Biomedicine & Pharmacotherapy最新文献

{"title":"Liquid biopsy in lung cancer: The role of circulating tumor cells in diagnosis, treatment, and prognosis","authors":"Chibo Liu,&nbsp;Yanqun Cai,&nbsp;Sihua Mou","doi":"10.1016/j.biopha.2024.117726","DOIUrl":"10.1016/j.biopha.2024.117726","url":null,"abstract":"<div><div>Despite numerous therapeutic advancements, such as immune checkpoint inhibitors, lung cancer continues to be the leading cause of cancer-related mortality. Therefore, the identification of cancer at an early stage is becoming a significant subject in contemporary oncology. Despite significant advancements in early detection tactics in recent decades, they continue to provide challenges because of the inconspicuous symptoms observed during the early stages of the primary tumor. Presently, tumor biomarkers and imaging techniques are extensively employed across different forms of cancer. Nevertheless, every approach has its own set of constraints. In certain instances, the detriments outweigh the advantages. Hence, there is an urgent need to enhance early detection methods. Currently, liquid biopsy is considered more flexible and not intrusive method in comparison to conventional test for early detection. Circulating tumor cells (CTCs) are crucial components of liquid biopsy and have a pivotal function in the spread and formation of secondary tumors. These indicators show great promise in the early identification of cancer. This study presents a comprehensive examination of the methodologies employed for the isolation and enrichment of circulating tumor cells (CTCs) in lung cancer. Additionally, it explores the formation of clusters of CTCs, which have a pivotal function in facilitating the effective dissemination of cancer to distant organs. In addition, we discuss the importance of CTCs in the detection, treatment, and prognosis of lung cancer.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117726"},"PeriodicalIF":6.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142746482","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":"Resveratrol alleviates heart failure by activating foxo3a to counteract oxidative stress and apoptosis","authors":"Kuang Liu ,&nbsp;Yihao Zhu ,&nbsp;Wenjie Gao ,&nbsp;Xuhui Han ,&nbsp;Qinghua Zhang ,&nbsp;Yanbin Zhao ,&nbsp;Yao Zu","doi":"10.1016/j.biopha.2024.117716","DOIUrl":"10.1016/j.biopha.2024.117716","url":null,"abstract":"<div><div>Resveratrol has been extensively studied for its multifaceted health benefits. Nonetheless, the pharmacological mechanisms of resveratrol for heart failure remain elusive, especially the cardioprotective effects. To address this knowledge gap, we performed high-throughput drug screening using zebrafish and discovered that resveratrol significantly alleviated heart failure, including rescuing abnormalities in heart rate, blood flow, cardiac output, and <em>nppb</em> overexpression. Mechanically, calcium optical mapping revealed that resveratrol diminished the prolongation of calcium duration at 90 % repolarization (CaD90). Membrane potential assay demonstrated that resveratrol alleviated mitochondrial damage, subsequently relieved the excessive accumulation of reactive oxygen species (ROS). Tunel staining further showed that resveratrol inhibited cardiomyocyte apoptosis both in zebrafish and human AC16 cell. Given the close relationship between the Forkhead Box O (<em>foxo</em>) family and oxidative stress and apoptosis, we used qPCR and noted that resveratrol could regulate the heart failure-induced expressions of <em>foxo1b</em> and <em>foxo3a</em> to normal levels. Furthermore, we conducted in situ hybridization to confirm the effective down-regulation patterns of <em>foxo3a</em> after resveratrol treatment. To investigate whether resveratrol’s effects are mediated via <em>foxo3a</em>, we used gardenoside to inhibit <em>foxo3a</em> expression, noting that resveratrol’s cardioprotective effects were reduced with <em>foxo3a</em> inhibition. Overall, our study underscores the molecular mechanisms by which resveratrol confers cardioprotection and provides a reference for heart failure therapeutic approaches.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117716"},"PeriodicalIF":6.