Biomedicine & Pharmacotherapy最新文献

{"title":"S-hydroxychloroquine prevents the antiphospholipid thrombogenic complexes for antiphospholipid syndrome treatment","authors":"Ming-Shou Hsieh ,&nbsp;Heng-Wei Liu ,&nbsp;Fu-You Guo ,&nbsp;Deng-Pan Song ,&nbsp;Meng-Yuan Li ,&nbsp;Tsu-Yi Chao ,&nbsp;Iat-Hang Fong ,&nbsp;Yu-Sheng Chang ,&nbsp;Chi-Tai Yeh","doi":"10.1016/j.biopha.2025.117968","DOIUrl":"10.1016/j.biopha.2025.117968","url":null,"abstract":"<div><div>Clinically used in systemic lupus erythematosus (SLE), Hydroxychloroquine (HCQ) exerts antithrombotic effects by inhibiting anti-β2-glycoprotein I (anti-β2GPI) antibody binding to phospholipid bilayers. However, HCQ is a racemic mixture, with only one enantiomer offering therapeutic benefits, while the other may contribute to toxicity. The current study evaluated the thromboprophylactic efficacy of <em>R</em>-enantiomer Hydroxychloroquine (<em>R</em>-HCQ), <em>S</em>-enantiomer Hydroxychloroquine (<em>S</em>-HCQ), and racemic HCQ (Rac-HCQ), with a focus on their impact on APS-associated markers. Both <em>in vitro</em> and <em>in vivo</em> models were employed, with human umbilical vein endothelial cells (HUVECs) and mice immunized with human β2-glycoprotein I antibodies used to evaluate the formation of antiphospholipid thrombotic complexes and their modulation by HCQ enantiomers. <em>S</em>-HCQ significantly reduced β2GPI complex binding and restored the AnxA5 anticoagulant shield <em>in vitro</em>, demonstrating superior efficacy over <em>R</em>-HCQ in disrupting β2GPI/anti-β2GPI interactions and preventing endothelial dysfunction in APS models. Pretreatment of HUVECs with S-HCQ significantly attenuated the expression of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-6, interleukin-1 beta, and C-C motif ligand 2) and endothelial activation markers (intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin). <em>S</em>-HCQ alleviates endothelial dysfunction by reducing proinflammatory cytokines, endothelial activation markers, and NO production while downregulating iNOS expression, highlighting its potential to mitigate oxidative stress and thrombogenic activity in APS-related endothelial damage. <em>In vivo</em>, <em>S</em>-HCQ effectively reduced clot formation in the femoral veins of APS mouse models. Among the HCQ enantiomers tested, <em>S</em>-HCQ demonstrated superior efficacy in modulating inflammatory and angiogenic pathways, influencing the formation of antiphospholipid thrombotic complexes and mitigating thrombosis. These findings underscore the potential of <em>S</em>-HCQ as a therapeutic alternative for APS management.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117968"},"PeriodicalIF":6.9,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143685088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting polyunsaturated fatty acids desaturase FADS1 inhibits renal cancer growth via ATF3-mediated ER stress response","authors":"Gioia Heravi ,&nbsp;Zhenjie Liu ,&nbsp;Mackenzie Herroon ,&nbsp;Alexis Wilson ,&nbsp;Yang-Yi Fan ,&nbsp;Yang Jiang ,&nbsp;Nivisa Vakeesan ,&nbsp;Li Tao ,&nbsp;Zheyun Peng ,&nbsp;Kezhong Zhang ,&nbsp;Jing Li ,&nbsp;Robert S. Chapkin ,&nbsp;Izabela Podgorski ,&nbsp;Wanqing Liu","doi":"10.1016/j.biopha.2025.118006","DOIUrl":"10.1016/j.biopha.2025.118006","url":null,"abstract":"<div><h3>Objective</h3><div>Fatty Acid Desaturase 1 (FADS1) is a rate-limiting enzyme controlling the bioproduction of long-chain polyunsaturated fatty acids (PUFAs). Increasing studies suggest that FADS1 is a potential cancer target. Our previous research has demonstrated the significant role of FADS1 in cancer biology and patient survival, especially in kidney cancers. We aim to explore the underlying mechanism in this study.</div></div><div><h3>Method and results</h3><div>We found that pharmacological inhibition or knockdown of the expression of FADS1 significantly reduced the intracellular conversion of long-chain PUFAs, effectively inhibits renal cancer cell proliferation, and induces cell cycle arrest. The stable knockdown of FADS1 also significantly inhibits tumor formation <em>in vivo</em>. Mechanistically, we showed that while FADS1 inhibition induces endoplasmic reticulum (ER) stress, FADS1 expression is augmented by ER-stress inducer, suggesting a necessary role of PUFA production in response to ER stress. FADS1-inhibition sensitized cellular response to ER stress inducers, leading to cell apoptosis. Also, FADS1 inhibition-induced ER stress leads to activation of the PERK/eIF2α/ATF4/ATF3 pathway. Inhibiting PERK or knockdown of ATF3 rescued FADS1 inhibition-induced ER stress and cell growth suppression, while ATF3-overexpression aggravates the FADS1 inhibition-induced cell growth suppression and leads to cell death. Metabolomic analysis revealed that FADS1 inhibition results in decreased level of UPD-N-Acetylglucosamine, a critical mediator of the unfolded protein response, as well as impaired biosynthesis of nucleotides, possibly accounting for the cell cycle arrest.