22, 27 Interestingly, INT-777 showed the lowest biliary enrichment, indicating limited bioavailability and, subsequently, the lack of choleretic effect of this compound in mice. In addition to pharmacological TGR5 activation, by using Tgr5-Tg mice, we could confirm that Tgr5 overexpression also had no impact on bile secretion. However, INT-777 decreased biliary PL and cholesterol output in Fxr+/+ mice in the presence of unchanged BA concentrations. These findings are consistent with a previous report showing that Tgr5−/− mice had higher Akt inhibitor biliary PL, compared
with Tgr5+/+ mice, and were protected from gallstone development upon lithogenic diet feeding.59 Altogether, these data suggest that despite a beneficial effect of TGR5 activation in diabesity,8, 27 TGR5 is unlikely to be beneficial in cholangiopathies and diseases with impaired bile composition as well as gallbladder function. However, the failure of INT-777 to improve disease progression in Mdr2−/− does not rule out the possibility that other TGR5 activators might help to delay or cure cholestatic liver injury in humans. In conclusion, our study demonstrates that FXR activation by INT-767, a novel, highly potent FXR/TGR5 agonist, modifies bile flow and reduces bile toxicity by decreasing endogenous BA output and increasing HCO output, resulting in the repression of hepatic inflammation as well
as biliary fibrosis in Mdr2−/− mice. The authors gratefully acknowledge Dr. W. Erwa (Graz) ITF2357 and colleagues for performing the biochemical analyses of serum liver tests and A. Thüringer for
help in primary myofibroblast 上海皓元医药股份有限公司 isolation. Additional Supporting Information may be found in the onbline version of this article. “
“Background and Aims: External beam radiotherapy currently has a limited role in the treatment of hepatocellular carcinoma (HCC). The purpose of this article was to review available radiobiological data on HCC and normal liver and incorporate these data into radiobiological models that may be used to explain and improve treatment. Methods: Volume doubling times of HCC were described and used to demonstrate growth of HCC with time, assuming both exponential and logistic growth. Radiosensitivity of HCC was described and used to demonstrate the probability of uncomplicated tumor control as tumor size increases. The relationship between tolerance of liver to irradiation and volume irradiated was examined. Results: The median volume doubling time for untreated HCC was 130 days. HCC have a long period of subclinical growth. Radiosensitivity of HCC lies within the range of other tumors commonly treated with radiotherapy. When treating small volumes of normal liver, relatively high doses may be used with low risk of late radiation damage. There is a high probability of sterilizing subclinical disease and small HCC with tolerable radiation doses.