Biomedicine & Pharmacotherapy最新文献

{"title":"Mechanisms and therapeutic potential of pharmacological agents targeting inflammasomes","authors":"Haitao Li ,&nbsp;Tiantian Liu ,&nbsp;Xuezhen Shi ,&nbsp;Hao Du ,&nbsp;Chengzhi Cai ,&nbsp;Duomeng Yang ,&nbsp;Lili Qu ,&nbsp;Huixin Dou ,&nbsp;Boyan Jiao ,&nbsp;Baihai Jiao","doi":"10.1016/j.biopha.2025.118164","DOIUrl":"10.1016/j.biopha.2025.118164","url":null,"abstract":"<div><div>Recent high-impact research has significantly advanced our understanding of inflammasomes as therapeutic targets for inflammatory diseases. Breakthrough studies have revealed new mechanisms of inflammasome regulation and innovative inhibition approaches. A key discovery identified NEK7 as an essential component for NLRP3 inflammasome activation, providing a new target for therapeutic intervention. Additionally, researchers developed CY-09, a small molecule inhibitor that directly binds to the ATP-binding site of NLRP3, offering a highly specific method for inflammasome inhibition. Further progress includes elucidating the role of metabolic reprogramming in inflammasome activation, with studies finding that itaconate can directly inhibit NLRP3 activation. This discovery bridges cellular metabolism and inflammasome regulation, suggesting new metabolic approaches to modulate inflammatory responses. Research has also highlighted the importance of the non-canonical inflammasome pathway in atherosclerosis progression, expanding therapeutic possibilities for cardiovascular diseases. In the field of targeted therapies, a nanoparticle-based delivery system for inhibiting AIM2 inflammasome in psoriasis demonstrated significant efficacy in preclinical models. This approach showcases the potential of nanotechnology in enhancing the specificity and effectiveness of inflammasome-targeted therapies. These latest advancements collectively underscore the rapid progress in understanding inflammasome biology and developing innovative therapeutic strategies, paving the way for more effective and precise treatments for a wide range of inflammatory diseases.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118164"},"PeriodicalIF":6.9,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144321396","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":"Optimized strategies for designing antimicrobial peptides targeting multidrug-resistant Gram-negative bacteria","authors":"Lingling Liu ,&nbsp;Xiaoming Cui ,&nbsp;Huan Zhang ,&nbsp;Jiahui Yao ,&nbsp;Lili Li ,&nbsp;Yun Cai","doi":"10.1016/j.biopha.2025.118264","DOIUrl":"10.1016/j.biopha.2025.118264","url":null,"abstract":"<div><div>Considering the escalating challenge posed by antimicrobial resistance among Gram-negative bacteria, there is an urgent and critical imperative to explore and develop novel candidates for antimicrobial peptides (AMPs). The present study employed two strategies, lipid modification and amino acid substitution, to design a series of antimicrobial peptides (AMPs) based on the peptide WRK (WRLRWKTRWRLK). Among them, a peptide named FWK was identified to exhibit self-assembly behavior, forming nanoparticles of approximately 38 nm in size, ultimately leading to membrane destruction. Peptide FWK demonstrated rapid bactericidal activity against a multidrug-resistant (MDR) strain of <em>Klebsiella pneumoniae</em> within 30 min and maintained its efficacy for 36 h <em>in vitro</em>. In a mouse model of acute abdominal infection, peptide FWK demonstrated remarkable safety and potent antibacterial activity. A comparative analysis of various peptide modification strategies indicated that, in terms of antimicrobial activity, the positive charge and amphiphilicity of the peptide were more critical parameters than hydrophobicity. The substitution of amino acids offered a more versatile strategy for modification compared to lipid modification, thereby reducing the risk of introducing hemolytic toxicity. The antibacterial activity of the peptides was influenced by the type, quantity, and placement of substituted amino acids. The antibacterial activity can be enhanced by appropriately increasing the number of lysine and arginine residues. The biocompatibility of lysine was superior to that of arginine. The findings of this study offer valuable insights for the development of antimicrobial peptides (AMPs) that exhibit high efficacy and low toxicity, specifically targeting the effective management of infections caused by multidrug-resistant Gram-negative bacteria.