Current medicinal chemistry最新文献

The maintenance of the functional potential of mitochondria is directly related to epigenetic factors, microRNAs (miRs), and mitomicroRNAs (mitomiRs). An important role in the development of metabolic syndrome (MetS)/obesity is attributed to miRs, which have pro-inflammatory or anti-inflammatory potential and can penetrate the mitochondrial matrix. Deciphering the mechanisms responsible for the transport of miRs into the mitochondria would, we believe, allow us to use the knowledge obtained to build designs for the transport of drugs/mitomiRs into cells/mitochondria with low toxicity. A thorough understanding of the polyfunctionality/versatility of individual mitomiRs in specific cells (cell cultures, tissues: adipocytes, brain cells) will allow targeting cellular metabolism to comprehensively block the central link in disease pathogenesis with low potential side effects of this treatment. In this review, we have attempted to identify the key miRs/mitomiRs associated with MetS that affect mitochondrial function. In our opinion, further research should focus specifically on the miR/mitomiRs described here and further investigate their potential in the development of MetS and its components.

Background: Gastric Cancer (GC) represents a highly prevalent and aggressive form of malignancy. Recent scholarly endeavors have implicated the RNA binding motif protein 15 (RBM15) gene in the onset and progression of cancer. The present study was designed to delve into the expression profile of RBM15 in GC, assess its prognostic significance, and explore its potential as a viable therapeutic target.

Methods: In this investigation, we conducted a comprehensive analysis of multiple facets related to the gene RBM15 in GC samples utilizing publicly accessible databases, including TCGA, GEPIA, TIMER, HPA, Kaplan-Meier Plotter, CPADS, and BEST. Specifically, we examined the mRNA expression levels, clinicopathological characteristics, and survival prognosis, conducted gene function enrichment assessments, analyzed mutation profiles, performed immune cell infiltration evaluations, and assessed drug sensitivity. Notably, all parameters employed in the online databases adhered to their respective default settings.

Results: The expression of RBM15 mRNA is upregulated in GC and exhibits a correlation with a favorable prognosis, with an HR of 0.74 (95% CI = 0.62-0.88, p = 0.00054). Specifically, its expression is notably higher in tumor tissues compared to normal tissues. Furthermore, RBM15 expression is associated with differences in pTNM stage, gender, and racial disparities in survival outcomes. Functionally, RBM15 is implicated in DNA replication and cell cycle regulation. Mutations within the RBM15 gene are frequently observed in GC. Additionally, a positive correlation has been identified between RBM15 expression and immune cell infiltration. Drug sensitivity analyses suggest that RBM15 may represent potential therapeutic targets for GC treatment, further highlighting its pivotal role in the progression of GC.

Conclusion: RBM15 mRNA is upregulated in GC and significantly associated with a favorable prognosis. It correlates with clinicopathological features, is enriched in DNA replication processes, and is commonly mutated. Its expression also impacts immune cell infiltration and drug sensitivity, indicating its potential as a prognostic marker and therapeutic target in GC.

Background: FKBP12.6 is a crucial calcium regulatory molecule involved in the regulation of bladder excitatory contraction. This study employed FKBP12.6 knockout mice to investigate the impact of FKBP12.6 on the expression and function of IP3R/TRPM4 and its subsequent effect on bladder contraction function.

Methods: The study selected 129S2/SvPasCrl and FKBP12.6 knockout mice and constructed a Partial Bladder Outlet Obstruction (PBOO) mouse model. GSE1595 data were utilized to analyze calcium signaling pathway changes. Void spot assays, urodynamic tests, and visceromotor response were employed to evaluate bladder function, while HE staining was used to assess bladder morphology. Immunofluorescence, co-immunoprecipitation, and Western blot techniques were employed to detect the localization, expression, and binding changes of FKBP12.6, Inositol-1,4,5 trisphosphate Receptor (IP3R), and TRPM4.

Results: FKBP12.6 was significantly downregulated in PBOO mice (0.9998±0.07 vs. 0.2911±0.04; p <0.05). The micturition frequency (31.42±4.93 vs. 12.17±3.186), bladder sensitivity (1.59 ± 0.22 vs. 3.57± 0.43; p<0.01), detrusor instability, and muscle strip sensitivity (3.470.51 vs. 5.77±0.35; p<0.01) were increased significantly in FKBP12.6 Knockout (KO) mice (p <0.05). FKBP12.6 knockout did not affect the expressions of IP3R and TRPM4 proteins, but FKBP12.6 directly bound to IP3R in mouse bladder detrusor. IP3R/TRPM4 pathway inhibitors, 2-APB and 9-PHE, notably inhibited detrusor sensitivity, micturition frequency, and urination urgency in FKBP12.6 KO mice.

