Current medicinal chemistry最新文献

Introduction: Type 1 Diabetes Mellitus (T1DM) is characterized by the damage of pancreatic β-cells induced by autoimmune responses. Circular RNAs (circRNAs) play important regulatory roles in the pathogenesis of T1DM, but the underlying mechanisms require further substantiation.

Method: This study focused on a novel circRNA, circ006029, to investigate its regulation on β-cell damage. The potential involvement of circ006029 in β-cell proliferation, apoptosis, autophagy, and inflammatory responses was investigated using CCK-8, qRTPCR, and immunoblot assays. The utilization of a cytokine mixture, and specific molecular blockers Rapamycin and Capivasertib, was applied to investigate the pathway by which circ006029 regulates β-cell damage. Transcriptome sequencing and bioinformatics analysis were conducted to explore differentially expressed mRNAs related to circ006029 regulation.

Result: The expression of circ006029 was observed to increase in damaged MIN6 cells. The inhibition of circ006029 serves a protective role in MIN6 β-cells by promoting β-- cell proliferation and attenuating apoptosis. circ006029-knockdown could augment β-- cell autophagy and attenuate apoptosis through the AKT/mTOR signaling pathway. Moreover, circ006029 might be involved in the inflammatory response of MIN6 cells.

Discussion: The knockdown of circ006029 was demonstrated to alleviate β-cell inflammation and reduce cell apoptosis. The promotion of β-cell proliferation and heightened autophagy also substantiated the protective effects of circ006029 silence. Furthermore, we also proved that circ006029 might contribute to autophagy via the AKT/mTOR signaling pathway. All the results implied that the presence of circ006029 may drive a detrimental regulatory role in pancreatic β-cells. This may provide valuable evidence that circ006029 might be a potential target for alleviating β-cell damage in T1DM and rebuilding β-cell function.

Conclusion: These findings suggest that circ006029 may serve a detrimental role in β-- cell damage, which provides new ideas for exploring the mechanism of β-cell damage in early insulitis in T1DM.

Introduction: Esophageal cancer (EC) remains a global health challenge with high incidence and mortality. While sEV-related genes (ERGs) are emerging as key players in the tumor microenvironment, their diagnostic and pathogenic roles in EC are still poorly characterized.

Methods: This study employed integrated bioinformatics approaches to identify ERGbased diagnostic biomarkers and molecular mechanisms in EC. Four GEO datasets were analyzed to identify differentially expressed genes (DEGs), which were cross-referenced with ERGs from GeneCards and the literature. Functional enrichment analyses (GO/KEGG), Cytoscape network analysis, and machine learning algorithms (LASSO, SVM, random forest) were used to prioritize diagnostic markers. Immune infiltration patterns were assessed via ssGSEA, and key genes were validated by qRT‒PCR in EC and normal cells.

Results: We identified 456 DEGs, including 34 sEV-related ERDEGs enriched in bacterial defense response, secretory granule lumen, calcium-dependent protein binding, and pathways such as proteoglycans in cancer and IL-17 signaling. GSEA highlighted cell cycle, ECM-receptor interaction, and DNA replication as central mechanisms.

Discussion: Machine learning pinpointed EpCAM and RUVBL1 as robust diagnostic biomarkers, validated by their elevated expression in EC cell lines. Immune infiltration analysis revealed correlations between these genes and 20 immune cell types, underscoring their relevance to the tumor microenvironment.

Conclusion: EpCAM and RUVBL1 are promising diagnostic biomarkers for EC, linking sEV-mediated pathways to disease progression. These findings provide insights into EC pathogenesis and highlight potential therapeutic targets.

Introduction: Sphingosine kinase 2 (SPHK2) plays a pivotal role in sphingolipid metabolism and has emerged as a therapeutic target in cancer due to its involvement in tumor proliferation and resistance mechanisms.

Methods: A dataset of 269 SPHK2-targeting compounds from ChEMBL was analyzed using five molecular descriptor sets: PubChem, MACCS, CDK, Substructure, and Klekota- Roth. Six machine learning algorithms were applied to develop QSAR models, and they were validated using ROC-AUC, PCA, R2, and Q2 metrics. Top-ranked compounds were subsequently evaluated using Glide docking and MMGBSA energy calculations.

