Biomedicine & Pharmacotherapy最新文献

{"title":"Obeticholic acid does not restore Western diet-induced alterations in hepatic mitochondrial respiration","authors":"Jan Melek ,&nbsp;Pavla Staňková ,&nbsp;Eva Peterová ,&nbsp;Tumisang Edward Maseko ,&nbsp;Veronika Špalková ,&nbsp;Reem Matar ,&nbsp;Ahmed Ibrahim ,&nbsp;Moustafa Elkalaf ,&nbsp;Miroslav Podhola ,&nbsp;Alžběta Štefela ,&nbsp;Zuzana Červinková ,&nbsp;Petr Pávek ,&nbsp;Otto Kučera","doi":"10.1016/j.biopha.2025.118542","DOIUrl":"10.1016/j.biopha.2025.118542","url":null,"abstract":"<div><h3>Introduction</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) affects a significant portion of the global population, with mitochondrial dysfunction playing a pivotal role in its pathogenesis. Although FXR agonists such as obeticholic acid (OCA) have been studied as potential treatments for MASLD, the direct effects of OCA on the liver are still not fully understood. This study aimed to evaluate the effects of OCA in an in vivo model of MASLD.</div></div><div><h3>Methods</h3><div>Male C57BL/6 J mice were fed a control diet (CD) or a Western diet (WD) enriched with glucose and fructose in the drinking water for 36 weeks. During the final 3 weeks, mice received OCA (5 or 10 mg/kg/day) or vehicle. Liver histology, biochemical parameters, gene expression, mitochondrial enzymes activity and mitochondrial respiration were assessed.</div></div><div><h3>Results</h3><div>WD-fed mice exhibited increased body and liver weights and elevated aminotransferases, none of which were altered by OCA. OCA treatment did not significantly impact steatosis, inflammation, fibrosis, or hepatic lipid content. WD feeding reduced succinate-stimulated hepatic mitochondrial respiration, associated with decreased succinate dehydrogenase (SDH) expression and activity. OCA partially restored Sdh subunits B and C expression but did not significantly improve respirometric parameters.</div></div><div><h3>Conclusion</h3><div>Our findings consistently demonstrate that OCA administration in an established diet-induced murine model of MASLD does not improve hepatic steatosis or inflammation. Moreover, the WD-induced decrease in succinate-stimulated mitochondrial respiration was not ameliorated by OCA.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"192 ","pages":"Article 118542"},"PeriodicalIF":7.5,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing nanotechnology for improving the druggability of opium poppy-derived pharmaceutical benzylisoquinoline alkaloids: A review","authors":"Zahra Aghaali,&nbsp;Mohammad Reza Naghavi","doi":"10.1016/j.biopha.2025.118557","DOIUrl":"10.1016/j.biopha.2025.118557","url":null,"abstract":"<div><div>The boom in using phytoconstituents for diseases treatment has been fueled by growth in the realm of nanotechnology. This is because nanomedicines not only expand the therapeutic applications of phytochemicals but also refine their physicochemical properties. Among multitude natural compounds prescribed for the treatment of health-related conditions are benzylisoquinoline alkaloids (BIAs). The BIAs predominantly found in opium poppy constitute morphine, noscapine, sanguinarine, papaverine, thebaine, and codeine, with a long history of applications in healing numerous diseases. However, they have problems regarding bioavailability, release, and targeting, which limit their druggability. Integration into nanoparticles has been found to hold great promise for improving the pharmaceutical properties of BIAs, while simultaneously mitigating their potential toxicity. Therefore, this review devotes special focus to recent studies demonstrating a considerable refinement in BIA therapeutic efficacy via the implementation of nanoencapsulation technology. However, the nanoformulations may pose the challenges of cost-efficiency, standard compliance, stability, and safety issue, necessitating further investigations to clear these drawbacks. We also discuss the capability of artificial intelligence (AI), organs-on-a-chip, and carrier-free nanoparticles for toxicity and efficacy assessment and druggability improvement, respectively. Taken together, information present here provides valuable insight into the power of nanoparticles for enriching BIAs and ultimately facilitating their clinical translation.