Biomedicine & Pharmacotherapy最新文献

{"title":"Illuminating the dark: PEGylated carboxylated graphene quantum dots and curcumin in nucleolar activity and PDT-induced DNA damage in cancer","authors":"Hanna Dilenko ,&nbsp;Kateřina Bartoň Tománková ,&nbsp;Elizabeth Hinde ,&nbsp;Lucie Válková ,&nbsp;Markéta Kolaříková ,&nbsp;Hana Kolářová","doi":"10.1016/j.biopha.2025.118096","DOIUrl":"10.1016/j.biopha.2025.118096","url":null,"abstract":"<div><div>Many photosensitive substances suitable for photodynamic therapy (PDT) have limited applications due to their insufficient solubility in polar solvents. Our research overcomes this challenge by means of nanotechnology in order to transform hydrophobic compounds into stable aqueous solutions, enabling them to use their full potential and unique properties in cancer therapy. In this study, the novel nano-composite cGQDs-PEG-curcumin was developed to overcome the insolubility of curcumin in water and its extraordinary efficacy in PDT was evaluated. Complex characterization was performed using high-resolution transmission electron microscopy (HR-TEM), FTIR, and UV-Vis spectroscopy. Further analysis involved fluorescence lifetime imaging (FLIM), and its cellular localization was mapped with confocal microscopy. In order to evaluate PDT effectiveness, cells treated with cGQDs-PEG-curcumin were irradiated with 5 J/cm² of 414 nm light. After irradiation, cell viability assay, scanning electron microscopy (SEM), reactive oxygen species (ROS) detection, comet assay, and γH2AX-based DNA double-strand breaks (DSBs) detection were assessed and revealed a remarkable ability of the nano-composite to induce DNA damage after irradiation without ROS production. Our findings highlight the potential of cGQDs-PEG-curcumin as a cutting-edge PDT agent, capable of disrupting cell membrane and nucleolar integrity and impairing ribosomal synthesis, which is crucial for proliferating tumour cells.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"187 ","pages":"Article 118096"},"PeriodicalIF":6.9,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143883039","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":"Drug repositioning: Identification of potent inhibitors of NS3 protease and NS5 RdRp for control of DENV infection","authors":"Md Haroon Or Rashid ,&nbsp;Sayeh Ezzikouri ,&nbsp;Ahmed M. Soliman ,&nbsp;Lipi Akter ,&nbsp;Kenki Momohara ,&nbsp;Tatsuro Hifumi ,&nbsp;Noriaki Miyoshi ,&nbsp;Takayuki Hishiki ,&nbsp;Ahmed S. Abdel-Moneim ,&nbsp;Michinori Kohara ,&nbsp;Kyoko Tsukiyama-Kohara","doi":"10.1016/j.biopha.2025.118104","DOIUrl":"10.1016/j.biopha.2025.118104","url":null,"abstract":"<div><div>Dengue virus (DENV) threatens global health; specific antiviral drugs are required to combat it. Such anti-DENV therapeutics can be rapidly developed by repositioning the drugs approved for other indications. This study investigated six medications of different classes drawn from a library of molecules. <em>In silico</em> analyses were performed to determine potential binding affinity for the DENV non-structural protein NS3 protease and NS5 RNA-dependent RNA polymerase (RdRp). Of the six candidates, galidesivir and tadalafil showed the highest binding affinities for the DENV NS3 protease and NS5 RdRp, with tadalafil demonstrating the highest binding affinity. Galidesivir and tadalafil substantially suppressed viral replication in DENV replicon cells without inducing cytotoxicity and showed half-maximal inhibitory concentrations of 10 μM and 2.56 μM, respectively. Both galidesivir and tadalafil effectively suppress DENV infection in human hepatoma and baby hamster kidney cells, and tadalafil demonstrates protease-inhibitory activity. In an AG129 mouse model of DENV infection, both galidesivir and tadalafil reduced viral loads in the serum, with tadalafil producing a notable reduction by day four. Both drugs markedly suppressed DENV replication in the hepatic tissue. Histopathologically, both galidesivir- and tadalafil-treated mice showed alleviation of DENV-induced lesions in the spleen and liver, indicating the potential therapeutic effects of these drugs. These findings highlight the potential of repositioning galidesivir and tadalafil as effective anti-DENV therapies with low cytotoxicity, meeting the urgent global need for new therapeutic agents against this pathogen.