Results: Random Forest models demonstrated the best predictive performance, especially with Klekota-Roth and PubChem descriptors (R2 = 0.78; Q2 = 0.72). Lead compounds, namely CHEMBL2409888 and CHEMBL2409889, exhibited strong binding affinities (ΔG = -58.02 and -58.13 kcal/mol), interacting with key residues GLU293, ARG652, and HIS289. Inactive compounds showed reduced binding strength and limited residue interactions.

Discussion: This integrative computational pipeline successfully identified structurally significant SPHK2 inhibitors and highlighted molecular features contributing to activity. While the results offer mechanistic insights and a rational framework for further optimization, findings are based solely on in silico predictions.

Conclusion: This study presents a predictive framework combining machine learning and molecular modeling to identify selective SPHK2 inhibitors, offering valuable candidates for further synthesis and biological validation.

Introduction: In the context of repurposing antimicrobial fluoroquinolones (FQs), we propose that their increased efficacy is attributable to the lipophilic properties of the newly developed FQs.

Methods: This study involved the synthesis of 21 lipophilic-acid chelating fluoroquinolones (FQs) and their subsequent screening approaches for selective antiproliferative, antioxidant, and anti-inflammatory activities.

Results: Notably, the reduced FQ series, specifically 14c, demonstrated radical scavenging activities for NO and DPPH that were comparable to the referencing agents. In contrast to the others, the reduced 10a, 10b, and 14b FQs exhibited significant antioxidant effects. Predominantly, MCF7, HT29, T47D, and SW480 were the best target cell lines for the new FQs to exhibit their antiproliferative activities. In fact, many FQ derivatives have revealed IC50 values below 10 µM, mainly with MCF7 and HT29cell lines. Among the three synthesized series (nitro, reduced, and triazolo), the compounds (10a-d and 14a-d) of the reduced series exhibited the highest activities (lowest IC50) against the strongest four cell lines. All reduced series of hexyl phenyl 14a, 14c, and 14d with para-halogens were stronger than their hexyl amine counterparts 10a, 10c, and 10d. The selectivity indices for the new FQs were either equipotent or more potent than the reference cisplatin.

Discussion: The remarkable effects of the reduced series 14a, 14b, 14c, 10a, 10c, and 10d stemmed from metal chelation within the C8-C7 ethylene diamine bridge. Furthermore, the spatial and steric constraints introduced by the N1 substituent ultimately influenced the chelation geometry. Complexation studies revealed that central iron chelation is the predominant intracellular mechanism, whereas zinc chelation is the primary mode of interaction with the zinc-dependent metalloenzyme Glo-I. Mechanistically, nitroFQs 9d, 13a, and 13d and their respective reduced FQs 14a and 14d were shown to exhibit unprecedentedly equipotent Glo-I enzymatic inhibition, matching the IC50 value of myricetin (3.5 µM). Appreciably significant GLo-I inhibition with IC50 values ranging from 24-52 µM was obtained for nitroFQs and their reduced FQs in the ascending order of 9c < 9b < 13b < 14b < 10b < 10c < 10d.

Conclusion: The mechanism of action of the FQs involved acidic functional groups and a C7-C8 ethylenediamine chelation bridge, with iron chelation being the predominant pathway.

Introduction: Lung cancer is a leading cause of cancer-related morbidity and mortality. The development and evaluation of effective treatment strategies for lung cancer are of high clinical importance. Everolimus (Eve) has been shown to upregulate the expression of phosphatases and inhibit the migration and proliferation of A549 cancer cells. The present study focuses on the synthesis of biodegradable bovine serum albumin (BSA) nanoparticles for the loading and delivery of Eve.

Methods: In the desolvation process, Eve molecules were kept in the BSA system. The physicochemical properties of the Eve drug containing BSA nanoparticles (Eve@BSA) have been exactly characterized. The loading and release assays of Eve were also studied at different glutaraldehyde percentages, times, and solvents.

