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In an effort to discover potent VEGFR-2 inhibitors, a series of 2,4 or 4,6-disubstituted <b>O</b>-linked indoles derivatives were designed and synthesized. The structural activity relationships led to identification of a potential VEGFR-2 inhibitor compound <b>18</b>.<br>Inhibition of VEGFR-2 signaling pathway has already become one of the most promising approaches for the treatment of cancer. In this study, we describe the design, synthesis, and biological evaluation of a series of <b>O</b>-linked indoles as potent inhibitors of VEGFR-2. Among these compounds, <b>18</b> showed significant anti-angiogenesis activities <b>via</b> VEGFR-2 in enzymatic proliferation assays, with IC50 value of 3.8 nmol/L. Kinase selectivity profiling revealed that <b>18</b> was a multitargeted inhibitor, and it also exhibited good potency against VEGFR-1, PDGFR-<b>α</b> and <b>β</b>.
Chrysosplenium nudicaule,Tibetan name " Yajima",is recorded as an effective medicine for the treatment of liver and gallbladder diseases by Tibetan Pharmacopoeia published in the past dynasties,but its traditional efficacy has not yet been investigated by means of modern pharmacological research methods. In this paper,the protective effect of extract of C. nudicaule(ECN) on liver injury in mice was observed by using the mice model of intrahepatic cholestasis(IC) induced by α-naphthyl isothiocyanate(ANIT) and the possible mechanism by which ECN work as the therapeutic agent was discussed. The results showed that the serum levels of AST,ALT,ALP,DBIL,TBIL and TBA of the model mice were notably reduced in dose-dependent manner(P<0. 01,P<0. 05). The activity of SOD and GSH-Px in the liver homogenate of mice was increased,while the content of MDA was decreased(P<0. 01,P<0. 05).Pathological examination of liver in mice showed that ECN could improve the pathological changes of liver tissue in mice. The mRNA expression level of genes related to bile acid metabolism were detected by RT-PCR and the results suggested that ECN could significantly increase the expression of genes such as BSEP,FXR and MRP2(P<0. 01,P<0. 05),meanwhile significantly reduce the expression of CYP7 A1(P<0. 01,P<0. 05). These results confirmed the protective effect of ECN on intrahepatic cholestasis-induced liver injury in mice,and indicated that the mechanism may be related to activating FXR and its target genes,reducing bile acid synthesis and increasing bile acid excretion. This study provides a modern pharmacological basis for the clinical application of Yajima in Tibetan medicine.
OBJECTIVE: To establish the method of quality control for traditional Tibetan Medicine Zsuotai.METHODS: Collecting the samples of Tsuotai from Qinghai, Tibet, Sichuan, and Gansu province, to detect Hg2+ by Zsuotai reacted with HCl-HNO3 (3:1), and to determine the quantity of HgS in Zsuotai by sulfocyanate volumetric method. RESULTS: The method for the determination of HgS in Zsuotai was in good reproducibility (RSD = 0.68%). The calibration curve was linear (r = 0.9999) within -0.0002 - 0.2123 g of mercuric sulfide. The recovery was 100.94% (RSD = 0.66%). CONCLUSIONS: This method is convenient and accurate, so it can be used to establish quality control of the medicinal material.