Hepatic stem cell Numb gene is a potential target of Huang Qi Decoction against cholestatic liver fibrosis

Numb is a negative regulator of Notch signal pathway. Previous study has demonstrated that Notch signal pathway activation is required for hepatic progenitor cell (HPC) differentiating into cholangiocytes in cholestatic liver fibrosis (CLF), and Huang Qi Decoction (HQD) could prevent CLF through inhibition of the Notch signal pathway. However, the role of Numb in HQD against CLF is yet unclear. Thus, CLF rats transplanted into rat bone marrow-derived mesenchymal stem cells with knocked down Numb gene (BMSCNumb-KD) were treated with HQD. Simultaneously, Numb gene knockdown was also performed in WB-F344 cell line and then treated with refined HQD in vitro. In vivo study revealed that liver fibrosis was inhibited by HQD plus BMSCNumb-KD treatment, while Hyp content in liver tissue, the gene and protein expression of α-SMA, gene expression of Col I, TNF-α, and TGF-β1 were increased compared to that in HQD group. Furthermore, Notch signal pathway was inhibited by HQD plus BMSCNumb-KD, while the protein expression of Numb was decreased and RBP-Jκ and Hes1 was increased compared to that in HQD group. In vitro, HQD reduced the differentiation of WB-F344 cells into cholangiocyte phenotype, while this effect was attenuated after Numb-knockdown. This study highlights that the absence of hepatic stem cell Numb gene decreases effect of HQD against CLF, which give rise the conclusion that Numb might be a potential target for HQD against CLF.

Endostar Rebuilding Vascular Homeostasis and Enhancing Chemotherapy Efficacy in Cervical Cancer Treatment

Background:The incidence rate of cervical cancer is the highest in the reproductive tract, and is not sensitive to chemotherapy. An appropriate amount of antiangiogenic agents can reconstruct tumor blood vessels in a short period of time and form vascular homeostasis, increase the function of blood vessel perfusion and reverse the multidrug resistance of chemotherapy, which is also called "vascular normalization".Endostar(a recombinant human endostatin) was developed by China and as a multi-target anti-angiogenesis agent.Endostar was mainly used in the treatment of non-small cell lung cancer, fewer reported in the treatment of cervical cancer.Purpose:To determine whether endostar can rebuild tumor vascular homeostasis and enhance chemotherapy effects for patients with cervical cancer.Methods:In this study,the patients with cervical cancer within stage IIB2 were selected,endostar combined with cisplatin+paclitaxel neoadjuvant chemotherapy(NACT) before radical surgical operation was adopted, patients outcome and adverse reaction were followed up.The changes of tumor vascular structure and perfusion function before and after endostar given were evaluated by histopathology and dynamic contrast-enhanced magnetic resonance imaging(DEC-MRI). VEGF-Notch signal pathway was detected for the regulating mechanism of vascular proliferation in different groups. GraphPad Prism 6 software were used for statistical analysis of the study results.Results:Endostar enhanced short-term (2 year) overall survival(OS) ,progression free survival(PFS) rates for cervical cancer patients.All the same,endostar increased long term (5 year) OS and PFS for cervical cancer patients.Endostar therapy exhibited with mild adverse reaction.MRI showed endostar+NACT further reduce tumor volume than NACT alone.The parameters of Ktrans,Ve for DEC-MRI in endostar group exhibited obviously increase than NACT group.Tumor vascular maturation index α-SMA/CD31 in endostar group increased obviously than NACT group, correspondingly Ki67 staining for tumor proliferative rates,lymphvascular space invasion in endostar group further declined than NACT group. The genes and proteins expression of VEGFR2,Notch1,Notch1,4,Dll4,Jagged-1 were obviously down regulated in endostar group comparing to NACT group.Conclusions: Endorstar restored vascular homeostasis in cervical cancer temporarily, enhanced chemotherapeutic agents resistance in cervical cancer, increased patient overall survival ratio.The VEGF-Notch connection blocked by endostar may play a role in this effects.

Endostar Rebuilding Vascular Homeostasis and Enhancing Chemotherapy Efficacy in Cervical Cancer Treatment

Background: The incidence rate of cervical cancer is the highest in the reproductive tract, and is not sensitive to chemotherapy. An appropriate amount of antiangiogenic agents can reconstruct tumor blood vessels in a short period of time and form vascular homeostasis, increase the function of blood vessel perfusion and reverse the multidrug resistance of chemotherapy, which is also called "vascular normalization".Endostar(a recombinant human endostatin) was developed by China and as a multi-target anti-angiogenesis agent.Endostar was mainly used in the treatment of non-small cell lung cancer,less reported in the treatment of cervical cancer.Purpose: To determine whether endostar can rebuild tumor vascular homeostasis and enhance chemotherapy effects for patients with cervical cancer.Methods: In this study,the patients with cervical cancer were selected,endostar combined with cisplatin+paclitaxel neoadjuvant chemotherapy(NACT) before surgical operation was adopted, patients outcome and adverse reaction were followed up.The changes of tumor vascular structure and perfusion function before and after endostar given were evaluated by histopathology and dynamic contrast-enhanced magnetic resonance imaging(DEC-MRI). VEGF-Notch signal pathway was detected for the regulating mechanism of vascular proliferation in different groups. GraphPad Prism 6 software were used for statistical analysis of the study results.Results: Endostar enhanced short-term (2 year) overall survival(OS) ,progression free survival(PFS) rates for cervical cancer patients.All the same,endostar increased long term (5 year) OS and PFS for cervical cancer patients.Endostar therapy exhibited with mild adverse reaction.MRI showed endostar+NACT further reduce tumor volume than NACT alone.The parameters of Ktrans,Ve for DEC-MRI in endostar groups exhibited obviously increase than NACT groups.Tumor vascular maturation index α-SMA/CD31 in endostar groups increased obviously than that of NACT groups, correspondingly tumor proliferative rate Ki67 staining in endostar groups further declined than NACT groups.The genes and proteins expression of VEGFR2,Notch1,Notch1,4,Dll4,Jagged-1 were obviously down regulated in endostar group comparing to that of NACT group.Conclusions: Endorstar restored vascular homeostasis in cervical cancer temporarily, provided a new way to reverse chemotherapeutic agents resistance in cervical cancer, increased patient survival time.The VEGF-Notch connection was blocked by endostar playing a role in this effects.

Hepatocyte Growth Factor Attenuates the Development of TGF-β1- Induced EndMT through Down-regulating the Notch Signaling

Background and objective: Endothelial-mesenchymal transition (EndMT) not only occurs during embryonic development, but also contributes to various diseases including cardiovascular diseases, fibrosis, and even cancer. However, the specific molecular biological mechanism and relationship of related pathways have not been fully elucidated. This study aims to explore the inhibitory effect of HGF on EndMT and the molecular mechanism of Notch signal in this process. Methods: HUVECs were treated with TGF-β1 and/or HGF for 72 hours. Expression levels of EndMT markers and the key transcriptional regulators of Notch signaling pathway were assessed by qRT-PCR and western blotting. C-Met expression was measured by qRT-PCR. Results: CD31 was downregulated and α-SMA, FSP1 were upregulated during TGF-β1-induced EndMT. HGF treatment significantly attenuates the development of TGF-β1-induced EndMT by down-regulating the signal transduction of the Notch signal pathway. Conclusion: This study proves that HGF treatment significantly attenuates the development of TGF- β1-induced EndMT by inhibiting the Notch signaling, which may provide new theoretical basis for the treatment of vascular diseases and numerous fibrotic diseases caused by EndMT.