Biomedicine & Pharmacotherapy最新文献

{"title":"Antimicrobial and anticancer activity of Streptomyces ambofaciens (Myt 8) and S. globisporus ONU 1019 (Myt 11) secondary metabolites isolated from the Odesa Bay, the Black Sea: An in vitro study","authors":"Kateryna Potapenko ,&nbsp;Gennadii Lisiutin ,&nbsp;Nataliia Vasylieva ,&nbsp;Iryna Strashnova ,&nbsp;Raimo Franke ,&nbsp;Nataliia Petriv ,&nbsp;Oladimeji Paul Duduyemi ,&nbsp;Kyrylo Baklan ,&nbsp;Nadiia Korotaieva ,&nbsp;Tetyana Gudzenko ,&nbsp;Michael P. Manns ,&nbsp;Mark Broenstrup ,&nbsp;Henrike Lenzen ,&nbsp;Marius Vital ,&nbsp;Volodymyr Ivanytsia ,&nbsp;Tetyana Yevsa","doi":"10.1016/j.biopha.2025.117981","DOIUrl":"10.1016/j.biopha.2025.117981","url":null,"abstract":"<div><div>We investigated the antimicrobial and anticancer capacity of secondary metabolites from six strains of marine actinobacteria belonging to the genus <em>Streptomyces</em>. Bacteria strains were isolated from the Black Sea and identified using 16S rRNA gene sequencing. Exometabolites were extracted using ethyl acetate. Antagonistic activity was investigated by agar block-diffusion method against ten strains of indicator microorganisms. The anticancer activities of the extracts were assessed on murine cholangiocarcinoma (CCA) cells while normal mouse fibroblasts CBA-310 served as a control. The extracts were tested as monotherapy or in combination with a standard chemotherapeutic drug for CCA, gemcitabine. Cell proliferation and viability were assessed using crystal violet and cell counting kit-8 assays. The induction of cellular senescence was investigated by senescence-associated β-galactosidase assay. Fluorescence-activated cell sorting analysis was used to determine cellular apoptosis and necroptosis. Liquid chromatography-mass spectrometry (LC-MS/MS) analysis was used to define the main players in the extracts. <em>Streptomyces</em> strains showed antagonistic activity against at least one indicator microorganism. Two extracts, <em>S. ambofaciens</em> (Myt 8) and <em>S. globisporus</em> ONU 1019 (Myt 11), displayed anticancer activity. Extracts Myt 8 and Myt 11 alone or in combination with low doses of gemcitabine inhibited CCA cells in a time and dose-dependent manner and induced early apoptosis and cellular senescence. LC-MS/MS analysis identified daidzein, germicidin, staurosporine alpha-curcumene, and alpha-calacorene - with potential antibacterial and anticancer effects. <em>Streptomyces</em> extracts showed antimicrobial and anticancer properties, potentially reducing chemotherapy doses for CCA. These findings suggest a dual therapeutic role against infections and CCA, warranting further <em>in vivo</em> studies.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117981"},"PeriodicalIF":6.9,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143706468","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":"Current knowledge on the mechanisms underpinning vasculogenic mimicry in triple negative breast cancer and the emerging role of nitric oxide","authors":"Belete Kassa Alemu ,&nbsp;Sara Tommasi ,&nbsp;Julie-Ann Hulin ,&nbsp;Jai Meyers ,&nbsp;Arduino A. Mangoni","doi":"10.1016/j.biopha.2025.118013","DOIUrl":"10.1016/j.biopha.2025.118013","url":null,"abstract":"<div><div>Vasculogenic mimicry (VM) is the process by which cancer cells form vascular-like channels to support their growth and dissemination. These channels lack endothelial cells and are instead lined by the tumour cells themselves. VM was first reported in uveal melanomas but has since been associated with other aggressive solid tumours, such as triple-negative breast cancer (TNBC). In TNBC patients, VM is associated with tumour aggressiveness, drug resistance, metastatic burden, and poor prognosis. The lack of effective targeted therapies for TNBC has stimulated research on the mechanisms underpinning VM in order to identify novel druggable targets. In recent years, studies have highlighted the role of nitric oxide (NO), the NO synthesis inhibitor, asymmetric dimethylarginine (ADMA), and dimethylarginine dimethylaminohydrolase 1 (DDAH1), the key enzyme responsible for ADMA metabolism, in regulating VM. Specifically, NO inhibition through downregulation of DDAH1 and consequent accumulation of ADMA appears to be a promising strategy to suppress VM in TNBC. This review discusses the current knowledge regarding the molecular pathways underpinning VM in TNBC, anti-VM therapies under investigation, and the emerging role of NO regulation in VM.