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"187 ","pages":"Article 118104"},"PeriodicalIF":6.9,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143883038","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 novel noninvasive test based on near-infrared fluorescent cholephilic probes for hepatobiliary secretory function assessment","authors":"Beatriz Sanchez de Blas ,&nbsp;Alvaro G. Temprano ,&nbsp;Candela Cives-Losada ,&nbsp;Oscar Briz ,&nbsp;Elisa Lozano ,&nbsp;Maria L. Martinez-Chantar ,&nbsp;Matias A. Avila ,&nbsp;Mattia Mori ,&nbsp;Ahmed Ghallab ,&nbsp;Jan G. Hengstler ,&nbsp;Concepción Perez-Melero ,&nbsp;Francisco A. Bermejo-Gonzalez ,&nbsp;Maria J. Monte ,&nbsp;Marta R. Romero ,&nbsp;Jose J.G. Marin","doi":"10.1016/j.biopha.2025.118074","DOIUrl":"10.1016/j.biopha.2025.118074","url":null,"abstract":"<div><div>Routine serum biomarkers do not always accurately reflect impaired liver function. To overcome this limitation, we synthesized novel bile acid (BA) derivatives (NIRBADs) with near-infrared (NIR) fluorescence that can penetrate the abdominal wall and be detected extracorporeally. NIRBAD dynamics in the liver parenchyma were recorded through intravital imaging in mice and extracorporeally in both rats and mice. NIRBAD metabolism was analyzed using HPLC-MS/MS and fluorimetry. Transport was investigated in cells expressing BA transporters, whose interactions with NIRBADs were assessed through molecular docking and dynamics simulations. The hepatic NIRBAD clearance time (NCT) was evaluated in animal models with impaired secretory function: rats with hepatocellular cholestatic damage induced by phalloidin and mice with obstructive cholestasis caused by bile duct ligation (BDL), as well as with spontaneous development of sclerosing cholangitis (<em>Mdr2</em>^<em>-/-</em>). NIRBADs were taken up by cells expressing NTCP or OATP1B3, but minimally by OATP1B1. These findings were consistent with the NIRBAD dynamics in the liver parenchyma and <em>in silico</em> studies. Following intravenous administration of a non-toxic dose, the time course of NIR fluorescence in the rat liver aligned with biliary output. In mice with BDL, hepatic NIR fluorescence remained stable throughout the experimental period. Phalloidin administration impaired rat bile flow, induced a decrease in biliary NIRBAD-1 output, and caused an increase in NCT. Furthermore, the NCT was significantly longer in <em>Mdr2</em>^<em>-/</em>^<em>-</em> than in wild-type mice. In conclusion, a novel, noninvasive, real-time test based on cholephilic probes with NIR fluorescence detectable extracorporeally serves as a valuable tool for assessing hepatobiliary secretory function.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"187 ","pages":"Article 118074"},"PeriodicalIF":6.9,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879240","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":"O6-methylguanine-DNA methyltransferase inhibition leads to cellular senescence and vascular smooth muscle dysfunction","authors":"Jakub Krivy ,&nbsp;Svetozar Misuth ,&nbsp;Marina Puchovska,&nbsp;Sona Sykorova,&nbsp;Diana Vavrincova-Yaghi,&nbsp;Peter Vavrinec","doi":"10.1016/j.biopha.2025.118103","DOIUrl":"10.1016/j.biopha.2025.118103","url":null,"abstract":"<div><div>Inhibiting O6-methylguanine-DNA methyltransferase (MGMT) is crucial for overcoming chemoresistance to alkylating agents, though its use is limited by myelosuppression. Beyond bone marrow, other adverse effects were not studied. Given chemotherapy-induced senescence in healthy tissues, e.g., cardiovascular damage, we investigated