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118264"},"PeriodicalIF":6.9,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144314100","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":"Bromophenanthrenequinones as antimicrobial and antibiofilm agents against Staphylococcus aureus","authors":"Saurav Paramanya ,&nbsp;Jin-Hyung Lee ,&nbsp;Hailong Che ,&nbsp;Jintae Lee","doi":"10.1016/j.biopha.2025.118270","DOIUrl":"10.1016/j.biopha.2025.118270","url":null,"abstract":"<div><div><em>Staphylococcus aureus</em> is a pathogen infamous for causing a multitude of infections, ranging from mild to life-threatening. Its ability to form biofilms exacerbates its pathogenicity, conferring antibiotic resistance and complicating treatments, particularly in hospital settings. To address this challenge, we investigated the efficacy of phenanthrenes against <em>S. aureus</em>. Among the 14 phenanthrenes tested, 2,7-dibromophenanthrenequinone (2,7-DBPQ) and 3,6-dibromophenanthrenequinone (3,6-DBPQ) showed promising results, with MICs of 20 and 50 µg/mL, respectively, and were bacteriostatic. Both compounds significantly inhibited biofilm formation in methicillin-sensitive and methicillin-resistant <em>S. aureus</em> strains. In addition to biofilm suppression, they markedly reduced key virulence factors, including hemolysis, extracellular lipase activity, and slime production. They also induced metabolic suppression and reactive oxygen species (ROS) generation. Notably, DBPQs exhibited synergistic effects with gentamicin and tetracycline, showing resilience against resistance development. Gene expression analysis via qRT-PCR confirmed the downregulation of biofilm- and virulence-associated genes <em>(arlR, arlS, hla, saeR, sigB, psm-α, isaA, and nuc1</em>). Collectively, these findings highlight the therapeutic potential of brominated analogues of phenanthrenequinones in treating biofilm-associated infections caused by <em>S. aureus.</em></div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118270"},"PeriodicalIF":6.9,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144314099","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":"Synthesis, characterization, and anti-inflammatory potential of serotonin- and dopamine-conjugates of urolithin A","authors":"Maciej Korczak ,&nbsp;Martina Redl ,&nbsp;Piotr Roszkowski ,&nbsp;Sebastian Granica ,&nbsp;Judith M. Rollinger ,&nbsp;Elke Heiss ,&nbsp;Jakub P. Piwowarski","doi":"10.1016/j.biopha.2025.118282","DOIUrl":"10.1016/j.biopha.2025.118282","url":null,"abstract":"<div><div>Advancements in understanding xenobiotic interactions with gut microbiota highlight bacteria-derived metabolites as a promising source of novel bioactive compounds. Urolithin A (UA), a postbiotic metabolite derived from ellagitannins, has been recognized for its anti-inflammatory properties. To enhance the bioactivity of UA, its derivatives (UADs) conjugated with dopamine (DopUA) or serotonin (SerUA) were synthesized, characterized and subjected to various <em>in vitro</em> bioassays</div><div>A synthesis strategy for UADs was developed and optimized. The identity and purity of the compounds were confirmed through HPLC-DAD-MS/MS and NMR analyses. The anti-inflammatory potential of UADs was evaluated in immortalized bone marrow-derived macrophages (iBMDMs) using qPCR to measure inflammatory markers expression, as well as FACS analysis and Griess assay to determine impact on cytokine secretion and nitrite production, respectively. Moreover, reporter cell lines were utilized to investigate the modulation of NF-κB and Nrf2 signaling pathways. Additionally, experiments using <em>Caenorhabditis elegans</em> Parkinson’s disease model aimed to provide first insight into UADs toxicity <em>in vivo</em> and impact on α-synuclein aggregation.</div><div><em>In vitro</em> experiments demonstrated that at non-cytotoxic concentrations, DopUA showed the most potent reduction in nitrite production and secretion of key pro-inflammatory cytokines in comparison with parent compounds and SerUA. DopUA also modestly inhibited NF-κB activation in reporter cells. Neither of the compounds activated Nrf2 signaling in a respective reporter gene assay. In <em>C</em>. <em>elegans</em>, UADs neither impacted survival adversely nor influenced α-synuclein accumulation.</div><div>These findings indicate that neurotransmitter conjugation enhances UA's immunomodulatory effects. The study promotes the idea of utilizing UA as promising scaffold for the development of therapeutics targeting pro-inflammatory pathways.