Integrative biology : quantitative biosciences from nano to macro最新文献

{"title":"Association between inflammatory burden index and cardiovascular and all-cause mortality in individuals living with diabetes and prediabetes: a NHANES cohort study.","authors":"Xiu Wu, Wei Cao","doi":"10.1093/intbio/zyag019","DOIUrl":"https://doi.org/10.1093/intbio/zyag019","url":null,"abstract":"<p><strong>Background: </strong>Diabetes mellitus (DM) and its cardiovascular complications represent one of the most prevalent causes of death worldwide, closely linked to chronic inflammatory states. Inflammatory Burden Index (IBI) is a composite inflammatory marker that comprehensively assesses systemic inflammation levels. Currently, the prognostic association of IBI with outcomes in individuals living with DM and prediabetes (pre-DM) remains unclear.</p><p><strong>Objective: </strong>To investigate association of IBI with all-cause and cardiovascular mortalities in individuals living with DM and pre-DM.</p><p><strong>Methods: </strong>Utilizing data from NHANES 1999-2010, we enrolled 8738 participants. Kaplan-Meier analysis and weighted multivariate Cox proportional hazards models were employed to examine relationship of IBI tertiles with mortality risk. RCS analysis tested for non-linear associations, while subgroup analyses evaluated effect modification. Sensitivity analysis was performed by excluding deaths occurring during the early follow-up period.</p><p><strong>Results: </strong>During a median 11.7 years of follow-up, 2726 all-cause deaths (31.2%) and 893 cardiovascular deaths (10.2%) were recorded. Results demonstrated significant associations of IBI with mortality risks in individuals living with pre-DM and DM. In fully adjusted model, compared with the lowest IBI tertile (T1), the highest tertile (T3) was associated with a 42% elevated risk of all-cause mortality (HR = 1.42, 95%CI: 1.24-1.63, P < 0.001) and a 38% elevated risk of cardiovascular mortality (HR = 1.38, 95%CI: 1.08-1.76, P = 0.011). RCS analysis revealed an overall significant association of IBI with mortality risks without evidence of non-linearity (P-non-linear>0.05). No significant interaction effects were seen in subgroup analyses. After excluding deaths occurring within the first 1 and 2 years of follow-up in sensitivity analyses, the above associations remained generally consistent.</p><p><strong>Conclusion: </strong>Elevated IBI was significantly associated with elevated risks of all-cause and cardiovascular mortalities in persons with DM and pre-DM, suggesting that IBI may help identify subjects at higher mortality risk within this population.</p><p><strong>Highlights: </strong>Elevated inflammatory burden index was significantly associated with increased risks of all-cause and cardiovascular mortality in individuals with diabetes and prediabetes. Insight Box This study identifies the Inflammatory Burden Index as a stable, integrative biomarker linking systemic inflammation to elevated all-cause and cardiovascular mortality in prediabetic and diabetic individuals. By quantifying cumulative inflammatory burden rather than single markers, it provides a biologically coherent, clinically accessible tool for risk stratification. These findings support integrated inflammatory monitoring as a rational strategy to improve prognostic evaluation and targeted interventio","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":"18 ","pages":""},"PeriodicalIF":1.4,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149149383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmaco-Epigenomic response of Pimozide is mediated through miR-2909.","authors":"Deepti Malik, Ashvinder Raina, Jitender Singh, Hitaishi Kaushik, Gurjeet Kaur, Seema Bansal, Phulen Sarma, Ashish Jain, Bikash Medhi","doi":"10.1093/intbio/zyag008","DOIUrl":"10.1093/intbio/zyag008","url":null,"abstract":"<p><p>A recent study delves into intricate relationship between microRNAs (miRNAs), specifically focusing on their role in cancer development. miRNAs are highlighted for their capacity to modify genetic profile and modulate epigenetic architecture, establishing regulatory circuit between epigenetic modulation and miRNAs. Notably, antipsychotic drugs, particularly pimozide, is reported to influence miRNA expression, impacting essential processes in cancer development such as cell proliferation and apoptosis. Anti-cancer properties of pimozide have sparked interest in its potential role in cancer treatment, although precise mechanism of its antitumor function remains elusive. The study focuses on a newly discovered miRNA, miR-2909, encoded by the apoptosis antagonizing transcription factor (AATF) gene, which has been implicated in oncogenesis. This research aims to unravel the interplay between pimozide and miR-2909, investigating their influence on epigenetic modulations and their functional relevance to cellular proliferation and apoptosis in cancer cells. Utilizing bioinformatic tools for structural prediction, pharmacokinetic property assessment, and molecular docking interactions, the study reveals a strong binding affinity between pimozide and miR-2909.Validation through various experimental methods, including qRT-PCR, western blotting, immunofluorescence, transient transfection, CHIP assay, and flow cytometry confirms the interplay between pimozide and miR-2909. The results demonstrate a pivotal role in the regulation of genes responsible for cellular proliferation and apoptosis. Additionally, the study uncovers that pimozide's pharmaco-epigenomic response is mediated through miR-2909, promoting DNA methylation and leading to decreased cellular proliferation, increased apoptosis, ROS generation, and altered cell-cycle dynamics. In conclusion, the findings identify pimozide as a potential chemotherapeutic agent acting through the regulation of the oncomiR-2909. Insight Box This study uncovers a novel pharmaco-epigenomic mechanism by which the antipsychotic drug pimozide exerts anti-cancer effects in breast and lung cancer cells. We demonstrate that pimozide downregulates oncogenic miR-2909, leading to the upregulation of DNMT3B, which mediates epigenetic silencing of key proliferation genes and promotes apoptosis. This integrative approach-combining molecular biology, gene expression profiling, and epigenetic analysis-provides new biological insight into the repurposing of psychiatric drugs for cancer therapy. Our findings highlight the therapeutic potential of targeting microRNA-epigenetic interactions and suggest a broader applicability of integrating pharmacology with systems biology to uncover unconventional roles of known drugs in cancer treatment.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":"18 ","pages":""},"PeriodicalIF":1.4,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148207612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"POSTN+ cancer-associated fibroblasts promote bladder cancer progression via angiogenesis and immune modulation: an analysis based on single-cell Transcriptomics.","authors":"Qun Zhang, Bo Zhang, Jirui Niu, Shiheng Sun","doi":"10.1093/intbio/zyag001","DOIUrl":"10.1093/intbio/zyag001","url":null,"abstract":"<p><strong>Background: </strong>Bladder cancer (BCa) progression is driven by the tumor microenvironment, with cancer-associated fibroblasts (CAFs) playing a pivotal role. Periostin (POSTN), secreted by CAFs, is linked to tumor malignancy, but its specific role in BCa remains unclear.</p><p><strong>Methods: </strong>This study is a secondary analysis of publicly available single-cell and bulk transcriptomic data. Single-cell RNA sequencing (scRNA-seq) data from four BCa and four control samples were analyzed to construct a transcriptomic atlas. CAFs and monocytes were subclustered, and POSTN+ CAFs were characterized using differential gene expression, GSVA, and KEGG analyses. CellChat and NicheNet assessed cell-cell communication. TCGA data were used to validate POSTN's prognostic significance. Additionally, POSTN expression was detected in transfected CAF cell lines, and scratch and invasion assays were performed using the co-culture system of CAFs and bladder cancer cells (T24).</p><p><strong>Results: </strong>Nine cell clusters were identified, with monocytes and CAFs enriched in BCa. POSTN+ CAFs, significantly increased in BCa, promoted angiogenesis, migration, and invasion. CellChat revealed enhanced CAF-monocyte communication via the IL1B/IL1R1 axis, contributing to an immunosuppressive microenvironment. KLRC1+ monocytes were enriched in BCa, regulating cell cycle and angiogenesis. Pseudotime analysis showed CAFs' differentiation toward pro-tumorigenic states. TCGA analysis confirmed POSTN's upregulation and association with poor prognosis (P < 0.05). Functional assays revealed CAFs markedly enhanced T24 migration and invasion, and POSTN knockdown suppressed this CAF-induced effect (P < 0.01).</p><p><strong>Conclusion: </strong>POSTN+ CAFs drive BCa progression by enhancing angiogenesis, migration, and immune suppression, mediated partly by the IL1B/IL1R1 axis.