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758933","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":"Decoding tumor microenvironment: EMT modulation in breast cancer metastasis and therapeutic resistance, and implications of novel immune checkpoint blockers","authors":"Jie Yuan ,&nbsp;Li Yang ,&nbsp;Hua Zhang ,&nbsp;Narasimha M. Beeraka ,&nbsp;Danfeng Zhang ,&nbsp;Qun Wang ,&nbsp;Minghua Wang ,&nbsp;Hemanth Vikram PR ,&nbsp;Gautam Sethi ,&nbsp;Geng Wang","doi":"10.1016/j.biopha.2024.117714","DOIUrl":"10.1016/j.biopha.2024.117714","url":null,"abstract":"<div><div>Tumor microenvironment (TME) and epithelial-mesenchymal transition (EMT) play crucial roles in the initiation and progression of tumors. TME is composed of various cell types, such as immune cells, fibroblasts, and endothelial cells, as well as non-cellular components like extracellular matrix (ECM) proteins and soluble factors. These elements interact with tumor cells through a complex network of signaling pathways involving cytokines, growth factors, metabolites, and non-coding RNA-carrying exosomes. Hypoxic conditions within the TME further modulate these interactions, collectively influencing tumor growth, metastatic potential, and response to therapy. EMT represents a dynamic and reversible process where epithelial cells undergo phenotypic changes to adopt mesenchymal characteristics in several cancers, including breast cancers. This transformation enhances cell motility and imparts stem cell-like properties, which are closely associated with increased metastatic capability and resistance to conventional cancer treatments. Thus, understanding the crosstalk between the TME and EMT is essential for unraveling the underlying mechanisms of breast cancer metastasis and therapeutic resistance. This review uniquely examines the intricate interplay between the tumor TME and epithelial-mesenchymal transition EMT in driving breast cancer metastasis and treatment resistance. It explores the therapeutic potential of targeting the TME-EMT axis, specifically through CD73-TGF-β dual-blockade, to improve outcomes in triple-negative breast cancer. Additionally, it underscores new strategies to enhance immune checkpoint blockade (ICB) responses by modulating EMT, thereby offering innovative insights for more effective cancer treatment.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117714"},"PeriodicalIF":6.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142746484","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":"Tissue damage alleviation and mucin inhibition by P5 in a respiratory infection mouse model with multidrug-resistant Acinetobacter baumannii","authors":"Jun Hee Oh ,&nbsp;Jonggwan Park ,&nbsp;Hee Kyoung Kang ,&nbsp;Hee Joo Park ,&nbsp;Yoonkyung Park","doi":"10.1016/j.biopha.2024.117724","DOIUrl":"10.1016/j.biopha.2024.117724","url":null,"abstract":"<div><div>Although the discovery of antibiotics has made significant positive contributions to public health and medicine, it now poses a serious threat due to the increasing antibiotic resistance in various bacteria. Carbapenem-resistant and multidrug-resistant (MDR) <em>Acinetobacter baumannii</em> is spreading globally, exacerbating respiratory diseases such as chronic obstructive pulmonary disease and cystic fibrosis. Antimicrobial peptides (AMPs), with broad antibacterial activity, have emerged as promising alternatives for treating MDR <em>A. baumannii</em> infections. The AMP P5 exhibits strong antibacterial and anti-biofilm activities against MDR <em>A. baumannii</em> strains isolated from patients. Compared to colistin, a commonly used antibiotic for MDR <em>A. baumannii</em> infections, P5 has a lower potential for inducing drug resistance. Additionally, P5 displays stability in human serum and minimal cytotoxicity in human cell lines. P5 not only suppressed the overexpression of pro-inflammatory cytokines and inflammatory transcription factors in lung epithelial cells (A549) and in a mouse model of respiratory infection but also alleviated lung tissue damage caused by infection. Moreover, P5 effectively alleviated excessive mucin secretion <em>in vitro</em> and <em>in vivo</em> by inhibiting inflammatory transcription factors, epidermal growth factor receptor, and signal transducer and activator of transcription 3—key regulators of mucin expression, a hallmark of inflammatory respiratory diseases. These findings highlight the therapeutic potential of P5 in treating MDR <em>A. baumannii</em> infections and associated inflammatory respiratory conditions.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117724"},"PeriodicalIF":6.