Biomedicine & Pharmacotherapy最新文献

{"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}

{"title":"A novel missense mutation Smad4 V354L enhances the efficacy of docetaxel in non-small cell lung cancer","authors":"Xia Xue ,&nbsp;Yongjia Zhou ,&nbsp;Huiping Liu ,&nbsp;Yan Gao ,&nbsp;Xinyu Ma ,&nbsp;Zhaohua Xiao ,&nbsp;Wenhao Zhang ,&nbsp;Peichao Li ,&nbsp;Zhongxian Tian ,&nbsp;Yun Luan ,&nbsp;Xiaogang Zhao","doi":"10.1016/j.biopha.2025.117899","DOIUrl":"10.1016/j.biopha.2025.117899","url":null,"abstract":"<div><div>NSCLC is a heterogeneous disease with unique combinations of somatic molecular alterations in individual patients. The different mutations in tumor oncogene and suppressors might be associated with the response to therapy. However, little is known about how Smad4 genomic alterations cause the therapeutic effect of docetaxel. The retrospective analysis was conducted on 49 patients with stage IIB or IIIA non-small cell lung cancer receiving docetaxel chemotherapy. One novel missense variant, c.1060 G &gt; C in Smad4 was identified by next-generation sequencing. The Smad4c.1060 G &gt; C variant results in the substitution of valine with leucine at amino acid 354 (p.Val354Leu, V354L). The clinical analysis showed that the patients with Smad4 V354L mutation receiving docetaxel treatment manifested better prognosis with prolonged disease-free survival and overall survival compared with patients with the wild-type. Smad4 V354L cells demonstrated increased sensitivity to docetaxel with apoptosis and G2/M cell cycle arrest. Furthermore, the cell-cycle related protein expression of CDK2 was remarkably decreased, while the expression of cyclin-dependent kinase inhibitor p21 Waf1 and p27 Kip1 was significantly increased. <em>In vivo</em> experiments further demonstrated the increased inhibitory effects of docetaxel in the nude mice inoculated with Smad4 V354L cells compared to the mice inoculated with wild-type cells group. The novel V354L missense mutation of Smad4 gene enhances the efficacy of docetaxel in non-small cell lung cancer, which would provide new opportunities for precise clinical therapy of NSCLC.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"184 ","pages":"Article 117899"},"PeriodicalIF":6.9,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143350678","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":"Oregano polyphenols reduce human insulin amyloid aggregation","authors":"Silvia Bittner Fialová ,&nbsp;Miroslav Gančár ,&nbsp;Elena Kurin ,&nbsp;Svetlana Dokupilová ,&nbsp;Zuzana Gažová ,&nbsp;Milan Nagy","doi":"10.1016/j.biopha.2025.117904","DOIUrl":"10.1016/j.biopha.2025.117904","url":null,"abstract":"<div><div>Human insulin may undergo fibrillization under specific conditions, impairing its function and promoting its accumulation in amyloid deposits. Oregano (<em>Origanum vulgare</em> L.) leaves are rich in biologically active compounds such as polyphenols. Thus, we investigated their ability to inhibit insulin amyloid aggregation. The oregano aqueous extract phytochemical analysis (LC-MS/MS-DAD) revealed the presence of four major compounds: lithospermic acid (LA), rosmarinic acid (RA), oreganol A (OA), and luteolin-7-<em>O</em>-diglucuronide (L7dG), respectively. Compounds and their mixtures were subsequently screened for anti-amyloid activity and evaluated against oregano lyophilizate (LYO) utilizing ThT assay, AFM and ATR-FTIR analyses. LYO inhibited insulin fibrillization more effectively than its main constituent RA, prolonging the lag phase approximately two-fold. L7dG has been the most effective of the tested individual compounds, prolonging the lag phase by roughly 20 %, followed by LA, whereas OA was ineffective. Subsequently, we measured the anti-amyloid activity of two kinds of equimolar mixtures: either containing individually active compounds or analogous mixtures to which inactive OA was added. Surprisingly, LA:OA mixture proved to be the most effective. However, adding L7dG to the OA mixtures led to activity loss. The interactions of oregano polyphenols with the amyloidogenic regions of insulin were elucidated using molecular docking, explaining observed changes in their anti-amyloid activity. We conclude that when investigating the anti-amyloid activity of samples of natural origin and determining the activity of the extracts and their individual main components, it is necessary to consider their mutual interactions, which can significantly affect the final effect of the analyzed mixture.