Current Medicinal Chemistry - Online First

Ischemic Stroke (IS) represents the most prevalent subtype of cerebrovascular disease, characterized by complex pathophysiological mechanisms that remain inadequately characterized, particularly concerning mitochondrial dysfunctions. These mitochondrial impairments are increasingly recognized as contributory factors in IS pathogenesis, emphasizing the need for further investigation into the underlying molecular mechanisms involved.

In this study, we integrated transcriptomic datasets from the Gene Expression Omnibus (GEO) with the comprehensive MitoCarta3.0 mitochondrial proteome inventory to elucidate the role of dysregulated Mitochondrial-Related Genes (MRGs) in IS. We employed an advanced bioinformatics and machine learning pipeline, incorporating differential expression profiling alongside network-based prioritization using CytoHubba. Rigorous feature selection was conducted through LASSO regression, Support Vector Machine (SVM), and Random Forest (RF) algorithms to derive a robust core MRG signature. Our methodology included training and validation cohorts to construct diagnostic models, which were critically evaluated via Receiver Operating Characteristic (ROC) curves, nomograms, and calibration analyses.

Our analysis identified a seven-gene signature comprising DNAJA3, ACSL1, HSDL2, ECHDC2, ECHDC3, ALDH2, and PDK4, which demonstrated significant correlation with activated CD8⁺ T-cell and natural killer cell infiltration. Furthermore, integrative network analyses revealed intricate regulatory interactions among MRGs, microRNAs, and transcription factors. Notably, drug-target predictions indicated Bezafibrate as a promising therapeutic agent for modulating mitochondrial homeostasis in the context of IS.

These findings offer a novel framework for ischemic stroke diagnosis and therapy, yet their computational derivation underscores the need for thorough experimental validation of MRGs and drug candidates, along with the integration of diverse clinical data to confirm their real-world applicability.

Our findings underscore mitochondrial dysfunction not only as a critical factor in IS pathogenesis but also as a viable therapeutic target. The identified MRG signature presents potential for clinical application in diagnostic and pharmacological strategies aimed at ameliorating ischemic injury. This study highlights the translational significance of systems biology approaches within cerebrovascular medicine, warranting further mechanistic exploration of mitochondrial-immune interactions in stroke pathology.

Neuroinflammation, primarily mediated by activated microglia, is a significant contributor to neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Quercetin (QCT), a dietary flavonoid, has demonstrated anti-inflammatory and neuroprotective properties; however, the detailed molecular mechanisms behind these effects remain unclear. This study aimed to investigate the anti-inflammatory actions of QCT, particularly focusing on its potential to suppress the activation of microglia and subsequent neuroinflammation.

BV2 microglial cells were stimulated with lipopolysaccharide (LPS) to induce an inflammatory response and were subsequently treated with various concentrations of QCT. Cell viability was assessed using the MTT assay. Levels of pro-inflammatory cytokines (IL-6, TNF-α) and nitric oxide (NO) were quantified through ELISA and Griess reaction methods, respectively. Western blot analysis was conducted to examine inducible nitric oxide synthase (iNOS), NF-κB, IκBα, and phosphorylated IκBα protein expressions. In silico approaches, including protein-protein interaction (PPI) network analysis and molecular docking, were employed to explore potential molecular mechanisms involving NF-κB signaling pathways.

Treatment with QCT significantly reduced the secretion of IL-6 (96%) and TNF-α (87%), as well as NO production (42%), in a dose-dependent manner. Western blot results demonstrated a marked reduction in iNOS expression and inhibition of NF-κB activation through reduced phosphorylation of IκBα following QCT treatment. Molecular docking indicated a strong binding affinity between QCT and IKKβ, suggesting inhibition of the NF-κB pathway.

The findings indicated QCT to exert potent anti-inflammatory effects in LPS-stimulated BV2 cells by modulating key proteins involved in the NF-κB signaling pathway. Specifically, the docking results implied QCT’s direct interaction with the catalytic subunit IKKβ, inhibiting IκBα phosphorylation and subsequent NF-κB activation. The results have been found to be consistent with previous literature, reinforcing QCT's role in reducing neuroinflammation through specific molecular targets and pathways. Further in vivo studies are necessary to validate the findings.