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118282"},"PeriodicalIF":6.9,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144308008","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":"Ugonin L ameliorates pulmonary fibrosis as a novel TβRs inhibitor by regulating the TGF-β/TβRs signaling and autophagy","authors":"Tzu-Lan Hsia ,&nbsp;Wei-Chung Chiou ,&nbsp;Hsiu-Chen Huang ,&nbsp;Hui-Kang Liu ,&nbsp;Jui-Chieh Chen ,&nbsp;Pin-Kuei Fu ,&nbsp;Cheng Huang","doi":"10.1016/j.biopha.2025.118267","DOIUrl":"10.1016/j.biopha.2025.118267","url":null,"abstract":"<div><div>Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease of unknown etiology, affecting about 3 million individuals worldwide. Significant risk factors for IPF include advanced age and infectious agents. Current FDA-approved antifibrotic drugs slow the progression of pulmonary fibrosis with limited outcomes in overall survival, highlighting the need for novel pharmacological agents. Ugonin L (UL), a cyclized geranylflavonoid derived from <em>Helminthostachys zeylanica</em>, has been reported to have anti-inflammatory and antioxidant activities. However, the therapeutic potential of UL for pulmonary fibrosis remains unexplored. In this study, we demonstrated that UL mitigated pulmonary fibrosis in bleomycin (BLM)-induced mice. Specifically, UL improved the alveolar-capillary barrier integrity, decreasing inflammatory cytokines (TGF-β1, TNF-α, IL-1β, IL-6) in bronchoalveolar lavage fluid (BALF). UL ameliorated lesions in BLM-induced fibrotic lungs, reducing radiological signs of lung injury, alveolar septal thickening, and collagen deposition. In RNA-seq analysis, UL downregulated genes related to cell migration and ECM remodeling in TGF-β1-induced LL29 human lung fibroblasts. In particular, UL decreased cell migration, fibrotic marker expression, MMP-2 activity, and myofibroblast activation. In molecular modeling, UL interacted with key pharmacophores and the putative ATP-binding sites of the TβRI and TβRII kinase domains. Correspondingly, UL reduced the phosphorylation of key mediators in both the canonical (SMAD2/3) and non-canonical (ERK1/2 and PI3K) TGF-β signaling pathways. Furthermore, UL downregulated the PI3K/Akt/mTOR axis and promoted autophagy in TGF-β1-induced LL29 cells. Taken together, our findings demonstrate that UL acts as a novel TβRs inhibitor and shows therapeutic potential for pulmonary fibrosis.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118267"},"PeriodicalIF":6.9,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144308091","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":"Cabergoline counteracts adipose and skeletal muscle lipid accumulation: A novel therapeutic approach to obesity?","authors":"Mariarosaria Negri ,&nbsp;Claudia Pivonello ,&nbsp;Renata Simona Auriemma ,&nbsp;Feliciana Amatrudo ,&nbsp;Donatella Paola Provvisiero ,&nbsp;Roberta Patalano ,&nbsp;Maria Anna Marciano ,&nbsp;Guendalina Del Vecchio ,&nbsp;Laura Rinaldi ,&nbsp;Davide Menafra ,&nbsp;Antonio Feliciello ,&nbsp;Annamaria Colao ,&nbsp;Raffaella Crescenzo ,&nbsp;Rosario Pivonello","doi":"10.1016/j.biopha.2025.118243","DOIUrl":"10.1016/j.biopha.2025.118243","url":null,"abstract":"<div><h3>Objective</h3><div>Obesity represents a global health problem with large costs for public health. Cabergoline (CAB), a potent dopamine agonist with a high affinity for type 2 receptor (D2R), usually used in clinical practice for hyperprolactinemia management, has been reported to significantly decrease metabolic syndrome prevalence and visceral adiposity associated with improved insulin sensitivity in prolactinoma patients. Nevertheless, scant data are reported about CAB effects on obesity condition.</div></div><div><h3>Methods</h3><div>The current preclinical study investigated the <em>in vivo</em> chronic effects of CAB on obese rat models by exploring energy homeostasis and tissue molecular modifications. Simultaneously, the current study evaluated CAB's <em>in vitro</em> chronic effects on adipocyte and myocyte models by investigating cellular lipid accumulation, respiration and glucose internalization.</div></div><div><h3>Results</h3><div>This study demonstrated for the first time that CAB, chronically administered to an obese rat model, positively impacts body composition, energy balance, insulin secretion and sensitivity and lipid profile, while outlining the molecular mechanisms fundamentally based on the reduction of the expression of the main markers of lipid accumulation and on the activation of proteins classically involved in fat oxidation, PKA-Cα and pAMPKα Thr172. The <em>in vitro</em> study further demonstrated that treatment with CAB, alone or in combination with insulin, significantly reduces lipid accumulation both in adipocytes and myocytes, confirming the in vivo results by activating catabolic pathways, enhancing respiration in adipocytes and promoting glucose uptake in myocytes.</div></div><div><h3>Conclusions</h3><div>The current preclinical study demonstrated that chronic treatment with CAB improves metabolic disorders obesity-associated such as dyslipidemia and hyperinsulinemia by regulating the expression of lipid accumulation markers and reducing skeletal muscle ectopic lipid accumulation.