Combinatorial chemistry & high throughput screening最新文献

{"title":"Mechanistic Insights into the Therapeutic Effects of Zishen Yutai Pill on Premature Ovarian Insufficiency via the RIPK1/RIPK3/MLKL Necroptosis Pathway.","authors":"Yihui Feng, Yingyin Chen, Ying Zhao","doi":"10.2174/0113862073476000260411110248","DOIUrl":"https://doi.org/10.2174/0113862073476000260411110248","url":null,"abstract":"<p><strong>Introduction/objective: </strong>Zishen Yutai Pill (ZYP) has shown clinical efficacy in the treatment of Premature Ovarian Insufficiency (POI). However, its underlying mechanisms remain unclear. This study aimed to investigate the therapeutic effects and underlying mechanism of ZYP in cyclophosphamide (CTX)-induced POI in rats.</p><p><strong>Methods: </strong>A total of 119 female rats were divided into two groups: blank controls (n=17) and POI rat model (n=102). POI rats were randomly assigned (n = 17 per group) to six groups: POI model controls or five treatments, including low-dose ZYP, high-dose ZYP, caspase inhibitor, RIPK1 inhibitor, or estradiol valerate (positive control). Sex hormone levels of follicle-stimulating hormone (FSH), estradiol (E2), and Anti-Müllerian Hormone (AMH) were assessed by enzyme-linked immunosorbent assay. Ovarian morphology was assessed by Hematoxylin and Eosin (H&E) staining and Transmission Electron Microscopy (TEM). The expression of apoptosis- and necroptosis-related proteins, including caspase-3, caspase-8, tumor necrosis factor-alpha (TNF-α), RIPK1, RIPK3, and MLKL, was assessed by immunohistochemistry, western blot (WB), and immunofluorescence (IF).</p><p><strong>Results: </strong>ZYP improved general condition and stabilized body weight in POI rats. It significantly decreased FSH while increasing E2 and AMH (p<0.001). High-dose ZYP increased primary (p<0.05) and antral follicles (p<0.001), and reduced atretic follicles (p<0.001). Ultrastructural damage was alleviated. ZYP downregulated apoptosis- and necroptosis-related proteins (caspase- 8, caspase-3, TNF-α, RIPK1, RIPK3, MLKL) (p<0.001), comparable to the RIPK1 inhibitor. WB and IF further showed that ZYP high-dose group significantly downregulated RIPK3 and MLKL expression (p<0.001).</p><p><strong>Discussion: </strong>These findings provide mechanistic insight into the protective role of ZYP and support its potential as a therapeutic strategy for POI.</p><p><strong>Conclusion: </strong>ZYP ameliorates CTX-induced POI by regulating hormones, improving ovarian morphology, and inhibiting the RIPK1/RIPK3/MLKL pathway.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Qixian Decoction Improves Airway Hyperresponsiveness by Inhibiting TRPV1 and Downstream PI3K-Akt/HIF-1α Signaling.","authors":"Linyun Zhu, Wei Yang, Qingge Chen, Xiongbiao Wang","doi":"10.2174/0113862073472389260405212404","DOIUrl":"https://doi.org/10.2174/0113862073472389260405212404","url":null,"abstract":"<p><strong>Introduction: </strong>Qixian Decoction (QXT), a traditional Chinese medicine formula, exerts favorable therapeutic effects on asthma, but its underlying mechanisms remain incompletely elucidated.</p><p><strong>Materials and methods: </strong>This study combined network pharmacology and experimental validation. Employing the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), we screened active compounds of QXT and their targets. A herbcompound- target network was constructed. DEGs were recognized from the GSE161245 asthma dataset. Molecular docking was utilized to validate the interaction of key compounds with selected core targets. The effects of QXT on the Potential Vanilloid 1 (TRPV1)/Phosphatidylinositol 3-Kinase-Protein Kinase B (PI3K-Akt)/Hypoxia-Inducible Factor-1α (HIF-1α) axis and Epithelial- Mesenchymal Transition (EMT) were evaluated using in vivo (asthmatic mice) and in vitro (TGF-β-stimulated 16HBE cells) models.</p><p><strong>Results: </strong>A total of 83 active compounds and 308 potential targets were identified, with significant enrichment observed in the PI3K-Akt pathway. Key targets (IGF1R, CDK6, and EGFR) were positively correlated with TRPV1. Luteolin, quercetin, and EGCG stably bind to their targets. QXT suppressed TRPV1, p-AKT, and HIF-1α, and ameliorated airway hyperresponsiveness and EMT in vivo and in vitro.