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142746491","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 interplay between aging, testosterone, and mitochondrial dysfunction: Revisiting the role of hormonal regulation in urological health","authors":"Yu-Hsiang Lin,&nbsp;Kou-Jen Lin,&nbsp;Jau-Yuan Chen","doi":"10.1016/j.biopha.2024.117722","DOIUrl":"10.1016/j.biopha.2024.117722","url":null,"abstract":"","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117722"},"PeriodicalIF":6.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142746495","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":"Nanotherapeutic strategy against glioblastoma using enzyme inhibitors","authors":"Rekha Thiruvengadam,&nbsp;Boluwatife Olamide Dareowolabi,&nbsp;Eun-Yi Moon,&nbsp;Jin Hee Kim","doi":"10.1016/j.biopha.2024.117713","DOIUrl":"10.1016/j.biopha.2024.117713","url":null,"abstract":"<div><div>Glioblastoma is the most aggressive brain cancer and thus patients with glioblastoma have a severely low 5-year survival rate (&lt;5 %). Glioblastoma damages neural centers, causing severe depression, anxiety, and cognitive disorders. Glioblastoma is highly resistant to most of available anti-tumor medications, due to heterogeneity of glioblastoma as well as the presence of stem-like cells. To overcome the challenges in the current medications against glioblastoma, novel medications that are effective in treating the aggressive and heterogenous glioblastoma should be developed. Enzyme inhibitor and nanomedicine have been getting attention because of effective anticancer efficacies of enzyme inhibitors and a role of nanomedicine as effective carrier of chemotherapeutic drugs by targeting specific tumor areas. Furthermore, a tumor-initiating neuroinflammatory microenvironment, which is crucial for glioblastoma progression, was linked with several carcinogenesis pathways. Therefore, in this review, first we summarize neuroinflammation and glioblastoma-related neuropathways. Second, we discuss the importance of enzyme inhibitors targeting specific proteins in relation with neuroinflammation and glioblastoma-related molecular mechanisms. Third, we summarize recent findings on the significance of nanotherapeutic anticancer drugs developed using natural or synthetic enzyme inhibitors against glioblastoma as well as currently available Food and Drug Administration (FDA)-approved drugs against glioblastoma.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117713"},"PeriodicalIF":6.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142746485","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":"Protective effects of sulfated polysaccharides from Enteromorpha intestinalis on oxidative stress, liver iron overload and Ferroptosis in Zebra fish exposed to ethanol","authors":"Marziyeh Khazaei ,&nbsp;Rashid Alijani Ardeshir","doi":"10.1016/j.biopha.2024.117715","DOIUrl":"10.1016/j.biopha.2024.117715","url":null,"abstract":"<div><div>The study investigates the protective effects of sulfated polysaccharides extracted from <em>Enteromorpha intestinalis</em> (EIP) against oxidative stress, liver iron overload, and ferroptosis in zebrafish exposed to ethanol, a model for alcohol-related liver disease (ALD). The extracted polysaccharides were characterized for sulfate and sugar content, molecular weight, and functional groups. Adult male zebrafish were divided into three groups: control, ethanol-exposed (EE) (0.2 % ethanol (v/v) in the water), and ethanol-exposed with EIP supplementation (1 % EIP incorporated into the basal diet) (EE+EIP) for 30 days. The study measured liver oxidative stress indexes, serum enzymological indexes, liver and serum lipid profiles, liver iron ion content, and expression of ferroptosis-related genes. Histological analysis was conducted to assess lipid accumulation and iron deposition in liver tissues. The findings indicate that EIP supplementation significantly mitigates ethanol-induced liver damage. Specifically, EIP reduced malondialdehyde levels, increased antioxidant enzyme and non-enzymatic antioxidant activity, and decreased iron ion accumulation and the area of iron granules in the liver tissue. Additionally, EIP treatment lowered lipids levels and aminotransferase enzyme activity in the serum. In the ALD model, EIP inhibited ethanol-induced ferroptosis by modulating the expression of key genes: it decreased the expression of transferrin (<em>tf</em>), transferrin receptor (<em>tfr</em>), ferroportin (<em>fpn</em>), and ferritin heavy chain (<em>fth</em>), while increasing the expression of glutathione peroxidase 4 (<em>gpx4</em>) and solute carrier family 7 member 11 (<em>slc7a11</em>). EIP has protective effects against ethanol-induced liver injury in zebrafish, offering a foundation for further research into its hepatoprotective action and potential application in preventing and treating ALD.