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":"18 ","pages":""},"PeriodicalIF":1.4,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145992868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel discovery framework: harnessing adaptive learning for breakthroughs in drug development and clinical applications.","authors":"Auste Kanapeckaite, Christopher John Peters, Arvydas Laurinavicius, Liesbet Geris","doi":"10.1093/intbio/zyaf024","DOIUrl":"10.1093/intbio/zyaf024","url":null,"abstract":"<p><p>The costly process of bringing new therapeutics to market and high attrition rates have motivated the search for new frameworks in drug research and development (R&D). These challenges extend to the clinical space with the need for better patient stratification and therapy matching. Moreover, despite significant leaps in deep learning, even the most sophisticated methods rely on static analytical structures. Thus, unaddressed needs in therapy development and applications call for unconventional thinking to capture dynamic processes across preclinical and clinical spaces. With this review, we trace how crucial algorithmic pieces have been coming together over the past decades for the next generation of deep learning, which we define as adaptive learning. This new class of robust analytical architectures will be enabled through self-organised models where inputs changing over time can guide deep networks to adapt to biases and optimise learning. There have already been glimpses of such groundbreaking solutions in liquid neural networks (LNNs), graph attention algorithms, digital twins, and engineering research. As we review multiple examples and applications, we want to highlight the emerging fundamental shifts in discovery and analytical paradigms. Only by continuing to develop new frameworks can we capture complex disease interactomes and identify or improve therapeutic avenues. Insight Box Our work underscores the emerging shifts in research and development (R&D) and drug discovery from a deep learning perspective. First, we identify and discuss the missing link in drug discovery that affects multiple areas in translational research. We then demonstrate how critical algorithmic, analytical, and technological pieces have been coming together to address these challenges. Furthermore, we illustrate how applied AI and deep learning frameworks will need to change and what solutions are already available. Consequently, we employ examples of novel deep learning architectures, digital twins, and clinical research. Notably, there has been very little discussion to acknowledge current limitations in deep learning from a translational perspective. Thus, our work offers not only new insights but also a direction of travel for future developments, which we define as adaptive learning.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":"18 ","pages":""},"PeriodicalIF":1.4,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146160038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Si Jun Zi tang on premature ovarian failure through regulation of ROCK1/PTEN/PI3K/Akt pathway.","authors":"Xinbin Wang, Haorui Wang, Jing Li, Yating Dai, Yuying Sang, Rujuan Xin","doi":"10.1093/intbio/zyag014","DOIUrl":"https://doi.org/10.1093/intbio/zyag014","url":null,"abstract":"<p><strong>Background: </strong>The main cause of decreased or absent female fertility is a complex, heterogeneous condition known as premature ovarian failure (POF). Surprisingly, POF can be effectively treated using traditional Chinese medicine. Si Jun Zi Tang (SJZT) has unique approaches for treating POF, although they have not been thoroughly investigated. This study aims to explore the impact of SJZT on ovarian function.</p><p><strong>Methods: </strong>The POF mouse model was induced using the Cyclophosphamide (CTX) method. Throughout the therapy, the mice's body weight was monitored, and ovarian tissue pathology was observed using HE staining. Serum levels of FSH, E2, and LH were quantified using the ELISA method. qRT-PCR was employed to measure ROCK1 and PTEN mRNA levels in the ovaries. Protein expressions of PTEN, PI3K, p-PI3K, Akt, p-Akt, and apoptosis-related proteins Cleaved Caspase3, Caspase3, Bax, and Bcl-2 were assessed via Western blot analysis. Additionally, the TUNEL assay was utilized to quantify apoptotic cells in the ovaries.</p><p><strong>Results: </strong>In a dose-dependent manner, SJZT therapy reversed the CTX-induced decrease in developing follicles and the increase in atretic follicles, maintaining relatively normal blood levels of LH, FSH, and E2. By modulating the mRNA expression of ROCK1 and PTEN, SJZT treatment was associated with reduced activation of PI3K/Akt signaling and mitigated ovarian dysfunction. Additionally, SJZT effectively decreased apoptosis in the ovarian tissues of mice serving as models for POF.