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118243"},"PeriodicalIF":6.9,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144308092","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":"Animal models for preclinical research on multifactorial human conditions: The case of cardiovascular-kidney-metabolic syndrome","authors":"Magdalena Jasińska-Stroschein","doi":"10.1016/j.biopha.2025.118269","DOIUrl":"10.1016/j.biopha.2025.118269","url":null,"abstract":"<div><div>Cardiovascular-kidney-metabolic (CKM) syndrome is a combined disease condition in which diabetes impacts the cardiovascular and renal systems via a range of multiple pathways. However, no robust rodent phenotype that resembles CKM is currently available for preclinical research. The aim of the study is to determine the extent to which particular rodent models can replicate the multiple comorbidities of human CKM, including diabetes, obesity, dyslipidemia, hypertension, kidney and cardiovascular disease. Two databases were searched for experimental studies published between 1993 and 2024, and these were reviewed using sensitivity analysis (leave-one-out method) and publication bias across studies (Egger’s weighted regression and Duval and Tweedie ‘trim and fill’) according to the PRISMA Protocol. In total, data was extracted from 919 papers. The analysis included a wide spectrum of parameters (metabolic, cardiac and renal), and the possible associations between them. Substantial heterogeneity (P &lt; 0.0001) was observed among particular experimental approaches, and the fullest image of the condition, <em>viz.</em> significant body weight gain, and increased systolic blood pressure, blood glucose with HbA1c and triglyceride level, was demonstrated by rodents with mutations for the leptin gene (receptor) (<em>Lep</em>^{<em>ob/ob</em>}<em>, Lepr</em>^<em>db</em> mice or Ob-ZSF1, ZDF rats). Significant discrepancies were observed between models with regard to renal performance (P &lt; 0.0001), and most pronounced multifactorial effect was demonstrated by Ob-ZSF1 and Zucker diabetic fatty rats. There is an increasing need for development of multi-factorial animal models that are able to resemble the complexity of human conditions.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118269"},"PeriodicalIF":6.9,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144314098","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":"Antidiabetic sitagliptin influences tissue regeneration by affecting progenitor cells","authors":"Bárbara Torrecillas-Baena ,&nbsp;Victoria Pulido-Escribano ,&nbsp;José Manuel Quesada-Gómez ,&nbsp;Paloma Moreno-Moreno ,&nbsp;Aura D. Herrera-Martínez ,&nbsp;Gabriel Dorado ,&nbsp;María Ángeles Gálvez-Moreno ,&nbsp;Marta Camacho-Cardenosa ,&nbsp;Antonio Casado-Díaz","doi":"10.1016/j.biopha.2025.118279","DOIUrl":"10.1016/j.biopha.2025.118279","url":null,"abstract":"<div><h3>Background</h3><div>Diabetes mellitus may adversely affect the regenerative capacities of tissues, including skin healing and bone health (osteoporosis). Dipeptidyl peptidase-4 (DPP4) inhibitors (DPP4i) are antidiabetic drugs that increase the half-life of incretins, improving glucose levels. Several proteins that regulate important physiological processes are also substrates of DPP4. Therefore, DPP4i may have multiple effects. The aim of this work was to study if DPP4i sitagliptin affects regenerative capacities in a diabetic animal model. Thus, its effects on skin wound healing were evaluated. Likewise, if it produces changes in serum composition that might affect the viability and differentiation of endothelial cells and mesenchymal stem cells (MSC).</div></div><div><h3>Methods</h3><div>Diabetic rats were dorsally wounded and treated with sitagliptin. At day six, CD34⁺ cells and endothelial progenitor cells (EPC) were quantified in blood by flow cytometry. At day 14, blood serum and wound samples were obtained for histological analyses. In vitro studies of viability, apoptosis and angiogenesis in human umbilical-cord vein endothelial cells (HUVEC) and MSC capabilities of differentiation into adipocytes or osteoblasts were tested using rat sera.</div></div><div><h3>Results</h3><div>Sitagliptin treatments accelerated wound closure, decreased wound inflammation, and increased circulating EPC. Serum from sitagliptin-treated rats increased angiogenesis in HUVEC, while in MSC, it negatively affected osteogenic differentiation, promoting adipogenesis.</div></div><div><h3>Conclusions</h3><div>Sitagliptin treatment may have positive effects on ulcer healing in diabetics. However, the possible changes produced in serum composition may negatively affect bone formation. Therefore, sitagliptin may affect regenerative capacity and induce different responses in progenitor cells, depending on their niche.