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117715"},"PeriodicalIF":6.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142746493","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":"Hydroxyurea inhibits proliferation and stimulates apoptosis through inducible nitric oxide synthase in erythroid cells","authors":"Teodora Dragojević ,&nbsp;Emilija Živković ,&nbsp;Miloš Diklić ,&nbsp;Olivera Mitrović Ajtić ,&nbsp;Miloš Lazarević ,&nbsp;Tijana Subotički ,&nbsp;Dragoslava Đikić ,&nbsp;Juan F. Santibanez ,&nbsp;Dejan Milenković ,&nbsp;Jasmina Dimitrić Marković ,&nbsp;Constance T. Noguchi ,&nbsp;Alan N. Schechter ,&nbsp;Vladan P. Čokić ,&nbsp;Milica Vukotić","doi":"10.1016/j.biopha.2024.117723","DOIUrl":"10.1016/j.biopha.2024.117723","url":null,"abstract":"<div><div>Hydroxyurea (hydroxycarbamide, HU) arrests cells in the S-phase by inhibiting ribonucleotide reductase and DNA synthesis, significantly contributing to the release of nitric oxide (NO). We investigated the involvement of inducible NO synthase (NOS2) in the cytostatic effect of HU using <em>in vitro</em> shRNA-induced knockdown of the NOS2 transcript (NOS2_kd) or a specific NOS2 inhibitor (1400W) in human erythroleukemic HEL92.1.7 cells, as well as murine erythroid progenitors (mERPs) from HU-treated wild-type (WT) and Nos2 knockout (Nos2^–/–) mice. Over the long-term, HU increased NOS2 expression in HEL92.1.7 cells (via nuclear factor kappa B [NFκB] signaling) and in mERP. In the short-term, HU increased the activity of human recombinant and erythroleukemic cell-derived NOS2, as confirmed by NO metabolite nitrite/citrulline production. <em>In silico</em> molecular docking predicted that HU binds to the NOS2 active site and substrate L-arginine via hydrogen bonds. Molecular dynamics simulations showed reduced rigidity of the NOS2 active site upon interaction with HU, indicating stabilization of the enzyme-substrate complex. Both 1400W and NOS2_kd prevented the <em>in vitro</em> reduction in proliferation and induction of apoptosis in HEL92.1.7 cells by HU. NOS2_kd preferentially blocked early apoptosis and HU-induced S-phase arrest in HEL92.1.7 cells. The HU-induced decrease in proliferation and stimulation of early apoptosis in mERP were prevented in Nos2^–/– mice and by 1400W in WT mice. This study demonstrated that HU induces NOS2 activity through direct interaction and increased protein expression via NFκB signaling. Moreover, NOS2 mediates the HU-induced inhibition of proliferation and stimulation of apoptosis in erythroid cells.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117723"},"PeriodicalIF":6.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142746492","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":"OM-85 attenuates high-fat diet-induced obesity, insulin resistance, gut dysbiosis and nonalcoholic steatohepatitis in a murine model","authors":"Sarah Hewady ,&nbsp;Clarence R. Manuel ,&nbsp;Christian Pasquali ,&nbsp;Jagadish Koya ,&nbsp;Sandra E. Reznik","doi":"10.1016/j.biopha.2024.117710","DOIUrl":"10.1016/j.biopha.2024.117710","url":null,"abstract":"<div><h3>Background</h3><div>Obesity is a global epidemic that is tied to a wide range of human disorders. Chronic consumption of a high-fat diet is linked to disruption of the intestinal microbiome, which drives obesity-related pathophysiology. Broncho-Vaxom® (OM-85), a bacterial lysate used for prophylaxis of recurrent respiratory tract infections, has both immunostimulatory and immunomodulatory functions.</div></div><div><h3>Methods</h3><div>Male C57Bl/6 mice were maintained on normal control vs. high-fat diets for 8 weeks and treated or untreated with OM-85 or with the probiotic <em>Lactobacillus plantarum</em>, as a positive control. Mice were evaluated for weight gain, glucose tolerance, insulin tolerance, gut microbiome composition and non-alcoholic steatohepatitis (NASH).</div></div><div><h3>Results</h3><div>High-fat diet mice developed obesity, insulin resistance, NASH and gut dysbiosis with a shift from the Bacteroidetes phylum, such as Bacteroidales order and <em>Muribaculaceae</em> family organisms to Firmicutes groups, such as the Clostridium and Blautia genuses<em>.