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"184 ","pages":"Article 117904"},"PeriodicalIF":6.9,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143350677","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":"Vagus nerve stimulation: A targeted approach for reducing tissue-specific ischemic reperfusion injury","authors":"Parmeshar Singh ,&nbsp;Manju Chaudhary ,&nbsp;Jacob S. Kazmi ,&nbsp;Cyrus E. Kuschner ,&nbsp;Bruce T. Volpe ,&nbsp;Timir D. Chaudhuri ,&nbsp;Lance B. Becker","doi":"10.1016/j.biopha.2025.117898","DOIUrl":"10.1016/j.biopha.2025.117898","url":null,"abstract":"<div><div>Vagus Nerve Stimulation (VNS), a neuromodulation technique of applying controlled electrical impulses to the vagus nerve, has now emerged as a potential therapeutic approach for ischemia-reperfusion insults. It provides a pivotal link in improving functional outcomes for the central nervous system and multiple target organs affected by ischemia-reperfusion injury (I/RI). Reduced blood flow during ischemia and subsequent resumption of blood supply during reperfusion to the tissue compromises cellular health because of the combination of mitochondrial dysfunction, oxidative stress, cytokine release, inflammation, apoptosis, intracellular calcium overload, and endoplasmic reticulum stress, which ultimately leads to cell death and irreversible tissue damage. Furthermore, inflammation and apoptosis also play critical roles in the acute progression of ischemic injury pathology. Emerging evidence indicates that VNS in I/RI may act in an anti-inflammatory capacity, reducing oxidative stress and apoptosis, while also improving endothelial and mitochondrial function leading to reduced infarct sizes and cytoprotection in skeletal muscle, gastrointestinal tract, liver, kidney, lung, heart, and brain tissue. In this review, we attempt to shed light on the mechanistic links between tissue-specific damage following I/RI and the therapeutic approach of VNS in attenuating damage, considering both direct and remote I/RI scenarios. Thus, we want to advance the understanding of VNS that could further warrant its clinical implementation, especially as a treatment for I/RI.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"184 ","pages":"Article 117898"},"PeriodicalIF":6.9,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143350676","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":"Examining the pharmacokinetic and pharmacodynamic interaction of N,N-dimethyltryptamine and harmine in healthy volunteers: Α factorial dose-escalation study","authors":"Klemens Egger ,&nbsp;Javier Jareño Redondo ,&nbsp;Jovin Müller ,&nbsp;Joëlle Dornbierer ,&nbsp;John Smallridge ,&nbsp;Helena D. Aicher ,&nbsp;Daniel Meling ,&nbsp;Per Müller ,&nbsp;Jonas Kost ,&nbsp;Maxim Puchkov ,&nbsp;Angela Äbelö ,&nbsp;Erich Seifritz ,&nbsp;Boris B. Quednow ,&nbsp;Robin von Rotz ,&nbsp;Milan Scheidegger ,&nbsp;Dario A. Dornbierer","doi":"10.1016/j.biopha.2025.117908","DOIUrl":"10.1016/j.biopha.2025.117908","url":null,"abstract":"<div><div>Ayahuasca, a traditional psychoactive Amazonian brew, usually contains <em>N,N</em>-dimethyltryptamine (DMT) and β-carboline (harmine, harmaline, tetrahydroharmine) monoamine oxidase inhibitors. However, the pharmacological interactions between these compounds remain incompletely understood. In this study, we developed an ayahuasca-inspired formulation containing DMT and harmine, aiming to systematically evaluate their pharmacokinetic and pharmacodynamic drug-drug interactions (DDI) across a range of dosage levels. We hypothesized that escalating harmine doses would enhance DMT bioavailability, increase its plasma half-life, and reduce the variability in DMT plasma concentrations between individuals. Additionally, we expected that harmine would attenuate the plasma levels of the main DMT metabolite, indole-3-acetic acid (3-IAA), while increasing levels of the secondary metabolite DMT-<em>N</em>-oxide (DMT-NO).