Life sciences最新文献

{"title":"Deciphering the functions of Spt20 in the SAGA complex: Implications for Cryptococcus neoformans virulence","authors":"Chendi Katherine Yu,&nbsp;Christina J. Stephenson,&nbsp;Tristan C. Villamor,&nbsp;Taylor G. Dyba,&nbsp;Benjamin L. Schulz,&nbsp;James A. Fraser","doi":"10.1016/j.lfs.2025.123509","DOIUrl":"10.1016/j.lfs.2025.123509","url":null,"abstract":"<div><h3>Aims</h3><div>The SAGA complex is a conserved transcriptional co-activator essential for eukaryotic gene regulation. In fungi of the Ascomycota, the core protein Spt20 contributes to the structure and function of SAGA. This study aimed to identify and characterize <em>SPT20</em> in <em>Cryptococcus neoformans</em>, the WHO top-ranked critical priority group species on their Fungal Priority Pathogen list.</div></div><div><h3>Materials and methods</h3><div>Identification of <em>C. neoformans SPT20</em> revealed the presence of a tRNA gene within its 5′ UTR. Precisely deleting the <em>SPT20</em> ORF preserved the tRNA gene while enabling analysis of Spt20 function. Phenotypic assays assessed growth under stress, capsule formation, and antifungal susceptibility. RT-qPCR divulged effects on transcriptional regulation of SAGA components, while Western blotting evaluated changes in histone acetylation and deubiquitination. A murine inhalation model assessed virulence.</div></div><div><h3>Key findings</h3><div>Loss of <em>SPT20</em> impaired growth under a number of stresses, influenced capsule formation, increased antifungal susceptibility, and disrupted expression of most genes encoding SAGA complex proteins. The mutant exhibited defects in several histone modifications as well as severely compromised virulence in mice.</div></div><div><h3>Significance</h3><div>Characterization of <em>SPT20</em> in <em>C. neoformans</em> has provided important insights into the role of this protein as a critical regulator of survival and virulence in this clinically important species.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"368 ","pages":"Article 123509"},"PeriodicalIF":5.2,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143512353","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":"Penta-1,4-dien-3-one and quinoxaline conjugates as potential anticancer agents via inhibiting EphB3/SRC/AKT axis","authors":"Qing Li ,&nbsp;Mei Zhou ,&nbsp;Ying Yang,&nbsp;Yangming Jiang,&nbsp;Chao Chen,&nbsp;Enming Hu,&nbsp;Jialin Chen,&nbsp;Daoping Wang","doi":"10.1016/j.lfs.2025.123510","DOIUrl":"10.1016/j.lfs.2025.123510","url":null,"abstract":"<div><div>Overexpression of EphB3 has been documented across various cancers and essential for cell proliferation, survive and metastasis, making it a valuable therapeutic target. In this study, a series of novel penta-1,4-dien-3-one and quinoxaline conjugates were designed and synthesized using pharmacophore fusion strategies to explore potential EphB3 inhibitors. CCK-8 experiments revealed significant anti-cancer activity of most newly synthesized compounds against hepatocellular carcinoma (HCC). Among them, compound <strong>W8</strong> displaying the highest inhibitory activity against MHCC97H (IC₅₀ = 1.87 μM), which arrests MHCC97H cells in the G0/G1 phase and induces apoptosis. Furthermore, compound <strong>W8</strong> suppresses tumor growth in an MHCC97H xenograft model <em>in vivo</em> by suppressing phosphorylation level of EphB3 and down-regulating the SRC-AKT signaling pathway, leading to a dose-dependent reduction in tumor volumes and weights, with a 40 mg/kg dose achieving decreases of 68.4 % and 65.3 %, respectively. Given its ability to modulate EphB3 signaling, <strong>W8</strong> represents a promising lead compound for further drug development, particularly for cancers characterized by EphB3 overexpression, and may offer new opportunities for targeted therapy in precision oncology.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"368 ","pages":"Article 123510"},"PeriodicalIF":5.2,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143512496","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":"Aging-related hyperphosphatemia triggers the release of TNF-α from macrophages, promoting indicators of sarcopenia through the reduction of IL-15 expression in skeletal muscle","authors":"Elena Alcalde-Estévez ,&nbsp;Ariadna Moreno-Piedra ,&nbsp;Ana Asenjo-Bueno ,&nbsp;María Martos-Elvira ,&nbsp;Mariano de la Serna-Soto ,&nbsp;Marta Ruiz-Ortega ,&nbsp;Gemma Olmos ,&nbsp;Susana López-Ongil ,&nbsp;María P. Ruiz-Torres","doi":"10.1016/j.lfs.2025.123507","DOIUrl":"10.1016/j.lfs.2025.123507","url":null,"abstract":"<div><h3>Aims</h3><div>The association between aging-related hyperphosphatemia and sarcopenia has been documented, and evidence suggests that inflammaging is involved in the manifestation of sarcopenia. The present study investigates whether hyperphosphatemia triggers inflammation, thereby inducing the appearance of sarcopenia along with the cytokines involved in these processes.