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"192 ","pages":"Article 118557"},"PeriodicalIF":7.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Innovative nanotechnology for infectious and inflammatory disease control: From diagnostics to therapeutics","authors":"Fatemeh Khosravi ,&nbsp;Parham Rahmani ,&nbsp;Rana Jahanban Esfahlan","doi":"10.1016/j.biopha.2025.118551","DOIUrl":"10.1016/j.biopha.2025.118551","url":null,"abstract":"<div><div>The global burden of infectious diseases continues to pose significant health threats, especially in low- and middle-income regions with limited healthcare access. This review explores cutting-edge innovations in combating these threats, emphasizing the role of nanotechnology. As traditional methods often fail to keep pace against rapidly evolving pathogens and antimicrobial resistance, nanotechnology offers promising solutions through novel diagnostic, therapeutic, and preventive approaches. Nanoparticles (NPs), with their unique properties, enhance vaccine efficacy, enable targeted drug delivery, and provide advanced diagnostic capabilities. This paper reviews diverse nanostructures such as liposomes, polymeric, inorganic, carbon-based NPs, exosomes, and protein-based NPs, detailing their applications in vaccine development and infection targeting. Additionally, this paper highlights how nanotechnology can modulate inflammatory responses in infectious diseases to improve therapeutic outcomes. Nanodiagnostics advance pathogen detection with high specificity and sensitivity, crucial for effective disease management. Nanotechnology helps treat non-infectious inflammatory diseases by providing precise delivery systems for conditions such as rheumatoid arthritis and cardiovascular diseases. It also examines the latest advancements and opportunities in this field while addressing the challenges associated with clinical translation. In summary, nanotechnology offers integrated solutions for the treatment of inflammatory and infectious illnesses.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"191 ","pages":"Article 118551"},"PeriodicalIF":7.5,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145060378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral nutraceutical intervention to improve endothelial function: Evidence from in vitro and pilot clinical studies","authors":"Vincenza Valerio ,&nbsp;Veronika A. Myasoedova ,&nbsp;Ilaria Massaiu ,&nbsp;Alessio Ravani ,&nbsp;Beatrice Frigerio ,&nbsp;Valentina Rusconi ,&nbsp;Francesca Bertolini ,&nbsp;Giulio Pompilio ,&nbsp;Paolo Poggio","doi":"10.1016/j.biopha.2025.118552","DOIUrl":"10.1016/j.biopha.2025.118552","url":null,"abstract":"<div><h3>Objective</h3><div>Aortic valve sclerosis affects 30 % of individuals over 65 and is associated with coronary artery disease, with risk of progression to aortic stenosis. Endothelial dysfunction, mediated by oxidative stress, impaired nitric oxide (NO) signaling, inflammation, and lipoprotein deposition, plays a central role in disease initiation and progression. This study investigated whether a combination of bioactive compounds could counteract these mechanisms and support vascular health.</div></div><div><h3>Methods</h3><div>The effects of curcuma longa, coenzyme Q10, black garlic, vitamin B1, and vitamin D3 were tested <em>in vitro</em> on aortic valve endothelial cells. Cell viability, reactive oxygen species (ROS), and NO levels were quantified by commercially available kits, while gene expression was analyzed by RNA sequencing. A 4-week prospective pilot clinical study in 10 healthy volunteers without cardiovascular disease evaluated endothelial function and arterial stiffness.