Biomedicine & Pharmacotherapy最新文献

{"title":"Prevention of motor relapses and associated trigeminal pain in experimental autoimmune encephalomyelitis by reducing neuroinflammation with a purple corn extract enriched in anthocyanins","authors":"Giulia Magni ,&nbsp;Benedetta Riboldi ,&nbsp;Alessandra Marinelli ,&nbsp;Patrizia Uboldi ,&nbsp;Fabrizia Bonacina ,&nbsp;Chiara Di Lorenzo ,&nbsp;Katia Petroni ,&nbsp;Stefania Ceruti","doi":"10.1016/j.biopha.2025.117906","DOIUrl":"10.1016/j.biopha.2025.117906","url":null,"abstract":"<div><div>Multiple sclerosis (MS) is the leading cause of disability in young adults, with about 2.5–3 million cases currently diagnosed. Pain is a common comorbid symptom of MS, and develops independently from motor impairments. Currently utilized drugs bear severe side effects; thus, new therapeutic strategies are needed, and nutraceutical supplements represent innovative and safe opportunities. We have selected a variety of anthocyanin-enriched purple corn, from which a water-soluble extract (Red extract) has been obtained and administered to male rats exposed to experimental autoimmune encephalomyelitis (EAE). Animals developed relapsing-remitting motor symptoms, accompanied by early onset trigeminal allodynia. The preventive administration of Red extract facilitated the remission of motor symptoms, prevented the development of relapses, and delayed and reduced the development of EAE-associated trigeminal pain. An overall inhibition of neuroinflammation, blunted microgliosis and astrogliosis, activation of autophagy and reduced immune cell infiltration in the brainstem, cervical and lumbar spinal cord were observed. Yellow corn extract, lacking anthocyanins, had no behavioral effects, despite a limited anti-inflammatory action. Therapeutic Red extract administration did not affect EAE motor symptoms, only partially reduced the development of trigeminal pain but maintained its ability to reduce neuroinflammation and glial cell activation and to promote autophagy. Overall, our data suggest that a nutraceutical supplement from anthocyanin-enriched purple corn represents an interesting option to limit the development of motor relapses and the chronicization of multiple sclerosis-associated pain, through the mitigation of neuroinflammation, of the infiltration of immune cells and the promotion of autophagy.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"184 ","pages":"Article 117906"},"PeriodicalIF":6.9,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143421269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural optimization and biological evaluation of indolin-2-one derivatives as novel CDK8 inhibitors for idiopathic pulmonary fibrosis","authors":"Jui-Yi Hsu ,&nbsp;Kai-Cheng Hsu ,&nbsp;Ching-Hsuan Chou ,&nbsp;Tzu-Ying He ,&nbsp;Tony Eight Lin ,&nbsp;Tzu-Ying Sung ,&nbsp;Shih-Chung Yen ,&nbsp;Jui-Hua Hsieh ,&nbsp;Chia-Ron Yang ,&nbsp;Wei-Jan Huang","doi":"10.1016/j.biopha.2025.117891","DOIUrl":"10.1016/j.biopha.2025.117891","url":null,"abstract":"<div><div>Cyclin-dependent kinase 8 (CDK8) plays a crucial role in the transforming growth factor beta (TGF-β) signaling pathway, which is critical to the pathology of idiopathic pulmonary fibrosis (IPF). CDK8 promotes the epithelial-mesenchymal transition (EMT) and excessive extracellular matrix (ECM) deposition, making it a promising target for IPF treatment. This study focused on optimizing <strong>F059–1017</strong>, a previously identified CDK8 inhibitor, to enhance its potency. Through integrated structure-based modifications, a series of compounds was synthesized, and their inhibitory effects on CDK8 were tested. Results indicated that substituting with cyclopentanone significantly improved the inhibitory activity, and compound <strong>4j</strong> demonstrated the best potency (IC₅₀ = 16 nM). Notably, compared to <strong>F059–1017</strong>, its potency increased 35-fold, and kinase profiling revealed that the compound was selective for CDK8. Compound <strong>4j</strong> inhibited the TGF-β1-induced EMT, cell migration, and morphological changes in A549 cells at a concentration of 0.1 μM and inhibited ECM and EMT protein expressions. In addition, the compound blocked TGF-β1-induced transcriptional changes and inhibited Smad3 and RNA polymerase II phosphorylation. These results highlight the potential of the optimized CDK8 inhibitor as a prospective drug for IPF treatment.