European journal of pharmacology最新文献

{"title":"The mitochondria-gut microbiota crosstalk – A novel frontier in cardiovascular diseases","authors":"Hrushikesh Kulkarni,&nbsp;Anil Bhanudas Gaikwad","doi":"10.1016/j.ejphar.2025.177562","DOIUrl":"10.1016/j.ejphar.2025.177562","url":null,"abstract":"<div><div>Cardiovascular diseases (CVDs), including hypertension, atherosclerosis, and cardiomyopathy among others, remain the leading cause of global morbidity and mortality. Despite advances in treatment, the complex pathophysiology of CVDs necessitates innovative approaches to improve patient outcomes. Recent research has uncovered a dynamic interplay between mitochondria and gut microbiota, fundamentally altering our understanding of cardiovascular health. However, while existing studies have primarily focused on individual components of this axis, this review examines the bidirectional communication between these biological systems and their collective impact on cardiovascular health. Mitochondria, serving as cellular powerhouses, are crucial for maintaining cardiovascular homeostasis through oxidative phosphorylation (OXPHOS), calcium regulation, and redox balance. Simultaneously, the gut microbiota influences cardiovascular function through metabolite production, barrier integrity maintenance, and immune system modulation. The mitochondria-gut microbiota axis operates through various molecular mechanisms, including microbial metabolites such as trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFA), and secondary bile acids, which directly influence mitochondrial function. Conversely, mitochondrial stress signals and damage-associated molecular patterns (DAMPs) affect gut microbial communities and barrier function. Key signalling pathways, including AMP-activated protein kinase (AMPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and the silent information regulator 1-peroxisome proliferator-activated receptor gamma coactivator 1-alpha (SIRT1-PGC-1α) axis, integrate these interactions, highlighting their role in CVD pathogenesis. Understanding these interactions has revealed promising therapeutic targets, suggesting new therapies aimed at both mitochondrial function and gut microbiota composition. Thus, this review provides a comprehensive framework for leveraging the mitochondria-gut microbiota axis in providing newer therapeutics for CVDs by targeting the AMPK/SIRT-1/PGC-1α/NF-κB signalling.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"998 ","pages":"Article 177562"},"PeriodicalIF":4.2,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Minocycline treatment attenuates high-refined carbohydrate diet-induced gut bacterial dysbiosis, anxiety-like behaviour, and cardiac damage in mice","authors":"Alessandra Oliveira Silva ,&nbsp;Jéssyca Milene Ribeiro ,&nbsp;Nícia Pedreira Soares ,&nbsp;Karla Caroline Marques Oliveira ,&nbsp;Patrícia Ferreira Espuri ,&nbsp;Thiago Caetano Andrade Belo ,&nbsp;Luis Felipe Cunha dos Reis ,&nbsp;Daniele Cristina de Aguiar ,&nbsp;Fernanda Borges de Araújo Paula ,&nbsp;Sílvia Graciela Ruginsk ,&nbsp;Leonardo Augusto de Almeida ,&nbsp;Marcos José Marques ,&nbsp;Antunes-Rodrigues José ,&nbsp;Lucila Leico Kagohara Elias ,&nbsp;Larissa Helena Lobo Torres ,&nbsp;Stefany Cau ,&nbsp;Carla Speroni Ceron","doi":"10.1016/j.ejphar.2025.177552","DOIUrl":"10.1016/j.ejphar.2025.177552","url":null,"abstract":"<div><div>The high-refined carbohydrate diet (HC diet) is linked to anxiety development and oxidative damage to heart tissue. However, little is known about how the gut microbiota profile is modulated in this diet model. Minocycline is an antibiotic with anti-inflammatory, antioxidant, and matrix metalloproteinases (MMPs) inhibitor properties. Therefore, we evaluated the effects of minocycline treatment on HC diet-induced cardiac damage, anxiety-like behaviour, and bacterial gut dysbiosis in mice. Male BALB/C mice were divided into two groups, which received standard diet or HC diet for 12 weeks. In the 10th week, both groups were subdivided and received water or minocycline (50 mg/kg) by gavage for 15 days. The gut bacterial populations, behavioural parameters, adiposity index, biochemical