Multi-omics characterization of macrophage polarization-related features in osteoarthritis based on a machine learning computational framework.

Background: OA imposes a heavy burden on patients and society in that its mechanism is still unclear, and there is a lack of effective targeted therapy other than surgery. Methods: The osteoarthritis dataset GSE55235 was downloaded from the GEO database and analyzed for differential genes by limma package, followed by analysis of immune-related modules by xcell immune infiltration combined with the WGCNA method, and macrophage polarization-related genes were downloaded according to the Genecard database, and VennDiagram was used to determine their intersection. These genes were also subjected to gene ontology (GO), disease ontology (DO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses. Using machine learning, the key osteoarthritis genes were finally screened. Using single gene GSEA and GSVA, we examined the significance of these key gene functions in immune cell and macrophage pathways. Next, we confirmed the correctness of the hub gene expression profile using the GSE55457 dataset and the ROC curve. Finally, we projected TF, miRNA, and possible therapeutic drugs using the miRNet, TargetScanHuman, ENCOR, and NetworkAnalyst databases, as well as Enrichr. Results: VennDiagram obtained 71 crossover genes for DEGs, WGCNA-immune modules, and Genecards; functional enrichment demonstrated NF-κB, IL-17 signaling pathway play an important role in osteoarthritis-macrophage polarization genes; machine learning finally identified CSF1R, CX3CR1, CEBPB, and TLR7 as hub genes; GSVA analysis showed that CSF1R, CEBPB play essential roles in immune infiltration and macrophage pathway; validation dataset GSE55457 analyzed hub genes were statistically different between osteoarthritis and healthy controls, and the AUC values of ROC for CSF1R, CX3CR1, CEBPB and TLR7 were more outstanding than 0.65. Conclusions: CSF1R, CEBPB, CX3CR1, and TLR7 are potential diagnostic biomarkers for osteoarthritis, and CSF1R and CEBPB play an important role in regulating macrophage polarization in osteoarthritis progression and are expected to be new drug targets.

Prospects of focal adhesion kinase inhibitors as a cancer therapy in preclinical and early phase study.

INTRODUCTION: FAK, a nonreceptor cytoplasmic tyrosine kinase, plays a crucial role in tumor metastasis, drug resistance, tumor stem cell maintenance, and regulation of the tumor microenvironment. FAK has emerged as a promising target for tumor therapy based on both preclinical and clinical data. AREAS COVERED: This paper aims to summarize the molecular mechanisms underlying FAK's involvement in tumorigenesis and progression. Encouraging results have emerged from ongoing clinical trials of FAK inhibitors. Additionally, we present an overview of clinical trials for FAK inhibitors, examining their potential as promising treatments. The pertinent studies gathered from databases including PubMed, ClinicalTrials.gov. EXPERT OPINION: Since the first finding in 1990s, targeting FAK has became the focus of interests in many pharmaceutical companies. Through 30 years' discovery, the industry and academy gradually realized the features of FAK target which may not be a driver gene but a solid defense system for the cancer initiation and development. Currently, the ongoing clinical regimens involving FAK inhibition are all the combination strategies in which FAK inhibitors can further strengthen the cancer cell killing effects of other testing agents. The emerging positive signal in clinical trials foresee targeting FAK as class will be an effective mean to fight against cancers.

[Induction of apoptosis of human ovarian cancer CoC1 cells by 5-allyl-7-gen-difluoromethylenechrysin through activation of peroxisome-proliferator activated receptor-gamma].

OBJECTIVE: To investigate induction of apoptosis of human ovarian cancer CoC1 cells by 5-Allyl-7-Gen-Difluoromethylenechrysin (ADFMChR) in vitro, and its molecular mechanism. METHODS: The proliferative inhibition of CoC1 cells treated with ADFMChR was measured using (3, 4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) colorimetric assay. The apoptosis of CoC1 cells induced by ADFMChR was determined by DNA agarose gel electrophoresis assay and flow cytometry using PI staining. Effect of ADFMChR on PPARgamma, NF-kappaB, Bcl-2, Bax protein expression level of CoC1 cells was detected by Western blotting. RESULTS: The proliferation of CoC1 cells could be significantly inhibited by ADFMChR in a dose-dependent manner, The IC(50) was 7.76 micromol/L. ADFMChR significantly induced apoptosis in a concentration-dependent, the rate of apoptosis was 33.07% and 73.70% respectively after treatment with 10.0, 30.0 micromol/L of ADFMChR for 48 h, which was higher than either the control group (21.70%, 40.00%) at the same concentration ChR-treated cells. The ladder-shaped band could be shown in DNA agarose gel electrophoresis after treatment with ADFMChR at 30.0 micromol/L for 48 h and the ladder-shape band disappeared with GW9662. Western Blot analysis shown that expression of PPARgamma and Bax proteins were upregulation and protein levels of NF-kappaB and Bcl-2 were depress after treatment with ADFMChR in a concentration-dependent. CONCLUSION: The effect of ADFMChR on induction of apoptosis in CoC1 cells may be mediated by activation of PPARgamma, sequentially accompanied by reducing of protein levels of NF-kappaB and Bcl-2 and increasing of Bax expression.