Quercetin effectively suppressed neuroinflammation in microglial cells through inhibition of the NF-κB signaling pathway, reducing levels of critical pro-inflammatory mediators. The outcomes have highlighted the potential of quercetin as a preventive nutraceutical for neurodegenerative diseases, necessitating future in vivo investigations to confirm its therapeutic efficacy.

Several pathological conditions, including glaucoma, malignant brain tumors, and renal, gastric, and pancreatic carcinomas, are commonly associated with carbonic anhydrase type II (CA-II). Additionally, CA-II plays a critical role in regulating bicarbonate concentration in the eyes. The inhibition of CA-II reduces aqueous humor production and thus lowers intraocular pressure associated with glaucoma.

This study aimed to synthesize potent CA-II inhibitors, 5-nitro-1H-benzo[d]imidazole-2(3H)-thione (5NBIT) and acylhydrazone derivatives (1-13).

In this study, a new series of potent CA-II inhibitors, 5-nitro-1H-benzo[d]imidazole-2(3H)-thione (5NBIT) and acylhydrazone derivatives (1-13), were synthesized and characterized by IR, NMR, UV and mass spectroscopy and evaluated against bovine carbonic anhydrase-II (bCA-II).

Interestingly, most of the compounds showed better inhibition than the standard drug, acetazolamide (IC50: 18.2±0.51 µM), such as compounds 1 (IC50: 10.5±0.81 µM), 2 (IC50: 11.3±0.36 µM), 3 (IC50: 16.5±0.53 µM), 4 (IC50: 15.8±1.02 µM), 5 (IC50: 13.7±1.03 µM), and 9 (IC50: 12.2±1.03 µM). Among the synthesized compounds, compound 7 (IC50: 8.2±0.32 µM) exhibited the highest and compound 6 (IC50: 27.6±0.39 µM) showed the lowest inhibition. Structure-activity relationships suggest that the presence of nitro group on the phenyl ring contributed significantly to the overall inhibitory activity. Molecular docking of all the active compounds was performed to predict their binding behavior, which indicated good agreement between docking and experimental findings. Moreover, the MD simulation of compound 7 also showed excellent binding behavior and binding energy within the binding cavity of bCA-II.

These findings suggest that the synthesized 5NBIT and acylhydrazone derivatives exhibited potent CA-II inhibition, with several compounds outperforming the standard drug acetazolamide. These results provide valuable insights for the development of novel CA-II inhibitors with potential therapeutic applications in glaucoma and other related conditions.

Diffuse large B-cell lymphoma (DLBCL) pathogenesis is poorly understood, with limited causal evidence linking circulating inflammatory proteins (CIPs) and metabolites to disease risk. Observational studies face challenges from confounding and reverse causation, while existing Mendelian Randomization (MR) analyses lack bidirectional designs and multi-omics integration.

A bidirectional two-sample MR design was applied using inverse-variance weighting (IVW). Genetic instruments for 91 CIPs derived from Olink proteomic data (14,824 participants). DLBCL genetic associations (1,050 cases; 314,193 controls) were obtained from FinnGen (R10 release). Data for 1,091 blood metabolites and 309 metabolite ratios were sourced from the GWAS Catalog.

Ten CIPs exhibited causal effects on DLBCL. Risk-increasing proteins included: IL-10 (OR=1.46, 95%CI=1.05-2.03), TSLP (1.37,1.01-1.84), IL-17C (1.34,1.05-1.72), NRTN (1.30,1.02-1.66), OPG (1.29,1.01-1.66), and MCP1 (1.26,1.04-1.52). Protective proteins included: CD40 (0.82,0.67-1.00), CXCL9 (0.78,0.61-0.98), CD5 (0.77,0.61-0.97), and MCP3 (0.76,0.58-0.99). Reverse causation was absent for 7 proteins. Mediation analysis revealed 17.2% (p=0.048) of CD5’s protective effect was mediated by 1-methylhistidine.

These findings establish CIPs as causal factors in DLBCL pathogenesis and identify metabolite-mediated pathways as novel mechanistic links. The bidirectional design and multi-omics integration overcome key limitations of prior research, though statistical power for some mediation tests was limited by metabolite GWAS sample sizes.