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that PUFA desaturation is crucial for rescuing cancer cells from persistent ER stress, supporting FADS1 as a new therapeutic target.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 118006"},"PeriodicalIF":6.9,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143685089","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":"Musashi inhibitor Ro 08–2750 attenuates triple-negative breast cancer cell proliferation and migration and acts as a novel chemo- and radiosensitizer","authors":"Kathrin A. Brücksken ,&nbsp;Mark Sicking ,&nbsp;Eberhard Korsching ,&nbsp;Mayra Cecilia Suárez-Arriaga ,&nbsp;Nancy A. Espinoza-Sánchez ,&nbsp;Anne Marzi ,&nbsp;Ezequiel M. Fuentes-Pananá ,&nbsp;Björn Kemper ,&nbsp;Martin Götte ,&nbsp;Hans Theodor Eich ,&nbsp;Burkhard Greve ,&nbsp;Fabian M. Troschel","doi":"10.1016/j.biopha.2025.118002","DOIUrl":"10.1016/j.biopha.2025.118002","url":null,"abstract":"<div><h3>Introduction</h3><div>The Musashi RNA-binding proteins contribute to proliferation, stemness, and therapy resistance in triple-negative breast cancer (TNBC) and have been associated with reduced overall survival in patients.</div></div><div><h3>Objectives</h3><div>Leveraging the availability of a Musashi inhibitor, Ro 08–2750, we here aimed to assess the therapeutic potential of Musashi protein inhibition in TNBC.</div></div><div><h3>Methods</h3><div>Cell proliferation and clonogenic survival were quantified at different concentrations of the inhibitor in primary, patient-derived breast cancer cultures as well as established TNBC cell lines. Flow cytometry, spheroid formation, MTT assays and digital holographic microscopy were used to assess inhibitor-induced functional effects, while RNA sequencing, dot blot and western blot assays confirmed gene expression changes.</div></div><div><h3>Results</h3><div>Ro 08–2750 affects cell proliferation and survival in a dose-dependent manner by upregulating apoptosis and inducing a cell cycle arrest. Cell migration was reduced as stemness markers were downregulated. Inhibitor treatment also increased DNA double strand breaks after downregulation of Musashi-associated DNA repair mechanisms. Accordingly, Ro 08–2750 acted as a radio- and chemosensitizer in combined treatment applications. Gene expression findings were consistent with observed functional changes.</div></div><div><h3>Conclusion</h3><div>Our results indicate that Musashi protein inhibition may attenuate tumor progression and sensitize cells to conventional breast cancer therapy, underlining the therapeutic potential of this approach.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 118002"},"PeriodicalIF":6.9,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143686001","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":"Delavirdine modifies action potential configuration via inhibition of IKr and Ito in canine ventricular myocytes","authors":"József Óvári ,&nbsp;Zsigmond Máté Kovács ,&nbsp;Csaba Dienes ,&nbsp;János Magyar ,&nbsp;Tamás Bányász ,&nbsp;Péter P. Nánási ,&nbsp;Balázs Horváth ,&nbsp;Geraldo Jorge Domingos ,&nbsp;Adam Feher ,&nbsp;Zoltan Varga ,&nbsp;Norbert Szentandrássy","doi":"10.1016/j.biopha.2025.117994","DOIUrl":"10.1016/j.biopha.2025.117994","url":null,"abstract":"<div><div>Delavirdine is an anti-HIV agent with structural similarity (presence of methanesulfonamide group) to well-known rapid delayed rectifier potassium current (<em>I</em>_Kr) inhibitors like dofetilide and E-4031. In spite of this and the fact, that <em>I</em>_Kr blockade can lead to long QT syndrome with a risk of early afterdepolarization, cardiac arrhythmia and even sudden cardiac death development, there is no information on the cardiac electrophysiological effects of the delavirdine. Therefore, we examined the concentration-dependent acute effects of delavirdine on action potential morphology and on the underlying ion currents in enzymatically dispersed canine ventricular cardiomyocytes, as well as in a hERG-channel- and NaV1.5-expressing cell lines. Delavirdine application in the µM concentration range resulted in rapid, potent and reversible