Biomedicine & Pharmacotherapy最新文献

{"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}

{"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 ,&nbsp;Anna K. Drabczyk ,&nbsp;Przemysław Zaręba ,&nbsp;Jolanta Jaśkowska ,&nbsp;Grzegorz Satała ,&nbsp;Paula Zaręba ,&nbsp;Anna Więckowska ,&nbsp;Modesto de Candia ,&nbsp;Rosa Purgatorio ,&nbsp;Anna Boguszewska-Czubara ,&nbsp;Sylwia Sudoł-Tałaj ,&nbsp;Gniewomir Latacz ,&nbsp;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-HT₆. However, dual-action BuChE inhibitors and 5-HT₇ 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 IC₅₀ = 4.75 μM; 5-HT₇ <em>K</em>_i = 7 nM) and compound <strong>50</strong> (BuChE IC₅₀ = 2.53 μM; 5-HT₇ <em>K</em>_i = 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 ,&nbsp;Kitipong Soontrapa ,&nbsp;Sunisa Prasopporn ,&nbsp;Porncheera Chusorn ,&nbsp;Seiji Okada ,&nbsp;Siwanon Jirawatnotai ,&nbsp;Somponnat Sampattavanich ,&nbsp;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}

{"title":"The anti-atherosclerotic effect of chronic AT1 receptor blocker treatment also depends on the ACE2/Ang(1−7)/Mas axis","authors":"Tobias Klersy ,&nbsp;Leonie Achner ,&nbsp;Benedikt Fels ,&nbsp;Flavia Rezende ,&nbsp;Melina Lopez ,&nbsp;Natalia Alenina ,&nbsp;Frauke Spiecker ,&nbsp;Ines Stölting ,&nbsp;Walter Häuser ,&nbsp;Tobias Reinberger ,&nbsp;Zouhair Aherrahrou ,&nbsp;Carsten Kuenne ,&nbsp;Carl Vahldieck ,&nbsp;Urte Matschl ,&nbsp;Susanne Hille ,&nbsp;Michael Bader ,&nbsp;Ralf P. Brandes ,&nbsp;Oliver J. Müller ,&nbsp;Kristina Kusche-Vihrog ,&nbsp;Walter Raasch","doi":"10.1016/j.biopha.2025.117990","DOIUrl":"10.1016/j.biopha.2025.117990","url":null,"abstract":"<div><div>Blockade of AT₁-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^DY (2 ×10¹¹ VG) injections plus Western diet (WD) feeding (12w). Mice were treated (12w) with TEL or vehicle. Controls received no PCSK9^DY, 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^DY+WD but decreased by TEL. Cortical stiffness was also enhanced in all strains by AAV-PCSK9^DY+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^DY/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}

{"title":"Cannabidiol oil delays pancreatic islet dysfunction in Wistar rats under hypercaloric diet","authors":"Edgardo Cortes-Justo ,&nbsp;Rocío Ortiz-Butrón ,&nbsp;Alonso Vilches-Flores","doi":"10.1016/j.biopha.2025.117993","DOIUrl":"10.1016/j.biopha.2025.117993","url":null,"abstract":"<div><div>Hypercaloric diet (HCD) intake can lead to metabolic alterations, such as metabolic syndrome and type-2 diabetes mellitus. Phytocannabinoid cannabidiol (CBD) is a GPR55 receptor antagonist involved in insulin secretion and other functions in pancreatic islet. The therapeutic use of CBD has been suggested for diabetes, but little is known regarding its effects on pancreatic islet physiology. Our aim was to evaluate the effects of CBD oil on pancreatic islets, from Wistar rats under HCD. Male rats were divided in 4 groups: Normal diet vehicle-treated (control) and CBD-treated group. Rats under HCD were subdivided in treated with vehicle (HCD) and with CBD oil administered 21 mg/Kg orally, 0.5 ml in 3 days per week; controls received coconut oil as vehicle. Body weight, food intake, and water consumption were recorded. After 20 weeks, glucose tolerance curve was performed; serum insulin was determined by ELISA, and pancreas was removed for histological and gene expression analysis for insulin, glucagon, PDX-1, MafA and GPR55 receptor. CBD treatment reduced body weight and food intake but increased fluid consumption, independently of diets. In control group, CBD did not alter blood glucose and serum insulin, but modified expression for GPR55 receptor, glucagon, insulin and MafA. Rats under HCD and treated with CBD decreased glycaemia, insulinaemia, islets relative area, GPR55-positive cells, PDX-1 and MafA gene expression, meanwhile insulin and glucagon expression was increased. In conclusion, CBD ameliorated HCD effects through changes in insulin, glucagon and GPR55 receptor expressions. We assume CBD interacts with other receptors beside GPR55.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117993"},"PeriodicalIF":6.