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 118013"},"PeriodicalIF":6.9,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143706467","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":"EAAT3 modulation: A potential novel avenue towards remyelination in multiple sclerosis","authors":"Lieve van Veggel ,&nbsp;Melissa Schepers ,&nbsp;Assia Tiane ,&nbsp;Vijay Kumar ,&nbsp;Emily Willems ,&nbsp;Ben Rombaut ,&nbsp;Jurrie Noordijk ,&nbsp;Tim Vangansewinkel ,&nbsp;Anna Li ,&nbsp;Esther Wolfs ,&nbsp;Berra Ozcan ,&nbsp;Evelien Nouboers ,&nbsp;Pablo R. Moya ,&nbsp;David B. Sauer ,&nbsp;Hanne Diliën ,&nbsp;Niels Hellings ,&nbsp;Rudy Schreiber ,&nbsp;Tim Vanmierlo","doi":"10.1016/j.biopha.2025.117960","DOIUrl":"10.1016/j.biopha.2025.117960","url":null,"abstract":"<div><div>Modulating the excitatory amino acid transporter 3 (EAAT3) can be considered a novel approach for the treatment of multiple sclerosis (MS). EAAT3 plays a crucial role in regulating oxidative stress and oligodendrocyte function through its ability to transport cysteine, the rate-limiting building block in the synthesis of the antioxidant glutathione. Therefore, EAAT3 activation is hypothesised to improve oligodendrocyte health and relieve its differentiation block in MS, improving remyelination capacity. Using a cuprizone-induced demyelination model, the effects of EAAT3 overexpression by viral transduction of oligodendrocytes and pharmacological inhibition of EAAT3 were examined. Surprisingly, EAAT3 overexpression significantly hampered remyelination, while EAAT3 inhibition prevented demyelination and improved functional remyelination as assessed by visual evoked potentials and post mortem myelin basic protein fluorescent staining.</div><div>Next, cellular mechanisms underlying these results were investigated. Consistent with the <em>in vivo</em> findings, post mortem gene expression analysis of the corpus callosum of cuprizone treated animals revealed a trend towards upregulation of oligodendrocyte lineage genes in response to EAAT3 inhibition, supporting its role in oligodendrocyte health and myelination processes. <em>In vitro</em> studies using the human oligodendroglioma (HOG) cell line demonstrated the beneficial effects of EAAT3 inhibition on cellular morphology, indicating potential roles in promoting oligodendrocyte maturation and myelination. In contrast, EAAT3 overexpression appears to hamper these processes.</div><div>These findings suggest that, contrary to our initial hypothesis, EAAT3 inhibition could improve oligodendrocyte function and myelination processes, highlighting its potential as a therapeutic target for demyelinating disorders. Future studies should address the exact molecular mechanism through which this effect is obtained.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117960"},"PeriodicalIF":6.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143704383","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":"Chemical constituents from the Korean endemic plant Pseudolysimachion pusanensis inhibit diffuse-type gastric cancer cells","authors":"Su-Yeon Cho ,&nbsp;Hoseong Hwang ,&nbsp;Hyeon-Seong Lee ,&nbsp;Yujin Kwon ,&nbsp;Ngoc Khanh Vu ,&nbsp;Jong Gwon Baek ,&nbsp;Mukyeong Jeon ,&nbsp;Joonbeom Bae ,&nbsp;Hak Cheol Kwon ,&nbsp;Won Kyu Kim ,&nbsp;Jaeyoung Kwon","doi":"10.1016/j.biopha.2025.118005","DOIUrl":"10.1016/j.biopha.2025.118005","url":null,"abstract":"<div><div>Diffuse-type gastric cancer (GC) is closely associated with genetic abnormalities; however, its