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"184 ","pages":"Article 117891"},"PeriodicalIF":6.9,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143421270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dichotomous effects of Galectin-9 in disease modulation in murine models of inflammatory bowel disease","authors":"Samantha Tull ,&nbsp;Anella Saviano ,&nbsp;Areeba Fatima ,&nbsp;Jenefa Begum ,&nbsp;Adel Abo Mansour ,&nbsp;Noemi Marigliano ,&nbsp;Anna Schettino ,&nbsp;Julie Blaising ,&nbsp;Patrick Trenkle ,&nbsp;Virginie Sandrin ,&nbsp;Francesco Maione ,&nbsp;Daniel Regan-Komito ,&nbsp;Asif J. Iqbal","doi":"10.1016/j.biopha.2025.117902","DOIUrl":"10.1016/j.biopha.2025.117902","url":null,"abstract":"<div><div>Inflammatory bowel disease (IBD) is a multifaceted disease characterised by compromised integrity of the epithelial barrier, the gut microbiome, and mucosal inflammation. While leukocyte recruitment and infiltration into intestinal tissue are well-studied and targeted in clinical practice, the role of galectins in modulating mucosal immunity remains underexplored. Galectins, a family of lectin-binding proteins, mediate critical interactions between immune cells and the intestinal epithelium. This study investigated the effect of endogenous Galectin-9 (Gal-9), as well as the combined effects with Galectin-3 (Gal-3), in modulating disease progression in murine models of colitis, using global knockout (KO) models for Gal-3, Gal-9, and Gal-3/Gal-9. Global deficiency in both galectins demonstrated improved disease parameters in Dextran sodium sulfate (DSS)-driven colitis. In contrast, in a model of adoptive T cell driven colitis, the addition of recombinant Gal-9 (rGal-9) was associated with reduced intestinal inflammation and an improvement in disease parameters. Further <em>in vitro</em> studies revealed no change in bone marrow-derived macrophage cytokine production in the absence of endogenous Gal-9, whereas the addition of rGal-9 to human macrophages stimulated pro-inflammatory cytokine production. Collectively, these findings demonstrate that Gal-9 plays distinct, context-dependent effects in intestinal inflammation, with both pro-inflammatory and anti-inflammatory effects. The contrasting functions of endogenous and exogenous Gal-9 underscore its complex involvement in IBD pathogenesis and highlight the need to differentiate its physiological function from therapeutic applications.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"184 ","pages":"Article 117902"},"PeriodicalIF":6.9,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances in chemodynamic nanotherapeutics to overcome multidrug resistance in cancers","authors":"Wenjia Xu,&nbsp;Min Wang,&nbsp;Xinyu Liu,&nbsp;Yucui Ding,&nbsp;Jianlong Fu,&nbsp;Peng Zhang","doi":"10.1016/j.biopha.2025.117901","DOIUrl":"10.1016/j.biopha.2025.117901","url":null,"abstract":"<div><div>Multidrug resistance (MDR) has become a major challenge in cancer therapy, it results in the failure of chemotherapy and anticancer drug development. Chemodynamic therapy (CDT), an emerging cancer treatment strategy, has been reported as a novel approach for cancer treatment characterized by low toxicity and minimal side effects. By generating robust cytotoxic hydroxyl radicals (·OH) via Fenton/Fenton-like reaction, CDT may cause cellular damage and oxidative stress-induced cell death. In recent years, many therapies based on CDT and/or combined with other treatment modalities are reported and exhibit exciting treatment efficacy in cancer treatment, such as photothermal therapy, photodynamic therapy, sonodynamic therapy, chemotherapy, starvation therapy and gas therapy etc. These combination therapies exhibit synergistic effects, significantly improving anticancer outcomes compared to CDT alone. Herein, we provide a comprehensive overview of CDT-based strategies in cancer treatment, highlighting developments of CDT and CDT-based combination strategies in tumor therapy, especially in overcoming MDR challenges. Finally, the opportunities and challenges of CDT and CDT-combination therapy in the clinical application are also addressed.