</p><p><strong>Conclusion: </strong>These findings suggest that SJZT may protect ovaries from CTX-induced damage, potentially through modulation of the ROCK1/PTEN/PI3K/Akt pathway, providing insights into possible mechanisms of damage and CTX-induced cellular apoptosis. The study indicates a potential role of SJZT in the treatment of POF.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":"18 ","pages":""},"PeriodicalIF":1.4,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148665596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting D-alanine ligase from methicillin-resistant Staphylococcus aureus using natural compounds.","authors":"Shweta Tiwari, Rashmi Prabha Singh, Joyabroto Ghosh, Aarshu Acharya, Ankit Kumar Singh, Ankit Kumar, Amit Kumar Singh","doi":"10.1093/intbio/zyag018","DOIUrl":"https://doi.org/10.1093/intbio/zyag018","url":null,"abstract":"<p><p>Methicillin-resistant Staphylococcus aureus (MRSA) infections pose a critical threat in healthcare and community settings. Meanwhile, the effectiveness of treatment is limited by vancomycin, which remains the only frontline drug against MRSA. The emergence of new strains of MRSA, along with the development of vancomycin-resistant S. aureus (VRSA), emphasises the need for alternative therapies. This study explores the use of natural compounds as a sustainable alternative to treat MRSA. The inhibition potential of natural compounds against D-alanine-d-alanine ligase, a key enzyme in the peptidoglycan synthesis, which belongs to the ATP Grasp Protein family. The ATP binding is responsible for the formation of the intermediate through enzyme catalysis. The 1252 molecules selected from the COCONUT database, with high predicted potency, low toxicity, and bioavailability, were subjected to virtual high-throughput screening (vHTS) against the ATP-binding site of the target protein. The two promising molecules were identified based on their orientations and interactions with ATP-binding residues. The selected protein-drug complexes were further evaluated by MD simulation to comprehend their effects under physiological conditions, followed by calculation of binding affinity using the MM-PBSA approach. The essential dynamics studies and MM-PBSA results suggested that CNP0475353 (ΔG = -98.78 kcal/mol) and CNP0263347 (ΔG = -10.63 kcal/mol) could act as potential inhibitors of Ddl by interacting with key ATP-binding residues. The study proposes that CNP0475353 and CNP0263347 may be explored for therapeutic potential against MRSA.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":"18 ","pages":""},"PeriodicalIF":1.4,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148868864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNMT1 stabilizes MAPK10 via m5C RNA methylation to ameliorate hepatic steatosis and mitochondrial dysfunction in non-alcoholic fatty liver disease.","authors":"Jing Liu, Chuang Liu, Huanzhi Xiao, Peng Cao, Sufang Zhou","doi":"10.1093/intbio/zyag006","DOIUrl":"10.1093/intbio/zyag006","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Non-alcoholic fatty liver disease (NAFLD) represents a highly prevalent metabolic disorder; however, the functional role of mitogen-activated protein kinase 10 (MAPK10) in the initiation and progression of NAFLD remains incompletely understood. This study investigated MAPK10's role in NAFLD and its regulatory mechanisms.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Materials and methods: &lt;/strong&gt;Bioinformatics analysis was performed on the GSE89632 dataset to screen for differentially expressed genes (DEGs) associated with NAFLD. An in vivo NAFLD model was established in C57BL/6 J mice by feeding a high-fat diet (HFD), and subsequent lentiviral transduction was used to achieve hepatic overexpression or knockdown of MAPK10 and DNA methyltransferase 1 (DNMT1). In vitro, HepG2 cells were transfected with DNMT1 overexpression plasmids. Molecular analyses, including RT-qPCR and Western blot, were used to measure gene and protein expression levels. RNA immunoprecipitation (RIP) and dual-luciferase reporter assays were employed to assess the m5C modification of MAPK10 mRNA and its transcriptional activity, respectively. An RNA stability assay was used to evaluate mRNA half-life.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;MAPK10 expression was significantly reduced in the liver tissues of HFD-fed mice. Overexpression of MAPK10 alleviated hepatic steatosis, oxidative stress, and mitochondrial damage in vivo. Mechanistically, DNMT1 enhanced MAPK10 expression and stability in an m5C-dependent manner. RIP assay confirmed increased m5C modification of MAPK10 mRNA upon DNMT1 overexpression. Luciferase reporter assay demonstrated that DNMT1 specifically enhanced the activity of wild-type, but not m5C-site-mutated, MAPK10. RNA stability assay further showed that DNMT1 overexpression stabilized MAPK10 mRNA. Rescue experiments indicated that MAPK10 knockdown reversed the protective effects (improved lipid accumulation, oxidative stress, and mitochondrial function) induced by DNMT1 overexpression in HFD-fed mice.