</div><div>This single-blind, randomized, two-arm, factorial, dose-finding study included 16 healthy participants (9 males, 7 females), each receiving six dose combinations (0–120 mg DMT, 0–180 mg harmine) administered via a microcarrier-based transmucosal delivery system. We then evaluated the pharmacokinetics of DMT and harmine and their main metabolites, subjective effects, autonomic responses, and the safety profile of the combined preparation.</div><div>All DMT-harmine combinations reliably induced dose-dependent subjective effects lasting 4–5 h, with peak DMT and harmine levels (C_max) reaching 33 ng/mL and 49 ng/mL, respectively. T_max, the time to maximum concentrations, increased with dose escalation for both compounds. The interactions between DMT and harmine were not unidirectional, i.e., harmine reduced the metabolism of DMT, while DMT altered harmine pharmacokinetics. Our novel formulation demonstrated a favorable safety profile, supporting its potential for further testing in patients with various affective disorders.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"184 ","pages":"Article 117908"},"PeriodicalIF":6.9,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143372312","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":"Tailor-made Biochar enhances the anti-tumour effects of butyrate-glycerides in colorectal cancer","authors":"Laura Fei ,&nbsp;Arianna Pia Propato ,&nbsp;Giulia Lotti ,&nbsp;Patrizia Nardini ,&nbsp;Daniele Guasti ,&nbsp;Simone Polvani ,&nbsp;Daniele Bani ,&nbsp;Andrea Galli ,&nbsp;David Casini ,&nbsp;Giulia Cantini ,&nbsp;David Chiaramonti ,&nbsp;Michaela Luconi","doi":"10.1016/j.biopha.2025.117900","DOIUrl":"10.1016/j.biopha.2025.117900","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is the third most common cancer and the second cause of cancer death in the world. Emerging evidence suggests that the short-chain-fatty-acid butyrate diet-assumed or produced by gut microbiota may interfere with CRC. Novel, more focused and effective anti-cancer natural molecules selectively acting on tumour cells are required to improve patients’ compliance compared to more aggressive drug-based schemes.</div><div>This study explored the <em>in vitro</em> anti-cancer effects of a novel green compound consisting of butyrate-glycerides (BMDG) alone or absorbed on tailor-made Biochar (BMDG-Biochar) or on activated-carbon Norit-B (BMDG-Norit), by using two CRC cell lines, HCT116 and HT29.</div><div>Tailor-made Biochar characterised by a larger share of meso and macroporosity compared to commercially available activated-carbon Norit-B, with micro-pored ultrastructure, displayed superior performances as a BMDG carrier, with higher absorption/release properties.</div><div>BMDG, in particular when absorbed on Biochar, interfered significantly with CRC cell proliferation compared to BMDG-Norit that showed no effect.</div><div>Analysis of cell metabolism revealed a superior sensitivity of HCT116 to the inhibitory effect of BMDG-Biochar. This compound specifically induced a shift from a glycolytic metabolism in particular in HCT116 cells where glycolysis supports the aggressive phenotype, towards the mitochondrial respiration that characterises the more differentiated and less aggressive HT29 cells.</div><div>Biochar’s ability to deliver the butyrate-glyceride bioactive mixture and to exert <em>in vitro</em> combined anti-cancer activity in colorectal cancer, interfering with the Warburg effect that characterises the aggressive CRC forms, opens future translational opportunities to develop new orally assumed green molecules as promising anti-cancer strategies for CRC.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"184 ","pages":"Article 117900"},"PeriodicalIF":6.9,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143228953","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":"Exploring the immuno-nano nexus: A paradigm shift in tumor vaccines","authors":"Yuanyuan Li ,&nbsp;Yike Xu ,&nbsp;Wenwen Su ,&nbsp;Jia Xu,&nbsp;Zifei Ye,&nbsp;Zhuoyi Wang,&nbsp;Qihui Liu,&nbsp;Fangfang Chen","doi":"10.1016/j.biopha.2025.117897","DOIUrl":"10.1016/j.biopha.2025.117897","url":null,"abstract":"<div><div>Tumor vaccines have become a crucial strategy in cancer immunotherapy. Challenges of traditional tumor vaccines include inadequate immune activation and low efficacy of antigen delivery. Nanoparticles, with their tunable properties and versatile