weights, or histopathology. Histological analysis did not show any liver or kidney alteration. We concluded that the 13-week repeated oral administration of SST did not cause any adverse effects in rats at dosage levels of ≤2000 mg/kg/day. Under these experimental conditions, the no-observed-adverse-effect level was concluded to be 2000 mg/kg/day for both sexes.