Conclusion: The expression of FKBP12.6 was decreased in the bladder of PBOO mice, and the deletion of FKBP12.6 may lead to bladder dysfunction in mice by affecting the functional activity of IP3R/TRPM4.

This review produces information about the role of protein phosphatase-6 (PPP6C) in various biological processes such as cell proliferation, cell cycle regulation, apoptosis, autophagy, cell migration and differentiation, and DNA damage repair. The issues of the participation of PPP6C in the formation of tumor progression and the role of PPP6C in the epigenetic regulation of the tumor process are covered. The article presents in detail the classification of mutations depending on the biological effects they have. It has been shown that various types of mutations in the PPP6C gene can change the composition of the heterotrimeric complex, favoring some regulatory subunits over others, which promotes selective dephosphorylation of substrates to maintain cell viability and change their biological behavior. In particular, their proliferative activity is disrupted, leading to mitosis arrest at various cell cycle stages. An increase in the activity of Aurora A or a decrease in the activity of DNA-dependent protein kinase is considered the main molecular mechanism of tumor development associated with the inactivation of the pp6c protein. The article also discusses the topic of pharmacological modulation of PPP6C activity. PP6 is a protein involved in many biological processes. In this regard, it is especially important to clarify the role of each PP6 holoenzyme and the molecular mechanisms that regulate the formation of the PP6 complex. Changes in the activity of this phosphatase can disrupt cell functioning.

Objective: The main objective of the study was to investigate potential anticancer activity in vitro of newly synthesized O-alkyl chalcone derivative (E)-1-(3-metoxy- 4-propoxyphenyl)-5-methylhex-1-en-3-on, (Chalcone 5) on cervical HeLa, colorectal HCT-116 carcinoma cells and healthy MRC-5 cells.

Methods: Using the MTT assay, the cytotoxic effect of Chalcone 5 and reference substances dehydrozingerone and cisplatin were assessed. Using flow cytometry analysis, the labeling process with Annexin V-FITC/7-AAD was carried out to assess the type of cell death, while labeling with PI was used to examine the cell cycle progression in Chalcone 5 treated HeLa and HCT-116 cells. JC-10 probe was used to observe changes in the mitochondrial membrane potential after Chalcone 5 therapy. The expression and cellular localization of the important apoptotic proteins Bcl-2, Bax, caspase 3, and cytochrome c were investigated using flow cytometry and immunofluorescence techniques.

Results: The treatment of HeLa and HCT-116 cells with Chalcone 5 selectively induced cytotoxicity, and apoptosis and increased the expression of active Bax and caspase-3 while decreasing the expression of Bcl-2, compared to healthy MRC5 cells. Furthermore, Chalcone 5 decreased mitochondrial membrane potential and caused the release of cytochrome c from mitochondria, thereby triggering the mitochondrial inner apoptotic pathway. Moreover, Chalcone 5 arrested cell cycle progression in the G0/G1 phase in both HeLa and HCT-116 cells.

Conclusion: According to the study's findings, Chalcone 5 is a potentially useful candidate drug for additional in vivo research on its anticancer properties against cervical and colon cancer.

Objective: This study aimed to construct a diagnostic risk model for Bipolar Disorder (BD) using inflammation-related genes (IRGs) and to explore the role of immune cell infiltration in BD pathogenesis.

Methods: BD datasets (GSE23848, GSE124326, GSE39653, and GSE46449) were retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using the edgeR package. The intersection of DEGs and IRGs was defined as differentially expressed IRGs. A LASSO regression model was used to identify optimal biomarkers, which were then utilized to construct a diagnostic risk model. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic accuracy of the biomarkers. Internal validation was performed with GSE124326, while external validation utilized GSE23848, GSE39653, and GSE46449. The xCell module in the IOBR package was employed to assess immune cell infiltration proportions. The relationship between IRGs, the diagnostic risk model, and immune cell dynamics was further analyzed.

Results: A total of 2345 DEGs were identified in GSE124326. GO and KEGG pathway enrichment analyses indicated that inflammatory pathways are critically involved in BD pathogenesis. A total of 69 BD-related IRGs were identified. Six key IRGs (IL33, DNASE1L3, IL2RA, CD70, CLEC5A, and SLPI) were identified through LASSO regression analysis and used to develop a diagnostic risk model. Internal and external validations confirmed the robust diagnostic performance of the risk model. Immuno-infiltration analysis showed significant differences in immune cell infiltration between BD patients and healthy controls. The diagnostic risk model and four potential biomarkers (DNASE1L3, IL2RA, CD70, and SLPI) showed strong correlations with various immune cell types.