Results: Field emission scanning electron microscopy (FE-SEM) analysis of BSA nanoparticles revealed a spherical morphology with an average size of 93.7 ± 3.7 nm. The results demonstrated that BSA nanoparticles are highly efficient carriers, achieving an Eve loading efficiency of approximately 54% at 4% glutaraldehyde. The release of Eve from the BSA nanoparticles was dependent on the solvent and duration of incubation. According to the MTT assay, Eve@BSA exhibited low cytotoxicity and high biocompatibility against L929 fibroblast cells. In contrast, the cytotoxicity of Eve@BSA against A549 cells (IC50 ≈ 47 μg/mL) was significantly higher than that of free Eve (IC50 ≈ 283 μg/m- L) after 48 hours.

Discussion: The synergistic effects of Eva@BSA nanoformulation due to functional groups-rich BSA seemed to improve in vitro antiproliferation efficacies compared with the single treatment of Eve.

Conclusion: The findings confirm the synergistic anticancer effect of Eve@BSA, indicating that this nanosystem may serve as a promising candidate for the treatment of lung cancer.

Introduction: The development and progression of non-small cell lung cancer (NSCLC) are intricately linked to immune cell activation, but its related signature has not been reported.

Methods: This study combines in silico and in vitro approaches. TCGA-NSCLC and Gene Expression Omnibus (GEO) datasets were utilized to develop and validate a prognostic signature based on cell activation genes. The signature's validity was assessed through the identification of genomic, transcriptomic, tumor microenvironment (TME), and single-cell infiltration characteristics. The function of the candidate gene RORA was verified using CCK8, apoptosis, colony formation, wound healing, and transwell assays. The detailed mechanism of RORA was investigated through ChIP-PCR, luciferase assays, Western blot, and ROS detection.

Results: The prognostic signature was constructed from TCGA-NSCLC datasets and validated in six independent datasets (GSE30219, GSE33072, GSE37745, GSE41271, GSE42127, GSE50081). The signature was associated with LRP1B and RYR2 mutations, NSCLC-related pathways, drug response, and immune cell infiltration. The candidate gene RORA significantly inhibits the proliferation and migration abilities of NSCLC cell lines (A549 and NCI-H1299). Furthermore, the transcription factor RORA promotes ZNF490 expression, which subsequently inhibits NUDFs expression and oxidative phosphorylation (oxphos).

Discussion: The signature highlighted its significance with genomic features that were frequently reported as prognostic indicators (LRP1B and RYR2 mutations, cancer-related infiltration and pathway infiltration), and putative treatment response (IC50 in the TCGA dataset). Its detailed mechanism of candidate gene RORA revealed its role in oxphos, highlighting the crosstalk between metabolism and immune activation.

Conclusion: The model is robust and effectively reflects NSCLC heterogeneity while predicting prognosis. RORA promotes the expression of ZNF490 to inhibit NUDFs and oxidative phosphorylation.

Background: Respiratory syncytial virus (RSV) causes more than 30 million cases of lower respiratory tract infections (LRTIs) and approximately 3 million hospitalizations globally each year. Although RSV is particularly dangerous for young children, older adults and individuals with underlying health conditions or weakened immune systems are also at risk. Rapid diagnosis of RSV infection is crucial to ensure timely treatment and prevent disease spread. While conventional diagnostic techniques exist, many are time-consuming, expensive, or labor-intensive. Biosensors have recently emerged as a promising alternative.

Methods: This review involved gathering original articles published in English from various databases, including PubMed, Scopus, Web of Science, and Embase, between August and October, 2024. Additionally, reference lists from these articles were examined in Google Scholar for further relevant sources. Out of 147 electronically searched citations, 15 articles met the inclusion criteria.

Results: Genosensors, particularly those employing Surface-Enhanced Raman Scattering (SERS) and electrochemical detection, demonstrated the most significant potential for RSV diagnosis. Biosensors are increasingly being applied for RSV detection due to their high sensitivity, accuracy, and rapid results. The most prevalent conventional techniques for RSV detection include immunofluorescence (IF), ELISA, cell culture, and RT-PCR (Real-time PCR). While molecular methods are fast and sensitive, they require advanced laboratory equipment and trained personnel. In contrast, biosensors offer a rapid, reliable, and cost-effective diagnostic approach.

Conclusion: Biosensors represent a significant advancement in RSV diagnostics, particularly in resource-limited settings. Enhancing biosensor technology could improve accessibility, speed, and accuracy in RSV detection, ultimately leading to better patient outcomes and reduced disease transmission.