</div></div><div><h3>Materials and methods</h3><div>RAW 264.7 macrophages were incubated with β-glycerophosphate (BGP), as a phosphate donor, at different time intervals, to assess the production of proinflammatory markers. Conditioned medium from macrophages was collected and added to cultured C2C12 myoblasts to analyse whether proinflammatory molecules, released by macrophages, modified myogenic differentiation, cell senescence or myokine IL-15 expression. A neutralising antibody anti-TNF-α and recombinant IL-15 were added to evaluate the role of these cytokines in the observed effects. Additionally, TNF-α, IL-15, serum phosphate, and sarcopenia signs were evaluated in 5-month-old mice, 24-month-old mice and 24-month-old mice fed with a hypophosphatemic diet.</div></div><div><h3>Key findings</h3><div>BGP increased TNF-α expression in macrophages through NFkB activation. Conditioned medium from BGP-treated macrophages impaired myogenic differentiation in differentiating myoblasts and promoted cellular senescence and reduced IL-15 expression in undifferentiated myoblasts. These effects were mediated by TNF-α. Old mice displayed reduced expression of muscle IL-15 and elevated circulating TNF-α, along with increased serum phosphate levels, which correlated with the appearance of sarcopenia indicators. The hypophosphatemic diet prevented these changes in old mice.</div></div><div><h3>Significance</h3><div>Hyperphosphatemia induces TNF-α production in macrophages, which contributes to the reduced expression of muscular IL-15. This mechanism may play a role in inducing sarcopenia in elderly mice.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"368 ","pages":"Article 123507"},"PeriodicalIF":5.2,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515951","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":"Integrated insights into gene expression dynamics and transcription factor roles in diabetic and diabetic-infectious wound healing using rat model","authors":"Vikash Sharma ,&nbsp;Jitender Singh ,&nbsp;Yash Kumar ,&nbsp;Ashish Kumar ,&nbsp;Kumar Venkatesan ,&nbsp;Monalisa Mukherjee ,&nbsp;Arun K. Sharma","doi":"10.1016/j.lfs.2025.123508","DOIUrl":"10.1016/j.lfs.2025.123508","url":null,"abstract":"<div><h3>Background</h3><div>Diabetic or diabetic infectious wounds pose a global challenge, marked by delayed healing and high amputation/mortality rates. This study of participating transcriptomes and their regulators unveils critical alterations.</div></div><div><h3>Methods</h3><div>Transcriptome data from GEO analyzed DEGs in diabetic foot ulcers vs. controls using RNA-Seq, limma, STRINGdb, Cytoscape, and clusterProfiler for PPI networks and functional enrichment. TRRUST database was used to predict transcriptional factors (TFs). Adverse molecular pathology in different models of wounds (non-diabetic, acute diabetic, diabetic infectious wounds) was validated by RT-PCR, Western blotting, oxidative stress markers, cytokines, and histological analysis.</div></div><div><h3>Results</h3><div>RNA-Seq dataset ‘GSE199939’ was analyzed after normalization to identify DEGs (total 47 DEG, 31 upregulated, 16 downregulated) in diabetic wound healing using limma. PPI networks revealed seven hub genes which were further processed for functional enrichment and highlighted oxidative stress, ECM remodeling, AGE-RAGE, and IL-17 signaling in diabetic wound pathology. Additionally, 17 key TFs were identified as hub gene regulators. The healing rate was significantly impaired in diabetic wounds, with delayed contraction, elevated pro-inflammatory cytokines, oxidative stress, reduced anti-inflammatory cytokines, antioxidants, angiogenesis, collagen deposition, and re-epithelialization. Further, RT-PCR and Western blot analysis validated the expression of target genes including the overexpression of <em>HSPA1B</em>, <em>FOS</em>, and down-expression of <em>SOD2</em>, <em>COL1A1</em>, and <em>CCL2</em>, whereas TFs including upregulation of RELA, NFKB1, STAT3, and downregulation of SP1 and JUN in diabetic and diabetic infectious wounds.