OSW-1 triggers necroptosis in colorectal cancer cells through the RIPK1/RIPK3/MLKL signaling pathway facilitated by the RIPK1-p62/SQSTM1 complex.

BACKGROUND: Necroptosis has emerged as a novel molecular pathway that can be targeted by chemotherapy agents in the treatment of cancer. OSW-1, which is derived from the bulbs of Ornithogalum saundersiae Baker, exerts a wide range of pharmacological effects. AIM: To explore whether OSW-1 can induce necroptosis in colorectal cancer (CRC) cells, thereby expanding its range of clinical applications. METHODS: We performed a sequence of functional experiments, including Cell Counting Kit-8 assays and flow cytometry analysis, to assess the inhibitory effect of OSW-1 on CRC cells. We utilized quantitative proteomics, employing tandem mass tag labeling combined with liquid chromatography-tandem mass spectrometry, to analyze changes in protein expression. Subsequent bioinformatic analysis was conducted to elucidate the biological processes associated with the identified proteins. Transmission electron microscopy (TEM) and immunofluorescence studies were also performed to examine the effects of OSW-1 on necroptosis. Finally, western blotting, siRNA experiments, and immunoprecipitation were employed to evaluate protein interactions within CRC cells. RESULTS: The results revealed that OSW-1 exerted a strong inhibitory effect on CRC cells, and this effect was accompanied by a necroptosis-like morphology that was observable via TEM. OSW-1 was shown to trigger necroptosis via activation of the RIPK1/RIPK3/MLKL pathway. Furthermore, the accumulation of p62/SQSTM1 was shown to mediate OSW-1-induced necroptosis through its interaction with RIPK1. CONCLUSION: We propose that OSW-1 can induce necroptosis through the RIPK1/RIPK3/MLKL signaling pathway, and that this effect is mediated by the RIPK1-p62/SQSTM1 complex, in CRC cells. These results provide a theoretical foundation for the use of OSW-1 in the clinical treatment of CRC.

Dearomative Iodocyclization of N-(o-Alkynyl)aryl Isoindole.

We present a dearomative iodocyclization of N-(o-alkynyl)aryl isoindole here, which affords various biologically active benzoindoleazine skeletons containing alkenyl iodine. The products can further undergo cycloaddition or coupling reactions to afford a series of highly functionalized N-fused polycyclic scaffolds.

Integrated Analysis of miRNA-mRNA Regulatory Networks Associated with Osteonecrosis of the Femoral Head.

Osteonecrosis of the femoral head (ONFH) accounts for as many as 18% of total hip arthroplasties. Knowledge of genetic changes and molecular abnormalities could help identify individuals considered to be at a higher risk of developing ONFH. In this study, we sought to identify differentially expressed miRNAs (DEmiRs) and genes (DEGs) associated with ONFH by integrated bioinformatics analyses as well as to construct the miRNA-mRNA regulatory network involving in the pathogenesis of ONFH. We performed differential expression analysis using a gene expression profile GSE123568 and a miRNA expression profile GSE89587 deposited in the Gene Expression Omnibus and identified 47 DEmiRs (24 upregulated miRNAs and 23 downregulated miRNAs) and 529 DEGs (218 upregulated genes and 311 downregulated genes). Gene Ontology enrichment analyses of DEGs suggested that DEGs were significantly enriched in neutrophil activation, cytosol, and ubiquitin-protein transferase activity. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of DEGs revealed that DEGs were significantly enriched in transcriptional misregulation in cancer. DEGs-based miRNA-mRNA regulatory networks were obtained by searching miRNA-mRNA prediction databases, TargetScan, miTarBase, miRMap, miRDB, and miRanda databases. Then, overlapped miRNAs were selected between these putative miRNAs and DEmiRs between ONFH and non-ONFH, and pairs of the DEmiR-DEG regulatory network were finally depicted. There were 12 nodes and 64 interactions for upDEmiR-downDEG regulatory networks and 6 nodes and 16 interactions for downDEmiR-upDEG regulatory networks. Using the STRING database, we established a protein-protein interaction network based on the overlapped DEGs between ONFH and non-ONFH. C5AR1, CDC27, CDC34, KAT2B, CPPED1, TFDP1, and MX2 were identified as the hub genes. The present study characterizes the miRNA profile, gene profile, and miRNA-mRNA regulatory network in ONFH, which may contribute to the interpretation of the pathogenesis of ONFH and the identification of novel biomarkers and therapeutic targets for ONFH.

Palladium-Catalyzed Intermolecular Heck-Type Dearomative [4 + 2] Annulation of 2H-Isoindole Derivatives with Internal Alkynes.

Here, an interesting palladium-catalyzed intermolecular Heck-type dearomative [4 + 2] annulation of 2H-isoindole derivatives with internal alkynes has been developed, affording diverse polycyclic pyrrolidine scaffolds in good yield. This reaction is a useful method for the transformation of 2H-isoindole.

Copper-Catalyzed Chemodivergent Cyclization of N-(ortho-alkynyl)aryl-Pyrrole and Indoles.

Herein, we described an efficient copper-catalyzed chemo-divergent tandem reaction of N-(ortho-alkynyl)aryl-pyrrole and (iso)indoles, delivering ring-fused N-heterocycles in good yields in an atom-economical manner. N-(ortho-alkynyl)aryl-pyrrole and indoles undergo the tandem cyclization/migration reaction, in which the group at 2-position was migrated to 3-position. In contrast, the dearomative cyclization of N-(ortho-alkynyl)aryl-isoindoles would occur to deliver the N-fused tetracyclic products efficiently.

Catalyst-Enabled Chemodivergent Construction of Alkynyl- and Vinyl-Substituted Diarylmethanes from p-Quinone Methides and Alkynes.

Here, a catalyst-controlled chemodivergent 1,6-addition of p-quinone methides with alkynes was developed, affording diverse alkynyl- and vinyl-substituted diarymethanes. In this transformation, copper catalyzed the direct 1,6-addition of p-QMs with alkynes, while iron promoted the three components reaction of p-QMs, alkynes, and halogens from iron salts or added HX acid. The salient features of this transformation include completely controllable chemoselectivity, mild conditions, inexpensive catalysts, and good substrates scopes.

Advanced development of ErbB family-targeted therapies in osteosarcoma treatment.

Osteosarcoma (OS) is the most common primary aggressive and malignant bone tumor. Newly diagnostic OS patients benefit from the standard therapy including surgical resection plus radiotherapy and neoadjuvant chemotherapy (MAP chemotherapy: high-dose methotrexate, doxorubicin and cisplatin). However, tumor recurrence and metastasis give rise to a sharp decline of the 5-year overall survival rate in OS patients. Little improvement has been made for decades, urging the development of more effective therapeutic approaches. ErbB receptor family including EGFR, HER2, HER3 and HER4, being important to the activation of PI3K/Akt and MAPK signaling pathways, are potential targets for OS treatment. Genetic aberrations (amplification, overexpression, mutation and altered splicing) of ErbB are essential to the growth, apoptosis, motility and metastasis in a variety of cancers. Overexpression of ErbB family is associated with the poor prognosis of cancer patients. A number of monoclonal antibodies or inhibitors specific for ErbB family have entered clinical trials in a range of solid tumors including breast carcinoma, lung carcinoma and sarcoma. Here, we summarized the roles and expression of ErbB family in OS and the current development of ErbB-targeted therapeutic strategies including chemotherapies and immunotherapies for OS treatment.