blockade of expressed hERG channels. NaV1.5 channels were slightly reduced by delavirdine. Moreover, APD increase, reduction of maximal rates of phases 1 and 3 and a small increase of Plateau20 amplitude were detected in canine left ventricular isolated cardiomyocytes in a concentration-dependent manner. Accordingly, the delavirdine-sensitive current contained an early and transient, as well as a late outward component corresponding to phases 1 and 3 of the AP. These results support the delavirdine-evoked inhibition of <em>I</em>_Kr, transient outward potassium current as well as sodium current. As these concentrations are similar to therapeutic plasma values (7–30 µM), delavirdine application might carry some risk of cardiac side effects especially in HIV-infected patients with altered cardiac function or patients with co-administration of drugs metabolized by certain cytochrome P450 isoforms.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117994"},"PeriodicalIF":6.9,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143685090","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":"Dual-action steroid derivatives with anti-inflammatory and antioxidant potency: An in vitro study","authors":"Beatrice Di Marco ,&nbsp;Filippo Marchetti ,&nbsp;Stefania Costa ,&nbsp;Erika Baldini ,&nbsp;Anna Baldisserotto ,&nbsp;Irene Gugel ,&nbsp;Silvia Vertuani ,&nbsp;Enrica Strettoi ,&nbsp;Stefano Manfredini","doi":"10.1016/j.biopha.2025.117940","DOIUrl":"10.1016/j.biopha.2025.117940","url":null,"abstract":"<div><div>In a recent study, we obtained two novel cortisone-derived molecules: 1,9β,17,21- tetrahydroxy-4-methyl-19-nor-9β-pregna-1,3,5(10)-trien-11,20-dione(SCA)and 1,9β,17,20β,21-pentahydroxy-4-methyl-19-nor-9β-pregna-1,3,5(10)-trien-11-one(SCB). These compounds showed a dual activity combining potent anti-inflammatory and antioxidant properties, suggesting their potential as therapeutic agents for conditions characterized by inflammation and oxidative stress, such as severe ocular disorders. In this study, in vitro experiments using human ARPE-19 and mouse 661 W cell lines, which model the retinal pigment epithelium and retinal photoreceptors respectively, revealed that pretreatment with SCA and SCB under oxidative stress with H₂O₂ preserved cell viability, reduced intracellular ROS levels, maintained tight junction integrity and Trans Epithelial Electrical Resistance (TEER). Moreover, both compounds enhanced mitochondrial respiration, thereby improving cellular bioenergetics. These results indicate that SCA and SCB could provide an effective alternative to traditional corticosteroids in treating complications in which oxidative stress and inflammation are combined, including diseases such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Preclinical studies on animal models and trials on human ocular diseases are necessary to validate these findings in vivo and explore their therapeutic potential.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117940"},"PeriodicalIF":6.9,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674464","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":"Chemotherapy against Toxoplasma gondii: A bibliometric analysis of in vitro and mouse model studies (2015–2024)","authors":"Juliana Quero Reimão ,&nbsp;Fernanda Ferreira Evangelista ,&nbsp;Stephanie Ortega Alves ,&nbsp;Tayline Torres ,&nbsp;Josinara do Espirito Santo Lobo ,&nbsp;Kayo Thiago Ribeiro Perroni ,&nbsp;Rafael Meyer Mariante","doi":"10.1016/j.biopha.2025.117956","DOIUrl":"10.1016/j.biopha.2025.117956","url":null,"abstract":"<div><div>Toxoplasmosis, caused by <em>Toxoplasma gondii</em>, is a widespread parasitic infection with significant health impacts, especially in immunocompromised individuals. Chemotherapy remains the main treatment, but current therapies are limited by side effects and contraindications. This bibliometric analysis reviews research from 2015 to 2024 to identify key trends and future directions for <em>T. gondii</em> chemotherapy. We used the Web of Science Core Collection database to identify original articles on chemotherapy and <em>T. gondii</em> published in the last ten years. After screening, the data was transferred to visualization tools, including VOSviewer, Bibliometrix, and CiteSpace, for comprehensive analysis. Our analysis covered 433 articles from 164 journals, authored by 2,346 researchers from 577 institutions across 48 countries. China, Egypt, the USA, Iran, and Brazil made the largest contributions in terms of both publications and citation counts. Leading authors based on publication