</div></div><div><h3>Conclusion</h3><div>Molecular analyses reveal disrupted oxidative stress, ECM remodeling, and inflammatory signaling in diabetic and diabetic infectious, emphasizing impaired healing dynamics and identifying therapeutic targets.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"368 ","pages":"Article 123508"},"PeriodicalIF":5.2,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143512355","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":"The combination of BET and METTL3 inhibitors elicits synergistic antitumor effects in ovarian cancer cells via reducing SP1 and BCL-2 expression","authors":"Ying-Jie Ou ,&nbsp;Ben-Jin Liu ,&nbsp;Yi-Fei Xuan ,&nbsp;Xu-Bin Bao ,&nbsp;Xia-Juan Huan ,&nbsp;Shan-Shan Song ,&nbsp;Ai-Ling Su ,&nbsp;Ze-Hong Miao ,&nbsp;Ying-Qing Wang","doi":"10.1016/j.lfs.2025.123505","DOIUrl":"10.1016/j.lfs.2025.123505","url":null,"abstract":"<div><div>Ovarian cancer (OC) remains a major health threat to woman despite treatment advances. New therapeutic strategies are demanded to persistently explored. In this study, we found that inhibitors of bromodomain and extra-Terminal domain (BET) and methyltransferase-like 3 (METTL3) exerted synergistic proliferative inhibition in different OC cell lines. <em>In vitro</em> synergism was translated into <em>in vivo</em> antitumor activity through the combination of BET inhibitor HJP-178 and METTL3 inhibitor STM2457. Mechanistically, this combination mainly enhanced apoptosis rather than affecting cell cycle arrest. Furthermore, it was revealed that HJP-178 decreased the transcription of <em>Specificity protein 1</em> (<em>SP1</em>) while STM2457 lowered the N⁶-methyladenosine (m⁶A) levels of <em>SP1</em> mRNA. Consequently, their combination synergistically reduces <em>SP1</em> RNA and protein levels through both transcriptional and post-transcriptional modifications. Further exploration demonstrated that inhibiting SP1 directly downregulates the anti-apoptotic protein B-cell lymphoma-2 (BCL-2), activating the caspase-mediated apoptotic pathway and triggering programmed cell death. Importantly, <em>SP1</em> overexpression significantly reducing the apoptosis induction and proliferation inhibition induced by the combination. Similarly, <em>BCL-2</em> overexpression mimicked the effects of increased <em>SP1</em>. These results demonstrate the critical roles of SP1 and BCL-2 in the synergistic antitumor activity between BET and METTL3 inhibitors. Collectively, our findings broaden the potential applications of both drug types and present a promising therapeutic approach for OC, warranting further investigation in clinical settings.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"368 ","pages":"Article 123505"},"PeriodicalIF":5.2,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143512356","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":"The canonical Wnt/β-catenin signaling pathway upregulates carbonic anhydrase 2 via transcription factor 7-like 2 to promote cardiomyopathy in type 2 diabetic mice","authors":"Conglin Li ,&nbsp;Daofeng Cai ,&nbsp;Wenchang Yuan ,&nbsp;Rui Cai ,&nbsp;Xiaoxia Qiu ,&nbsp;Yuan Qin ,&nbsp;Yaofeng Feng ,&nbsp;Qiulian Zhu ,&nbsp;Yun Liu ,&nbsp;Yilin Chen ,&nbsp;Xun Yuan ,&nbsp;Wenyue Jiang ,&nbsp;Ning Hou","doi":"10.1016/j.lfs.2025.123506","DOIUrl":"10.1016/j.lfs.2025.123506","url":null,"abstract":"<div><div>Excessive activation of the canonical Wnt/β-catenin pathway contributes to the development of diabetic cardiomyopathy (DCM). Transcription factor 7-like 2 (TCF7L2) is the main β-catenin partner of the TCF family in adult human hearts. Carbonic anhydrase 2 (CA2) is implicated in various hypertrophic cardiomyopathy. In this study, we aimed to investigate the role of the Wnt/β-catenin/TCF7L2 signaling and CA2 in the development of DCM. Streptozotocin (STZ)/high-fat diet (HFD)-induced diabetic mice and high glucose-stimulated neonatal rat cardiomyocytes (NRCMs) were used as in-vivo and in-vitro models of Type 2 diabetes (T2DM), respectively. Histopathological changes in the mouse myocardium were assessed with hematoxylin-eosin (HE) or Masson's trichrome staining. Cardiac function was evaluated with echocardiography. TCF7L2, β-catenin, and CA2 expression was determined with RT-qPCR, western blotting, and immunohistochemistry. Immunoprecipitation (IP) was used to evaluate the formation of the β-catenin/TCF7L2 bipartite. The regulatory relationship between the β-catenin/TCF7L2 bipartite and CA2 was investigated with chromatin immunoprecipitation (ChIP) and a luciferase