Plasma inflammatory proteins causally influence DLBCL risk, partially mediated by metabolites. This underscores metabolite pathways as potential targets for therapeutic intervention.

Klotho is a multifunctional protein with anti-aging properties that plays a role in regulating vitamin D and phosphate metabolism. Sarcopenia is characterized by the loss of muscle mass and strength and is an important public health concern due to its negative effects on health. The aim of this study was to investigate the association between α-Klotho levels and the frequency of sarcopenia in a diverse population.

This study analyzed data from 1,250 participants in the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2016. Participants were divided into four subgroups based on serum α-Klotho levels. Sarcopenia was assessed using skeletal muscle index and handgrip strength measurements. Multivariable logistic regression analysis was used to determine the association between serum α-Klotho levels and sarcopenia.

There was a significant difference in serum α-Klotho levels between patients with sarcopenia and patients without sarcopenia. In an unadjusted multivariable logistic regression model, higher α-Klotho serum levels were associated with a lower risk of sarcopenia (p < 0.05). This trend was maintained in the partially adjusted model, indicating that higher levels of α-Klotho were associated with a lower risk of sarcopenia. However, the fully adjusted model did not show significance.

Several factors significantly influence the relationship between serum α-Klotho levels and sarcopenia, including sex, ethnicity, alcohol consumption, body mass index (BMI), vitamin D levels, and disease status. Our findings indicate that the risk of sarcopenia is elevated in individuals within the lowest quartile of serum α-Klotho levels. Furthermore, a negative correlation exists between α-Klotho levels and grip strength, observed in both the overall sample and the aging-related subgroup. These results highlight the necessity for further investigation into the complex interplay between α-Klotho and grip strength, particularly in the context of sarcopenia associated with renal disease.

Serum α-Klotho levels in different populations are negatively correlated with the risk of sarcopenia, suggesting that α-Klotho may be involved in the occurrence and development of sarcopenia. Therefore, measuring α-Klotho levels in clinical practice may be a valuable diagnostic tool to identify individuals at high risk of developing sarcopenia.

Hepatocellular Carcinoma (HCC) exhibits high recurrence rates, particularly when accompanied by Microvascular Invasion (MVI). We identified MVI-related biomarkers and established a prognostic model for personalized HCC treatment.

Data were downloaded from The Cancer Genome Atlas (TCGA) and HCCDB databases. Key radiomics features were identified using the support vector machine-recursive feature elimination (SVM-RFE) algorithm, and differential expression analysis was performed with DESeq2. This was followed by functional enrichment analysis using the clusterProfiler package. Through univariate and Lasso regression analyses, we constructed a robust RiskScore model to effectively stratify HCC patients into distinct risk groups based on the median RiskScore value. The model prediction performance was evaluated using ROC curves and Kaplan-Meier (KM) analysis. We used the CIBERSORT algorithm to characterize immune cell infiltration patterns and conducted GSEA to identify differentially activated pathways between the risk groups.

Radiomic analysis revealed four significant features strongly associated with MVI, enabling the construction of a nomogram model with robust classification performance (AUC = 0.742). Subsequent analysis identified 241 overlapping MVI-related Differentially Expressed Genes (DEGs) enriched in critical tumor proliferation and invasion pathways. A 10-gene RiskScore model was developed, demonstrating excellent prognostic discrimination in training and validation cohorts. CIBERSORT analysis revealed significant correlations between specific immune cell infiltration and the 10 genes. GSEA analysis showed significant enrichment of cell cycle regulation pathways in the high-risk group, suggesting their important role in MVI.

The RiskScore was established using MVI-related features for prognosis assessment in HCC.

Our findings provided novel biomarkers and a theoretical basis for the early diagnosis and personalized treatment of HCC.

To identify the critical genes, biological mechanisms, and signaling pathways involved in the therapeutic effects of quercetin on diabetic foot ulcers using network pharmacology and molecular docking approaches.

We identified pathological targets of diabetic foot ulcers (DFU) from GeneCards, OMIM, and TTD, and pharmacological targets of quercetin from STP, TCMSP, and PharmMapper. Intersection analysis revealed potential therapeutic targets. Core targets were determined via GO/KEGG enrichment, PPI network construction, and Cytoscape screening algorithms (Degree, Closeness, Betweenness). Molecular docking and dynamics simulations assessed quercetin-core target interactions and binding affinity.

