A novel 2-iminobenzimidazole compound, XYA1353, displays in vitro and in vivo anti-myeloma activity via targeting NF-κB signaling.

Multiple myeloma (MM) is an accumulated disease of malignant plasma cells, which is still incurably owing to therapeutic resistance and disease relapse. Herein, we synthesized a novel 2-iminobenzimidazole compound, XYA1353, showing a potent anti-myeloma activity both in vitro and in vivo. Compound XYA1353 dose-dependently promoted MM cell apoptosis via activating caspase-dependent endogenous pathways. Moreover, compound XYA1353 could enhance bortezomib (BTZ)-mediated DNA damage via elevating γH2AX expression levels. Notably, compound XYA1353 interacted synergistically with BTZ and overcame drug resistance. RNA sequencing analysis and experiments confirmed that compound XYA1353 inhibited primary tumor growth and myeloma distal infiltration by disturbing canonical NF-κB signaling pathway via decreasing expression of P65/P50 and p-IκBα phosphorylation level. Due to its importance in regulating MM progression, compound XYA1353 alone or combined with BTZ may potentially exert therapeutic effects on multiple myeloma by suppressing canonical NF-κB signaling.

Discovery of small molecule c-Maf inhibitors using molecular docking-based virtual screening, molecular dynamics simulation, and biological evaluation.

Multiple myeloma (MM) is a prevalent plasma cell malignancy in the blood system that remains incurable. Given the abnormally high expression of c-Maf in most MM patients, targeting c-Maf presents an attractive therapeutic approach for treating MM malignancies. In this study, we employed a combined strategy involving molecular docking-based virtual screening, molecular dynamics (MD) simulation, and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation on existing FDA-approved drugs. Six compounds were selected for further experimental assay: vemurafenib, sorafenib, sildenafil, fluvastatin, erlotinib, and glimepiride. Among these compounds, sorafenib and glimepiride exhibited significant inhibition of myeloma cell proliferation in the RPMI-8226 cell line. Moreover, both compounds simultaneously downregulated c-Maf protein expression to induce G1 phase arrest and apoptosis in myeloma cells. Collectively, sorafenib and glimepiride may be considered promising candidates for developing more potent c-Maf inhibitors in the future.

Novel c-Myc G4 stabilizer EP12 promotes myeloma cytotoxicity by disturbing NF-κB signaling.

Multiple myeloma (MM) is a B-cell malignancy characterized by the excessive proliferation of bone marrow plasma cells and the production of abnormal immunoglobulins. Despite advances in therapeutic strategies, it remains an incurable disease. Recently, innovative anticancer drugs have been developed and approved, leading to improvements in MM therapy; however, drug resistance continues to be a major obstacle that results in treatment failure. Therefore, the development of novel agents is imperative to achieve superior therapeutic outcomes for relapsed/refractory multiple myeloma (MM) patients. Previously, we identified EP12 as a c-Myc G4 stabilizer that could induce cytotoxicity in MM cells in vitro. However, further investigation is required to elucidate the underlying molecular mechanisms and anti-MM activity of EP12 in vivo. In this study, we have discovered that the compound EP12 effectively inhibits primary myeloma growth in vivo by destabilizing c-Myc and disrupting the canonical nuclear factor-κB (NF-κB) signaling pathway. Overall, our findings suggest that EP12, as a potent c-Myc inhibitor, holds great promise as a therapeutic agent for MM.

Identifying potential prognosis markers in hepatocellular carcinoma via integrated bioinformatics analysis and biological experiments.

Background: Hepatocellular carcinoma is one kind of clinical common malignant tumor with a poor prognosis, and its pathogenesis remains to be clarified urgently. This study was performed to elucidate key genes involving HCC by bioinformatics analysis and experimental evaluation. Methods: We identified common differentially expressed genes (DEGs) based on gene expression profile data of GSE60502 and GSE84402 from the Gene Expression Omnibus (GEO) database. Gene Ontology enrichment analysis (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, REACTOME pathway enrichment analysis, and Gene Set Enrichment Analysis (GSEA) were used to analyze functions of these genes. The protein-protein interaction (PPI) network was constructed using Cytoscape software based on the STRING database, and Molecular Complex Detection (MCODE) was used to pick out two significant modules. Hub genes, screened by the CytoHubba plug-in, were validated by Gene Expression Profiling Interactive Analysis (GEPIA) and the Human Protein Atlas (HPA) database. Then, the correlation between hub genes expression and immune cell infiltration was evaluated by Tumor IMmune Estimation Resource (TIMER) database, and the prognostic values were analyzed by Kaplan-Meier plotter. Finally, biological experiments were performed to illustrate the functions of RRM2. Results: Through integrated bioinformatics analysis, we found that the upregulated DEGs were related to cell cycle and cell division, while the downregulated DEGs were associated with various metabolic processes and complement cascade. RRM2, MAD2L1, MELK, NCAPG, and ASPM, selected as hub genes, were all correlated with poor overall prognosis in HCC. The novel RRM2 inhibitor osalmid had anti-tumor activity, including inhibiting proliferation and migration, promoting cell apoptosis, blocking cell cycle, and inducing DNA damage of HCC cells. Conclusion: The critical pathways and hub genes in HCC progression were screened out, and targeting RRM2 contributed to developing new therapeutic strategies for HCC.

The rice pds1 locus genetically interacts with partner to cause panicle exsertion defects and ectopic tillers in spikelets.

BACKGROUND: Rice (Oryza sativa L.) is a staple food crop worldwide. Its yield and quality are affected by its tillering pattern and spikelet development. Although many genes involved in the vegetative and reproductive development of rice have been characterized in previous studies, the genetic mechanisms that control axillary tillering, spikelet development, and panicle exsertion remain incompletely understood. RESULTS: Here, we characterized a novel rice recombinant inbred line (RIL), panicle exsertion defect and aberrant spikelet (pds). It was derived from a cross between two indica varieties, S142 and 430. Intriguingly, no abnormal phenotypes were observed in the parents of pds. This RIL exhibited sheathed panicles at heading stage. Still, a small number of tillers in pds plants were fully exserted from the flag leaves. Elongated sterile lemmas and rudimentary glumes (occurred occasionally) were observed in the spikelets of the exserted panicles and were transformed into palea/lemma-like structures. Furthermore, more interestingly, tillers occasionally grew from the axils of the elongated rudimentary glumes. Via genetic linkage analysis, we found that the abnormal phenotype of pds manifesting as genetic incompatibility or hybrid weakness was caused by genetic interaction between a recessive locus, pds1, which was derived from S142 and mapped to chromosome 8, and a locus pds2, which not yet mapped from 430. We fine-mapped pds1 to an approximately 55-kb interval delimited by the markers pds-4 and 8 M3.51. Six RGAP-annotated ORFs were included in this genomic region. qPCR analysis revealed that Loc_Os080595 might be the target of pds1 locus, and G1 gene might be involved in the genetic mechanism underlying the pds phenotype. CONCLUSIONS: In this study, histological and genetic analyses revealed that the pyramided pds loci resulted in genetic incompatibility or hybrid weakness in rice might be caused by a genetic interaction between pds loci derived from different rice varieties. Further isolation of pds1 and its interactor pds2, would provide new insight into the molecular regulation of grass inflorescence development and exsertion, and the evolution history of the extant rice.