reporter assay. Compared with the control mice, the T2DM mice exhibited increased myocardial β-catenin and TCF7L2 expression that was concentrated in the nucleus. Treatment of diabetic mice with the β-catenin/TCF7L2 bipartite inhibitor iCRT14 prevented myocardial remodeling and improved cardiac dysfunction. iCRT14 also prevented high glucose-induced hypertrophy in NRCMs, while the β-catenin stabilizer SKL2001 worsened hypertrophy. IP experiments confirmed the formation of the β-catenin/TCF7L2 bipartite in the control and T2DM mouse cardiomyocytes. Moreover, based on the results of RNA-sequencing analysis, CA2 was upregulated in T2DM cardiomyocytes in vitro and in vivo. TCF7L2 overexpression upregulated CA2, while iCRT14 treatment or TCF7L2 knockdown downregulated CA2. CA2 knockdown ameliorated NRCM hypertrophy induced by high glucose and SKL2001. The ChIP experiments revealed an increased interaction between β-catenin/TCF7L2 and the transcription initiation region of CA2 in the heart tissue of T2DM mice. The luciferase reporter assay confirmed that CA2 is directly regulated by the β-catenin/TCF7L2 bipartite. The results indicate that the canonical Wnt/β-catenin pathway upregulates CA2 via TCF7L2 to promote DCM. This research sheds new light on the pathogenesis of DCM and presents new potential therapeutic targets for this disease.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"368 ","pages":"Article 123506"},"PeriodicalIF":5.2,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488603","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":"GLDC alleviates cisplatin-induced apoptosis, cellular senescence, and production of reactive oxygen species via regulating UCP1 in the kidney","authors":"Anh Phuc Bui ,&nbsp;Thi Tuyet Mai Pham ,&nbsp;Mikyung Kim ,&nbsp;Jae-Hyung Park ,&nbsp;Jee In Kim ,&nbsp;Ji Hae Seo ,&nbsp;Jeeyeon Jung ,&nbsp;Jin Young Kim ,&nbsp;Eunyoung Ha","doi":"10.1016/j.lfs.2025.123502","DOIUrl":"10.1016/j.lfs.2025.123502","url":null,"abstract":"<div><h3>Aims</h3><div>Glycine decarboxylase (GLDC) is a mitochondrial enzyme that mediates the degradation of glycine as part of the glycine cleavage system. Although GLDC expression in the kidney is second highest next to the liver, very little is known as to the role of GLDC in the kidney. Thus, this study aimed to elucidate the role of GLDC in the kidney.</div></div><div><h3>Materials and methods</h3><div>HK-2 renal proximal tubular cells with GLDC overexpression and knockdown were established to investigate function of GLDC in cells treated with cisplatin (CP). For in vivo experiments, C57BL/6J mice were used in a CP-induced AKI model, with and without treatment with (aminooxy)acetic acid (AOAA), a GLDC inhibitor.</div></div><div><h3>Key findings</h3><div>We found that GLDC overexpression attenuated CP-induced apoptosis, cellular senescence and production of reactive oxygen species (ROS) in HK2 cells, while GLDC knockdown aggravated these effects. Moreover, GLDC overexpression stimulated proliferation of HK-2 cells, while GLDC knockdown attenuated cell growth. Mechanistically, we found that effects of GLDC are mediated via modulating mitochondrial uncoupling protein 1 (UCP1). GLDC overexpression increased UCP1, while GLDC knockdown decreased UCP1. Knockdown of UCP1 reversed GLDC-mediated attenuation of CP-induced cellular senescence and ROS production. Treatment of AOAA into acute kidney injury (AKI)-induced mice aggravated AKI injury, increasing biomarkers, fibrosis and senescence associated-β-galactosidase staining.</div></div><div><h3>Significance</h3><div>GLDC protects CP-induced apoptosis, cellular senescence, and ROS production in proximal tubular cells via a UCP-mediated pathway and lays a scientific foundation that could support a therapeutic strategy that targets GLDC for the treatment of cisplatin-induced AKI.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"368 ","pages":"Article 123502"},"PeriodicalIF":5.2,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488594","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":"Corrigendum to “Modulation of autophagy and transient receptor potential vanilloid 4 channels by montelukast in a rat model of hemorrhagic cystitis” [Life Sci. 278 (2021) 119507]","authors":"Rania A. Elrashidy ,&nbsp;Rehab A. Hasan","doi":"10.1016/j.lfs.2025.123491","DOIUrl":"10.1016/j.lfs.2025.123491","url":null,"abstract":"","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"366 ","pages":"Article 