</p><p><strong>Discussion: </strong>QXT could alleviate asthma airway hyperresponsiveness and remodeling by inhibiting the TRPV1/PI3K-Akt/HIF-1α axis and EMT. The active compounds potentially exerted their therapeutic effects through multi-target mechanisms.</p><p><strong>Conclusion: </strong>QXT alleviated asthma airway remodeling and hyperresponsiveness via suppressing the TRPV1/PI3K-Akt/HIF-1α signaling axis and EMT, providing a scientific basis for its clinical application.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating Network Pharmacology, Molecular Docking, Molecular Dynamics Simulation, and Experimental Validation to Elucidate the Efficacy and Mechanism of Wanbi Hantong Yin in Rheumatoid Arthritis.","authors":"Zhenzhen Han, Xuewei Dou, Wenfei Cui, Yafei Zhang, Zhen Liu, Siyu Wang, Jing Zhang, Xiaobing Li, Hongtao Guo","doi":"10.2174/0113862073427123251208002047","DOIUrl":"https://doi.org/10.2174/0113862073427123251208002047","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Wanbi Hantong Yin (WHY), a traditional Chinese medicine (TCM) formulation, has demonstrated therapeutic efficacy in rheumatoid arthritis (RA). However, its underlying molecular mechanisms remain largely unclear. This study combined bioinformatics analyses, including network pharmacology, molecular docking, and molecular dynamics (MD) simulation, with in vivo validation to elucidate the pharmacological mechanisms of WHY in the treatment of RA.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A comprehensive WHY-Compound-Target-RA network was constructed to identify key bioactive compounds and their potential molecular targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to determine the relevant biological processes and signaling pathways. Molecular docking and MD simulations were conducted to evaluate the binding stability and interaction strength between core compounds and key targets. The therapeutic efficacy of WHY was further validated in vivo using a collagen-induced arthritis (CIA) rat model.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Network pharmacology analysis identified quercetin, luteolin, kaempferol, and sitosterol as major active compounds, and STAT3, IL-6, TNF, JAK2, and IL-1β as principal targets. KEGG pathway analysis indicated that WHY exerted its anti-RA effects primarily through the regulation of Th17 cell differentiation and the TNF signaling pathway. Molecular docking and MD simulation confirmed stable binding interactions between the core compounds and key targets. In the CIA rat model, WHY significantly reduced the CD4+/CD8+ T cell ratio, increased Treg expression, and modulated Th17 differentiation. Furthermore, WHY decreased serum levels of TNF-α, IL-1β, IL-6, and IL-17, while increasing IL-10. It also suppressed oxidative stress, downregulated IL-6 mRNA expression, and inhibited activation of the JAK2/STAT3 signaling pathway.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Discussion: &lt;/strong&gt;RA is a chronic autoimmune disease characterized by progressive symmetric joint inflammation, leading to cartilage and bone damage, disability, and significant individual and societal burdens. Affordable, effective, and safe anti-RA treatments are urgently needed. WHY, a TCM prescription, has demonstrated efficacy in treating RA. However, the mechanism of WHY in treating RA remains unclear. This study explored the pharmacological mechanism of WHY in treating RA through network pharmacological analysis, molecular docking, MD simulation, and experimental validation. Our findings demonstrated that WHY modulated the immune response and reduced inflammation in RA by restoring T-cell homeostasis through the inhibition of the JAK2/STAT3 signaling pathway. This study provides novel insights into the mechanisms of TCM in RA intervention, fostering progress in new drug development.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;This integrative study demonstrates that WHY restores T-cell homeostasis and alleviates inflamm","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Global Insights into Interstitial Lung Diseases and Pulmonary Sarcoidosis: Demographic and Developmental Disparities, Projections, and Biomolecular Implications.","authors":"Xinyun Zhao, Wenqiu Ding, Liwen Zhang, Qing Cai, Zixuan Lu, Wen Huang, Weiping Xie, Hui Kong","doi":"10.2174/0113862073468105260421052108","DOIUrl":"https://doi.org/10.2174/0113862073468105260421052108","url":null,"abstract":"<p><strong>Introduction: </strong>Interstitial Lung Diseases (ILDs) and lung sarcoidosis represent major global health challenges. Despite their increasing clinical incidence, comprehensive data on their global burden remain limited.