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"184 ","pages":"Article 117901"},"PeriodicalIF":6.9,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143379327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ibogalogs decrease neuropathic pain in mice through a mechanism involving crosstalk between 5-HT2A and mGlu2 receptors","authors":"Hugo R. Arias ,&nbsp;Laura Micheli ,&nbsp;Anders A. Jensen ,&nbsp;Sonya Galant ,&nbsp;Franck Vandermoere ,&nbsp;Daniel Venturi ,&nbsp;Dina Manetti ,&nbsp;Maria Novella Romanelli ,&nbsp;Carla Ghelardini ,&nbsp;Philippe Marin ,&nbsp;Lorenzo Di Cesare Mannelli","doi":"10.1016/j.biopha.2025.117887","DOIUrl":"10.1016/j.biopha.2025.117887","url":null,"abstract":"<div><div>The objective of this study was to determine the anti-neuropathic activity of a variety of ibogalogs, including tabernanthalog (TBG), ibogaminalog (DM506), ibogainalog (IBG), nor-IBG, catharanthalog (CAG), and PNU-22394 using the oxaliplatin (OXA) neuropathic pain model in mice, and to investigate whether there is crosstalk between the 5-HT_2A and mGlu₂ receptors. All tested ibogalogs induce pain-relieving activity using both cold plate and paw pressure tests, without toxic effects. The most potent ibogalogs were IBG and CAG, whereas nor-IBG and DM506 were the longest-acting compounds. The anti-neuropathic activity of ibogalogs was inhibited by ketanserin, a 5-HT_2A receptor antagonist, indicating a role for the 5-HT_2A receptor for these effects. Sub-threshold doses of IBG (1 mg/kg) and nor-IBG (3 mg/kg) produced pain relief only in the presence of a sub-threshold dose of LY379268, a selective mGlu₂ receptor agonist, indicating that signaling through both 5-HT_2A and mGlu₂ receptors improves efficacy. In the functional study using HEK293 cells co-expressing both 5-HT_2A and mGlu₂ receptors, Glu increased the apparent potency of ibogalogs in a concentration-dependent manner and sub-threshold concentrations of ibogalogs augmented the Glu-induced response through the mGlu₂ receptor, which collectively indicate functional crosstalk between both receptors. Ibogalogs increased mGlu₂ receptor phosphorylation on Ser⁸⁴³, a proposed key molecular event underlying the functional receptor crosstalk. Our study shows for the first time that diverse ibogalogs induce anti-neuropathic activity through a synergic mechanism involving both 5-HT_2A and mGlu₂ receptors.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"184 ","pages":"Article 117887"},"PeriodicalIF":6.9,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143386351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sodium Butyrate ameliorates pain and mood disorders in a mouse model of Parkinson disease","authors":"Carmen Avagliano ,&nbsp;Carmen De Caro ,&nbsp;Mariarosaria Cuozzo ,&nbsp;Roberta Roberti ,&nbsp;Emilio Russo ,&nbsp;Giovanna La Rana ,&nbsp;Roberto Russo","doi":"10.1016/j.biopha.2025.117903","DOIUrl":"10.1016/j.biopha.2025.117903","url":null,"abstract":"<div><div>Pain is one of non-motor features of Parkinson's disease (PD) that significantly impacts on patients’ quality of life and increases the risk of developing psychiatric disorders. The mechanisms underlying pain in PD are poorly understood and the classic pharmacological treatments supplying to dopamine depletion have limited therapeutic effects on this symptom. It has been demonstrated that short chain fatty acids (SCFAs) play a key role in several central nervous system diseases including PD; low serum and faecal levels of SCFAs have been described in PD patients. Among SCFAs, the gut microbial metabolite butyrate has a neuroprotective and anti-inflammatory effect, influencing neurological and behavioural processes. Using a 6-hydroxydopamine (6-OHDA) induced-PD mouse model, we evaluated the effects of sodium butyrate (BuNa) treatment on pain and mood-related behaviour, exporing the role of PPARs, opioid and endocannabinoid systems. Our results demonstrated that repeated BuNa treatment (100 mg/kg po) in PD-mice reduced pain hypersensitivity as well as depressive- and anxiety-lke behaviour both on day 7 and day 14 after 6-OHDA injection. Moreover, AM281(CB1R antagonist), GW6471 (PPAR-alpha antagonist), and naloxone (opioid receptor antagonist), reduced BuNa efficacy. Finally, BuNa treatment was associated with a significant reduction of pro-inflammatory cytokines at spinal and supraspinal levels. In conclusion, our results demonstrate that increasing endogenous butyrate concentration reduces PD comorbidities such as pain and psychiatric symptoms, restoring opioidergic and endocannabinergic pathways.