123491"},"PeriodicalIF":5.2,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483578","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":"Expanding the role of exosomes in drug, biomolecule, and nanoparticle delivery","authors":"Ongun Mehmet Saka ,&nbsp;Devrim Demir Dora ,&nbsp;Gunes Kibar ,&nbsp;Atakan Tevlek","doi":"10.1016/j.lfs.2025.123499","DOIUrl":"10.1016/j.lfs.2025.123499","url":null,"abstract":"<div><div>Exosomes are nanoscale extracellular vesicles released by diverse cell types, serving essential functions in intercellular communication and physiological processes. These vesicles have garnered considerable interest in recent years for their potential as drug delivery systems, attributed to their natural origin, minimal immunogenicity, high biocompatibility, and capacity to traverse biological barriers, including the blood-brain barrier. Exosomes can be obtained from diverse biological fluids, rendering them accessible and versatile vehicles for therapeutic medicines. This study emphasizes the burgeoning significance of exosomes in drug administration, concentrating on their benefits, including improved stability, target selectivity, and the capacity to encapsulate various biomolecules, such as proteins, nucleic acids, and small molecules. Notwithstanding their potential applications, other problems remain, including as effective drug loading, industrial scalability, and the standardization of isolation methodologies. Overcoming these hurdles via new research is essential for fully harnessing the promise of exosomes in therapeutic applications, especially in the treatment of intricate diseases like cancer and neurological disorders.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"368 ","pages":"Article 123499"},"PeriodicalIF":5.2,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488593","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":"Mesenchymal stem cell-derived small extracellular vesicles as a delivery vehicle of oncolytic reovirus","authors":"Konomu Uno ,&nbsp;Eiji Kubota ,&nbsp;Yoshinori Mori ,&nbsp;Ruriko Nishigaki ,&nbsp;Yuki Kojima ,&nbsp;Takuya Kanno ,&nbsp;Makiko Sasaki ,&nbsp;Shigeki Fukusada ,&nbsp;Naomi Sugimura ,&nbsp;Mamoru Tanaka ,&nbsp;Keiji Ozeki ,&nbsp;Takaya Shimura ,&nbsp;Randal N. Johnston ,&nbsp;Hiromi Kataoka","doi":"10.1016/j.lfs.2025.123489","DOIUrl":"10.1016/j.lfs.2025.123489","url":null,"abstract":"<div><h3>Aim</h3><div>The oncolytic reovirus has demonstrated efficacy against various cancer types in preclinical and clinical studies. However, its anti-tumor activity is limited. This study aimed to develop a novel drug delivery system (DDS) using small extracellular vesicles (sEVs) derived from human adipose-derived mesenchymal stem cells to enhance the therapeutic potential of reovirus.</div></div><div><h3>Materials and methods</h3><div>sEVs, which offer distinct advantages over traditional systems such as nanoparticles due to their natural biocompatibility, low immunogenicity, ability to cross biological barriers, and cell-derived targeting properties, were engineered to encapsulate reovirus particles (sEVs-reo). The anti-tumor activity of sEVs-reo was evaluated using colorectal cancer cell lines HCT116 and SW480. Additionally, resistance to neutralizing antibodies, internalization by cancer cells, and efficacy against junctional adhesion molecule-A(JAM-A)-knockout colon cancer cells resistant to reovirus, generated via CRISPR/Cas9, were assessed.</div></div><div><h3>Key findings</h3><div>sEVs-reo encapsulated reovirus particles effectively, and at a concentration of 0.5 μg/ml, reduced viable tumor cells by 60.3 % in HCT116 and 42.5 % in SW480. Remarkably, sEVs-reo exhibited significant efficacy even in the presence of neutralizing antibodies, including anti-σ1 antibodies and serum from reovirus-infected mice. sEVs-reo were rapidly internalized by cancer cells within 4 h while exhibiting reduced immunogenicity relative to reovirus, and demonstrated significant anti-tumor activity against JAM-A-deficient colon cancer cells.</div></div><div><h3>Significance</h3><div>This study demonstrates that sEVs-reo can address key challenges associated with oncolytic virotherapy. These findings support potential of sEVs as a novel and effective DDS for reovirus in colon cancer treatment, while offering a versatile platform to enhance the efficacy of other oncolytic viruses.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"368 ","pages":"Article 123489"},"PeriodicalIF":5.2,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483590","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}