</p><p><strong>Methods: </strong>Using data from the Global Burden of Disease (GBD) 2021 study, we analyzed the incidence, prevalence, mortality, and Disability-Adjusted Life Years (DALYs) of ILDs across 21 regions, 204 countries from 1990 to 2021. Disparities in burden were assessed in relation to sex, age, and Socio-Demographic Index (SDI), and Bayesian projections were performed to 2035.</p><p><strong>Results: </strong>From 1990 to 2021, global age-standardized rates (per 100,000) increased: Age- Standardized Incidence Rate (ASIR) from 3.77 (95% UI: 3.27-4.28) to 4.55 (4.06-5.04); Age- Standardized Prevalence Rate (ASPR) from 45.99 (39.42-53.78) to 50.01 (44.24-56.77); Age- Standardized Mortality Rate (ASMR) from 1.52 (1.25-1.87) to 2.28 (1.96-2.56); and DALYs from 37.15 (30.62-45.37) to 47.62 (41.26-53.17). Geographic heterogeneity was evident, with the highest burden in high-SDI regions. Males consistently exhibited higher rates than females, particularly in high-SDI areas. Burden increased with age, peaking at 85-89 years for ASPR. Projections to 2035 revealed a decline in age-standardized rates, but the decline in ASDR was expected to be more moderate.</p><p><strong>Discussion: </strong>The epidemiology of ILDs and lung sarcoidosis showed marked disparities by geography, age, and SDI. The rising absolute burden warrants equitable healthcare resource allocation and integration of emerging clinical technologies.</p><p><strong>Conclusions: </strong>The epidemiology of ILDs and sarcoidosis exhibited marked disparities across geography, age, sex, and SDI. Although standardized rates are projected to decline, absolute disease burdens will continue to rise due to aging populations. Addressing this challenge requires equitable distribution of healthcare resources, biomarker-guided surveillance, innovative targeted therapies, and emerging technologies.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Different Extracts from Citri Exocarpium Rubrum and Citri Grandis Exocarpium on Functional Dyspepsia Model Rats.","authors":"Xiaolu Liu, Yong Yang, Yanlei Guo, Xiaomei Zhang, Yunhong Wang, Junxuan Yang","doi":"10.2174/0113862073460296260417065547","DOIUrl":"https://doi.org/10.2174/0113862073460296260417065547","url":null,"abstract":"<p><strong>Introduction: </strong>This study aimed to systematically compare the therapeutic efficacy of Citri Exocarpium Rubrum (CER) and Citri Grandis Exocarpium (CGE) in a rat model of Functional Dyspepsia (FD), and to explore the potential material basis and mechanisms underlying their differential effects.</p><p><strong>Methods: </strong>A rat FD model was established via a 21-day protocol of irregular feeding, tail clamping, and forced swimming. Animals were then treated with three extract types (aqueous, ethanol, volatile oil) of CER or CGE for 14 days (n=8 per group). Therapeutic effects were assessed by gastric emptying rate, small intestinal propulsion rate, and serum levels of motilin, gastrin, and somatostatin. Chemical profiling of the aqueous extracts was performed using UPLC-Q-TOFMS, and network pharmacology predicted bioactive components, core targets, and key pathways.</p><p><strong>Results: </strong>All CER extracts significantly alleviated FD symptoms, with the aqueous extract (JS) showing the most comprehensive efficacy, improving all motility and hormonal parameters. In contrast, CGE extracts produced only partial or non-significant improvements. Chemical analysis revealed CER's unique enrichment in polymethoxyflavones and limonoids, which were scarce in CGE.</p><p><strong>Discussion: </strong>Network pharmacology predicted that these distinct components in the CER coregulate a network centered on targets such as OPRM1 and PTGS1, significantly enriching pathways related to the neuroactive ligand-receptor interaction and the serotonergic synapse-key systems in brain-gut axis regulation. CGE's mechanism appeared more associated with broad inflammatory pathways. This study's findings are limited to a rat model and require further validation.