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"184 ","pages":"Article 117903"},"PeriodicalIF":6.9,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143379289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced therapeutic precision using dual drug-loaded nanomaterials for targeted cancer photodynamic therapy","authors":"Aishat Adejoke Obalola,&nbsp;Heidi Abrahamse,&nbsp;Sathish Sundar Dhilip Kumar","doi":"10.1016/j.biopha.2025.117909","DOIUrl":"10.1016/j.biopha.2025.117909","url":null,"abstract":"<div><div>Combination therapy has expanded significantly, including dual drug-loaded nanomaterials in drug delivery systems. Cancer therapy can be developed by targeting cancer cells and lessening the adverse consequences of anticancer drugs, which are just two of the numerous intriguing possibilities in this research field. Dual-drug delivery nanosystems that utilize nanotechnology to combine dual-drug administration may overcome the limitations of free drugs, the properties of nanomaterials, and the combined action of two drugs work together to overcome several drug-resistant systems within cancerous cells. It is essential to design dual-drug delivery nanosystems that use various multidrug-resistant techniques to overcome drug resistance mechanisms and enhance the effectiveness of clinical antitumor therapy. In this study, we discuss the use of photosensitizers in cancer photodynamic therapy, nanomaterials with dual-drug loading for targeted drug delivery, and the function and impact of nanomaterials in cancer photodynamic therapy. Furthermore, an overview of the drug-loaded nanomaterials <em>in vitro</em> and <em>in vivo</em> activity for cancer photodynamic treatment is discussed. The commercial and clinical applications of photosensitizer-loaded nanoparticles in cancer photodynamic therapy are also briefly discussed in the study. A key finding of the study is the importance of nanomaterials and dual drugs as effective drug delivery systems in cancer treatment.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"184 ","pages":"Article 117909"},"PeriodicalIF":6.9,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143379288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synaptic plasticity deficits in a mouse model of Timothy syndrome: LTP saturation and its pharmacological rescue by nifedipine","authors":"Wudu Lado ,&nbsp;Xiaoping Wu ,&nbsp;Sejoon Choi ,&nbsp;Yuxin Dong ,&nbsp;Guang Yang ,&nbsp;Ottavio Arancio ,&nbsp;Filippo Tempia ,&nbsp;Maria Concetta Miniaci ,&nbsp;David Sulzer ,&nbsp;Eugene Mosharov ,&nbsp;Guomei Tang","doi":"10.1016/j.biopha.2025.117896","DOIUrl":"10.1016/j.biopha.2025.117896","url":null,"abstract":"<div><div>Timothy syndrome (TS) is a multisystem disorder characterized by cardiovascular abnormalities and a spectrum of neuropsychiatric symptoms, including language impairment, seizure, cognitive disability and autism. TS is caused by gain of function mutations in the <em>CACNA1C</em> gene that encodes the CaV1.2 L-type calcium channel. TS mutations have been reported to disrupt hippocampal long-term potentiation (LTP), a process implicated in memory formation. Here, we compared wild type (WT) and heterozygous G406R CaV1.2 mutant TS2-neo model mice using a LTP saturation protocol consisting of two successive theta burst stimuli. While WT mice showed potentiated synaptic strength in response to both theta-burst stimuli, TS2-neo mutants exhibited a smaller initial LTP and minimal responses to the second stimulus. The dihydropyridine L-type calcium channel blocker, nifedipine, inhibited LTP in WT mice, but enhanced both the initial and the second LTP in TS2-neo mutants. By measuring the phosphorylation activation of ERK, CREB and glutamate receptor GluR1, steps required for hippocampal LTP, we found that all were abnormally high at baseline in the mutant mice. Nifedipine blocked LTP-related phosphorylation in WT mice, but normalized baseline phosphorylation of ERK, CREB and GluR1 in TS2-neo mice, allowing their subsequent activity-dependent induction. Thus, while nifedipine inhibits LTP in WT mice, the drug reinstates LTP and normal synaptic plasticity in a TS model, suggesting potential therapeutic approaches for synaptic deficits in channelopathies such as TS.