exact pathological mechanisms are still not understood. It manifests without symptoms before advanced stages and is often difficult to diagnose using routine imaging tests. Therefore, specific targeted therapies for diffuse GC are currently unavailable. In this study, the extract of <em>Pseudolysimachion pusanensis</em>, which is endemic to Korea, inhibited the proliferation of GC cells, MKN1 and SNU668, while the other extracts of the two endemic <em>Pseudolysimachion</em> species did not show any activity. This led to the molecular networking analysis of <em>Pseudolysimachion</em> species to identify the molecules mostly observed only in <em>P. pusanensis</em>. Thirteen new (<strong>1</strong>–<strong>13</strong>) and eight known (<strong>14</strong>–<strong>21</strong>) compounds were obtained and structurally characterized. Of these, cucurbitacin derivative compounds <strong>1</strong> and <strong>14</strong>–<strong>16</strong> showed activity, and particularly, the IC₅₀ value of compound <strong>1</strong> was 0.65 and 0.21 μM. Ki-67 expression analysis, single-cell originated cell proliferation assay, and western blot analysis of apoptotic cell death-related molecules revealed that compound <strong>1</strong> mediated both cytostasis and cellular death via apoptosis. Particularly, this compound exhibited an anti-tumorigenic effect on the invasion of diffuse-type GC cells by perturbing the epithelial-to-mesenchymal transition (EMT) pathway, as demonstrated by invasion assays using both 2D models and in vivo-like 3D spheroid co-culture models, as well as western blot analysis of EMT markers. In addition, some functional groups that may or may not be necessary for the activity of cucurbitacin derivatives were identified, and some clues that the presence of metal ions may affect the activity were provided.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 118005"},"PeriodicalIF":6.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143686052","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":"Excess heme orchestrates progesterone resistance in uterine endometrial cancer through macrophage polarization and the IL-33/PAX8/PGR axis","authors":"Jia-Jing Lu ,&nbsp;Yan Ning ,&nbsp;Wen-Ting Hu ,&nbsp;Yan-Ran Sheng ,&nbsp;Yu-Kai Liu ,&nbsp;Feng Xie ,&nbsp;Ming-Qing Li ,&nbsp;Xiao-Yong Zhu","doi":"10.1016/j.biopha.2025.118008","DOIUrl":"10.1016/j.biopha.2025.118008","url":null,"abstract":"<div><div>Progesterone is an important drug for hormone therapy in uterine endometrial cancer (UEC). However, the therapeutic efficacy of progestogen is often limited by resistance, and the underlying mechanism remains unknown. In this study, we observed heme metabolism is more active in progesterone-insensitive patients. Heme induced macrophages (Mφs) bias towards M2-like phenotype and downregulated the expression of IL-33, resulting in increased levels of Paired box gene 8 (PAX8). Further study showed PAX8 inhibited the transcriptional activity of PGR by binding to the PGR promoter region. In addition, PGR can also act as a transcriptional factor to regulate the transcription of autophagy-related gene 7 (ATG). Low expression of PGR decreases the transcriptional activity of ATG7 promoter, which decreases cell autophagy and promotes the progression of UEC. Overall, this study reveals the important interaction between heme metabolism, IL-33 and PGR in progesterone-insensitive UEC, and is promising to provide new therapeutic targets for overcoming progesterone resistance.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 118008"},"PeriodicalIF":6.