</p><p><strong>Conclusion: </strong>CER, particularly its aqueous extract, demonstrates superior efficacy over CGE in treating FD. This advantage is chemically attributed to its abundance of polymethoxyflavones and limonoids and is predicted to involve multi-target modulation of the brain-gut axis, providing a scientific rationale for the preferential use of CER in FD management.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Network Pharmacology and Molecular Docking Analysis on the Mechanism of Hedyotis Diffusa in Overcoming Resistance in EGFR Mutant Cell Line HCC827-GR and Its Experimental Verification.","authors":"Xin Lv, JiaBin Qian, Yiheng Qian, Kaiwen Ni","doi":"10.2174/0113862073431922251129080912","DOIUrl":"https://doi.org/10.2174/0113862073431922251129080912","url":null,"abstract":"<p><strong>Introduction: </strong>Hedyotis diffusa is a Chinese herbal medicine commonly used to treat various forms of inflammation and tumors. In order to further study the molecular mechanism of its treatment of lung cancer and its possible active components.</p><p><strong>Methods: </strong>Active compounds were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform with criteria of drug-likeness ≥ 0.18 and oral bioavailability ≥ 30%. Lung cancer-related genes were retrieved from Online Mendelian Inheritance in Man, Therapeutic Target Database, and GeneCards， using the search term' Lung Cancer'. The protein-protein interaction networks were constructed using the STRING database, and enrichment analyses for the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology were performed via the DAVID platform. Molecular docking was conducted via the CB-Dock2 platform. In the cell experiment, we induced drug resistance in HCC827 cells by gradually increasing Gefitinib concentration. We evaluated the effect of Hedyotis diffusa extract on the proliferation, migration, and invasion of the drug-resistant cell lines.</p><p><strong>Results: </strong>The active components of Hedyotis diffusa exhibit strong interactions with numerous important targets in lung cancer, particularly key molecules such as AKT and EGFR. Cell experiments showed that Hedyotis diffusa significantly inhibited the migration and invasion of HCC827/GR cells and decreased the expression of EMT-related marker proteins.</p><p><strong>Discussion: </strong>Based on this study, Hedyotis diffusa can significantly inhibit the migration and invasion of EGFR-mutant, drug-resistant lung adenocarcinoma cells. This finding provides a mechanistic basis for overcoming acquired resistance to EGFR-TKIs and lays an experimental foundation for developing combination treatment strategies for lung cancer.</p><p><strong>Conclusions: </strong>Hedyotis diffusa can modulate the IGF-1R/PI3K/AKT-EMT pathway by targeting Akt, EGFR, and other key proteins, thereby intervening in acquired resistance to EGFR-TKIs in EGFR-mutant lung adenocarcinoma.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Integration of Pharmacokinetics, Cardiac Tissue Distribution, Network Pharmacology, and Experimental Verification to Reveal the Bioactive Components and Pharmacological Mechanisms of Guanxinning Tablet Against Coronary Heart Disease.","authors":"Jun Li, Yingchao Wang, Miaofu Li, Mulan Wang, Peiqiang Shen, Yi Tao, Yule Wang","doi":"10.2174/0113862073440242260212070253","DOIUrl":"https://doi.org/10.2174/0113862073440242260212070253","url":null,"abstract":"<p><strong>Introduction: </strong>Coronary heart disease (CHD) is a leading cause of morbidity and mortality worldwide, yet therapeutic options remain limited. Guanxinning tablet (GXNT), a component-based Chinese medicine containing Danshen and Chuanxiong, has demonstrated clinical efficacy and safety for CHD patients with heart-blood stagnation syndrome. However, its bioactive constituents and underlying pharmacological mechanisms remain undefined. This study aimed to identify the bioactive components of GXNT and elucidate its anti-CHD mechanisms.</p><p><strong>Methods: </strong>The pharmacokinetics and cardiac distribution of five GXNT constituents were investigated using a validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Network pharmacology revealed pivotal targets and pathways against CHD, which were verified by molecular docking and in vitro experiments.