the impact of the MGMT inhibitor O6-benzylguanine (BG) on aortic vascular smooth muscle cells (VSMCs) and aorta. Starting on day 3 of BG incubation, VSMCs exhibited altered morphology, reduced growth, increased SAβGal activity and elevated senescence markers p27 or γH2A.X. BG activated senescence-related pathways, including Erk1/2, p38α, Akt and mTORC1; induced BCl2, MnSOD and CDK1; and decreased αSMA and skp2 levels. These changes suggest BG-induced γH2A.X, p38 and Akt activation, resulting in G2/M cell cycle arrest via pCDK1. Functionally, BG impaired the vascular reactivity of aortic rings to phenylephrine, isoprenaline and sodium nitrite. In rats, systemic BG administration similarly reduced the response to sodium nitrite but left phenylephrine and isoprenaline responses unchanged. Our findings highlight BG’s potential adverse effects on vascular smooth muscle, marked by senescence activation and reduced vascular reactivity. These results emphasise the need for caution in the clinical use of MGMT inhibitors. Furthermore, we present the model of senescence in primary VSMCs characterised by the expression of several senescence markers and G2/M checkpoint arrest.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"187 ","pages":"Article 118103"},"PeriodicalIF":6.9,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879323","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":"Lipidomics reveals different therapeutic potential for natural and synthetic vitamin D formulations in hepatocyte lipotoxicity","authors":"Anna Migni ,&nbsp;Desirée Bartolini ,&nbsp;Ina Varfaj ,&nbsp;Isabelle Franco Moscardini ,&nbsp;Roccaldo Sardella ,&nbsp;Stefano Garetto ,&nbsp;Jacopo Lucci ,&nbsp;Francesco Galli","doi":"10.1016/j.biopha.2025.118068","DOIUrl":"10.1016/j.biopha.2025.118068","url":null,"abstract":"<div><div>Natural sources of vitamin D (VD), have been proposed to represent an alternative to synthetic vitamin D in nutritional interventions, also holding therapeutic potential in non-alcoholic fatty liver disease (NAFLD). In this study lipidomics was used to comparatively investigate the molecular mechanisms behind the therapeutic effects of a natural VD formulation consisting of a Shitake mushroom extracts (NVD) and a synthetic cholecalciferol formulation (SVD) in HepaRG human hepatocytes exposed to free fatty acid (FFA)-induced lipotoxicity. The results demonstrate that the two VD formulations prevent lipotoxicity with similar efficacy, but different lipidomic fingerprints. Differentially expressed lipids in NVD’ in vitro therapeutic effect indicated a reduced synthesis of cellular triglycerides; combined with a marked reshaping of glycerophospholipid metabolism and characteristic changes of the chain length and number of double bonds in the phosphatidylcholine pool that were absent in SVD treatment. Bioinformatics interpretation of lipidomics data associated NVD therapeutic properties to an enhanced insulin function and glycerophospholipid metabolism, whereas SVD was primarily associated with the inflammatory signaling and death pathways of the liver cell. These differences between the two VD formulations were further highlighted matching lipidomics data with gene microarray (transcriptomics) data available from previous studies on this experimental model; the resulting multiomics data identified lipid metabolism nodes specific for the multimolecular mechanisms of the two formulations which may deserve further pre-clinical investigation in the treatment of hepatocyte lipotoxicity.