</div></div><div><h3>Results</h3><div>The compounds reduced ROS production (&gt;27 %; p &lt; 0.05), enhanced endothelial viability (&gt;33 %; p &lt; 0.05; except curcuma and black garlic), and increased NO production (&gt;6 %; p &lt; 0.05; except black garlic). Beneficial effects were reflected in upregulation of anti-atherosclerotic (GIPR, +0.058 copies per million, CPM; p &lt; 0.05), antioxidant (GADL1, +0.55 CPM; p &lt; 0.001), and anti-inflammatory (IL12A, +0.17 CPM; p &lt; 0.01) genes. Clinically, daily supplementation improved endothelial function in participants found to have pre-existing endothelial dysfunction (p = 0.0336), with 50 % achieving normal levels after 4 weeks, while all subjects exhibited reduced arterial stiffness (p = 0.0016) without hepatic toxicity.</div></div><div><h3>Conclusions</h3><div>The oral supplementation of the combination of these bioactive compounds improved endothelial function and vascular health, particularly in individuals with endothelial dysfunction, offering potential therapeutic benefits for cardiovascular health.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"191 ","pages":"Article 118552"},"PeriodicalIF":7.5,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145060134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Light-enhanced cytotoxicity and intracellular trafficking of the PD-L1-targeting photoimmunoconjugate EITC-atezolizumab","authors":"Manuela Maria Alampi ,&nbsp;Magdaléna Kozlíková ,&nbsp;Matteo Mariangeli ,&nbsp;Simone Civita ,&nbsp;Pietro Delcanale ,&nbsp;Andrea Mussini ,&nbsp;Alberto Diaspro ,&nbsp;Paolo Bianchini ,&nbsp;Anette Weyergang ,&nbsp;Ellen Skarpen ,&nbsp;Kristian Berg ,&nbsp;Cristiano Viappiani ,&nbsp;Stefania Abbruzzetti ,&nbsp;Pål Kristian Selbo","doi":"10.1016/j.biopha.2025.118550","DOIUrl":"10.1016/j.biopha.2025.118550","url":null,"abstract":"<div><h3>Background</h3><div>Photodynamic therapy (PDT) uses light to generate reactive oxygen species (ROS) that initiate cytotoxic responses in cancer cells. Photoimmunotherapy (PIT) improves PDT specificity by linking photosensitizers (PS) to monoclonal antibodies. A promising monoclonal antibody (mAb) for immunoconjugates is atezolizumab (Tecentriq), an EMA/FDA-approved PD-L1 immune checkpoint inhibitor for treating non-small cell lung cancer (NSCLC).</div></div><div><h3>Objective</h3><div>Our goal was to: Optimize the cytotoxic efficacy of a photoimmunoconjugate of eosin-5-isothiocyanate and atezolizumab (EITC-atezolizumab) in NSCLC cells; Study the uptake and intracellular transport of atezolizumab; Evaluate EITC-atezolizumab as a candidate for photochemical internalization (PCI) of the ribosome-inactivating protein gelonin.</div></div><div><h3>Methods</h3><div>Cytotoxic efficacy of EITC-atezolizumab was evaluated in NSCLC cell lines H1975 (PD-L1-high) and A549 (PD-L1-low) using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Confocal microscopy was employed to observe the uptake and intracellular localization of AlexaFluor647-atezolizumab and its colocalization with either LysoTracker™Blue or an anti-CD63 antibody labelled with Alexa488.</div></div><div><h3>Results</h3><div>EITC-atezolizumab PIT significantly enhanced cytotoxicity, showing much higher sensitivity in H1975 than A549 NSCLC cells. PIT with EITC-atezolizumab did not enhance gelonin efficacy. Confocal microscopy of H1975 cells revealed near-plasmamembrane puncta fluorescence of Alexa647-atezolizumab, with fractions clustering in CD63⁺ organelles peaking at 6 h. In A549 cells, AlexaFluor647-atezolizumab showed sustained accumulation in LysoTracker™ Blue+ vesicles for up to 24 h.</div></div><div><h3>Conclusion</h3><div>To the best of our knowledge, this is the first documentation demonstrating that atezolizumab is transported to CD63-positive organelles, thereby enhancing our understanding of its intracellular trafficking. Our study also strengthens the concept of PIT and atezolizumab-based targeting of PD-L1⁺ NSCLCs.