Marine invertebrates exhibit a vast taxonomic diversity, encompassing multiple phyla ranging from Porifera (sponges) to Echinodermata. These organisms inhabit complex marine environments and have evolved a diverse array of unique bioactive substances with various pharmacological effects, including antibacterial, antiviral, antitumor, and anti-inflammatory properties. As a result, they have long served as a crucial source of active natural products. The application prospects of these natural products are expanding rapidly across various fields, including medicine, cosmetics, and biotechnology, offering new possibilities for human health and sustainable development. This review compiles information on 159 novel natural products derived from marine invertebrates, which were first discovered in 2024. These compounds, originating from a diverse range of marine invertebrates, encompass various chemical classes, including terpenoids, alkaloids, peptides, and other unique categories. This review places a strong emphasis on elucidating their origins, intricate chemical structures, and promising biological activities. By presenting the latest discoveries and advancements in the field, this comprehensive review aims to offer valuable references and novel insights for the research and development of innovative antibacterial, antitumor, and anti-inflammatory drugs.

Introduction: This study explores the evaluation of 2- or 4-methyl-9H-xanthen-9-one derivatives containing aminophenols or aromatic chiral/achiral aminoalkanols as potential blood vessel-sealing agents.

Methods: A series of xanthone derivatives were synthesized and evaluated through multiple bioassays, including hyaluronidase inhibition assays, antiplatelet activity via collagen-induced platelet aggregation, antioxidant potential using DPPH and FRAP assays, and vasodilatory responses in isolated rat aortic rings precontracted with phenylephrine.

Results: Among the obtained derivatives, compound 2 (2-hydroxy-N-((9-oxo-9H-xanthen-2-yl)methyl)-2-phenylethan-1-aminium chloride) demonstrated the highest hyaluronidase inhibition (19.09% at 100 μM/L), comparable to the reference compound quercetin (26.17% at 100 μM/L). Furthermore, compound 2 exhibited significant antiplatelet activity, reducing collagen-induced aggregation by 40.42% at 200 μM (p < 0.0001), similar to quercetin (40.38% at 200 μM), though weaker than acetylsalicylic acid (ASA, 71% in-hibition at 50 μM). Antioxidant studies using DPPH and FRAP assays indicated that compound 1 (4-hydroxy-N-((9-oxo-9H-xanthen-2-yl)methyl)benzenaminium chloride) surpassed vitamin C's antioxidant effect by 35%, while showing high ferric-reducing activity (91%). Additionally, compound 2 demonstrated a vasodilatory effect on rat aortic rings precontracted with phenylephrine, in contrast to quercetin, which enhanced vasoconstriction.

Discussion: Quercetin and α-mangostin were selected as reference compounds due to their well-established vasorelaxant mechanisms and structural similarities to the synthesized xanthone derivatives, providing a basis for comparison in evaluating vascular sealing potential and endothelial protective activity.

Conclusion: The study's findings suggest that 2-methylxanthone derivatives, particularly compound 2, hold potential as vascular sealing agents with additional antiplatelet and vasorelaxant properties. Compound 1, based on the present study, was chosen for further research due to its significant antioxidant properties. These results warrant further pharmacological evaluation for cardiovascular applications.

This review addresses the challenge of radioresistance in cervical cancer by exploring the role of ferroptosis in enhancing the efficacy of radiotherapy (RT). It emphasizes the radiosensitizing effect of β-sitosterol through modulation of the GPX4/ACSL4 axis. β-Sitosterol targets mitochondrial membranes, inhibits GPX4 activity, and activates ACSL4, promoting polyunsaturated fatty acid synthesis and thereby facilitating ferroptosis. Preclinical models demonstrate that β-sitosterol significantly improves RT sensitivity and increases tumor iron accumulation. The review further proposes a predictive framework based on ox-LDL levels and the ACSL4/GPX4 ratio for potential clinical application, alongside discussions on innovative delivery systems, ferroptosis-apoptosis interactions, microbiota-mediated metabolic effects, and AI-driven optimization of RT-- drug combinations. These insights contribute to advancing personalized radiotherapy strategies for cervical cancer.