AIM:To examine the influence of ghrelin on the regenerative potential of gastrointestinal(GI)epithelium.METHODS:Damage to GI epithelium was induced in mice by two intravenous injections of doxorubicin(10 and 6 mg/kg)....AIM:To examine the influence of ghrelin on the regenerative potential of gastrointestinal(GI)epithelium.METHODS:Damage to GI epithelium was induced in mice by two intravenous injections of doxorubicin(10 and 6 mg/kg).Some of the doxorubicin-treated mice received a continuous subcutaneous infusion of ghrelin(1.25μg/h)for 10 d via implanted mini-osmotic pumps.To label dividing stem cells in the S-phase of the cell cycle,all mice received a single intraperitoneal injection of 5'-bromo-2'-deoxyuridine(BrdU)one hour before sacrifice.The stomach along with the duodenum were then removed and processed for histological examination and immunohistochemistry using anti-BrdU antibody.RESULTS:The results showed dramatic damage to the GI epithelium 3 d after administration of chemotherapy which began to recover by day 10.In ghrelintreated mice,attenuation of GI mucosal damage was evident in the tissues examined postchemotherapy.Immunohistochemical analysis showed an increase in the number of BrdUlabeled cells and an alteration in their distribution along the epithelial lining in response to damage by doxorubicin.In mice treated with both doxorubicin and ghrelin,the number of BrdUlabeled cells was reduced when compared with mice treated with doxorubicin alone.CONCLUSION:The present study suggests that ghrelin enhances the regenerative potential of the GI epithelium in doxorubicintreated mice,at least in part,by modulating cell proliferation.展开更多
Gastrointestinal mucositis is one of the most debilitating side effects of the chemotherapeutic agent irinotecan(CPT-11). Andrographolide, a natural bicyclic diterpenoid lactone, has been reported to possess anti-coli...Gastrointestinal mucositis is one of the most debilitating side effects of the chemotherapeutic agent irinotecan(CPT-11). Andrographolide, a natural bicyclic diterpenoid lactone, has been reported to possess anti-colitis activity. In this study, andrographolide treatment was found to significantly relieve CPT-11-induced colitis in tumor-bearing mice without decreasing the tumor suppression effect of CPT-11. CPT-11 causes DNA damage and the release of double-stranded DNA(ds DNA) from the intestine, leading to cyclic-GMP-AMP synthase(c GAS)-stimulator of interferon genes(STING)-mediated colitis, which was significantly decreased by andrographolide both in vivo and in vitro. Mechanistic studies revealed that andrographolide could promote homologous recombination(HR) repair and downregulate ds DNA-c GAS-STING signaling and contribute to the improvement of CPT-11-induced gastrointestinal mucositis. These results suggest that andrographolide may be a novel agent to relieve gastrointestinal mucositis caused by CPT-11.展开更多
文摘AIM:To examine the influence of ghrelin on the regenerative potential of gastrointestinal(GI)epithelium.METHODS:Damage to GI epithelium was induced in mice by two intravenous injections of doxorubicin(10 and 6 mg/kg).Some of the doxorubicin-treated mice received a continuous subcutaneous infusion of ghrelin(1.25μg/h)for 10 d via implanted mini-osmotic pumps.To label dividing stem cells in the S-phase of the cell cycle,all mice received a single intraperitoneal injection of 5'-bromo-2'-deoxyuridine(BrdU)one hour before sacrifice.The stomach along with the duodenum were then removed and processed for histological examination and immunohistochemistry using anti-BrdU antibody.RESULTS:The results showed dramatic damage to the GI epithelium 3 d after administration of chemotherapy which began to recover by day 10.In ghrelintreated mice,attenuation of GI mucosal damage was evident in the tissues examined postchemotherapy.Immunohistochemical analysis showed an increase in the number of BrdUlabeled cells and an alteration in their distribution along the epithelial lining in response to damage by doxorubicin.In mice treated with both doxorubicin and ghrelin,the number of BrdUlabeled cells was reduced when compared with mice treated with doxorubicin alone.CONCLUSION:The present study suggests that ghrelin enhances the regenerative potential of the GI epithelium in doxorubicintreated mice,at least in part,by modulating cell proliferation.
基金supported by National Natural Science Foundation of China(81871944,81572389,81922067)Jiangsu 333 project(BRA2016517,China)+2 种基金Natural Science Foundation of Jiangsu Province(BK20190306,China)Jiangsu Province Key Medical Talents(ZDRCA2016026,China)Priority Academic Program Development of Jiangsu Higher Education Institutions and Fundamental Research Funds for the Central Universities(14380114,China)。
文摘Gastrointestinal mucositis is one of the most debilitating side effects of the chemotherapeutic agent irinotecan(CPT-11). Andrographolide, a natural bicyclic diterpenoid lactone, has been reported to possess anti-colitis activity. In this study, andrographolide treatment was found to significantly relieve CPT-11-induced colitis in tumor-bearing mice without decreasing the tumor suppression effect of CPT-11. CPT-11 causes DNA damage and the release of double-stranded DNA(ds DNA) from the intestine, leading to cyclic-GMP-AMP synthase(c GAS)-stimulator of interferon genes(STING)-mediated colitis, which was significantly decreased by andrographolide both in vivo and in vitro. Mechanistic studies revealed that andrographolide could promote homologous recombination(HR) repair and downregulate ds DNA-c GAS-STING signaling and contribute to the improvement of CPT-11-induced gastrointestinal mucositis. These results suggest that andrographolide may be a novel agent to relieve gastrointestinal mucositis caused by CPT-11.
