Biomedicine & Pharmacotherapy最新文献

{"title":"First lepidiline-inspired 1,3-dibenzyl 2-CF3S-imidazoliums: Design, synthesis and cytotoxic activity study","authors":"Wiktor K. Poper ,&nbsp;Marta Denel-Bobrowska ,&nbsp;Agnieszka B. Olejniczak ,&nbsp;Marcin Jasiński","doi":"10.1016/j.biopha.2025.118606","DOIUrl":"10.1016/j.biopha.2025.118606","url":null,"abstract":"<div><div>A series of lepidiline-type 4,5-dimethylimidazolium hexafluorophosphates, functionalized with F atom(s) as well as the CF₃, OCF₃, OCH₃ and SCF₃ groups located either in the central core or placed at benzyl-type <em>N</em>-substituents, was prepared, and the cytotoxicity against selected cancer cell lines was examined. The applied four-step protocol based on condensation of diacetyl monoxime with formaldimines (hexahydro-1,3,5-triazines), one-pot telescopic sulfur-transfer followed by electrophilic trifluoromethylation, and subsequent <em>N</em>-alkylation of the central imidazole ring, enabled access to symmetrical and unsymmetrical products. The counterion metathesis provided crystalline hexafluorophosphates, which were isolated in high overall yield. Analysis of biological activity of the intermediate CF₃S-imidazoles and the corresponding imidazoliums against HeLa, HepG2, and A549 cancer cell lines revealed amplified cytotoxicity of the final salts in comparison to natural lepidiline alkaloids, which is promising in the context of drug discovery.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"192 ","pages":"Article 118606"},"PeriodicalIF":7.5,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202410","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":"Inhibition of acid sphingomyelinase increases SMN levels and connects sphingolipid metabolism to Spinal Muscular Atrophy","authors":"Ana M. Brokate-Llanos ,&nbsp;María Beltran ,&nbsp;Andrés Garzón ,&nbsp;Ana Garcera ,&nbsp;María P. Miralles ,&nbsp;Ferrán Celma-Nos ,&nbsp;Alejandro Campoy-López ,&nbsp;Rosa M. Soler ,&nbsp;Manuel J. Muñoz ,&nbsp;Antonio J. Pérez-Pulido","doi":"10.1016/j.biopha.2025.118610","DOIUrl":"10.1016/j.biopha.2025.118610","url":null,"abstract":"<div><div>Spinal Muscular Atrophy (SMA) is a moderately rare disease that causes progressive motor neuron degeneration and presents the highest neonatal death rate of all human genetic diseases. It is associated with the deletion or mutation of the <em>SMN1</em> gene, encoding the SMN protein, mainly involved in the assembly of a ribonucleoprotein complex called Sm ring, essential for the splicing of mRNA molecules. In humans, there are usually multiple copies of another gene virtually identical in sequence, <em>SMN2</em>, which produces 10 % of complete SMN protein. It is known that increased expression of <em>SMN2</em> improves the SMA phenotype. We have developed a multidisciplinary protocol, by which negative regulatory genes of <em>SMN2</em> were discovered through an <em>in silico</em> approach based on analysis of gene expression profiles obtained from public transcriptomics experiments. We then knockdown these candidate genes in a <em>Caenorhabditis elegans</em> strain where the amount of SMN can be measured by fluorescence temporally and spatially. Thus, we have found that when a homolog of human <em>SMPD1</em>, a gene involved in sphingolipid metabolism, is inhibited by RNAi or specific drugs, SMN levels increase. We have also used motor neuron cultures of SMA patients, finding that the levels of <em>SMPD1</em> mRNA and protein are increased in these cells. Furthermore, when they are treated with the <em>SMPD1</em> inhibitor clomipramine, SMN levels also increase and a significant decrease in neurite degeneration is observed. Those results propose new therapeutic avenues for this devastating disease and represent a new method of finding modifiers and drugs for human diseases.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"192 ","pages":"Article 118610"},"PeriodicalIF":7.5,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202387","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":"N-Methyl-N-((1-methyl-5-(3-(piperidin-1-yl)propoxy)-1H-benzo[d]imidazol-2-yl)methyl)prop-2-yn-1-amine (MBA-159), a new multitarget small molecule for the therapy of Alzheimer’s disease","authors":"Óscar M. Bautista-Aguilera ,&nbsp;Aleksandra Manik ,&nbsp;Daniel Diez-Iriepa ,&nbsp;Natalia Szałaj ,&nbsp;Paula Zaręba ,&nbsp;Anna Więckowska ,&nbsp;Paweł Żmudzki ,&nbsp;Ewelina Honkisz-Orzechowska ,&nbsp;Damijan Knez ,&nbsp;Stanislav Gobec ,&nbsp;Kinga Sałat ,&nbsp;Borja Martínez-Alonso ,&nbsp;Víctor Guarnizo-Herrero ,&nbsp;Guillermo Torrado Durán ,&nbsp;Carlos Torrado-Salmerón ,&nbsp;Aina Bellver-Sanchis ,&nbsp;Inaya Nsiona-Defise ,&nbsp;Marta Ribalta-Vilella ,&nbsp;Mercè Pallàs ,&nbsp;Francisco López-Muñoz ,&nbsp;Isabel Iriepa","doi":"10.1016/j.biopha.2025.118603","DOIUrl":"10.1016/j.biopha.2025.118603","url":null,"abstract":"<div><div>As part of a project aimed at the pharmacological optimization of Contilisant, herein we describe molecular modelling studies that led to the identification of <strong>MBA-159</strong> as a new polyfunctionalized, multitarget-directed ligand and a promising drug candidate for the treatment of Alzheimer’s disease. We synthesized <strong>MBA-159</strong> and conducted comprehensive <em>in vitro</em> and <em>in vivo</em> evaluations. In <em>in vivo</em> studies <strong>MBA-159</strong> demonstrated favourable pharmacokinetics, anti-amnesic properties and significantly improved non-spatial memory (contextual and recognition memory) in a mouse model of scopolamine-induced amnesia. Additionally, <strong>MBA-159</strong> showed a tendency to increase synaptic plasticity biomarkers and reduce neuroinflammatory trends (assessed by qPCR), as well as cognitive enhancement in a senescence-accelerated prone mouse 8 model.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"192 ","pages":"Article 118603"},"PeriodicalIF":7.5,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145156827","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":"Plumbagin improves pulmonary vascular remodeling in PAH via miR-21-5p/MMP/TIMP regulation, with diagnostic implications for cardiac function","authors":"Chong-Chao Hsieh ,&nbsp;Hsuan-Fu Kuo ,&nbsp;Hsiao-Hsuan Wang ,&nbsp;Mo Da-Sang Hua ,&nbsp;I-Line Chen ,&nbsp;Jia-Ling Lin ,&nbsp;Yi-Ching Lo ,&nbsp;Zi-Jing Lin ,&nbsp;Yung-Hsiang Chen ,&nbsp;Yur-Ren Kuo ,&nbsp;Chih-Hsin Hsu ,&nbsp;Po-Len Liu","doi":"10.1016/j.biopha.2025.118604","DOIUrl":"10.1016/j.biopha.2025.118604","url":null,"abstract":"<div><div>Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disorder characterized by extensive pulmonary vascular remodeling and right ventricular dysfunction. Recent investigations have identified microRNA-21–5p (miR-21–5p) as a key driver of pulmonary artery smooth muscle cells (PASMCs) phenotypic transformation and extracellular matrix (ECM) dysregulation, thereby exacerbating disease pathology. In this study, we investigated the therapeutic potential of Plumbagin (PL)<strong>,</strong> a natural naphthoquinone compound, in attenuating PAH progression via modulation of the miR-21–5p and ECM remodeling. Using a monocrotaline (MCT)-induced PAH mouse model along with cultured human PASMCs, we evaluated the effects of PL on miR-21–5p expression<strong>,</strong> bone morphogenetic protein receptor type 2 (BMPR2) levels, and ECM-related factor expression. PL treatment significantly mitigated pulmonary vascular remodeling in the animal model. Mechanistically, PL suppressed miR-21–5p levels, restored BMPR2 expression, and reversed PASMC phenotypic switching, while modulating key ECM regulators including matrix metalloproteinase (MMP)-7, MMP-19, and tissue inhibitor of metalloproteinases-3 (TIMP-3). Clinical validation using serum samples from patients with PAH revealed that elevated miR-21–5p and MMP-7 levels correlated with increased disease severity, whereas higher MMP-19 and TIMP-3 levels were inversely associated. Collectively, these findings highlight targeting the miR-21–5p and ECM dynamics as a promising therapeutic strategy for PAH management and underscore the translational potential of PL in improving patient outcomes.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"192 ","pages":"Article 118604"},"PeriodicalIF":7.5,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145156828","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":"Immune cell dynamics and their role in cardiac injury: Mechanisms and therapeutic implications","authors":"Chunlei Liu ,&nbsp;Rihan Wu ,&nbsp;Hao Yang ,&nbsp;Yongming Yao","doi":"10.1016/j.biopha.2025.118608","DOIUrl":"10.1016/j.biopha.2025.118608","url":null,"abstract":"<div><div>Cardiovascular injury initiates a temporally regulated immune cascade that governs both tissue damage and repair. Neutrophils, macrophages, dendritic cells, and T cells contribute distinct yet overlapping functions during acute inflammation, resolution, and chronic remodeling. This review synthesizes recent findings from single-cell