functionalities, have redefined the landscape of tumor vaccine design. In this review, we outline the multifaceted roles of nanoparticles in tumor vaccines, ranging from their capacity as delivery vehicles to their function as immunomodulatory adjuvants capable of stimulating anti-tumor immunity. We discuss how this innovative approach significantly boosts antigen presentation by leveraging tailored nanoparticles that facilitate efficient uptake by antigen-presenting cells. These nanoparticles have been meticulously designed to overcome biological barriers, ensuring optimal delivery to lymph nodes and effective interaction with the immune system. Overall, this review highlights the transformative power of nanotechnology in redefining the principles of tumor vaccines. The intent is to inform more efficacious and precise cancer immunotherapies. The integration of these advanced nanotechnological strategies should unlock new frontiers in tumor vaccine development, enhancing their potential to elicit robust and durable anti-tumor immunity.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"184 ","pages":"Article 117897"},"PeriodicalIF":6.9,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143350027","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":"Liver-X receptor β-selective agonist CE9A215 regulates Alzheimer’s disease-associated pathology in a 3xTg-AD mouse model","authors":"So Young Ban ,&nbsp;Yunkwon Nam ,&nbsp;Thi Thuong Do ,&nbsp;Byeong-Hyeon Kim ,&nbsp;Soo Jung Shin ,&nbsp;My Tuyen Thi Nguyen ,&nbsp;Jaehan Kim ,&nbsp;Minho Moon ,&nbsp;Jong-Tae Park","doi":"10.1016/j.biopha.2025.117895","DOIUrl":"10.1016/j.biopha.2025.117895","url":null,"abstract":"<div><div>In Alzheimer's disease (AD), tau pathology is closely associated with disease progression. Therefore, therapeutics that alleviate tau pathology are essential. Liver-X receptor (LXR) has garnered interest as a potential target for the treatment of AD. We previously investigated the potent anti-allergic and anti-inflammatory effects of inotodiol, hereafter referred to as CE9A215, in various disease models. In this study, we explored the potential of CE9A215 as a treatment for AD. CE9A215 preferentially activated LXRβ (EC₅₀ &lt;10 nM), with no significant activation observed for LXRα at concentrations up to 1000 nM. Pharmacokinetic analysis confirmed that CE9A215 crosses the blood-brain barrier and accumulates in the brain. Moreover, CE9A215 modulated the expression of <em>ABCA1</em>, <em>APOE</em>, <em>SREBP-1c</em> and <em>AQP4</em> in the brains of wild-type and LXR α/β knockout mice in LXRβ-dependent manner. The efficacy of CE9A215 on AD-related pathologies was evaluated using 3xTg-AD mice. CE9A215 exerted both prophylactic and therapeutic effects on AD-associated behaviors and pathologies, including reductions in amyloid-β, phosphorylated tau, and neuroinflammation in the hippocampus. Transcriptomic analysis revealed that CE9A215 induced significant changes in genes associated with tau pathology, particularly in pathways related to protein phosphorylation and PI3K/AKT signaling. Our findings suggest that CE9A215 could be a promising therapeutic candidate for AD, particularly in mitigating tau hyperphosphorylation and related AD pathologies.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"184 ","pages":"Article 117895"},"PeriodicalIF":6.9,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143229165","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":"Breaking through with ultrasound: TP53-driven efficacy of calcium sonoporation in pediatric rhabdomyosarcoma cells","authors":"Dawid Przystupski ,&nbsp;Nina Rembiałkowska ,&nbsp;Julita Kulbacka ,&nbsp;Marek Ussowicz","doi":"10.1016/j.biopha.2025.117877","DOIUrl":"10.1016/j.biopha.2025.117877","url":null,"abstract":"<div><div>Ultrasound-mediated sonoporation is a promising technique that temporarily permeabilizes cell membranes to enhance delivery of therapeutic agents directly to tumor sites while minimizing systemic side effects. Calcium, a critical regulator of cell death and proliferation, can be introduced into cells by ultrasound, offering a novel therapeutic approach. This study investigates calcium sonoporation (CaSP), which combines ultrasound with calcium ions and microbubbles, to target pediatric