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"187 ","pages":"Article 118068"},"PeriodicalIF":6.9,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879325","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":"Enhanced tumor suppressive effect of a new HDAC inhibitor in bladder cancer in vitro and in vivo","authors":"Cheng-Huang Shen ,&nbsp;Jin-Yi Wu ,&nbsp;Shou-Chieh Wang ,&nbsp;Hsin-Ting Liu ,&nbsp;Pei-Xuan Wu ,&nbsp;Kun-Wei Chan ,&nbsp;Say-Wei Huang ,&nbsp;Ming-Yang Lee ,&nbsp;Yi-Wen Liu","doi":"10.1016/j.biopha.2025.118108","DOIUrl":"10.1016/j.biopha.2025.118108","url":null,"abstract":"<div><div>Bladder cancer has a high recurrence rate, which indicates that the therapeutic effects of advanced bladder cancers are still limited. In this study, we combined vorinostat and cyproheptadine as a new treatment for bladder cancer. When combining the two drugs, an additive to synergistic effect is discovered. Furthermore, we modified the structure of vorinostat using cyproheptadine tricyclic ring to get compounds 8 C and O8C, which keep HDAC inhibitory activity and have IC₅₀ lower than 10 μM in 5637, BFTC 905, and MB49 cells. In <em>in vitro</em> assay, vorinostat, 8 C and O8C increased the percentage of cell cycle in G2/M in 5637, while G0/G1 arrest in BFTC 905. Apoptosis was seen in 5637 and slightly in BFTC 905 by the Annexin V-PI staining assay, and a minor rescued cell viability after Z-VAD-FMK pretreatment in 5637. 8 C and O8C slightly decreased MMP, and increased ROS levels. Among different ROS scavenger treatments, only <em>N</em>-acetyl-L-cysteine shows a minor viability rescue, indicating ROS may not take an important role in 8C- and O8C-induced cell death. In the <em>in vivo</em> assay, mice underwent intraperitoneal injection of 8 C, delaying tumor growth compared to cyproheptadine, vorinostat, and O8C individually. Because the water solubility of 8 C is not good, we use its salt form 8C-HCl for further <em>in vivo</em> study. Mice underwent gavage of 8C-HCl, which resulted in delaying tumor growth. In conclusion, 8 C and 8C-HCl, from structure modification of vorinostat by cyproheptadine tricyclic ring, enhance tumor suppressive effect <em>in vitro</em> and <em>in vivo</em>.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"187 ","pages":"Article 118108"},"PeriodicalIF":6.9,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879239","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":"Nitric oxide synthases: A delicate dance between bone regeneration and neuronal birth","authors":"Niloofar Alahdad ,&nbsp;Shayesteh Kokabi Hamidpour ,&nbsp;Mohammad Ali Yazdanpanah ,&nbsp;Mobina Amiri ,&nbsp;Rafieh Alizadeh ,&nbsp;Seyed Mahdi Rezayat ,&nbsp;Shima Tavakol","doi":"10.1016/j.biopha.2025.118105","DOIUrl":"10.1016/j.biopha.2025.118105","url":null,"abstract":"<div><div>Spinal cord injury (SCI) is a devastating condition resulting from traumatic or nontraumatic injury/chronic disorder. The pathogenesis of SCI necessitates a comprehensive approach, as it involves therapeutic strategies addressing both bone (spine) and neural (spinal cord) damage. This review centers on the pivotal role of nitric oxide (NO) and its synthesizing enzymes, nitric oxide synthases (NOS), in mediating the crosstalk between osteogenesis and neurogenesis. NO's effects are context-dependent, exhibiting a delicate balance between beneficial and detrimental actions. Reduced levels of nitric oxide (NO), primarily derived from endothelial NOS (eNOS), tipically stimulate osteoblast activity and promote neurogenesis by influencing neural stem cell (NSC) migration and differentiation. Conversely, elevated NO levels, predominantly from inducible NOS (iNOS), tipically triggered by inflammation, inhibit both processes through pro-apoptotic mechanisms. Nevertheless, these phenomena are not merely simplistic; they can be influenced by a variety of other factors. We explore the intricate interplay of NO/NOS with key signaling pathways crucial in neurogenesis and osteogenesis, including mechanical stimuli, Wnt, interleukins, BMPs, NF-κB, etc., revealing their influence on neuroinflammation, neurogenesis, and osteoblast differentiation. The temporal and spatial dynamics of NO/NOS activity and the implications for therapeutic intervention have been discussed. Precise modulation of NO levels and NOS isoforms, potentially through targeted therapies manipulating these interacting signaling pathways, emerges as a promising strategy for promoting bone and neural regeneration. This review highlights the critical need for a balanced approach in therapeutic strategies to harness the beneficial effects of NO/NOS while mitigating its detrimental consequences.