transcriptomics, spatial omics, immunometabolism, and neuroendocrine–immune interactions to delineate immune cell dynamics across major cardiac diseases, including myocardial infarction, heart failure, viral myocarditis, hypertensive remodeling, and sepsis-induced cardiomyopathy. We further examine how immune cells communicate with cardiomyocytes, fibroblasts, endothelial cells, and neurohormonal regulators to shape the myocardial microenvironment. Particular emphasis is placed on macrophage polarization, regulatory T cell activity, extracellular vesicle–mediated signaling, and metabolic checkpoints as key determinants of immune behavior. Based on these mechanistic insights, we propose a framework for precision immunotherapy that integrates immune profiling, metabolic status, and neuroendocrine cues to guide individualized interventions. Emerging strategies—including low-dose interleukin-2, immune checkpoint blockade, mesenchymal stem cell–derived extracellular vesicles, and immunometabolic reprogramming—are highlighted as promising means to recalibrate immunity toward tissue repair. Overall, this review provides a translational perspective aimed at shifting cardiovascular therapy from non-specific immunosuppression to adaptive, stage-specific immunomodulation.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"192 ","pages":"Article 118608"},"PeriodicalIF":7.5,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145187982","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":"Developing a functional non-animal CNS stress model utilizing long-term potentiation with human iPSC-cortical neurons to evaluate therapeutics","authors":"Kaveena Autar ,&nbsp;Xiufang Guo ,&nbsp;Haley Powell ,&nbsp;Aakash Patel ,&nbsp;Mridu Malik ,&nbsp;Marcella Grillo ,&nbsp;Nesar Akanda ,&nbsp;Narasimhan S. Narasimhan ,&nbsp;Will Bogen ,&nbsp;Christopher Long ,&nbsp;Ramy M. Ammar ,&nbsp;James Hickman","doi":"10.1016/j.biopha.2025.118556","DOIUrl":"10.1016/j.biopha.2025.118556","url":null,"abstract":"<div><div>Cortisol, the main stress hormone of the hypothalamic-pituitary-adrenal (HPA) axis, has been hypothesized to cause considerable detriment to cognitive function in both a time and concentration-dependent manner. However, there is a current lack of functional <em>in vitro</em> models available to evaluate the stress condition. Long-term potentiation (LTP) has served as a quantitative correlate for memory and learning through <em>in vitro</em> neuronal network responses to electrical stimuli, where a high-frequency stimulation (HFS) protocol on microelectrode arrays (MEAs) evaluates synaptic integrity related to higher-order cognition. As a novel alternative to animal studies, this study has employed a human iPSC-cortical neuron organ-on-a-chip (HoaC) system to establish a stress phenotype for synaptic dysfunction and evaluate the effects of therapeutic compounds to ameliorate stress-induced cognitive dysfunction. In our HoaC system, cortisol exposure was found to alter cortical neuron LTP, synaptic integrity, cellular morphology, and electrophysiology, confirming a cortisol-induced stress phenotype consistent with previous findings. Using this novel system, we investigated the ability of <em>Echinacea purpurea</em> and its active ingredient, dodeca-2E,4E,8Z,10Z-tetraenoic acid N-isobutyl amide (dodeca), to mitigate stress-induced functional decline. Following exposure to chronic stress (1 µM cortisol dosing for 7 days), both <em>Echinacea purpurea</em> and dodeca were found to significantly alleviate cortisol-induced cortical neuron stress in a time-dependent rescue of LTP. Together, these results characterize a novel, biologically-relevant model of neurological stress, and highlight its utility in identifying new therapeutic compounds capable of restoring stress-induced cortical neuron network deficits.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"192 ","pages":"Article 118556"},"PeriodicalIF":7.5,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145156757","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":"Therapeutic role of resveratrol treatment on inflammation and oxidative stress-mediated renal and cardiac dysfunction in isoproterenol (ISO) administered ovariectomized female Long Evans rats","authors":"Tahmina Yasmin ,&nbsp;Mirza Alimullah ,&nbsp;Md Junaeid Rahman ,&nbsp;Shamima Sultana ,&nbsp;Shanaz Siddiqua ,&nbsp;Ishrat Jahan ,&nbsp;Sohel Rana ,&nbsp;Nusrat Subhan ,&nbsp;Ferdous Khan ,&nbsp;Md Ashraful Alam ,&nbsp;Nasrin