</em> Treatment with OM-85 led to 1) prevention of obesity, 2) prevention of insulin resistance, 3) attenuation of NASH and 4) attenuation of gut dysbiosis, with decreased levels of the organisms mentioned above and increases in Verrucomicrobiae phylum organisms such as <em>Akkermansia</em> family microbes as well as <em>Muribaculaceae</em> organisms. These shifts in the gut microbiome predict favorable effects on the short chain fatty acid profile in the gut and increased integrity of the intestinal barrier. Pathway analysis showed that OM-85 decreases rates of carbohydrate metabolism, providing an additional mechanism whereby OM-85 prevents obesity.</div></div><div><h3>Conclusion</h3><div>Immune modulators such as OM-85 should be investigated for their potential therapeutic effects on metabolism.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117710"},"PeriodicalIF":6.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758930","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":"A preclinical and phase I clinical study of ex vivo-expanded amyloid beta-specific human regulatory T cells in Alzheimer’s disease","authors":"Hyejin Yang ,&nbsp;Min Soo Byun ,&nbsp;Na-Yeon Ha ,&nbsp;Juwon Yang ,&nbsp;Seon-Young Park ,&nbsp;Jee Eun Park ,&nbsp;Dahyun Yi ,&nbsp;Young-Tae Chang ,&nbsp;Woo Sang Jung ,&nbsp;Jae Yoon Kim ,&nbsp;Jinsung Kim ,&nbsp;Dong Young Lee ,&nbsp;Hyunsu Bae","doi":"10.1016/j.biopha.2024.117721","DOIUrl":"10.1016/j.biopha.2024.117721","url":null,"abstract":"<div><h3>Introduction</h3><div>Despite advancements in adoptive regulatory T cell (Treg) therapy, its application in Alzheimer’s disease (AD) remains constrained by challenges in ex vivo Treg selection and expansion with antigen specificity. Our previous findings demonstrated the bystander suppressive immunomodulatory mechanism of <em>ex vivo</em> expanded amyloid β-specific mouse Tregs in AD models, prompting inquiry into the efficacy of <em>ex vivo</em> expanded human Tregs in AD.</div></div><div><h3>Methods</h3><div>We developed an effective <em>ex vivo</em> expansion method for manufacturing amyloid β-specific human Tregs (Aβ-hTreg) and evaluated their safety and efficacy in 3xTg mouse models of AD and a phase 1 clinical trial with six AD patients. The phenotype of Aβ-hTreg was analyzed using single-cell transcriptomics. The clinical trial involved intravenous administration of Aβ-hTreg, with three patients receiving a low dose and three receiving a high dose. Exploratory assessments of effectiveness, including cognitive tasks and functional evaluations, were conducted ninety days post-treatment.</div></div><div><h3>Results</h3><div>Behavioral spatial learning and memory impairment, neuroinflammatory and amyloid pathology were dramatically ameliorated by single intrathecal administration of <em>ex vivo</em> expanded Aβ−hTreg to 3xTg AD mice. Single cell transcriptomics analysis revealed alterations in five key genes within a cluster of Tregs under antigen-specific manufacturing conditions. In the clinical trial with six AD patients, dose-limiting toxicity was experienced by none of the participants within five days of receiving GMP-grade Aβ-hTreg (VT301), indicating its good tolerability. Although exploratory assessments of effectiveness did not reach statistically significant values among the groups, these findings offer valuable insights for AD treatment and management, guiding the planning of the next phase of clinical trials.</div></div><div><h3>Discussion</h3><div>This study suggests that hTregs may modulate Alzheimer's disease pathology by suppressing neuroinflammation, while VT301 shows promise as a safe treatment option. However, further research is necessary to confirm its clinical efficacy and optimize treatment strategies.</div></div><div><h3>Trial registration</h3><div>Title: A Study of Possibility of Using Regulatory T Cells (VT301) for Treatment of Alzheimer's Disease, ClinicalTrials.gov NCT05016427, Study approval date: Ministry of Food and Drug Safety of the Republic of Korea (MFDS) - August 31st, 2020, Institutional Review Board (IRB) of Seoul National University Hospital, Republic of Korea - September 29th, 2020, The date of first patient enrollment: December 7th, 2020. <span><span>https://clinicaltrials.gov/study/NCT05016427</span><svg><path></path></svg></span></div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117721"},"PeriodicalIF":6.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758932","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}