</p><p><strong>Results: </strong>A validated UPLC-MS/MS method was developed to quantify danshensu, salvianolic acid B, protocatechuic acid, ferulic acid, and senkyunolide I in biological samples. These compounds showed promising in vivo bioactivity, marked by rapid absorption, high systemic exposure, and efficient cardiac distribution. The detailed network analyses linked GXNT's efficacy to inflammation-related pathways, identifying TLR4, NFKB1, TNF, IL6, IL1B, and AKT1 as hub targets. The docking results confirmed strong binding affinities between five compounds and these targets. Cell experiments demonstrated that GXNT and its bioactive components exerted cardioprotection by normalizing the overexpression of key inflammatory factors.</p><p><strong>Discussion: </strong>Firstly, the pharmacokinetic properties of GXNT's bioactive components require further investigation using a rodent disease model of CHD. Secondly, in vivo follow-up animal experiments are needed to validate the present findings further. Thirdly, beyond inflammation-related signaling pathways, the relationship between GXNT's anti-CHD action and other enriched pathways (e.g., the AGE-RAGE signaling pathway in diabetic complications, the HIF-1 signaling pathway, and the PI3K-Akt signaling pathway) warrants further exploration.</p><p><strong>Conclusion: </strong>The favorable pharmacokinetics and cardiac distribution of five GXNT constituents underscored their bioactive potential. GXNT and its bioactive compounds exerted cardioprotective effects against CHD, partly by regulating TLR4/NF-κB-mediated inflammation-related pathways. These findings provide insights into the bioactive components and mechanisms of GXNT against CHD, supporting its further development and quality control.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of CD4+ T Cell-Related Biomarkers and Mechanisms for Hepatoma.","authors":"Zhewei Zhang, Liwen Guo, Jun Luo, Jiaping Zheng, Hui Zeng","doi":"10.2174/0113862073429920260224080043","DOIUrl":"https://doi.org/10.2174/0113862073429920260224080043","url":null,"abstract":"<p><strong>Introduction: </strong>The high incidence and recurrence of hepatoma necessitate better prognostic tools. Given the established cytotoxic role of CD4+ T cells, this study aimed to identify CD4+ T cell-related genes (TRGs) and their mechanisms in hepatoma.</p><p><strong>Methods: </strong>Transcriptome and clinical data from TCGA-LIHC were analyzed. TRGs were identified through differential analysis and univariate Cox regression analysis. Three machine learning algorithms (LASSO, Random Forest (RF), and xgboost) were used to select key biomarkers. A nomogram model was constructed and evaluated using Kaplan-Meier analysis, time-dependent receiver operating characteristic (ROC), and calibration curves. Functional enrichment and gene set enrichment (GSEA) analyses were performed. RT-qPCR analysis was performed to validate the biomarker expression.</p><p><strong>Results: </strong>Seventy-two TRGs were identified, with 38 exhibiting significant prognostic abilities. Four important biomarkers were identified, namely BMI1, CD4, GAPDH, and ZCRB1. The nomogram model based on the four biomarkers showed promising effectiveness in predicting survival in hepatoma, with an AUC value of 0.988. RT-qPCR confirmed the upregulation of BMI1, GAPDH, and ZCRB1, and downregulation of CD4 in tumor tissues.</p><p><strong>Discussion: </strong>The four TRGs are differentially expressed in hepatoma, and the nomogram model based on them shows promising predicting ability. These findings provide more prognostic insights and may guide therapeutic strategies.</p><p><strong>Conclusion: </strong>The results confirm BMI1, CD4, GAPDH, and ZCRB1 as effective biomarkers for constructing a nomogram model with high predictive value for hepatoma survival.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding Organ-Specific Vulnerability to Triptolide Toxicity: A Systems Toxicology Approach Targeting Glucose Metabolism.","authors":"Ying Wang, Bing Lin","doi":"10.2174/0113862073429598251128041732","DOIUrl":"https://doi.org/10.2174/0113862073429598251128041732","url":null,"abstract":"<p><strong>Introduction/objective: </strong>Triptolide, a diterpenoid epoxide derived from Tripterygium wilfordii Hook F, exhibits potent therapeutic activities but is clinically limited by severe multiorgan toxicity, the mechanisms of which remain poorly understood. This study aimed to elucidate these mechanisms using an integrative computational framework.