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"184 ","pages":"Article 117896"},"PeriodicalIF":6.9,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143387676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbial signatures and therapeutic strategies in neurodegenerative diseases","authors":"Mlaak Rob ,&nbsp;Mahmoud Yousef ,&nbsp;Arun Prasath Lakshmanan ,&nbsp;Anns Mahboob ,&nbsp;Annalisa Terranegra ,&nbsp;Ali Chaari","doi":"10.1016/j.biopha.2025.117905","DOIUrl":"10.1016/j.biopha.2025.117905","url":null,"abstract":"<div><div>Neurodegenerative diseases (NDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), arise from complex interactions between genetic factors, environmental exposures, and aging. Additionally, gut dysbiosis has been linked to systemic inflammation and neurodegeneration. Advances in microbiome and metabolome profiling techniques have provided deeper insights into how alterations in gut microbiota and dietary patterns affect metabolic pathways and contribute to the progression of NDs. This review explores the profiles of gut microbiome and metabolome derived biomarkers and their roles in NDs. Across phyla, families, and genera, we identified 55 microbial alterations in PD, 24 in AD, 4 in ALS, and 17 in MS. Some notable results include an increase in <em>Akkermansia</em> in PD, AD, and MS and a decrease in short-chain fatty acids (SCFAs) in PD and AD. We examined the effects of probiotics, prebiotics, fecal microbiota transplants (FMT), sleep, exercise, and diet on the microbiota, all of which contributed to delayed onset and alleviation of symptoms. Further, artificial intelligence (AI) and machine learning (ML) algorithms applied to omics data have been crucial in identifying novel therapeutic targets, diagnosing and predicting prognosis, and enabling personalized medicine using microbiota-modulating therapies in NDs patients.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"184 ","pages":"Article 117905"},"PeriodicalIF":6.9,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143376608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thiopurine S-methyltransferase – An important intersection of drug-drug interactions in thiopurine treatment","authors":"Dunja Urbančič ,&nbsp;Marko Jukič ,&nbsp;Alenka Šmid ,&nbsp;Stanislav Gobec ,&nbsp;Janez Jazbec ,&nbsp;Irena Mlinarič-Raščan","doi":"10.1016/j.biopha.2025.117893","DOIUrl":"10.1016/j.biopha.2025.117893","url":null,"abstract":"<div><div>Understanding the molecular mechanisms of medicines is crucial for developing novel drugs, for repurposing existing medicines, and for predicting toxicities. Thiopurine <em>S</em>-methyltransferase (TPMT) serves as an exemplary case in personalized medicine, as its activity is influenced by genetic variants, co-factors, substrates, and inhibitors, which lead to diverse outcomes in thiopurine therapy. This comprehensive review explores the role of TPMT in drug-drug interactions by investigating its interactions with co-factors, substrates, and inhibitors. We focus on the principal interactions of TPMT with clinically relevant inhibitors, and add to this information with molecular docking analyses for the substrate and co-factor binding sites of TPMT. Notably, methotrexate and sulfasalazine emerged as the top-ranked compounds with favorable docking scores for the co-factor binding site, while furosemide is presented as the highest ranked inhibitor for the substrate binding site. Furthermore, we highlight the chemical and structural properties governing ligand binding to TPMT. We support the molecular characteristics by using a summary of clinical implications. Examining the molecular interactions between substrates or inhibitors and TPMT not only addresses therapeutic consequences, but also reveals potential novel indications of interacting compounds. These insights are also invaluable for identifying endogenous ligands and enhancing our understanding of TPMT’s biological function.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"184 ","pages":"Article 117893"},"PeriodicalIF":6.9,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143372407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}