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"187 ","pages":"Article 118105"},"PeriodicalIF":6.9,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143877414","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":"Contemporary insights into elamipretide’s mitochondrial mechanism of action and therapeutic effects","authors":"Hani N. Sabbah ,&nbsp;Nathan N. Alder ,&nbsp;Genevieve C. Sparagna ,&nbsp;James E. Bruce ,&nbsp;Brian L. Stauffer ,&nbsp;Luke H. Chao ,&nbsp;Robert D.S. Pitceathly ,&nbsp;Christoph Maack ,&nbsp;David J. Marcinek","doi":"10.1016/j.biopha.2025.118056","DOIUrl":"10.1016/j.biopha.2025.118056","url":null,"abstract":"<div><div>Mitochondria are cellular hubs integral for metabolism, signaling, and survival. Mitochondrial dysfunction is centrally involved in the aging process and an expansive array of disease states. Elamipretide is a novel mitochondria-targeting peptide that is under investigation for treating several disorders related to mitochondrial dysfunction. This review summarizes recent data that expand our understanding of the mechanism of action (MOA) of elamipretide. Elamipretide is a potential first-in-class therapeutic that targets the inner mitochondrial membrane. Despite initial descriptions of elamipretide’s MOA involving reactive oxygen species scavenging, the last ten years have provided a significant expansion of how this peptide influences mitochondrial bioenergetics. The cardiolipin binding properties of elamipretide have been corroborated by different investigative teams with new findings about the consequences of elamipretide-cardiolipin interactions. In particular, new studies have shown elamipretide-mediated modulation of mitochondrial membrane electrostatic potentials and assembly of cardiolipin-dependent proteins that are centrally involved in mitochondrial physiology. These effects contribute to elamipretide’s ability to improve mitochondrial function, structure, and bioenergetics. In animal studies, elamipretide-mediated amelioration of organ dysfunction has been observed in models of cardiac and skeletal muscle myopathies as well as ocular pathologies. A number of clinical trials with elamipretide have been recently completed, and a summary of the results focusing on Barth syndrome, primary mitochondrial myopathy, and age-related macular degeneration, is also provided herein. Elamipretide continues to show promise as a potential therapy for mitochondrial disorders. New basic science advances have improved understanding of elamipretide’s MOA, enabling a better understanding of the molecular consequences of elamipretide-cardiolipin interactions.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"187 ","pages":"Article 118056"},"PeriodicalIF":6.9,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143877413","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":"Naphthalimide derivative attenuates tumor growth of wild-type p53–expressing U87 glioma cells in vitro and in vivo through a biphasic dose-dependent mechanism: A switch from cell cycle to apoptosis","authors":"Kuan-Hung Lin ,&nbsp;Jiun-Yi Li ,&nbsp;Ray-Jade Chen ,&nbsp;Yun-Ju Wang ,&nbsp;Hsueh-Hsiao Wang ,&nbsp;Hsien-Yu Peng ,&nbsp;Wan-Jung Lu","doi":"10.1016/j.biopha.2025.118097","DOIUrl":"10.1016/j.biopha.2025.118097","url":null,"abstract":"<div><div>Glioblastoma multiforme (GBM) is among the most lethal and recurrent malignant solid tumors. Compound <strong>5</strong> is a naphthalimide derivative that has rarely been investigated for glioma treatment. Therefore, we aimed to determine whether compound <strong>5</strong> exhibits anti-glioma activity. The results revealed that compound <strong>5</strong> reduced the cell viability