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143704382","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":"Biological solutions activated by cold plasma at atmospheric pressure: A new therapeutic approach for skin wound healing","authors":"Solène Roux ,&nbsp;Aurélie Marchès ,&nbsp;Stéphane Galiacy ,&nbsp;Nofel Merbahi ,&nbsp;Michel Simon","doi":"10.1016/j.biopha.2025.118001","DOIUrl":"10.1016/j.biopha.2025.118001","url":null,"abstract":"<div><div>Chronic wounds are a major public health problem, and nearly 35 % of them do not heal with conventional treatments. The direct application of cold plasmas at atmospheric pressure, partially ionized gases, is an emerging technology with a range of potential biomedical applications, including the improvement of wound healing. A new method that is easier to implement has been developed: the use of biological solutions exposed to cold plasmas at atmospheric pressure, known as plasma-activated media (PAM). Numerous preclinical studies and in vitro models indicate that PAM treatments facilitate wound healing by promoting the migration of cell types such as keratinocytes, fibroblasts and mesenchymal stem/stromal cells, stimulating angiogenesis, and inhibiting bacterial proliferation, all of which are critical to this vital process. PAM treatments modulate the inflammatory response, induce the expression of growth factors and matrix metalloproteinases, reduce cellular adhesion, promote cytoskeletal modifications and activate several biochemical pathways involved in the wound healing process, possibly through the action of plasma-generated reactive oxygen and nitrogen species. Some studies have shown that PAM may have applications in the treatment of other skin conditions either by reducing the production of pro-inflammatory cytokines or by inducing apoptosis of tumor cells. PAM treatments therefore represent a promising new therapy for the management of dermatological conditions, particularly for chronic skin and mucosal wounds.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 118001"},"PeriodicalIF":6.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143696661","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":"Rosuvastatin restores liver tissue-resident NK cell activation in aged mice by improving mitochondrial function","authors":"Johnny Amer ,&nbsp;Ahmad Salhab ,&nbsp;Rifaat Safadi","doi":"10.1016/j.biopha.2025.118000","DOIUrl":"10.1016/j.biopha.2025.118000","url":null,"abstract":"<div><h3>Background and aim</h3><div>Aging has an impact on Natural Killer (NK) cells surveillance against tumors and infections. Our study aims to assess the aging effects on metabolic and mitochondrial markers influencing NK cell activity.</div></div><div><h3>Methods</h3><div>C57BL/6 J mice aged 12, 24, 48, and 72 weeks were used. Liver injury serum and histological markers, pro-inflammatory cytokines [IL-1β, IL-2, IL-6] and chemoattractant markers [CCL2, CXCL8] were assessed. Moreover, cholesterol metabolic markers [HMG-CoA synthetase, HMG-CoA reductase, mevalonate kinase], mitochondrial biogenesis [PGC1α] and functional gene markers [TFAM, HSPA9, Seahorse, apoptosis] in liver trNK cells, were assessed by RT-PCR. Senescence [p16, p21], exhaustion [PD-1, TIGIT, LAG3], activation [CD107a, NKp46], and chemokine receptor [CCR2, CXCR1] markers were assessed in trNK cells using flow cytometry. Liver trNK cells of aged mice were treated with Rosuvastatin [10μM] for 12 h.</div></div><div><h3>Results</h3><div>Data showed a linear increase in liver injury markers, pro-inflammatory and chemotaxis along aging. These results were associated with reductions in liver trNK cell counts and activations with a noticeable decrease in their chemoattractant receptor expressions. TrNK cells of aged mice exhibited elevated markers of senescence and exhaustion with a gradual increase in cholesterol accumulation. Mitochondrial biogenesis and functional gene markers showed a decrease in their expressions in aged mice while ameliorated following rosuvastatin treatment. Results were correlated with a decrease in cholesterol metabolism and restoring their NK cell activity.</div></div><div><h3>Conclusion</h3><div>Our study demonstrates age-related cholesterol accumulation in trNK cells correlated with senescence and functional impairment. Rosuvastatin is suggested to boost, rejuvenate and recover NK cell functionality.