</p><p><strong>Methods: </strong>We employed a multi-step computational approach combining network pharmacology, Mendelian randomization (MR), molecular docking, molecular dynamics simulations, and single- cell RNA sequencing analysis to systematically identify and evaluate toxicity pathways.</p><p><strong>Results: </strong>Network analysis identified 29 common toxicity targets across hepatic, renal, cardiac, and reproductive systems. Functional enrichment revealed that disruption of glycolysis and the pentose phosphate pathway is a central mechanism. This supports a dual toxicity model involving: (1) a \"cellular energy crisis\" due to impaired ATP production (via enzymes such as GCK), and (2) an \"oxidative redox imbalance\" resulting from NADPH depletion (via enzymes such as RPIA). MR analysis further indicated potential causal links between these targets and organ damage. Molecular docking and dynamics simulations showed stable, high-affinity complexes with these enzymes (binding energies: -7.0 to -9.1 kcal/mol), providing a structural basis for the interactions. Single-cell RNA sequencing analysis highlighted organ-specific vulnerability related to the cell-type-specific expression of these target enzymes.</p><p><strong>Discussion: </strong>Triptolide-induced disruption of glucose homeostasis via direct enzyme interactions may underlie its multi-organ toxicity. This integrative framework bridges molecular-level interactions and organ pathology, providing a comprehensive strategy to dissect complex toxicity mechanisms.</p><p><strong>Conclusion: </strong>Our findings suggest that triptolide's multi-organ toxicity is mechanistically rooted in the disruption of glucose metabolism, driven by interactions with core metabolic enzymes. This integrative computational study offers novel insights into pan-organ toxicity and provides a potential basis for designing safer triptolide analogues.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic Investigation of Wenfei Huaxian Decoction in the Treatment of Pulmonary Fibrosis Based on UPLC/Q-TOF-MS/MS, Network Pharmacology, Experimental Validation, and Molecular Docking.","authors":"Yueqi Xu, Junxia Hu, Jun Wang, Guoshuang Zhu, Mingliang Qiu, Zenan Wu, Yicheng Yu, Nidan Chen, Yifan Ding, Shiwen Ke, Lisha Mo, Liangji Liu","doi":"10.2174/0113862073424516251127094853","DOIUrl":"https://doi.org/10.2174/0113862073424516251127094853","url":null,"abstract":"<p><strong>Introduction: </strong>Idiopathic pulmonary fibrosis (IPF) is increasing and poses a major health threat. Although current treatments slow progression, their efficacy remains limited. Wenfei Huaxian Decoction (WFHX), a traditional Chinese medicinal formula, shows potential against IPF, though its mechanism remains unclear. To systematically elucidate the multicomponent and multi-target mechanisms underlying the anti- pulmonary fibrosis effects of WFHX by integrating ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF-MS/MS), network pharmacology, animal experiments, and molecular docking approaches.</p><p><strong>Methods: </strong>WFHX components were analyzed using UPLC/Q-TOF-MS/MS, and potential targets were screened using online databases. Network pharmacology and enrichment analysis identified key components and pathways. A bleomycin-induced mouse model of pulmonary fibrosis validated these findings through cytokine profiling, histology, immunohistochemistry, and western blotting. Molecular docking assessed binding affinities between key components and their corresponding targets.</p><p><strong>Results: </strong>UPLC/Q-TOF-MS/MS identified 48 WFHX compounds. Network pharmacology screening identified 935 overlapping targets among the compounds and disease-related genes. Quercetin and apigenin were identified as core active components, while NAMPT and SIRT1 were key molecular targets. Enrichment analysis linked WFHX to biological processes, including the inflammatory response, cell proliferation, epithelial-mesenchymal transition (EMT), and multiple signaling pathways. WFHX significantly alleviated pulmonary tissue damage, reduced inflammatory responses, and inhibited the progression of pulmonary fibrosis.</p><p><strong>Conclusion: </strong>This study elucidated the multidimensional anti-fibrotic mechanisms of WFHX using integrated techniques, supporting its clinical potential and modernization.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}