of U87 glioma cells in a concentration-dependent manner. At lower concentrations, compound <strong>5</strong> arrested the G0/G1 phase through p21 upregulation, and at higher concentrations, it arrested the G2/M phase and induced marked apoptosis through p21 downregulation and p53 upregulation and stabilization. Additionally, compound <strong>5</strong> reduced CDK2 expression at lower concentrations but not at higher concentrations, suggesting that CDK2 plays a key role in the entry into the S phase in U87 glioma cells. At higher concentrations, compound <strong>5</strong> also accumulated cyclin B1 and CDK1, which may contribute to mitotic arrest and subsequent apoptosis. Moreover, compound <strong>5</strong> reduced the levels of antiapoptotic Bcl-w and Mcl-1 proteins, as well as those of inhibitors of apoptosis XIAP and survivin, enhancing compound <strong>5</strong>–medicated apoptosis. In an in vivo study, compound <strong>5</strong> reduced tumor growth in a mouse xenograft tumor model. This study is the first to demonstrate that compound <strong>5</strong> inhibits the growth of U87 glioma cells in vitro and in vivo through a biphasic dose–dependent switch from cell cycle arrest to apoptosis in a p21 level–dependent manner. These findings suggest that naphthalimide-based compounds can serve as lead compounds for designing new and more potent anti-glioma drugs.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"187 ","pages":"Article 118097"},"PeriodicalIF":6.9,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143877418","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":"Exacerbated cardiac dysfunction from combined alcohol binge and synthetic cannabinoid use","authors":"Janos Paloczi ,&nbsp;Ozge Gunduz-Cinar ,&nbsp;Burhan Yokus ,&nbsp;Bruno Paes-Leme ,&nbsp;György Haskó ,&nbsp;George Kunos ,&nbsp;Andrew Holmes ,&nbsp;Pal Pacher","doi":"10.1016/j.biopha.2025.118053","DOIUrl":"10.1016/j.biopha.2025.118053","url":null,"abstract":"<div><div>Alcohol remains the most frequently used intoxicant, posing a significant global health concern. Binge drinking has been linked to acute cardiovascular complications, including reduced cardiac performance, arrhythmias, and blood pressure instability. Additionally, there is a growing number of clinical reports describing severe adverse cardiac events associated with the recreational use of synthetic cannabinoids. Recent surveys reveal a troubling rise in polydrug misuse, particularly among young adults, with an increasing number of cases linked to fatal outcomes. This study aimed to characterize left ventricular performance in mice following combined acute alcohol and synthetic cannabinoid exposure using complex hemodynamic measurements via the pressure-volume (P-V) approach. Our findings revealed that alcohol ingestion or intravenous synthetic cannabinoid (CP55,940) administration led to a dose-dependent decline in systolic cardiac performance in mice. Moreover, the concurrent administration of alcohol and CP55,940 led to cardiodepression, surpassing the contractile dysfunction observed with each drug administered individually. Intravenous administration of the cannabinoid type-1 receptor (CB1R) antagonist rimonabant largely improved the combined drug administration-induced left ventricular contractile dysfunction in mice, while its intracerebroventricular administration resulted in only partial restoration of normal cardiac function, implicating a role for both central and peripheral CB1R signaling. Our results emphasize the severe cardiac consequences of simultaneous alcohol and synthetic cannabinoid misuse and offer a potential therapeutic avenue for mitigating the adverse cardiac effects of their combined use by repurposing CB1R antagonists.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"187 ","pages":"Article 118053"},"PeriodicalIF":6.9,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143873901","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}