Akhter","doi":"10.1016/j.biopha.2025.118571","DOIUrl":"10.1016/j.biopha.2025.118571","url":null,"abstract":"<div><div>This study aimed to evaluate the protective effects of resveratrol on renal and cardiac dysfunction in isoproterenol (ISO) administered ovariectomized female Long Evans rats. ISO was administered at 50 mg/kg (twice weekly) to induce infarct-like symptoms, while resveratrol was given daily at 100 mg/kg for two weeks. All animals received a standard chow diet and water <em>ad libitum</em>. The echocardiography was done on day 14 for all rats to acquire functional data. On day 15, rats were sacrificed, and plasma and tissue samples were collected for analysis. Various markers, including malondialdehyde (MDA), nitric oxide (NO), advanced oxidation protein products (AOPP), catalase, superoxide dismutase (SOD), glutathione (GSH), creatinine kinase – muscle brain (CK-MB), myeloperoxidase (MPO), creatinine, and uric acid, were assessed. This investigation revealed that ISO impaired antioxidant defenses, while resveratrol treatment helped restore redox balance and prevented cardiac and renal injury. Resveratrol treatment preserved the ejection fraction (EF%), fractional shortening (FS%), and lowered cardiac mass in ISO-administered rats. Gene expression analysis revealed that ISO downregulated key antioxidant mediators, while upregulating the pro-inflammatory genes. Resveratrol reversed these effects, suggesting reduced oxidative stress and inflammation. The histopathological analysis supported the protective role of resveratrol, showing reduced tissue damage and collagen deposition in heart and kidney tissues. Moreover, network pharmacology analysis showed potential interactions with key molecular pathways for resveratrol. In conclusion, resveratrol mitigated ISO-induced cardiac and renal damage by enhancing antioxidant defenses and suppressing inflammation, suggesting its potential clinical application in preventing or treating oxidative stress-related cardiovascular and renal disorders.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"192 ","pages":"Article 118571"},"PeriodicalIF":7.5,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145156758","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":"Nanofibers for paclitaxel delivery: A promising avenue for cancer therapy","authors":"Alireza Noori ,&nbsp;Mojdeh Salehi Namini ,&nbsp;Ehsaneh Azaryan ,&nbsp;Mahshid Ataei ,&nbsp;Nima Beheshtizadeh","doi":"10.1016/j.biopha.2025.118607","DOIUrl":"10.1016/j.biopha.2025.118607","url":null,"abstract":"<div><div>Paclitaxel (PTX), a potent anticancer agent, is hindered by its poor water solubility, systemic toxicity, and non-targeted delivery, limiting its clinical efficacy in treating various types of cancer. To overcome these challenges, researchers have developed numerous nanoformulations, including inorganic nanoparticles, polymeric nanoparticles, and liposomes, for PTX delivery. However, the potential of nanofibers as PTX carriers remains underexplored. This review aims to bridge this knowledge gap by providing a comprehensive overview of nanofiber-based systems for PTX delivery. By highlighting the unique advantages of nanofibers; such as their superior drug loading capacity, enhanced stability, and ease of manipulation and implantation; this review underscores their promise as effective carriers for PTX. We examine the materials used in nanofiber fabrication, the interactions between PTX and nanofibers that influence drug release, and the key factors governing release mechanisms. Additionally, we discuss the therapeutic efficacy of PTX-loaded nanofibers in treating various cancers, highlighting innovative strategies to enhance PTX's anticancer effects. Special attention is given to the integration of nanofibers with complementary therapies, such as radiotherapy and hyperthermia, to achieve synergistic outcomes. Finally, we outline future directions for research, including the development of multifunctional systems that eliminate residual cancer cells while promoting tissue healing post-surgery, and the scale-up of production using novel methods like electro-centrifugal spinning to enable clinical translation. This article aims to provide valuable insights into the current state of nanofiber-based PTX delivery, inspire further advancements in the field, and pave the way for their clinical application.