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;MAPK10 plays a protective role in NAFLD by ameliorating hepatic steatosis and mitochondrial dysfunction. Its expression is positively regulated by DNMT1 via m5C-mediated RNA stabilization. This study highlights the DNMT1-MAPK10 axis as a potential therapeutic target for NAFLD. Insight Box This study uncovers a previously unrecognized RNA epigenetic regulatory axis in NAFLD, demonstrating that DNMT1 post-transcriptionally regulates MAPK10 expression and stability through m5C RNA methylation. We establish MAPK10 as a key metabolic protector against NAFLD, ameliorating hepatic steatosis, oxidative stress, and mitochondrial dysfunction. By integrating bioinformatics, molecular biology, and functional validation across in vivo and in vitro models, we delineate a mechanistic pathway where m5C modification critically modulates MAPK10 activity. These findings not only provide fresh insight into the RNA-centric regulatory layer of NAFLD pa","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":"18 ","pages":""},"PeriodicalIF":1.4,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147438959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular and pharmacological impacts of phytochemicals on the enoyl-acyl carrier protein reductase: potential therapeutic implications in tuberculosis.","authors":"Mony Thakur, Bhanu Pratap Gurjar, Khushboo, Usha Nagarajan, Bhaskar Gogoi, Tikam Chand Dakal, Vinod Yadav","doi":"10.1093/intbio/zyag007","DOIUrl":"10.1093/intbio/zyag007","url":null,"abstract":"<p><p>Tuberculosis (TB) remains a major global health challenge, necessitating the development of novel therapeutic interventions. Enoyl-acyl carrier protein (ACP) reductase (InhA), a key enzyme in the fatty acid biosynthesis pathway of Mycobacterium tuberculosis, has emerged as a promising target for anti-TB drug discovery. Exploration of InhA-inhibitors is important for advancing the drug discovery process. This study systematically investigates the molecular and pharmacological interactions of bioactive phytochemicals from Indian traditional medicinal plants with InhA to elucidate their therapeutic potential. Among 42 screened phytocompounds, the top five (Ebastine, 2-Phenylaminoadenosine, Gosogliptin, Lorcainide, and Levomefolic acid) showed promising binding affinities towards InhA (PDB: 2X22), with binding free energy ranging from -9.6 to -10.9 kcal/mol. Comprehensive computational analyses, including pharmacokinetic predictions, drug-likeness evaluation, and biological activity assessment, highlighted their potential as a drug candidate. These top-ranking ligands exhibited potential target-lead interactions, forming stable hydrogen bonds and hydrophobic contacts crucial for inhibitory activity. This multidisciplinary computational approach, including molecular docking and dynamic simulations, identifies these phytochemicals as high-affinity and stable inhibitors of InhA. These identified phytocompounds could serve as promising scaffolds for further optimization and experimental validation in the quest for new plant-based anti-TB agents. Insight Our study targets the essential mycobacterial enzyme, enoyl-ACP reductase (InhA), a validated pathway crucial for tuberculosis drug discovery. Understanding structural characteristics of InhA and its interaction with potential phytochemical ligands enhances our grasp of the mechanisms underlying anti-mycobacterial activity. Computational tools such as molecular docking, molecular dynamics simulations, and predictive toxicology models, provides a rational framework for selecting promising leads for further experimental validation. This integrated approach not only facilitates the translation of traditional medicinal plant knowledge into evidence-based drug discovery but also maximizes the efficiency of the drug development pipeline.