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143654883","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":"Chlorogenic acid attenuates 5-fluorouracil-induced intestinal mucositis in mice through SIRT1 signaling-mediated oxidative stress and inflammatory pathways","authors":"Che-Hsuan Lin ,&nbsp;Wen-Ping Jiang ,&nbsp;Nanae Itokazu ,&nbsp;Guan-Jhong Huang","doi":"10.1016/j.biopha.2025.117982","DOIUrl":"10.1016/j.biopha.2025.117982","url":null,"abstract":"<div><div>Mucositis, a common side effect of the chemotherapeutic drug 5-Fluorouracil (5-FU), causes severe and aggravating effects on mucosal cells in the oral cavity and intestine. This study in mice aimed to assess the antioxidant, anti-inflammatory, and mucosal protective properties of chlorogenic acid in mitigating 5-FU-induced intestinal mucositis. To investigate these potential protective effects, we developed a mouse model by administering an initial intraperitoneal (i.p.) injection of 5-FU, followed by daily i.p. injections of chlorogenic acid (10 and 20 mg/kg) for 10 consecutive days. Chlorogenic acid mitigated intestinal histopathological damage, reduced proinflammatory mediators and malondialdehyde (MDA) levels, and increased the glutathione (GSH) level by 5-FU. Chlorogenic acid treatment led to a significant reduction in the expression of inflammation-related proteins decreased oxidative stress-related proteins and, attenuated the expression of apoptosis and autophagy-related proteins in small intestinal tissues. Additional investigations are necessary to verify our findings and enhance our comprehension of how SIRT1 inhibition (EX-527) counteracts the anti-inflammatory effects of chlorogenic acid in intestinal tissues. In conclusion, our mice study has shown that chlorogenic acid exerts its protective effects on 5-FU-induced intestinal tissue damage, by reducing oxidative stress and inflammation through the modulation of multiple signaling pathways, including the TLR4/NF-κB/MAPK, AMPK/ SIRT1, and PI3K/AKT axis. These findings highlight the potential of chlorogenic acid as a therapeutic agent for mucositis, given its anti-inflammatory and antioxidant properties.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117982"},"PeriodicalIF":6.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143654884","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 phthalimide-triazole derivative obtained by click chemistry exhibits trypanocidal activity, induces autophagy and ameliorates Trypanosoma cruzi infection","authors":"Lucas Eduardo Bezerra de Lima ,&nbsp;Maria Letícia Gomes de Almeida ,&nbsp;Gleicyane Silva Gomes ,&nbsp;Pedro Henrique do Nascimento ,&nbsp;Carla Jasmine Oliveira e Silva ,&nbsp;Cecilãne Regina Dioclecia da Silva ,&nbsp;Yuri Mouzinho Ramos Tanaka ,&nbsp;Tatiany Patrícia Romão ,&nbsp;Thaíses Brunelle Santana de Lima ,&nbsp;Elmo Silvano de Araújo ,&nbsp;Patricia Lopes Barros de Araújo ,&nbsp;Paulo Euzébio Cabral Filho ,&nbsp;Vanderlan Nogueira Holanda ,&nbsp;Ronaldo Nascimento de Oliveira ,&nbsp;Regina Celia Bressan Queiroz de Figueiredo","doi":"10.1016/j.biopha.2025.117963","DOIUrl":"10.1016/j.biopha.2025.117963","url":null,"abstract":"<div><div>Chagas disease (CD), caused by <em>Trypanosoma cruzi,</em> remains a leading cause of cardiomyopathy and heart failure in Latin America. Since the 1970s, benznidazole (BNZ) and nifurtimox (NFX) have been the only chemotherapeutic agents used to treat CD. However, their toxicity and low effectiveness in the chronic phase of the disease, make the development of more efficient chemotherapeutics imperative. Here, we investigated the effects of 1,2,3-triazole hybrids, synthesized <em>via</em> click chemistry, containing either phthalimide (<strong>FT1</strong>, <strong>FT2</strong>, <strong>FT3, FT4)</strong> or naphthoquinone (<strong>NT1</strong>) moieties on <em>T. cruzi</em> and their cytotoxicity on mammalian cells. <strong>NT1</strong> and <strong>FT1</strong> were the most effective against intracellular parasite with an IC₅₀ = 31.1 and 189.2 µM, respectively. <strong>FT1</strong>-<strong>FT4</strong> showed low cytotoxicity to mammalian cells (CC₅₀ &gt; 754 µM), while <strong>NT1</strong> exhibited moderate toxicity (CC₅₀ ≥ 96.1 µM). <strong>FT1</strong> demonstrated the highest selectivity towards trypomastigotes and amastigotes with selectivity indexes (SeI) of 6.9 and 6.7, respectively. Ultrastructural analysis of trypomastigotes treated with <strong>FT1</strong> revealed mitochondrial alterations, lipid accumulation and Golgi complex disorganization. <strong>FT1</strong> also decreased the mitochondrial membrane potential, increased mitochondrial reactive oxygen species (ROS) production, and induced late apoptosis in trypomastigotes. In infected cardiac cells, <strong>FT1</strong> treatment led to degradation of amastigotes and Golgi disruption. An increase in autophagosomes in treated host cells and their interaction with intracellular parasites suggest that <strong>FT1</strong>-induced host cell autophagy may play a role in mitigating the infection and protecting cardiac cells from its deleterious effects.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117963"},"PeriodicalIF":6.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143637300","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":"Discovery of N-substituted-2-((arylethyl)amino)-2-(2-methoxyphenyl) acetamides: A novel family of antiplatelet agents","authors":"Lyanne Rodríguez ,&nbsp;Carlos Rodríguez ,&nbsp;Jhonny Azuaje ,&nbsp;Rubén Prieto-Díaz ,&nbsp;Antón L. Martínez ,&nbsp;María I. Loza ,&nbsp;José Brea ,&nbsp;David Reza ,&nbsp;Eddy Sotelo ,&nbsp;Eduardo Fuentes","doi":"10.1016/j.biopha.2025.117971","DOIUrl":"10.1016/j.biopha.2025.117971","url":null,"abstract":"<div><div>The development of new antiplatelet agents is essential due to the limitations of existing therapies and the high prevalence of thrombotic disorders. As part of a project aimed at harnessing multicomponent-assisted synthetic strategies for drug discovery, we identified a novel class of potent antiplatelet compounds. Herein we report the design, synthesis, and pharmacological evaluation of a new series of N-substituted-2-((arylethyl)amino)-2-(2-methoxyphenyl)acetamides, along with structure-activity relationship analysis and a preliminary investigation of their mechanism of action. The most active compounds, 7d, 9e, and 6f, exhibited IC₅₀ values of 0.92 ± 0.24, 0.59 ± 0.10, and 0.39 ± 0.07 µM, respectively, in serotonin (30 µM) plus collagen (1 µg/mL)-induced platelet aggregation assays, outperforming sarpogrelate (IC₅₀ 5.41 ± 1.25). Functional and binding studies confirmed that these compounds act as low-affinity, weak partial agonists at 5-HT_2A, suggesting their antiplatelet effects arise from serotonin-dependent pathways rather than direct 5-HT_2A receptor antagonism. Additional experiments confirmed that the selected compounds are non-cytotoxic and significantly suppress P-selectin expression and CD63 secretion, demonstrating inhibition of both early and late stages of platelet activation. These findings introduce a new mechanistic approach to platelet inhibition, expanding the chemical space for antiplatelet drug development. Further studies should focus on molecular target identification and combination therapy potential for thrombosis treatment.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117971"},"PeriodicalIF":6.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143637301","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":"Anti-inflammatory, antioxidant, and acute toxicity of Brugmansia arborea extracts from wild plants and shoots obtained by indirect organogenesis. A thermographic assay to anti-inflammatory evaluation","authors":"Mariana Zuleima Pérez-González ,&nbsp;María del Carmen Juárez-Vázquez ,&nbsp;Mariana Sánchez-Ramos ,&nbsp;Leonardo Moreno-Villalba ,&nbsp;María Adelina Jiménez-Arellanes","doi":"10.1016/j.biopha.2025.117972","DOIUrl":"10.1016/j.biopha.2025.117972","url":null,"abstract":"<div><div>Inflammation is a condition that affects a large percentage of the population, rendering the search for alternative treatments urgent. Medicinal plant such as <em>Brugmansia arborea</em> has been employed in traditional medicine, it is used to alleviate menstrual pain, acne, promote wound healing, and ease joint pain, headaches, and other ailments. Some alkaloids (mainly