After screening and intersecting the targets of quercetin and diabetic foot ulcers, 236 genes related to quercetin's anti-diabetic foot ulcer effects were identified, with six key genes emerging as critical: SRC, TP53, MAPK1, JUN, HSP90AA1, and AKT1. Enrichment analysis suggested that quercetin may modulate inflammatory imbalance(HSP90AA1), immunosuppression(JUN), and oxidative stress(SRC, TP53, MAPK1, and AKT1) during diabetic foot ulcer progression.

The relationship between these core targets and biological pathways in diabetic foot ulcers requires further experimental validation. Notably, molecular docking and dynamics simulation results confirmed strong binding affinity between quercetin and the core targets, supporting their potential therapeutic relevance.

Quercetin exerts anti-diabetic foot ulcer effects by regulating SRC, TP53, MAPK1, JUN, HSP90AA1, and AKT1. These hub genes may serve as promising candidates for future therapeutic interventions in diabetic foot ulcers.

Chronic Renal Failure (CRF) is a progressive disease that severely affects patients' quality of life, but its current treatment options remain limited. This study explores the potential mechanism of Eriobotryae Folium (EF) in treating CRF by targeting ferroptosis.

Active compounds and targets of EF were identified through multiple databases (TCMSP, SwissTargetPrediction, UniProt, GeneCards, DrugBank). Using Cytoscape and STRING, both a compound-target network and a PPI network were generated. GO and KEGG analyses were conducted to explore relevant biological functions and pathways. The binding affinity and stability between critical compounds and target proteins were investigated through molecular docking and Molecular Dynamics (MD) simulations.

Eighteen active compounds and 366 targets of EF were identified, along with 1,267 CRF-related and 1,673 ferroptosis-related targets, with 40 overlapping genes. PPI analysis highlighted AKT1, EGFR, HIF1A, SRC, and ESR1 as key targets. The KEGG analysis indicated MAPK and HIF-1 pathways as major regulatory pathways. Molecular docking suggested quercetin, ellagic acid, and oleanolic acid as potential active compounds, with EGFR and SRC as promising targets. MD simulations confirmed strong and stable binding, especially for EGFR-ellagic acid (-21.38 kcal/mol) and EGFR-oleanolic acid (-24.02 kcal/mol).

This study suggests that EF treats CRF by targeting ferroptosis-related pathways and key proteins, such as EGFR and AKT1. MAPK and HIF-1 signaling pathways further substantiate its significant role in disease regulation.

EF may regulate ferroptosis through multiple targets and pathways, offering potential therapeutic benefits for CRF. The findings offer foundational insights for subsequent research and therapeutic development.

Diabetes mellitus, a chronic metabolic disorder characterized by elevated blood glucose levels, has emerged as a significant global health burden. Chronic inflammation and insulin resistance are central to the pathogenesis of non-insulin-dependent (type 2) diabetes mellitus. PTGS2 (prostaglandin-endoperoxide synthase 2) has been implicated in inflammatory pathways associated with diabetic complications, making it a potential therapeutic target.

Advanced computational methodologies were employed to identify potential natural compounds with anti-diabetic activity. Techniques included network pharmacology to establish compound-target-pathway relationships and in silico molecular docking to evaluate binding affinity and interaction profiles of selected phytochemicals with PTGS2.

PTGS2 and its downstream prostaglandin pathways were strongly associated with diabetic inflammation and insulin resistance. Molecular docking identified Corytuberine and Nuciferine as having high binding affinities with PTGS2. Network pharmacology analysis confirmed Nuciferine’s connection to PTGS2, supporting its role as a bioactive agent targeting diabetes-related inflammatory processes.

The findings suggest that PTGS2 contributes to the progression of insulin resistance and chronic inflammation in type 2 diabetes. Targeting this enzyme with bioactive compounds such as Nuciferine may offer therapeutic benefits. However, translational studies and clinical trials are essential to validate these computational predictions and assess safety and efficacy in vivo.

Nuciferine exhibits promising potential in modulating PTGS2 activity and improving insulin sensitivity. Continued research and clinical validation are needed to confirm its efficacy and support the development of novel anti-diabetic therapies targeting inflammatory pathways.