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"191 ","pages":"Article 118550"},"PeriodicalIF":7.5,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145057194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the cellular mechanisms of thiopurine-induced pancreatitis in pediatric inflammatory bowel disease: Insights from induced pluripotent stem cell models","authors":"Paola Rispoli ,&nbsp;Elena Genova ,&nbsp;Fengming Yue ,&nbsp;Kohei Johkura ,&nbsp;Martina Franzin ,&nbsp;Ute Hofmann ,&nbsp;Matthias Schwab ,&nbsp;Rosalba Monica Ferraro ,&nbsp;Elena Laura Mazzoldi ,&nbsp;Silvia Clara Giliani ,&nbsp;Giovanna Piovani ,&nbsp;Matteo Bramuzzo ,&nbsp;Stefano Martelossi ,&nbsp;Erasmo Miele ,&nbsp;Massimo Martinelli ,&nbsp;Federico Marchetti ,&nbsp;Marco Pelin ,&nbsp;Giuliana Decorti ,&nbsp;Marianna Lucafò ,&nbsp;Gabriele Stocco","doi":"10.1016/j.biopha.2025.118539","DOIUrl":"10.1016/j.biopha.2025.118539","url":null,"abstract":"<div><div>Thiopurines are effective drugs for inflammatory bowel disease, but their use is limited by side effects such as pancreatitis, whose mechanism remains unknown and may be more severe in children. This study investigated in a personalized way thiopurine-induced pancreatitis mechanism using induced pluripotent stem cells from pediatric inflammatory bowel disease patients.</div><div>Ten pediatric patients, five developing pancreatitis (cases) and five without it (controls), were enrolled. Patient-specific stem cells and their pancreatic differentiated counterparts were used to evaluate thiopurine cytotoxicity, to quantify metabolites levels by liquid chromatography-tandem mass spectrometry, and to assess thiopurine pharmacodynamics by western-blot assay. Statistical analyses were performed applying Student’s t-test or two-way ANOVA followed by Bonferroni’s post-hoc test for multiple comparisons. Cytotoxicity assays revealed higher thioguanine cytotoxicity in stem and pancreatic cells from cases; pancreatic cells from cases were also more sensitive to mercaptopurine. Moreover, thioguanine treatment on stem cells produced thioguanosine monophosphate and its methylated form, but their concentration did not differ significantly between the groups. In addition, higher <em>TPMT</em> gene expression was observed in stem cells from cases, but no differences were observed in pancreatic cells. No significant differences were detected in <em>HPRT</em>, <em>NUDT15</em>, <em>ITPA</em>, or <em>PACSIN2</em> expression. Lastly, Rac1 protein concentration was similar in stem cells from cases and controls, but pancreatic cells from cases exhibited significantly higher Rac1 expression. These findings suggest that thiopurine cytotoxicity differences might be linked to pharmacokinetics in stem cells, while altered Rac1 expression in pancreatic cells might contribute to pancreatitis, implicating distinct mechanisms between stem and differentiated cells.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"191 ","pages":"Article 118539"},"PeriodicalIF":7.5,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145057195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Smart co-delivery of Erlotinib and Camptothecin using silica-coated gold nanorods functionalized with recombinant anti-bone morphogenetic protein receptor type I (BMPR-AI)","authors":"Fatemeh Sabzalizadeh ,&nbsp;Hamed Mirshekari ,&nbsp;Nediljko Budisa ,&nbsp;Khosro Khajeh ,&nbsp;Hamid-Reza Karbalaei-Heidari","doi":"10.1016/j.biopha.2025.118540","DOIUrl":"10.1016/j.biopha.2025.118540","url":null,"abstract":"<div><div>Non-small cell lung carcinoma is a highly aggressive cancer with a poor prognosis. Although Erlotinib (ELT) and Camptothecin (CPT) are commonly used together in chemotherapy, their effectiveness is limited when given as free drugs. To improve their efficacy, we developed a novel nanomedicine consisting of gold nanorods (Au-NRs) coated with a functionalized silica network to deliver both drugs simultaneously. This approach aims to enhance cancer cell targeting, inhibit cell proliferation, and induce apoptosis. The nanomedicine was further engineered with a recombinant anti-BMP receptor AI (BMPR-AI) single-chain variable fragment (scFv) fused with maltose-binding protein for targeted delivery. Successful coating and functionalization were confirmed through various analyses, including HR-TEM, EDS/EDAX, zeta potential measurements, and FT-IR. The resulting CPT/ELT/scFv@Au-NR nanomedicine effectively targeted BMPR-AI-overexpressing cancer cells (A549) while showing minimal cytotoxicity toward normal lung fibroblasts (MRC-5), significantly inhibiting growth and inducing apoptosis more efficiently than the free drugs. This promising strategy demonstrates enhanced cytotoxic effects and holds potential for more effective chemotherapy and future advances in cancer treatment.