The link of hedgehog (Hh) signaling activation to human cancer and synthesis of a variety of Hh signaling inhibitors raise great expectation that inhibiting Hh signaling may be effective in human cancer treatment. Cyc...The link of hedgehog (Hh) signaling activation to human cancer and synthesis of a variety of Hh signaling inhibitors raise great expectation that inhibiting Hh signaling may be effective in human cancer treatment. Cyclopamine (Cyc), an alkaloid from the Veratrum plant, is a specific natural product inhibitor of the Hh pathway that acts by targeting smoothened (SMO) protein. However, its poor solubility, acid sensitivity, and weak potency relative to other Hh antagonists prevent the clinical development of Cyc as a therapeutic agent. Here, we report properties of cyclopamine tartrate salt (CycT) and its activities in Hh signaling-mediated cancer in vitro and in vivo. Unlike Cyc, CycT is water soluble (5-10 mg/mL). The median lethal dose (LD50) of CycT was 62.5 mg/kg body weight compared to 43.5 mg/kg for Cyc, and the plasma half-life (T1/2) of CycT was not significantly different from that of Cyc. We showed that CycT had a higher inhibitory activity for Hh signaling-dependent motor neuron differentiation than did Cyc (IC50 = 50 nmol/L for CycT vs. 300 nmol/L for Cyc). We also tested the antitumor effectiveness of these Hh inhibitors using two mouse models of basal cell carcinomas (K14cre:Ptch1neo/neo and K14cre:SmoM2YFP). After topical application of CycT or Cyc daily for 21 days, we found that all CycT-treated mice had tumor shrinkage and decreased expression of Hh target genes. Taken together, we found that CycT is an effective inhibitor of Hh signaling-mediated carcinogenesis.展开更多
A new pulsed chemical vapor deposition（PCVD） process has been developed to fabricate iron（Fe） and iron carbide(Fe1-xCx) thin films at low temperature range from 150 ℃ to 230 ℃.The process employs bis（1,4-di-ter...A new pulsed chemical vapor deposition（PCVD） process has been developed to fabricate iron（Fe） and iron carbide(Fe1-xCx) thin films at low temperature range from 150 ℃ to 230 ℃.The process employs bis（1,4-di-tert-butyl-1,3-diazabutadienyl）iron（Ⅱ） as iron source and hydrogen gas or hydrogen plasma as the coreactant.The films deposited with hydrogen gas are demonstrated polycrystalline with body-centered cubic Fe.However,for the films deposited with hydrogen plasma,the amorphous phase of iron carbide is obtained.The influence of the deposition temperature on iron and iron carbide characteristics have been investigated.展开更多
基金supported by a grant from the National Institute of Health, USA (No. R01-CA94160)
文摘The link of hedgehog (Hh) signaling activation to human cancer and synthesis of a variety of Hh signaling inhibitors raise great expectation that inhibiting Hh signaling may be effective in human cancer treatment. Cyclopamine (Cyc), an alkaloid from the Veratrum plant, is a specific natural product inhibitor of the Hh pathway that acts by targeting smoothened (SMO) protein. However, its poor solubility, acid sensitivity, and weak potency relative to other Hh antagonists prevent the clinical development of Cyc as a therapeutic agent. Here, we report properties of cyclopamine tartrate salt (CycT) and its activities in Hh signaling-mediated cancer in vitro and in vivo. Unlike Cyc, CycT is water soluble (5-10 mg/mL). The median lethal dose (LD50) of CycT was 62.5 mg/kg body weight compared to 43.5 mg/kg for Cyc, and the plasma half-life (T1/2) of CycT was not significantly different from that of Cyc. We showed that CycT had a higher inhibitory activity for Hh signaling-dependent motor neuron differentiation than did Cyc (IC50 = 50 nmol/L for CycT vs. 300 nmol/L for Cyc). We also tested the antitumor effectiveness of these Hh inhibitors using two mouse models of basal cell carcinomas (K14cre:Ptch1neo/neo and K14cre:SmoM2YFP). After topical application of CycT or Cyc daily for 21 days, we found that all CycT-treated mice had tumor shrinkage and decreased expression of Hh target genes. Taken together, we found that CycT is an effective inhibitor of Hh signaling-mediated carcinogenesis.
基金financially supported by National Natural Science Foundation of China(No.11775028)Collaborative Innovation Center of Green Printing&Publishing Technology(No.15208)Beijing Institute of Graphic Communication Project(Nos.Ea201801 04190119001-020 and 12000400001)
文摘A new pulsed chemical vapor deposition（PCVD） process has been developed to fabricate iron（Fe） and iron carbide(Fe1-xCx) thin films at low temperature range from 150 ℃ to 230 ℃.The process employs bis（1,4-di-tert-butyl-1,3-diazabutadienyl）iron（Ⅱ） as iron source and hydrogen gas or hydrogen plasma as the coreactant.The films deposited with hydrogen gas are demonstrated polycrystalline with body-centered cubic Fe.However,for the films deposited with hydrogen plasma,the amorphous phase of iron carbide is obtained.The influence of the deposition temperature on iron and iron carbide characteristics have been investigated.
