Nelson Siukei Lam , Xinxin Long , Xin-Zhuan Su , Fangli Lu
{"title":"Corrigendum to “Melaleuca alternifolia (tea tree) oil and its monoterpene constituents in treating protozoan and helminthic infections” [Biomed. Pharmacother. 130 (2020) 1–13]","authors":"Nelson Siukei Lam , Xinxin Long , Xin-Zhuan Su , Fangli Lu","doi":"10.1016/j.biopha.2025.117974","DOIUrl":"10.1016/j.biopha.2025.117974","url":null,"abstract":"","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117974"},"PeriodicalIF":6.9,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694789","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}
Beatrice Di Marco , Filippo Marchetti , Stefania Costa , Erika Baldini , Anna Baldisserotto , Irene Gugel , Silvia Vertuani , Enrica Strettoi , Stefano Manfredini
{"title":"Dual-action steroid derivatives with anti-inflammatory and antioxidant potency: An in vitro study","authors":"Beatrice Di Marco , Filippo Marchetti , Stefania Costa , Erika Baldini , Anna Baldisserotto , Irene Gugel , Silvia Vertuani , Enrica Strettoi , 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 H<sub>2</sub>O<sub>2</sub> 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 , Fernanda Ferreira Evangelista , Stephanie Ortega Alves , Tayline Torres , Josinara do Espirito Santo Lobo , Kayo Thiago Ribeiro Perroni , 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 , Ya-Juan Wang , 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<sub>A</sub>Rs) are ligand-gated anion channels that mediate fast inhibitory neurotransmission in the mammalian central nervous system. GABA<sub>A</sub>Rs form heteropentameric assemblies comprising two α1, two β2, and one γ2 subunits as the most common subtype in mammalian brains. Proteostasis regulation of GABA<sub>A</sub>Rs involves subunit folding within the endoplasmic reticulum, assembling into heteropentamers, receptor trafficking to the cell surface, and degradation of terminally misfolded subunits. As GABA<sub>A</sub>Rs are surface proteins, their trafficking to the plasma membrane is critical for proper receptor function. Thus, variants in the genes encoding GABA<sub>A</sub>Rs 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<sub>A</sub>Rs. Additionally, emerging pharmacological approaches that restore proteostasis of pathogenic GABA<sub>A</sub>R 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, Vyoma Sharma, Nirmal Kumar Ganguly, 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}
Ji Hun Wi , Hyelim Lee , Ji Min Park , Yeonju Heo , Seongman Jo , Jeehee Lee , Yeseul Kim , Cheulhee Jung , Nam-Jung Kim , Gyu Yong Song , Pilho Kim , Hyejin Kim , Sanghee Lee
{"title":"Development of a TBK1 and ALK dual inhibitor for alleviating depressive behavior via anti-inflammatory effects","authors":"Ji Hun Wi , Hyelim Lee , Ji Min Park , Yeonju Heo , Seongman Jo , Jeehee Lee , Yeseul Kim , Cheulhee Jung , Nam-Jung Kim , Gyu Yong Song , Pilho Kim , Hyejin Kim , 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}
Federica Liotti , Maria Marotta , Mattia Costanzo , Chiara De Simone , Sara Zirpoli , Valentina De Falco , Rosa Marina Melillo , Nella Prevete
{"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 , Maria Marotta , Mattia Costanzo , Chiara De Simone , Sara Zirpoli , Valentina De Falco , Rosa Marina Melillo , 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}
Damian Kułaga , Anna K. Drabczyk , Przemysław Zaręba , Jolanta Jaśkowska , Grzegorz Satała , Paula Zaręba , Anna Więckowska , Modesto de Candia , Rosa Purgatorio , Anna Boguszewska-Czubara , Sylwia Sudoł-Tałaj , Gniewomir Latacz , Damian Plażuk
{"title":"Discovery of new dual butyrylcholinesterase (BuChE) inhibitors and 5-HT7 receptor antagonists as compounds used to treat Alzheimer’s disease symptoms","authors":"Damian Kułaga , Anna K. Drabczyk , Przemysław Zaręba , Jolanta Jaśkowska , Grzegorz Satała , Paula Zaręba , Anna Więckowska , Modesto de Candia , Rosa Purgatorio , Anna Boguszewska-Czubara , Sylwia Sudoł-Tałaj , Gniewomir Latacz , Damian Plażuk","doi":"10.1016/j.biopha.2025.117995","DOIUrl":"10.1016/j.biopha.2025.117995","url":null,"abstract":"<div><div>Alzheimer's disease is a neurodegenerative condition with no effective cure, and current therapies, like donepezil, only alleviate symptoms. Research has explored cholinesterase inhibitors and strategies targeting tau protein, often combining inhibitors with 5-HT receptor antagonists, particularly 5-HT<sub>6</sub>. However, dual-action BuChE inhibitors and 5-HT<sub>7</sub> antagonists have not been studied until now. This study evaluated such compounds in an animal model, focusing on two candidates: compound <strong>18</strong> (BuChE IC<sub>50</sub> = 4.75 μM; 5-HT<sub>7</sub> <em>K</em><sub>i</sub> = 7 nM) and compound <strong>50</strong> (BuChE IC<sub>50</sub> = 2.53 μM; 5-HT<sub>7</sub> <em>K</em><sub>i</sub> = 1 nM). Compound <strong>50</strong> showed robust cognitive improvements, enhancing memory consolidation and acquisition, particularly in reversing scopolamine-induced deficits. In contrast, compound <strong>18</strong> exhibited limited or dose-dependent efficacy, potentially limiting its applicability. These findings highlight the strong potential of compound <strong>50</strong> for cognitive enhancement therapies and suggest it warrants further investigation.