atropine, scopolamine, and nor-hyoscyamine) have been described. In this paper, the <em>in-vitro</em> cultivation from leaf explants of <em>B. arborea</em> through indirect organogenesis is described. From wild plants (BA) and shoots (BAB) their extracts were prepared, and were analyzed by thin-layer chromatography and gas chromatography-mass spectrometry, identifying 18 main metabolites. Antioxidant activity was assessed with EC₅₀ = 199.52 and 31.63 mg/mL for BA and BAB, respectively. Boths extracts showed a DL₅₀ &gt; 2 g/kg and is classified as non-toxic. In Acetylated and Hydrolyzed extracts, acetyl-rutin and kaempferol, respectively were identified. Anti-inflammatory activity was assayed employing carrageenan model. The ED₅₀ values were &lt; 158.48 mg/kg by BA, BAB, Ac-BA, and H-BA, being more active the hydrolyzed extract (ED₅₀ = 63.09 and 64.56 mg/kg) for females and male mice. In topical TPA model, the ED₅₀ value were &lt; 0.47 mg/ear for BA, BAB, Ac-BA, and H-BA. Thermographic analysis is a non-invasive, cheap, effective and reproducible method to evaluate the anti-inflammatory effect of substances, since it quantifies the increase in temperature in an inflammatory process, so this technique constitutes an alternative in the search for this type of agent.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117972"},"PeriodicalIF":6.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143637355","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":"Two concurrent mechanisms are responsible for the INa increase produced by dapagliflozin and empagliflozin in healthy and heart failure cardiomyocytes","authors":"Josu Rapún ,&nbsp;Sara Pérez-Martín ,&nbsp;Anabel Cámara-Checa ,&nbsp;Gorka San José ,&nbsp;Roberto Núñez-Fernández ,&nbsp;Teresa Crespo-García ,&nbsp;Adam Hoban ,&nbsp;Marcos Rubio-Alarcón ,&nbsp;Elena Martínez-Blanco ,&nbsp;Juan Tamargo ,&nbsp;F. Javier Díez-Guerra ,&nbsp;Begoña López ,&nbsp;Ricardo Gómez ,&nbsp;Arantxa González ,&nbsp;Eva Delpón ,&nbsp;Ricardo Caballero","doi":"10.1016/j.biopha.2025.117984","DOIUrl":"10.1016/j.biopha.2025.117984","url":null,"abstract":"<div><div>Dapagliflozin and empagliflozin exert many cardiovascular protective actions in heart failure (HF) patients. HF-induced electrical remodelling decreases the expression of Nav1.5 channels (encoded by <em>SCN5A</em>) that generate the cardiac Na⁺ current (I_Na) impairing excitability and promoting arrhythmias. We aimed to mechanistically decipher the peak I_Na increase produced by dapagliflozin and empagliflozin in healthy and HF cardiomyocytes. We recorded macroscopic and single-channel currents and action potentials (AP) using the patch-clamp technique and generated a mouse model of HF with reduced ejection fraction by transverse aortic constriction (TAC). Single-channel recordings showed that dapagliflozin and empagliflozin (1 μM) increased the open probability (<em>P</em>_o) of Nav1.5 channels by augmenting channel re-openings and the number of traces with openings and by doubling the open time constant, respectively. Both drugs increased <em>SCN5A</em> mRNA levels and the membrane expression of Nav1.5 channels. Empagliflozin also enhanced the cytoplasmic mobility of Nav1.5 channels. Molecular modelling and site-directed mutagenesis analysis demonstrated that both drugs bind to a previously unknown site at the Nav1.5 DIII-DIV fenestration. Dapagliflozin and empagliflozin hyperpolarized the resting membrane potential and increased the action potential amplitude in human cardiomyocytes derived from induced pluripotent stem cells. Importantly, in TAC cardiomyocytes dapagliflozin and empagliflozin restored the HF-reduced peak I_Na to control levels. Dapagliflozin and empagliflozin bind to a novel site within cardiac Nav1.5 increasing I_Na by augmenting the <em>P</em>_o and the membrane expression of the channels. We hypothesized that this unique effects could be of interest for the treatment of arrhythmias associated with decreased Nav1.5 channel expression.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117984"},"PeriodicalIF":6.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143637434","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}