profile, cardiac oxidative stress indicators, MMPs, cardiac remodelling, and contractile analyses by Langendorff-perfused hearts were analysed. The HC diet induced bacterial gut dysbiosis and anxiety-like behaviour increased the adiposity index with changes in the lipid profile and creatine kinase fraction MB (CK-MB). In the heart, the HC diet increased tissue oxidative stress, MMP-2 and MMP-9 activity, collagen deposition, and altered cardiac performance. Minocycline treatment reversed diet-induced bacterial gut dysbiosis and anxiety-like behaviour, ameliorated the biochemical profile, diminished oxidative stress, MMP activity, cardiac collagen deposition, and improved cardiac performance. These findings suggest that minocycline treatment modulated the microbiota and attenuated behavioural changes and cardiac damage caused by the HC diet, suggesting an interplay between the gut-microbiota-brain axis and cardiac damage caused by the HC diet consumption.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177552"},"PeriodicalIF":4.2,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143739975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transforming Growth Factor-β-mediated attenuation of cardio-renal oxidative stress, inflammation and fibrosis by L-arginine in fludrocortisone acetate induced-hypertensive rats","authors":"Astrid Mukta Biswas,&nbsp;Tushar Emran,&nbsp;Sabrin Islam Khan,&nbsp;Sadia Shabnam,&nbsp;Preeti Jain,&nbsp;Asim Kumar Bepari,&nbsp;Manik Chandra Shill,&nbsp;Md Murad Hossain,&nbsp;Hasan Mahmud Reza","doi":"10.1016/j.ejphar.2025.177559","DOIUrl":"10.1016/j.ejphar.2025.177559","url":null,"abstract":"<div><div>Uncontrolled hypertension is a primary contributor to tissue damage in multiple organs, including the heart and kidneys. In this study, we explored the protective roles of L-arginine in a mineralocorticoid-induced rat model of hypertension. To induce hypertension and subsequent organ damage, rats were nephrectomized unilaterally and fed with the mineralocorticoid fludrocortisone acetate and dietary salt (FCA-Salt). These rats were treated with L-arginine for 28 days, and subsequent tests were performed. Biochemical analysis revealed the increased level of inflammation and oxidative stress biomarkers in the plasma, heart, and kidney of the FCA-salt-treated rats. L-arginine treatment decreased the oxidative stress marker malondialdehyde (MDA) by 18 %, 22 %, and 18 % in the heart, kidney, and plasma, respectively. L-arginine also attenuated the advanced oxidative protein products (AOPP). The activity of superoxide dismutase (SOD) increased by 62 %, 45 %, and 16 % in the heart, kidney, and plasma, respectively, in the L-arginine-treated animals compared to the FCA-Salt group. Significant augmentation was also revealed for the nitric oxide (NO), catalase (CAT), and reduced glutathione (GSH). The plasma levels of the kidney function biomarkers uric acid and creatinine were significantly improved after L-arginine treatment. Furthermore, L-arginine remarkably reduced the elevated plasma cytokines IL-1β, IL-17A, TNF-α, and TGF-β1 in FCA-salt-induced hypertensive rats. Histopathological data showed a reduction in fibrosis and tissue damage by L-arginine in the FCA-salt-treated group. We propose that L-arginine could be an effective agent in preventing cardiac and renal dysfunction in hypertensive rats.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177559"},"PeriodicalIF":4.2,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of cmpd D6 (FH-001) as a efficiency enhancement and myelosuppression degradation small-molecule fms-like tyrosine kinase 3 inhibitor for the treatment of FLT3-ITD positive acute myeloid leukemia","authors":"Yanan Qi ,&nbsp;Xinyi Zhu ,&nbsp;Jingjing Han ,&nbsp;Yuanyuan Yan ,&nbsp;Mengting Cui ,&nbsp;Yanmei Hao ,&nbsp;Lin Yang ,&nbsp;Wenting Dai ,&nbsp;Hongyan Wu ,&nbsp;Yu Tao ,&nbsp;Qiwei He ,&nbsp;Chen Yu ,&nbsp;Fang Liu ,&nbsp;Fangtian Fan","doi":"10.1016/j.ejphar.2025.177541","DOIUrl":"10.1016/j.ejphar.2025.177541","url":null,"abstract":"<div><div>AML is the most common and lethal type of leukemia. The mutant of FLT3 kinase is the most common mutation in AML. Based on the structure