output include Andrew Hemphill (University of Bern, Switzerland), Ahmad Daryani (Mazandaran University of Medical Sciences, Iran), and Chunmei Jin (Yanbian University, China). The highest citation counts were attributed to Andrew Hemphill, Wesley Van Voorhis (University of Washington, USA), and Kayode Ojo (University of Washington). Key journals shaping this area include <em>Experimental Parasitology</em>, <em>Parasitology Research</em>, and <em>Antimicrobial Agents and Chemotherapy</em>. The most-cited article is from the <em>Journal of Medicinal Chemistry</em>, describing a novel inhibitor of Calcium-Dependent Protein Kinase 1 (CDPK1) as a promising toxoplasmosis treatment. Emerging topics include nanocarrier-based delivery systems and natural product derivatives. This study offers a comprehensive overview and visual analysis of chemotherapy and <em>T. gondii</em>, highlighting key areas for future research.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117956"},"PeriodicalIF":6.9,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674544","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":"Proteostasis regulation of GABAA receptors in neuronal function and disease","authors":"Xi Chen ,&nbsp;Ya-Juan Wang ,&nbsp;Ting-Wei Mu","doi":"10.1016/j.biopha.2025.117992","DOIUrl":"10.1016/j.biopha.2025.117992","url":null,"abstract":"<div><div>The γ-aminobutyric acid type A receptors (GABA_ARs) are ligand-gated anion channels that mediate fast inhibitory neurotransmission in the mammalian central nervous system. GABA_ARs form heteropentameric assemblies comprising two α1, two β2, and one γ2 subunits as the most common subtype in mammalian brains. Proteostasis regulation of GABA_ARs involves subunit folding within the endoplasmic reticulum, assembling into heteropentamers, receptor trafficking to the cell surface, and degradation of terminally misfolded subunits. As GABA_ARs are surface proteins, their trafficking to the plasma membrane is critical for proper receptor function. Thus, variants in the genes encoding GABA_ARs that disrupt proteostasis result in various neurodevelopmental disorders, ranging from intellectual disability to idiopathic generalized epilepsy. This review summarizes recent progress about how the proteostasis network regulates protein folding, assembly, degradation, trafficking, and synaptic clustering of GABA_ARs. Additionally, emerging pharmacological approaches that restore proteostasis of pathogenic GABA_AR variants are presented, providing a promising strategy to treat related neurological diseases.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117992"},"PeriodicalIF":6.9,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671995","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":"Unravelling the modified T cell receptor through Gen-Next CAR T cell therapy in Glioblastoma: Current status and future challenges","authors":"Bhavya Bhutani,&nbsp;Vyoma Sharma,&nbsp;Nirmal Kumar Ganguly,&nbsp;Rashmi Rana","doi":"10.1016/j.biopha.2025.117987","DOIUrl":"10.1016/j.biopha.2025.117987","url":null,"abstract":"<div><h3>Purpose</h3><div>Despite current technological advancements in the treatment of glioma, immediate alleviation of symptoms can be catered by therapeutic modalities, including surgery, chemotherapy, and combinatorial radiotherapy that exploit aberrations of glioma. Additionally, a small number of target antigens, their heterogeneity, and immune evasion are the potential reasons for developing targeted therapies. This oncologic milestone has catalyzed interest in developing immunotherapies against Glioblastoma to improve overall survival and cure patients with high-grade glioma. The next-gen CAR-T Cell therapy is one of the effective immunotherapeutic strategies in which autologous T cells have been modified to express receptors against GBM and it modulates cytotoxicity.</div></div><div><h3>Methods</h3><div>In this review article, we examine preclinical and clinical outcomes, and limitations as well as present cutting-edge techniques to improve the function of CAR-T cell therapy and explore the possibility of combination therapy.</div></div><div><h3>Findings</h3><div>To date, several CAR T-cell therapies are being evaluated in clinical trials for GBM and other brain malignancies and multiple preclinical studies have demonstrated encouraging outcomes.