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"191 ","pages":"Article 118540"},"PeriodicalIF":7.5,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145057152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into histone deacetylase inhibitors-induced cell death in cancer cell lines","authors":"María Fuentes-Baile ,&nbsp;Pilar García-Morales ,&nbsp;Elizabeth Pérez-Valenciano ,&nbsp;Trinidad Mata-Balaguer ,&nbsp;María P. Menéndez-Gutiérrez ,&nbsp;Camino de Juan Romero ,&nbsp;Álvaro Rodríguez-Lescure ,&nbsp;Elena Martín-Orozco ,&nbsp;Ricardo Mallavia ,&nbsp;Víctor M. Barberá ,&nbsp;Miguel Saceda","doi":"10.1016/j.biopha.2025.118541","DOIUrl":"10.1016/j.biopha.2025.118541","url":null,"abstract":"<div><div>Histone deacetylase inhibitors (HDACis) induce cell death in many chemoresistant cancer models, suggesting their potential as alternative treatments for these malignancies. However, their efficacy in solid tumors remains limited. Therefore, understanding the molecular mechanisms underlying HDACi-induced cell death is essential for developing targeted activators of these pathways, enabling the selective elimination of chemoresistant cancer cells while minimizing the widespread transcriptional effects of HDACis. In this study, we investigated HDACi-induced cell death across models of different cellular origins to determine whether a universal molecular mechanism triggers this process. Our findings demonstrate that HDACi-induced cell death is TP53-independent, resistant to caspase inhibitors, and sensitive to serine protease inhibitors. This form of cell death requires intracellular calcium mobilization to induce mitochondrial depolarization. Using DNA arrays, apoptosis protein arrays, and ELISA assays, combined with siRNA-mediated gene silencing, we identified genes with a causal relationship to TSA-induced cell death. These include dual-specificity phosphatases such as DUSP3 and DUSP10; endoplasmic reticulum stress-related genes such as XBP1, MBTPS1, MBTPS2, and RPS6KA5; and other genes like BAX, AIF, EAF2, NANOS1, and CCNYL1. Our findings reveal novel potential targets for developing antineoplastic agents designed to exploit HDACi-induced cell death pathways, providing a strategy to overcome chemoresistance in cancer therapy.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"191 ","pages":"Article 118541"},"PeriodicalIF":7.5,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145057153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Givinostat inhibits in vitro differentiation of cardiac fibroadipogenic precursors from a mouse model of arrhythmogenic cardiomyopathy","authors":"Sara Vencato ,&nbsp;Chiara Romanato ,&nbsp;Monica Forino ,&nbsp;Gianluca Fossati ,&nbsp;Angelo Velle ,&nbsp;Nicola Facchinello ,&nbsp;Paola Braghetta ,&nbsp;Simonetta Andrea Licandro ,&nbsp;Chiara Romualdi ,&nbsp;Martina Calore ,&nbsp;Libero Vitiello ,&nbsp;Christian Steinkuhler ,&nbsp;Alessandra Rampazzo","doi":"10.1016/j.biopha.2025.118549","DOIUrl":"10.1016/j.biopha.2025.118549","url":null,"abstract":"<div><div>Arrhythmogenic cardiomyopathy (ACM) is a rare genetic cardiac disease and one of the leading causes of sudden cardiac death in young individuals and athletes. Current treatments focus on preventing arrhythmias and sudden cardiac death, but no effective therapy targeting disease progression is available. Myocardial replacement with fibro-fatty tissue, a hallmark of ACM, is primarily driven by the activation of cardiac fibroadipogenic precursors (cFAPs). Here, we