The unexpected rise in cancer and diabetes statistics has been a significant global threat, inciting ongoing research into various biomarkers that can act as innovative therapeutic targets for their management. The recent discovery of how EZH2-PPARs' regulatory function affects the metabolic and signalling pathways contributing to this disease has posed a significant breakthrough, with the synergistic combination of inhibitors like GSK-126 and bezafibrate for treating these diseases. Nonetheless, no findings on other protein biomarkers involved in the associated side effects have been reported. As a result of this virtual study, we identified the gene-disease association, protein interaction networks between EZH2-PPARs and other protein biomarkers regulating pancreatic cancer and diabetes pathology, ADME/Toxicity profiling, docking simulation and density functional theory of some natural products. The results indicated a correlation between obesity and hypertensive disease for the investigated biomarkers. At the same time, the predicted protein network validates the link to cancer and diabetes, and nine natural products were screened to have versatile binding capacity against the targets. Among all natural products, phytocassane A outperforms the standard drugs' (GSK-126 and bezafibrate) in silico validation for drug-likeness profiles. Hence, these natural products were conclusively proposed for additional experimental screening to complement the results on their utility in drug development for diabetes and cancer therapy against the EZH2-PPARs' new target.
Biological Products , Diabetes Mellitus , Neoplasms , Humans , Insulin , Peroxisome Proliferator-Activated Receptors , Bezafibrate , Prospective Studies , Neoplasms/drug therapy , Neoplasms/genetics , Diabetes Mellitus/drug therapy , Diabetes Mellitus/genetics , Biological Products/pharmacology , Biomarkers , Molecular Docking Simulation , Enhancer of Zeste Homolog 2 Protein/genetics
BACKGROUND: Prostate cancer (PC) is a silent but potent killer among men. In 2018, PC accounted for more than 350, 000 death cases while more than 1.2 million cases were diagnosed. Docetaxel, a chemotherapeutic drug belonging to the taxane family of drugs, is one of the most potent drugs in combating advanced PC. However, PC cells often evolve resistance against the regimen. Hence, necessitating the search for complementary and alternative therapies. Quercetin, a ubiquitous phytocompound with numerous pharmacological properties, has been reported to reverse docetaxel resistance (DR) in docetaxel-resistant prostate cancer (DRPC). Therefore, this study aimed to explore the mechanism via which quercetin reverses DR in DRPC using an integrative functional network and exploratory cancer genomic data analyses. RESULTS: The putative targets of quercetin were retrieved from relevant databases, while the differentially expressed genes (DEGs) in docetaxel-resistant prostate cancer (DRPC) were identified by analysing microarray data retrieved from the Gene Expression Omnibus (GEO) database. Subsequently, the protein-protein interaction (PPI) network of the overlapping genes between the DEGs and quercetin targets was retrieved from STRING, while the hub genes, which represent the key interacting genes of the network, were identified using the CytoHubba plug-in of Cytoscape. The hub genes were further subjected to a comprehensive analysis aimed at identifying their contribution to the immune microenvironment and overall survival (OS) of PC patients, while their alterations in PC patients were also revealed. The biological roles played by the hub genes in chemotherapeutic resistance include the positive regulation of developmental process, positive regulation of gene expression, negative regulation of cell death, and epithelial cell differentiation among others. CONCLUSION: Further analysis revealed epidermal growth factor receptor (EGFR) as the most pertinent target of quercetin in reversing DR in DRPC, while molecular docking simulation revealed an effective interaction between quercetin and EGFR. Ultimately, this study provides a scientific rationale for the further exploration of quercetin as a combinational therapy with docetaxel.
Various studies have established that molecules specific for MDMX inhibition or optimized for dual inhibition of p53-MDM2/MDMX interaction signaling are more suitable for activating the Tp53 gene in tumor cells. Nevertheless, there are sparse numbers of approved molecules to treat the health consequences brought by the lost p53 functions in tumor cells. Consequently, this study explored the potential of a small molecule ligand containing 1, 8-naphthyridine scaffold to act as a dual inhibitor of p53-MDM2/X interactions using computational methods. The results obtained from quantum mechanical calculations revealed our studied compound entitled CPO is more stable but less reactive compared to standard dual inhibitor RO2443. Like RO2443, CPO also exhibited good non-linear optical properties. The results of molecular docking studies predicted that CPO has a higher potential to inhibit MDM2/MDMX than RO2443. Furthermore, CPO was stable over 50 ns molecular dynamics (MD) simulation in complex with MDM2 and MDMX respectively. On the whole, CPO also exhibited good drug-likeness and pharmacokinetics properties compared to RO2443 and was found with more anti-cancer activity than RO2443 in bioactivity prediction. CPO is anticipated to elevate effectiveness and alleviate drug resistance in cancer therapy. Ultimately, our results provide an insight into the mechanism that underlay the inhibition of p53-MDM2/X interactions by a molecule containing 1, 8-naphthyridine scaffold in its molecular structure.
Allium cepa, commonly known as onion, is a widely consumed spice that possesses numerous pharmacological properties. A. cepa bioactive components are often explored in the treatment of inflammation-related complications. However, the molecular mechanism via which they exert their anti-inflammatory effects remains unknown. Therefore, this study aimed to elucidate the anti-inflammatory mechanism of A. cepa bioactive components. Consequently, the bioactive compounds of A. cepa were obtained from a database, while the potential targets of the sixty-nine compounds with desirable pharmacokinetic properties were predicted. Subsequently, the targets of inflammation were acquired from the GeneCards database. The protein-protein interaction (PPI) between the sixty-six shared targets of the bioactive compounds and inflammation was retrieved from the String database and visualized using Cytoscape v3.9.1 software. Gene Ontology (GO) analysis of the ten core targets from the PPI network revealed that A. cepa bioactive compounds could be involved in regulating biological processes such as response to oxygen-containing compounds and response to inflammation while Kyoto Encyclopaedia of Genes and Genomes (KEGG) analysis revealed that A. cepa compounds might modulate pathways including AGE-RAGE signaling pathway, interleukin (IL)-17 signalling pathway, and tumor necrosis factor signaling pathway. Molecular docking analysis showed that 1-O-(4-Coumaroyl)-beta-D-glucose, stigmasterol, campesterol, and diosgenin have high binding affinities for core targets including EGFR, ALB, MMP9, CASP3, and CCL5. This study successfully elucidated the potential anti-inflammatory mechanism of A. cepa bioactive compounds, hence, providing new insights into the development of alternative anti-inflammatory drugs.