Conclusion: A diagnostic risk model for BD was constructed based on IRGs, highlighting the critical role of immune cell infiltration in BD pathogenesis.

Skin is the human body's largest organ, protecting it from various environmental threats. At the same time, it is the most accessible organ of the body, which ensures the reception of stimuli and contact with the environment. Such common signs of skin aging, such as wrinkles, fine lines, and discoloration, result from both extrinsic and intrinsic factors that act for a long time. If the skin does not look well enough, it is worth investigating whether minerals or trace elements are deficient. The positive role of some minerals (calcium, potassium, sodium, sulfur, and magnesium) and trace elements (iron, zinc, selenium, copper, manganese, and silicon) was found in maintaining skin health. There are also a variety of skin conditions, such as inflammatory disorders (eczema, psoriasis), acne, lichen planus, vitiligo, alopecia areata, or even skin cancer, which require specific approaches for their prevention and treatment considering the saturation of the body and the skin with mineral elements. They could be supplied internally (through adequate nutrition or food additives) or externally (by application of cosmetics). Some aspects of the danger of the toxic trace elements used in cosmetics are also described in this review.

Specific regions of plasma membrane enriched with cholesterol and sphingolipids, recognized as lipid rafts or membrane rafts, play an essential part in cell signal transduction. The ability to actively utilize or exempt signaling proteins for the reinforcement or inactivation of specific signaling pathways is the prominent characteristic of lipid rafts, enabling them to act as lipid-based units that can affect signal transduction and cell activity. A connection between lipid raft structure changes and enhancement of the mitogen-activated protein kinase (MAPK) pathway has been reported. Moreover, alteration in lipid raft construction in cancer has also been confirmed. Thus, this review aimed to study the relationship between lipid rafts and the MAPK signaling pathway in a variety of cancer types.

Introduction: The development of Methicillin-Resistant Staphylococcus aureus (MRSA) presents a significant risk to worldwide health and necessitates the creation of novel antimicrobial approaches. The enzyme dehydrosqualene synthase (CrtM), necessary for the bacterial species Staphylococcus aureus to produce staphyloxanthin, is a viable candidate for medicinal investigation. Blocking CrtM hampers the synthesis of staphyloxanthin, reducing the pathogen's ability to cause disease and making it more vulnerable to both the immune system and conventional antibiotics. This study aimed to target the CrtM protein using in-silico approaches and identified its inhibitors.

Method: Tanimoto's similarity of 406,621 unique natural compounds collected from the COCONUT database was calculated using the known inhibitor of CrtM, hesperidin. Further, machine learning-based QSAR screening was performed on these natural compounds where two compounds showed promising binding with the CrtM protein (4299376 and 12897366). A binding score of -9.49 kcal/mol was found for 4299376 and 12897366, respectively, via molecular docking; this value was close to that of the control drug, hesperidin, which was -9.55 kcal/mol. Molecular dynamics simulations conducted at 30 ns and with complexes of MM/GBSA demonstrated binding free energies of -14.38 kcal/mol for 12897366 and -42.72 kcal/mol for 4299376, respectively. 4299376 was selected further for 200 ns MD simulation because of its high binding affinity and stability in the RMSD plots.

Results: Additionally, post 200 ns MD analysis and MM/GBSA analysis showed the consistent stability and strong binding of 4299376 with CrtM (RMSD = 0.3 nm and binding free energy of -37.30 kcal/mol). Moreover, the critical residue Gln165 of CrtM was found to have a hydrogen bond with 4299376 in the 0 ns, 100 ns, and 200 ns conformation. Overall, 4299376 performed well in the PCA, free energy landscape, and per-residue decomposition, proving it is an effective CrtM binder. The free energy perturbation (FEP) analysis revealed that as the system progressed from fully bound (λ = 0) to decoupled (λ = 10), the free energy (ΔG) changed from 6.56 kT to -4.38 kT, signifying a reduction in binding free energy and implying an increase in entropy and solvation effects that stabilize the ligand in the decoupled state. This underscores the entropic contribution and solvent interactions as critical determinants in the lowering of binding free energy.

Conclusion: This study concluded that 4299376 exhibits considerable therapeutic potential and could be investigated further for its potential use as an inhibitor against CrtM of S. aureus.