evaluate the efficacy of a pan inhibitor of histone deacetylases (givinostat) in reducing cFAP proliferation and differentiation. These cells were found to be enriched in the hearts of a transgenic ACM murine model (Tg-hQ), which overexpresses the DSG2 p.Q558* mutation, compared to wild-type (WT) controls. We observed that givinostat reduced the proliferation of both Tg-hQ and WT isolated cFAPS. Additionally, cFAPS were induced to differentiate into adipocytes or fibroblasts and treated with givinostat. The drug treatment led to a reduction in the number of adipocytes under pro-adipogenic conditions. RNA sequencing analysis revealed a significant downregulation of key regulators of adipogenic differentiation and lipid metabolism (<em>Pparg</em>, <em>Cebpa</em> and <em>Adipoq</em>). In parallel, cells cultured under pro-fibrotic conditions showed decreased expression of genes encoding components of the extracellular matrix (<em>Col1a1</em>, <em>Col6a1</em> and <em>Postn</em>) upon givinostat treatment. Overall, these results support the potential of givinostat in modulating cFAP proliferation and differentiation <em>in vitro</em>, warranting further <em>in vivo</em> studies to assess its impact on fibro-fatty tissue replacement in ACM.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"191 ","pages":"Article 118549"},"PeriodicalIF":7.5,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145057193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel antitubercular agents based on 2,4-disubstituted 5-(aryl-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidines","authors":"Vladimir Finger ,&nbsp;Martin Vrbicky ,&nbsp;Lubica Muckova ,&nbsp;Lukas Prchal ,&nbsp;Martin Novak ,&nbsp;Jan Marek ,&nbsp;Ondrej Soukup ,&nbsp;Michaela Hympanova ,&nbsp;Ales Sorf ,&nbsp;Marketa Benkova ,&nbsp;Jan Bartacek ,&nbsp;Pavel Drabina ,&nbsp;Martin Kufa ,&nbsp;Ondrej Kovar ,&nbsp;Lenka Fikejzlová ,&nbsp;Martin Hruby ,&nbsp;Oksana Ozhelevska ,&nbsp;Johannes Jagob ,&nbsp;Jana Zdarova-Karasova ,&nbsp;Jitka Odvarkova ,&nbsp;Jan Korabecny","doi":"10.1016/j.biopha.2025.118537","DOIUrl":"10.1016/j.biopha.2025.118537","url":null,"abstract":"<div><div>Tuberculosis (TB), caused by <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>), remains a global health challenge, especially with the rise of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. Current treatment regimens are prolonged and associated with significant toxicity, underscoring the need for novel therapeutic agents. This study investigates a new series of 2,4-disubstituted 5-(aryl-2-ylmethyl)-5<em>H</em>-pyrrolo[3,2-<em>d</em>]pyrimidine derivatives as potential antitubercular agents. The most promising compound, <strong>74</strong>, exhibited potent anti-TB activity, including against MDR strains, with a MIC₉₉ of 2 µM. Structure-activity relationship studies identified critical substitutions at positions 2- and 4- of the core scaffold that enhanced antimycobacterial potency, while bulkier aromatic moieties at position 5- were preferred. Despite its high efficacy, <strong>74</strong> demonstrated significant cytotoxicity, inhibition of cytochrome P450 enzymes and cardiotoxicity through hERG channel inhibition, highlighting challenges in further development. Pharmacokinetic studies of <strong>74</strong> revealed favorable systemic exposure with a prolonged half-life, suggesting its potential for less frequent dosing. Nonetheless, <em>in vitro</em> assays demonstrated rapid metabolic turnover, likely due to high intrinsic clearance, and the compound's elevated logD values further indicate the need for structural modifications to improve both solubility and metabolic stability. Efforts to introduce more polar substituents at the 4-position led to a loss of anti-TB activity, emphasizing the complexity of balancing potency and safety.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"191 ","pages":"Article 118537"},"PeriodicalIF":7.5,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145057154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}