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118279"},"PeriodicalIF":6.9,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144308096","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":"Propionate suppresses colitis-associated colorectal cancer in mice by Or51e2","authors":"Ji-Sun Kim ,&nbsp;Mi-Young Jeong ,&nbsp;Ye Eun Yoon ,&nbsp;Yeonji Kim ,&nbsp;InRyeong Lee ,&nbsp;Jung-Won Choi ,&nbsp;Ha Lim Lee ,&nbsp;Min-Jeong Shin ,&nbsp;SungHoi Hong ,&nbsp;Sung-Gil Chi ,&nbsp;Sung-Joon Lee","doi":"10.1016/j.biopha.2025.118268","DOIUrl":"10.1016/j.biopha.2025.118268","url":null,"abstract":"<div><div>Dietary fiber intake is associated with a reduced risk of colorectal cancer (CRC), partly through the microbial fermentation of fiber into short-chain fatty acids (SCFAs). Among these, propionate binds to olfactory receptor 51E2 (Or51e2), which is ectopically expressed in the colon, but its role in CRC remains unclear. In this study, we evaluated Or51e2 expression in murine CT26 CRC cells and mouse colon tissues. Intracellular cAMP levels and CRE-luciferase activity were measured in CT26 and Or51e2-transfected Hana3A cells. The effects of propionate on proliferation, apoptosis, and MEK/ERK signaling were examined in CT26 cells. In vivo, a colitis-associated CRC model was established in wild-type (WT) and Or51e2-knockout (Or51e2 KO) mice using azoxymethane and dextran sulfate sodium (AOM/DSS). Propionate was administered intraperitoneally, and tumor burden, colon length, polyp number, histological changes, and MEK/ERK phosphorylation were assessed. Or51e2 expression was higher than other SCFA receptors in both CT26 cells and mouse colon tissues. Propionate treatment increased intracellular cAMP, activated CRE-luciferase, inhibited cell proliferation, induced apoptosis, and suppressed MEK/ERK phosphorylation in an Or51e2-dependent manner. In vivo, propionate reduced tumor growth, polyp formation, and MEK/ERK activation in WT mice, but not in Or51e2 KO mice. These findings suggest that Or51e2 mediates the anti-tumor effects of propionate through modulation of cAMP and MEK/ERK signaling, supporting its potential as a therapeutic strategy for CRC treatment.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118268"},"PeriodicalIF":6.9,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144308009","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":"Epac (RAPGEF3) promotes betaglycan expression to mediate ciprofloxacin-induced suppression of cancer cell migration and metastasis: Mechanistic insights and drug repurposing potential","authors":"Hui-Pu Liu ,&nbsp;Shun-Ban Tai ,&nbsp;Jun-Lin Jiang ,&nbsp;Shu-Farn Tey ,&nbsp;Pei-Feng Liu ,&nbsp;Ming-Wei Lin ,&nbsp;Shuen-Chiu Wu ,&nbsp;Yung-Che Chen ,&nbsp;Chun-Lin Chen","doi":"10.1016/j.biopha.2025.118261","DOIUrl":"10.1016/j.biopha.2025.118261","url":null,"abstract":"<div><div>Fluoroquinolones (FQs), potent antimicrobials, have shown potential in curbing cancer invasion and metastasis by affecting cell migration and extracellular matrix reshaping. However, the molecular mechanisms behind their impact remain unclear. The type III TGF-β receptor (TβR3, also called betaglycan), a co-receptor in the TGF-β superfamily, is often found to be downregulated in various human cancers. This receptor plays a crucial role in suppressing cancer progression and metastasis, independent of TGF-β signaling. In this study, we investigated the effects of ciprofloxacin (a member of FQs) on TβR3 production in cancer cells and their subsequent impact on cancer cell migration and invasion. Our results demonstrated that ciprofloxacin and other FQs dose-dependently elevated TβR3 levels, which was associated with reduced cell migration and invasion. Gene silencing and pharmacological approaches confirmed that exchange protein directly activated by cAMP (Epac) and JNK/AP1 pathways are critical for FQ-induced TβR3 expression. <em>In vivo</em> studies showed that mice receiving clinically relevant doses of ciprofloxacin exhibited elevated TβR3 levels in the liver and lung, which were associated with inhibited tumor progression. Furthermore, histological analysis of human non-small cell lung cancer (NSCLC) tissues revealed that metastatic lung cancers had lower TβR3 protein expression compared to matched normal lung tissues. Overall; our findings indicate that cancer invasion and malignancy are associated with reduced TβR3 levels, and that FQs can inhibit cancer cell migration and invasion by upregulating TβR3 expression. These results elucidate the potential for repositioning FQs as a supplemental therapeutic strategy in cancer treatment.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118261"},"PeriodicalIF":6.9,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144308093","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}