rhabdomyosarcoma A204 and RD cells. Our findings showed that CaSP disrupted cellular homeostasis by facilitating the controlled influx of calcium, leading to oxidative stress, mitochondrial dysfunction, cell cycle arrest and activation of apoptotic pathways. The study revealed that the <em>TP53</em> mutational status significantly influences the cellular response to CaSP. <em>TP53</em>-wild-type A204 cells were particularly susceptible to CaSP, exhibiting marked increases in apoptosis and oxidative damage. In contrast, <em>TP53</em>-mutated RD cells exhibited a reduced oxidative stress and apoptotic response, highlighting the critical role of <em>TP53</em> in mediating the effects of CaSP. This differential response underscored the potential of <em>TP53</em> gene as a biomarker for predicting the efficacy of CaSP, offering a pathway toward more personalized cancer therapies. Furthermore, the study demonstrated that CaSP can selectively target cancer cells while sparing healthy tissue. The research laid the groundwork for future studies to optimise sonoporation parameters and explore its integration with existing cancer treatments. The insights gained from this study pave the way for developing more personalized cancer treatment strategies, particularly for tumors influenced by specific genetic contexts, such as <em>TP53</em> mutations.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"184 ","pages":"Article 117877"},"PeriodicalIF":6.9,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143228954","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":"Ferula sesquiterpenes, ferutinin, galbanic acid and karatavic acid, suppress thymocyte volume regulation and proliferation by blocking the volume-sensitive anion channel","authors":"Ravshan Z. Sabirov ,&nbsp;Sarvinoz I. Rustamova ,&nbsp;Gulnoza A. Toshtemirova ,&nbsp;Nargiza A. Tsiferova ,&nbsp;Sirojbek A. Khojiboev ,&nbsp;Diyor D. Fayziev ,&nbsp;Utkir K. Inogamov ,&nbsp;Ranokhon Sh. Kurbannazarova ,&nbsp;Vladimir N. Syrov ,&nbsp;Petr G. Merzlyak","doi":"10.1016/j.biopha.2025.117875","DOIUrl":"10.1016/j.biopha.2025.117875","url":null,"abstract":"<div><h3>Background</h3><div>T cell development and maturation requires efficient cell volume regulation (CVR) system. Although the molecular basis of CVR is being rapidly elucidated, pharmacology of its key components remains poorly developed. Biopharmaceuticals specifically targeting CVR and its central player, the volume-sensitive outwardly rectifying anion channel (VSOR/VRAC), are necessary to uncover relationships between the channel, CVR and cell proliferation and survival.</div></div><div><h3>Methods</h3><div>The effects of three <em>Ferula</em> sesquiterpenes, ferutinin, galbanic acid and karatavic acid on the regulatory volume decrease (RVD) of freshly isolated thymocytes by light transmittance, on proliferation of primary cultured thymocytes by cell counting and on the VSOR/VRAC by patch-clamp were evaluated.</div></div><div><h3>Results</h3><div>Ferutinin, galbanic acid and karatavic acid exerted a profound inhibitory effect on RVD of thymocytes, leading to proliferation arrest. All three sesquiterpenes blocked VSOR/VRAC in a voltage-independent “cork-in-bottle” manner with half-maximal efficiencies comparable to those for RVD. Hill coefficients of 2.0–3.3 imply that positively cooperated binding of 2–3 molecules of the <em>Ferula</em> sesquiterpenes to VSOR/VRAC is required to suppress cell proliferation via inhibition of CVR. The <em>Ferula</em> sesquiterpenes were not apoptogenic, but induced necrotic cell death, which was pronounced for ferutinin and less manifested for galbanic and karatavic acids. VSOR/VRAC and RVD inhibition did not correlate with necrotic cell death induction.</div></div><div><h3>Conclusion</h3><div>The VSOR/VRAC channel blockage by <em>Ferula</em> sesquiterpenes was found to impair the CVR machinery of thymocytes, resulting in suppression of cell proliferation. The necrotic cell death is not a direct consequence of VSOR/VRAC and RVD inhibition, likely involving other cellular pathways.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"184 ","pages":"Article 117875"},"PeriodicalIF":6.9,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143229164","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}