</div></div><div><h3>Implications</h3><div>CAR-T cell therapy represents a promising therapeutic paradigm in the treatment of solid tumors but a few limitations include, the blood-brain barrier (BBB), antigen escape, tumor microenvironment (TME), tumor heterogeneity, and its plasticity that suppresses immune responses weakens the ability of this therapy. Additional investigation is required that can accurately identify the targets and reflect the similar architecture of glioblastoma, thus optimizing the efficiency of CAR-T cell therapy; allowing for the selection of patients most likely to benefit from immuno-based treatments.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117987"},"PeriodicalIF":6.9,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674467","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":"Development of a TBK1 and ALK dual inhibitor for alleviating depressive behavior via anti-inflammatory effects","authors":"Ji Hun Wi ,&nbsp;Hyelim Lee ,&nbsp;Ji Min Park ,&nbsp;Yeonju Heo ,&nbsp;Seongman Jo ,&nbsp;Jeehee Lee ,&nbsp;Yeseul Kim ,&nbsp;Cheulhee Jung ,&nbsp;Nam-Jung Kim ,&nbsp;Gyu Yong Song ,&nbsp;Pilho Kim ,&nbsp;Hyejin Kim ,&nbsp;Sanghee Lee","doi":"10.1016/j.biopha.2025.117991","DOIUrl":"10.1016/j.biopha.2025.117991","url":null,"abstract":"<div><div>Polypharmacology offers innovative strategies for treating immune and inflammatory dysregulation in complex diseases. Here, we identified ALS-04, a dual inhibitor of TANK-binding kinase 1 (TBK1) and anaplastic lymphoma kinase (ALK), which are closely linked to stimulator of interferon genes (STING)-mediated immune responses. ALS-04 effectively suppressed 2’3’-cyclic GMP-AMP (cGAMP)- and lipopolysaccharide (LPS)-induced type I interferon and pro-inflammatory responses by targeting the STING-TBK1 and STING-ALK pathways. Furthermore, ALS-04 significantly alleviated depressive symptoms, including anhedonia and behavioral despair, in an LPS-induced mouse model of depression. These findings highlight the therapeutic potential of dual TBK1 and ALK inhibition in depression by modulating immune and inflammatory pathways.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117991"},"PeriodicalIF":6.9,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674548","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":"Formyl peptide receptor 1 signaling strength orchestrates the switch from pro-inflammatory to pro-resolving responses: The way to exert its anti-angiogenic and tumor suppressor functions","authors":"Federica Liotti ,&nbsp;Maria Marotta ,&nbsp;Mattia Costanzo ,&nbsp;Chiara De Simone ,&nbsp;Sara Zirpoli ,&nbsp;Valentina De Falco ,&nbsp;Rosa Marina Melillo ,&nbsp;Nella Prevete","doi":"10.1016/j.biopha.2025.117961","DOIUrl":"10.1016/j.biopha.2025.117961","url":null,"abstract":"<div><div>The well-paced trigger of inflammation resolution following an inflammatory response is crucial for tissue homeostasis and cancer. In gastrointestinal tumors the Formyl peptide receptor 1 (FPR1) stimulates an inflammation resolution response able to restrain cancer angiogenesis and growth. A preceding inflammatory signal is necessary for the induction of the pro-resolving response. However, if FPR1-induced inflammation resolution and tumor suppressor function require an early pro-inflammatory trigger and how this is achieved remains unknown. A ROS-dependent signaling is activated in response to FPR1 activation. In colorectal carcinoma (CRC) cells, we carefully analyzed this signal showing that FPR1 activation by the fMLF peptide induces biphasic ROS production: a first wave, early, mitochondrial (mROS), followed by a second, late, NADPH oxidase (NOX1)-dependent. mROS cause SHP2 phosphatase inactivation restraining its ability to dephosphorylate and inactivate SRC. SRC, in turn, allows the activation of RAS and Rac1 GTPases. RAS activates MAPK signaling, while Rac1 supports NOX1 activation, that causes the second wave of ROS, reinforcing this signaling cycle. Importantly, for the first time, we demonstrate that mROS production precedes and is necessary for pro-inflammatory mediators’ release, while NOX1-dependent ROS are only required for pro-resolving mediators’ synthesis. Pharmacological and genetic approaches and functional assays show that this signaling cascade is essential for the pro-resolving and anti-angiogenic properties of FPR1 in CRC. In conclusion, we show that FPR1 elicits pro-resolving effects in CRC activating two waves of ROS production characterized by different strength and kinetics, that parallel and are necessary for pro-inflammatory or pro-resolving mediators’ production.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117961"},"PeriodicalIF":6.9,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143654886","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}