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"192 ","pages":"Article 118607"},"PeriodicalIF":7.5,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145156759","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":"A millifluidic esophagus on-a-chip model for evaluating a natural remedy-mediated mucosal repair in GERD","authors":"Maria Elisabetta Federica Palamà ,&nbsp;Ketty Gianesin ,&nbsp;Elisa Caracciolo ,&nbsp;Maurizio Aiello ,&nbsp;Silvia Scaglione ,&nbsp;Paolo Lucchese ,&nbsp;Vincenzo Savarino","doi":"10.1016/j.biopha.2025.118609","DOIUrl":"10.1016/j.biopha.2025.118609","url":null,"abstract":"<div><div>Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder, characterized by the retrograde flow of gastric contents into the esophagus, causing symptoms such as heartburn and regurgitation. Although many patients with symptomatic GERD show no visible mucosal injury, impairment of its integrity at microscopic level is considered a relevant factor contributing to symptom generation and inflammation. In this scenario, protection of esophageal mucosa by topical agents has become a potential therapeutic approach. We investigated the protective and regenerative effects of a new natural formulation (GSE Reflusolve Rapid), using a dynamic culture based on MIVO® esophagus-on-chip platform, compared to an alginate/carbonate-based product. Results demonstrate that both products preserved esophageal integrity following acid stimulation, mitigating transepithelial electrical resistance (TEER) decline and upregulating MUC5B expression. Moreover, the natural formulation showed a significant reduction in IL-8 levels (<em>p</em> &lt; 0.05) in contrast to the alginate-based formulation, despite the lack of a buffer action. TEER measurement, FITC-dextran permeability assay and histological analysis showed also the reparative properties of both mucosal protectants after acidic insult. In particular, the natural formulation showed a more pronounced and uniform expression of MUC5B throughout the tissue. These findings highlight that GSE Reflusolve Rapid may be a valid alternative to control long-term GERD-symptoms.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"192 ","pages":"Article 118609"},"PeriodicalIF":7.5,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145156798","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":"Unlocking withaferin-A: Structural design toward next-generation antikinetoplastid agents","authors":"Eduardo Hernández-Álvarez ,&nbsp;Carlos J. Bethencourt-Estrella ,&nbsp;Meriam Ben Youssef ,&nbsp;Atteneri López-Arencibia ,&nbsp;Jacob Lorenzo-Morales ,&nbsp;Isabel L. Bazzocchi ,&nbsp;José E. Piñero ,&nbsp;Ignacio A. Jiménez","doi":"10.1016/j.biopha.2025.118591","DOIUrl":"10.1016/j.biopha.2025.118591","url":null,"abstract":"<div><div>Current therapies for Chagas disease and leishmaniasis have limited efficacy, significant toxicity, and suboptimal cure rates. In this context, natural products represent a powerful tool for the discovery and development of new agents to overcome these limitations. Here we report the synthesis, antikinetoplastid activity, and proposed mechanism of action of a unique class of withaferin A derivatives (<strong>2</strong>-<strong>19</strong>). These compounds showed a potent inhibitory effect on the proliferation of <em>Trypanosoma cruzi</em> epimastigotes (compounds <strong>5</strong>, <strong>6</strong>, <strong>12</strong>-<strong>14</strong>, <strong>16</strong> and <strong>17</strong>) and <em>Leishmania amazonensis</em> promastigotes (compounds <strong>4</strong>-<strong>6</strong>, <strong>9</strong>, <strong>12</strong>-<strong>14</strong>, <strong>16</strong> and <strong>17</strong>). Notably, compounds <strong>14</strong> and <strong>16</strong> emerged as the most promising compounds, exhibiting higher potency than the reference drug, against promastigotes and amastigotes stage of <em>L. amazonensis</em>, along with a high selectivity index on a normal eukaryotic cell line. Additionally, compounds <strong>14</strong> and <strong>16</strong> induced apoptosis-like programmed cell death on <em>L. amazonensis</em>, mediated by the disruption of ATP levels, mitochondrial membrane potential, and chromatin condensation, and energy depletion. These findings reinforce the therapeutic potential of withanolides, providing strong support for the continued development of withaferin A (WA) derivatives as potential antikinetoplastid agents.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"192 ","pages":"Article 118591"},"PeriodicalIF":7.5,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145156756","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}