Salvianolic Acid B Significantly Suppresses the Migration of Melanoma Cells via Direct Interaction with ß-Actin.

Melanoma is the most aggressive and difficult to treat of all skin cancers. Despite advances in the treatment of melanoma, the prognosis for melanoma patients remains poor, and the recurrence rate remains high. There is substantial evidence that Chinese herbals effectively prevent and treat melanoma. The bioactive ingredient Salvianolic acid B (SAB) found in Salvia miltiorrhiza, a well-known Chinese herbal with various biological functions, exhibits inhibitory activity against various cancers. A375 and mouse B16 cell lines were used to evaluate the main targets and mechanisms of SAB in inhibiting melanoma migration. Online bioinformatics analysis, Western blotting, immunofluorescence, molecular fishing, dot blot, and molecular docking assays were carried out to clarify the potential molecular mechanism. We found that SAB prevents the migration and invasion of melanoma cells by inhibiting the epithelial-mesenchymal transition (EMT) process of melanoma cells. As well as interacting directly with the N-terminal domain of ß-actin, SAB enhanced its compactness and stability, thereby inhibiting the migration of cells. Taken together, SAB could significantly suppress the migration of melanoma cells via direct binding with ß-actin, suggesting that SAB could be a helpful supplement that may enhance chemotherapeutic outcomes and benefit melanoma patients.

Ponicidin-induced conformational changes of HSP90 regulates the MAPK pathway to relieve ulcerative colitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is a recurring chronic intestinal disease that can be debilitating and in severe cases, may further lead to cancer. However, all these treatment techniques still suffer from drug dependence, adverse effects and poor patient compliance. Therefore, there is an urgent need to seek new therapeutic strategies. In traditional Chinese medicine, Rabdosia rubescens (Hemsl.) H.Hara has the effects of clearing heat-toxin and promoting blood circulation to relieve pain, it is wildly used for treating inflammatory diseases such as sore throats and tonsillitis. Ponicidin is an important molecule for the anti-inflammatory effects of Rabdosia rubescens, but it has not been studied in the treatment of colitis. HSP90 is the most critical regulator in the development and progression of inflammatory diseases such as UC. AIM OF THE STUDY: The aim of this study was to explore the anti-inflammatory activity of ponicidin and its mechanism of effect in vitro and in vivo, as well as to identify the target proteins on which ponicidin may interact. MATERIAL AND METHODS: 2.5% (w/v) dextran sulfate sodium (DSS) was used to induce C57BL/6 mice to form an ulcerative colitis model, and then 5 mg/kg and 10 mg/kg ponicidin was given for treatment, while the Rabdosia rubescens extract group and Rabdosia rubescens diterpene extract group were set up for comparison of the efficacy of ponicidin. At the end of modeling and drug administration, mouse colon tissues were taken, and the length of colon was counted, inflammatory factors and inflammatory signaling pathways were detected. RAW264.7 cells were induced to form cell inflammation model with 1 µg/mL Lipopolysaccharide (LPS) for 24 h. 1 µM, 2 µM and 4 µM ponicidin were given at the same time, and after the end of the modeling and administration of the drug, the inflammatory factors and inflammatory signaling pathways were detected by qRT-PCR, western blotting, immunofluorescence and other methods. In vitro, target angling and combined with mass spectrometry were used to search for relevant targets of ponicidin, while isothermal titration calorimetry (ITC), protease degradation experiments and molecular dynamics simulations were used for further confirmation of the mode of action and site of action between ponicidin and target proteins. RESULTS: Ponicidin can alleviate DSS and LPS-induced inflammation by inhibiting the MAPK signaling pathway at the cellular and animal levels. In vitro, we confirmed that ponicidin can interact with the middle domain of HSP90 and induce the conformational changes in the N-terminal domain. CONCLUSION: These innovative efforts identified the molecular target of ponicidin in the treatment of UC and revealed the molecular mechanism of its interaction with HSP90.

Pregnane X receptor as a therapeutic target for cholestatic liver injury.

Cholestatic liver injury (CLI) is caused by toxic bile acids (BAs) accumulation in the liver and can lead to inflammation and liver fibrosis. The mechanisms underlying CLI development remain unclear, and this disease has no effective cure. However, regulating BA synthesis and homeostasis represents a promising therapeutic strategy for CLI treatment. Pregnane X receptor (PXR) plays an essential role in the metabolism of endobiotics and xenobiotics via the transcription of metabolic enzymes and transporters, which can ultimately modulate BA homeostasis and exert anticholestatic effects. Furthermore, recent studies have demonstrated that PXR exhibits antifibrotic and anti-inflammatory properties, providing novel insights into treating CLI. Meanwhile, several drugs have been identified as PXR agonists that improve CLI. Nevertheless, the precise role of PXR in CLI still needs to be fully understood. This review summarizes how PXR improves CLI by ameliorating cholestasis, inhibiting inflammation, and reducing fibrosis and discusses the progress of promising PXR agonists for treating CLI.

Screening biomarkers of prostate cancer by integrating microRNA and mRNA microarrays.

OBJECTIVE: In this study, we screened microRNA (miRNA) target genes of prostate cancer by integrating miRNA and mRNA expression profiles after target prediction and performed function enrichment analysis for selected candidate genes. METHODS: The miRNA expression profile (GSE36802) and mRNA expression profile (GSE36801) were downloaded from the Gene Expression Omnibus database. We processed data and identified the differentially expressed miRNAs and mRNAs with R packages. Verified targets of miRNAs were identified through miRecods and miRTarBase. Then, software of Search Tool for the Retrieval of Interacting Genes was used to construct the interaction network of target genes. Finally, we performed function enrichment analysis for genes in the interaction network with the Functional Classification Tool. RESULTS: A total of 22 upregulated and 8 downregulated miRNAs were detected in this study, of which, hsa-mir-31 was the most overexpressed miRNA in prostate cancer. Both ITGA5 and RDX, two target genes of hsa-mir-31, were found to be differentially expressed from mRNA profiles by overexpressing hsa-mir-31. The cell adhesion molecule was found to be the most significant pathway enriched by ITGA5 and RDX. CONCLUSION: Overexpression of hsa-mir-31 can be a significant marker to distinguish cancer tissues from benign tissues. The targets such as ITGA5 and RDX regulated by hsa-mir-31 are candidate genes of prostate cancer, which provide new treatment strategies for its gene therapy.

[Effects of recombinant soluble MICA protein on the biologic activities of NK cells].

AIM: To study the effects of recombinant soluble MHC class I chain-related protein A (sMICA) on the cytotoxicity, secretion of IFN-gamma, proliferation and apoptosis of peripheral NK cells. METHODS: After NK cells were co-cultured with recombinant soluble MICA proteins overnight, the cytotoxicity of NK cell on target cells was detected by flow cytometry. The supernant was collected to determine the concentration of IFN-gamma by ELISA. The proliferation of NK cells to sMICA was detected by MTS/PMS. NK cells were labeled with annexin V and PI to analyze their apoptosis. RESULTS: Soluble MICA inhibited the cytotoxicity of NK cells and down-regulated the secretion of IFN-gamma, but it showed no effects on the proliferation and apoptosis of freshly isolated peripheral NK cells. CONCLUSION: The soluble MICA shedding from tumor cells could be a pathway of cancer immune evasion by down-regulating the biologic activities of NK cells.