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 118000"},"PeriodicalIF":6.9,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143686131","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":"The inhibitory effects of proteins secreted from trigonelline-treated renal cells on calcium oxalate crystals in vitro: Implications for kidney stone prevention","authors":"Sunisa Yoodee,&nbsp;Paleerath Peerapen,&nbsp;Wanida Boonmark,&nbsp;Visith Thongboonkerd","doi":"10.1016/j.biopha.2025.118003","DOIUrl":"10.1016/j.biopha.2025.118003","url":null,"abstract":"<div><div>Trigonelline is a bioactive alkaloid with therapeutic effects on various kidney diseases. Although previous studies have implicated its potential to prevent kidney stone disease (KSD), its anti-lithiatic mechanisms were poorly understood and thus addressed herein. Secretome (a set of secreted proteins) was collected and purified from MDCK renal cells treated with 100 µM trigonelline (termed “trigonelline-treated secretome”) to examine its effects on calcium oxalate (CaOx) crystals compared with that derived from untreated cells (termed “control secretome”). Trigonelline-treated secretome significantly reduced CaOx crystal size, number and abundance during initial crystallization, and also inhibited crystal growth, aggregation and adhesion to renal cells. Quantitative proteomics using nanoLC-ESI-Qq-TOF tandem mass spectrometry revealed 46 differentially secreted (11 decreased and 35 increased) proteins, mainly from extracellular compartments, in the trigonelline-treated secretome. While most of the identified proteins were acidic, significantly increased secreted proteins had an increased proportion of basic proteins, resulting in a slightly greater isoelectric point. In concordance, significantly increased secreted proteins had a greater proportion of positively charged amino acids as compared with significantly decreased secreted proteins. However, proportions of aromatic, polar, non-polar, and negatively charged amino acids were comparable. In summary, we report herein direct evidence of the inhibitory effects of trigonelline against CaOx crystallization, growth, aggregation and adhesion to renal cells via the altered secreted proteins that show some unique physicochemical properties when the increased secreted proteins were compared with the decreased compartments. These data may lead to a better understanding of mechanisms underlying the anti-lithiatic effects of trigonelline to prevent KSD.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 118003"},"PeriodicalIF":6.9,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143686130","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":"Rescue of respiratory and cognitive impairments in Rett Syndrome mice using NLX-101, a selective 5-HT1A receptor biased agonist","authors":"Daniela Monteiro-Fernandes ,&nbsp;Ian Charles ,&nbsp;Sara Guerreiro ,&nbsp;Daniela Cunha-Garcia ,&nbsp;Joana Pereira-Sousa ,&nbsp;Stéphanie Oliveira ,&nbsp;Andreia Teixeira-Castro ,&nbsp;Mark A. Varney ,&nbsp;Mark S. Kleven ,&nbsp;Adrian Newman-Tancredi ,&nbsp;Ana P. Sheikh Abdala ,&nbsp;Sara Duarte-Silva ,&nbsp;Patrícia Maciel","doi":"10.1016/j.biopha.2025.117989","DOIUrl":"10.1016/j.biopha.2025.117989","url":null,"abstract":"<div><div>Rett Syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked gene encoding the <em>methyl-CpG-binding protein 2 (MECP2)</em>. Impaired function of this transcriptional regulator leads to profound neurological defects, among which respiratory distress, motor function and cognitive disorders are prominent. Despite great advances in understanding RTT neurobiology, therapies that can meaningfully improve patients’ symptoms are still needed. Here, we focused on 5-HT_1A receptor-mediated serotonergic signaling as a potential therapeutical route for RTT. We report the effects of a drug candidate, NLX-101, a highly selective, biased agonist of 5-HT_1A post-synaptic receptors at brainstem and cortical regions, on key phenotypes of RTT. Unrestrained