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":"18 ","pages":""},"PeriodicalIF":1.4,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147597697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of interpretable machine learning to analyze DNA methylation sites in the progression from oral Leukoplakia to oral squamous cell carcinoma.","authors":"Khushi Yadav, Yasha Hasija","doi":"10.1093/intbio/zyag003","DOIUrl":"10.1093/intbio/zyag003","url":null,"abstract":"<p><p>Epigenetic alterations, particularly DNA methylation, play a crucial role in the progression of oral squamous cell carcinoma (OSCC) from oral leukoplakia (OL). However, the molecular mechanisms driving this transition remain poorly understood. Using interpretable machine learning (IML) on genome-wide methylation data from 118 samples (22 OL, 74 OSCC, and 22 controls), we identified 20 key CpG sites among 820 193 loci through SHAP (SHapley Additive exPlanations) analysis. Notably, cg19853638, cg25393842, cg01743793, and cg10784570 mapped to pivotal genes such as TNFRSF19, ALOX5, and SH3PXD2A, which regulate cell morphology, inflammatory pathways, and immune responses- critical processes influencing OSCC malignancy and progression. To assess generalizability and confirm the robustness of classifier, the predictive model was validated on an independent Taiwanese cohort (GSE38532) profiled on a different array platform, achieving 98.8% accuracy and ROC-AUC of 0.999 demonstrating robust cross-population performance. Furthermore, cross-omics integration with an independent transcriptomic dataset (GSE31056) identified eight genes, including ALOX5, FOXP1, and VTI1A, showing consistent methylation and expression patterns, underscoring their biological relevance. Our findings highlight the functional relevance of SH3PXD2A, TNFRSF19, and ALOX5 in OSCC pathophysiology: SH3PXD2A mediates cell migration and invasion, TNFRSF19 is involved in survival signaling, and ALOX5 regulates inflammatory responses. These multi-layered analyses provide novel insights into epigenetic mechanisms underlying OL to OSCC progression and highlight candidate biomarkers with strong translational potential. By combining IML based methylation modeling with external and cross-omics validation, this study advances the development of reliable, interpretable biomarkers for precision oral cancer diagnostics and management.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":"18 ","pages":""},"PeriodicalIF":1.4,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146260587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA Hypermethylation-induced LRRC4 downregulation: a driver of glycolysis and lung adenocarcinoma progression.","authors":"Xudong Wei, Guangcheng Yue, Xiaodong Zheng, Weimin Zhang","doi":"10.1093/intbio/zyag002","DOIUrl":"10.1093/intbio/zyag002","url":null,"abstract":"<p><strong>Background: </strong>Lung adenocarcinoma (LUAD) remains a significant health threat, with high incidence and mortality rates that necessitate innovative treatment strategies. A critical step forward is to elucidate the molecular mechanisms driving LUAD progression. Although LRRC4 has been well-documented as a tumor suppressor in gliomas, its role in LUAD remains largely unknown, suggesting a need for further investigation.</p><p><strong>Methods: </strong>In LUAD and normal tissues, LRRC4 expression were examined using TCGA data. Methylation differences were assessed using the MethylMix package, and CpG island distribution in the LRRC4 promoter was predicted with MethPrimer. Gene set enrichment analysis (GSEA) was performed to identify pathways associated with LRRC4 and its correlation with key glycolytic genes. LRRC4 mRNA levels were measured by qPCR, and protein expression was detected by western blot for LRRC4 and glycolysis-related proteins. Methylation-specific PCR (MSP) was used to analyze methylation status in normal and LUAD cells. Cellular functions, specifically viability, proliferation, and invasiveness, were evaluated via CCK-8, colony formation, and Transwell assays. Glycolytic activity was determined through glucose consumption, lactate production, ATP levels, and Seahorse XF analysis.</p><p><strong>Results: </strong>LRRC4 was steeply downregulated in LUAD, with a strong negative correlation between its expression and methylation levels. Multiple CpG sites were identified in the promoter region, and MSP demonstrated higher methylation in LUAD cells compared to normal cells. Functionally, LRRC4 acted as a suppressor of LUAD cell viability, proliferation, and invasiveness. GSEA indicated that LRRC4 was enriched in the glycolysis pathway and negatively correlated with key glycolytic genes. LRRC4 also inhibited glucose consumption, lactate and ATP production, and facilitated a metabolic shift toward oxidative phosphorylation.</p><p><strong>Conclusion: </strong>Promoter hypermethylation of LRRC4 triggers its downregulation, which promotes glycolysis and fuels the aggressive progression of LUAD.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":"18 ","pages":""},"PeriodicalIF":1.4,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}