Colorectal cancer (CRC) is one of the most common gastrointestinal cancers that results in death in worldwide. The Hedgehog (HH) signalling pathway regulates the initiation and progression of CRC. Inhibiting the HH pathway has been presented as a potential treatment strategy in recent years. Cynanbungeigenin C (CBC) is a new type of C 21 steroid that has been previously reported for the treatment of medulloblastoma. However, its further investigation was limited by its poor water solubility. In this study, six new CBC derivatives were synthesized through the structural modification of CBC, and four of them showed better water solubility than CBC. Moreover, their antiproliferative activities on CRC were evaluated. It was found that CBC-1 presented the best inhibitory effect on three types of CRC cell lines, and this effect was superior to that of CBC. Mechanistically, CBC-1 inhibited the proliferation of CRC cells through regulation of mRNA and proteins of the HH pathway according to qRT–PCR and Western blotting analysis. Furthermore, Cellular Thermal Shift Assay results indicated that CBC-1 regulated this signalling pathway by targeting glioma‑associated oncogene (GLI 1).In addition, cell apoptosis was induced increasingly by transfection with GLI 1 siRNA or treatment with CBC-1 to downregulate GLI 1. Last, the in vivo results demonstrated that CBC-1 significantly reduced tumour size and downregulated GLI 1 in CRC. Therefore, this study suggests that CBC-1, a new GLI 1 inhibitor derived from natural products, may be developed as a potential antitumour candidate for CRC treatment.
Liver fibrosis is a result of chronic liver disease; without treatment, it can progress to cirrhosis and even liver cancer. The occurrence and development of liver fibrosis is closely related to the activation of hepatic stellate cells (HSCs). Many events, including induction of the hedgehog signal and angiogenesis, occur during HSCs activation. Transforming growth factor-β (TGF-β) acts as a critical regulator of HSCs activation. We found that Dendrobium officinale polysaccharide (DOP) markedly reduced the level of hepatic fibrosis in carbon tetrachloride (CCl 4 )-treated rats and TGF-β-stimulated HSC-T6 cells. DOP significantly inhibited smooth (SMO) protein expression and Gli1 transcription into the nucleus. Moreover, DOP inhibited the expression of angiogenesis-related proteins and angiogenesis markers. In conclusion, our results indicated that DOP might ameliorate CCl 4 -induced liver fibrosis and TGF-β-induced HSC-T6 cells activation by the SMO/Gli 1 pathway, suggesting that DOP could be used as a potential functional food.
Zhong Cheng,Zhanyuan Qu,Jiaxin Sun,Zhihua Duan,Yong An,Yan Zhang,Jun Yang
Renal fibrosis lacks experimentally tractable human-relevant models that integrate defined stromal programming with spatially controlled profibrotic cues. Here, we developed a dual E-/VE-cadherin-Fc (EVE) interface to condition human mesenchymal stem cells (MSCs) under CTGF/TGF-β stimulation. Cells showed increased expression of Gli-1, NG2, PDGFRβ, and FAP and activated transcription of extracellular matrix remodeling. These changes were consistent with the acquisition of a Gli-1 + perivascular-like profibrotic stromal phenotype, and were accompanied by reorganization of cadherin-catenin complexes, actin cytoskeletal rearrangement, and increased YAP nuclear localization. Cell-sized PLGA/chitosan-heparin microparticles were subsequently functionalized with E-/VE-cadherin-Fc and loaded with CTGF/TGF-β. Co-assembly of these microparticles with the conditioned stromal cells (gMSCs) and renal epithelial cells (HK-2) generated 3D renal fibrotic microtissues that combined cadherin-mediated adhesive presentation with localized cytokine delivery. The resulting microtissues exhibited a broader distribution of α-SMA, Collagen I, and Fibronectin, together with reciprocal epithelial-stromal signaling and spatially organized fibrotic activation. As a proof of concept for pharmacological evaluation, the microtissues responded to pirfenidone (PFD) in a dose-dependent manner, with 100 µM PFD reducing α-SMA expression by ∼73% while preserving microtissue viability. Together, these findings establish a material-enabled, cadherin-guided strategy for constructing disease-relevant stromal organization and spatially controlled profibrotic signaling in human renal fibrosis models.
危险品化学品经营许可证（带存储）