whole-body plethysmography studies confirmed and extended the previous observation that single i.p. administration of NLX-101 dose-dependently reduced the occurrence and length of apneic events in Mecp2^tm1.1Bird heterozygous female mice and largely corrected respiratory irregularity. Although no preservation of motor function was observed, early onset chronic administration of NLX-101 entirely prevented the cognitive deficits of the Mecp2^tm1.1Bird mice both in the short and the long-term memory paradigms of the Novel Object Recognition upon 10 weeks of treatment, an effect that was maintained throughout animals’ age. Similar effects were observed in the Fear Conditioning paradigm, with treated Rett mice performing as well as wild-type controls, highlighting the procognitive properties of NLX-101. This work provides compelling evidence of the therapeutic potential of targeting post-synaptic 5-HT_1A receptors to improve cognitive function in patients with RTT while supporting its respiratory-rescue properties.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117989"},"PeriodicalIF":6.9,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143686124","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":"S-hydroxychloroquine prevents the antiphospholipid thrombogenic complexes for antiphospholipid syndrome treatment","authors":"Ming-Shou Hsieh ,&nbsp;Heng-Wei Liu ,&nbsp;Fu-You Guo ,&nbsp;Deng-Pan Song ,&nbsp;Meng-Yuan Li ,&nbsp;Tsu-Yi Chao ,&nbsp;Iat-Hang Fong ,&nbsp;Yu-Sheng Chang ,&nbsp;Chi-Tai Yeh","doi":"10.1016/j.biopha.2025.117968","DOIUrl":"10.1016/j.biopha.2025.117968","url":null,"abstract":"<div><div>Clinically used in systemic lupus erythematosus (SLE), Hydroxychloroquine (HCQ) exerts antithrombotic effects by inhibiting anti-β2-glycoprotein I (anti-β2GPI) antibody binding to phospholipid bilayers. However, HCQ is a racemic mixture, with only one enantiomer offering therapeutic benefits, while the other may contribute to toxicity. The current study evaluated the thromboprophylactic efficacy of <em>R</em>-enantiomer Hydroxychloroquine (<em>R</em>-HCQ), <em>S</em>-enantiomer Hydroxychloroquine (<em>S</em>-HCQ), and racemic HCQ (Rac-HCQ), with a focus on their impact on APS-associated markers. Both <em>in vitro</em> and <em>in vivo</em> models were employed, with human umbilical vein endothelial cells (HUVECs) and mice immunized with human β2-glycoprotein I antibodies used to evaluate the formation of antiphospholipid thrombotic complexes and their modulation by HCQ enantiomers. <em>S</em>-HCQ significantly reduced β2GPI complex binding and restored the AnxA5 anticoagulant shield <em>in vitro</em>, demonstrating superior efficacy over <em>R</em>-HCQ in disrupting β2GPI/anti-β2GPI interactions and preventing endothelial dysfunction in APS models. Pretreatment of HUVECs with S-HCQ significantly attenuated the expression of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-6, interleukin-1 beta, and C-C motif ligand 2) and endothelial activation markers (intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin). <em>S</em>-HCQ alleviates endothelial dysfunction by reducing proinflammatory cytokines, endothelial activation markers, and NO production while downregulating iNOS expression, highlighting its potential to mitigate oxidative stress and thrombogenic activity in APS-related endothelial damage. <em>In vivo</em>, <em>S</em>-HCQ effectively reduced clot formation in the femoral veins of APS mouse models. Among the HCQ enantiomers tested, <em>S</em>-HCQ demonstrated superior efficacy in modulating inflammatory and angiogenic pathways, influencing the formation of antiphospholipid thrombotic complexes and mitigating thrombosis. These findings underscore the potential of <em>S</em>-HCQ as a therapeutic alternative for APS management.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117968"},"PeriodicalIF":6.9,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143685088","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}