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117995"},"PeriodicalIF":6.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143642276","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":"Vorinostat restores iNKT cell functionality in aggressive cholangiocarcinoma","authors":"Khin Su Su Htwe , Kitipong Soontrapa , Sunisa Prasopporn , Porncheera Chusorn , Seiji Okada , Siwanon Jirawatnotai , Somponnat Sampattavanich , Adisak Wongkajornsilp","doi":"10.1016/j.biopha.2025.117964","DOIUrl":"10.1016/j.biopha.2025.117964","url":null,"abstract":"<div><div>In this study, we explored the potential of histone deacetylase (HDAC) inhibitors, with a focus on Vorinostat, to restore the functionality of invariant natural killer T (iNKT) cells—a unique subset of T cells with potent anti-tumor activity that are often impaired within the tumor microenvironment. Using aggressive cholangiocarcinoma (CCA) cell lines lacking CD1d molecules, we observed a marked decline in iNKT cell reactivity within 48 h of exposure to CCA cells. Through a systematic approach that included the utilization of the L1000FWD search engine, Vorinostat emerged as a promising candidate for mitigating iNKT cell dysfunction. Vorinostat induced significant molecular alterations in iNKT-nonresponsive CCA cells, enhancing CD1d expression, the production of inflammatory cytokines and the activation of T cell receptor (TCR) signaling pathways. These changes effectively reactivated iNKT cells and restored their anti-tumor functionality. In the mouse xenograft model, combined treatment with Vorinostat significantly inhibited tumor growth. These findings suggest that Vorinostat may offer a novel therapeutic strategy for patients with cholangiocarcinoma who are resistant to conventional chemotherapy.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117964"},"PeriodicalIF":6.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143642275","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}
Tobias Klersy , Leonie Achner , Benedikt Fels , Flavia Rezende , Melina Lopez , Natalia Alenina , Frauke Spiecker , Ines Stölting , Walter Häuser , Tobias Reinberger , Zouhair Aherrahrou , Carsten Kuenne , Carl Vahldieck , Urte Matschl , Susanne Hille , Michael Bader , Ralf P. Brandes , Oliver J. Müller , Kristina Kusche-Vihrog , Walter Raasch
{"title":"The anti-atherosclerotic effect of chronic AT1 receptor blocker treatment also depends on the ACE2/Ang(1−7)/Mas axis","authors":"Tobias Klersy , Leonie Achner , Benedikt Fels , Flavia Rezende , Melina Lopez , Natalia Alenina , Frauke Spiecker , Ines Stölting , Walter Häuser , Tobias Reinberger , Zouhair Aherrahrou , Carsten Kuenne , Carl Vahldieck , Urte Matschl , Susanne Hille , Michael Bader , Ralf P. Brandes , Oliver J. Müller , Kristina Kusche-Vihrog , Walter Raasch","doi":"10.1016/j.biopha.2025.117990","DOIUrl":"10.1016/j.biopha.2025.117990","url":null,"abstract":"<div><div>Blockade of AT<sub>1</sub>-receptors by telmisartan (TEL) has anti-atherosclerotic efficacy. We investigated to what extent the ACE2/Ang1–7/Mas axis-dependent mechanism contributes to the TEL-induced protection of endothelial function.</div><div>Atherosclerosis was induced in C57BL/6 N, Mas-knock out (ko), and Ace2-ko mice by AAV-PCSK9<sup>DY</sup> (2 ×10<sup>11</sup> VG) injections plus Western diet (WD) feeding (12w). Mice were treated (12w) with TEL or vehicle. Controls received no PCSK9<sup>DY</sup>, chow-feeding, and vehicle-treatment. In the aortae of mice, the plaque burden was determined, RNAseq analyses were performed and functional properties were assessed by quantifying the mechanical properties of the endothelial surface by Atomic Force Microscopy.</div><div>Regardless of strain, plaque burden and total cholesterol were increased upon AAV-PCSK9<sup>DY</sup>+WD but decreased by TEL. Cortical stiffness was also enhanced in all strains by AAV-PCSK9<sup>DY</sup>+WD but reduced under TEL only in the C57BL/6 N, while remaining still high in both knockout strains. Plasma NO negatively correlated with cortical stiffness in C57BL/6 N, but not in transgenic mice. TNFα plasma levels and aortic MMP12 expression was increased in PCSK9<sup>DY</sup>/WD vehicle-treated controls and was normalized by TEL in C57BL/6 N but not in Mas-ko and Ace2-ko mice.</div><div>We conclude that TEL-induced reduction of endothelial stiffness occurred only in the C57BL/6 N but not in the Mas-ko and Ace2-ko mice. We suggest that the protective TEL effect is partly due to an Ang(1−7)/ACE2/Mas axis mediated mechanism. Since Mmp12 has well-known proatherogenic properties but was not altered in the two transgenic mouse lines, follow-up studies are required to further elucidate the correlation between Mmp12 and the Ang(1−7)/ACE2/Mas axis with respect to atherosclerosis.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117990"},"PeriodicalIF":6.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143654885","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}