analysis and deuteration modification of the cmpd 18 (CHMFL-FLT3-122), a potent and orally available FLT3 Kinase inhibitor, cmpd D6 (FH-001) was found, which demonstrated a remarkable inhibitory effect on the proliferation of FLT3 - ITD positive AML cancer cell lines. Specifically, it effectively suppressed the growth of the MV4-11 cell line (IC₅₀ = 42.8 nM versus 17.1 nM). Similarly, notable inhibitory activity was observed in the MOLM-13 (IC₅₀ = 20.8 nM versus 53.9 nM). More importantly, the IC₅₀ of cmpd D6 to inhibit FLT3 kinase was 338.689 nM and the IC₅₀ to inhibit c-KIT kinase was 3006.042 nM, which were much lower than the IC₅₀ of cmpd 18 to the two kinases, indicating that cmpd D6 may effectively avoid the synthetic lethal myelosuppression toxicity caused by FLT3/c-KIT double inhibition. Pharmacokinetic experiments showed that the deuterated cmpd D6 could prolong the half-life (T_1/2 = 4.333 h versus 3.646 h) and improve bioavailability (F = 42.51 % versus 35.93 %). Pharmacodynamic experiments of the three models showed that cmpd D6 (12.5 mg/kg) could significantly inhibit tumor growth compared with cmpd 18, and had no obvious toxicity. Based on the above results, cmpd D6 is a potential candidate drug for the future treatment of FLT3-ITD positive AML.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177541"},"PeriodicalIF":4.2,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of ferroptosis in breast cancer: Tumor progression, immune microenvironment interactions and therapeutic interventions","authors":"Yi Wang ,&nbsp;Chuanyun Tang ,&nbsp;Keqin Wang ,&nbsp;Xiaoan Zhang ,&nbsp;Lifang Zhang ,&nbsp;Xinghua Xiao ,&nbsp;Hui Lin ,&nbsp;Lixia Xiong","doi":"10.1016/j.ejphar.2025.177561","DOIUrl":"10.1016/j.ejphar.2025.177561","url":null,"abstract":"<div><div>Ferroptosis represents a distinctive and distinct form of regulated cellular death, which is driven by the accumulation of lipid peroxidation. It is distinguished by altered redox lipid metabolism and is linked to a spectrum of cellular activities, including cancer. In breast cancer (BC), with triple negative breast cancer (TNBC) being an iron-and lipid-rich tumor, inducing ferroptosis was thought to be a novel approach to killing breast tumor cells. However, in the recent past, a novel conceptual framework has emerged which posits that in addition to the promotion of tumor cell death, ferritin deposition has a potent immunosuppressive effect on the tumor immune microenvironment (TIME) via the influence on both innate and adaptive immune responses. TIME of BC includes various cell populations from both the innate and adaptive immune systems. In this review, the internal association between iron homeostasis and the progression of ferroptosis, along with the common inducers and protectors of ferroptosis in BC, are discussed in detail. Furthermore, a comprehensive analysis is conducted on the dual role of ferroptosis in immune cells and proto-oncogenic functions, along with an evaluation of the potential applications of immunogenic cell death-targeted immunotherapy in TIME of BC. It is anticipated that our review will inform future research endeavors that seek to integrate ferroptosis and immunotherapy in the management of BC.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177561"},"PeriodicalIF":4.2,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-inflammatory and anti-oxidant potential of dispiro-indanedione hybrid of parthenin via regulating Nrf2 and NF-κB/MAPK pathways","authors":"Diljeet Kumar ,&nbsp;Manzoor Ahmed ,&nbsp;Nusrit Iqbal Andrabi ,&nbsp;Chetan Paul Singh ,&nbsp;Diksha Saroch ,&nbsp;Yogesh P. Bharitkar ,&nbsp;Gurleen Kour ,&nbsp;Sreedhar Madishetti ,&nbsp;Asha Bhagat ,&nbsp;Sanket K. Shukla ,&nbsp;Zabeer Ahmed","doi":"10.1016/j.ejphar.2025.177547","DOIUrl":"10.1016/j.ejphar.2025.177547","url":null,"abstract":"<div><div>Steroidal and non-steroidal anti-inflammatory drugs are widely used for treating a spectrum of inflammatory conditions; however, their systemic adverse effects hinder their usage. Therefore, alternate therapeutic strategies are required to treat inflammatory disorders. Parthenin, a lactone derived from <em>Parthenium hysterophorus</em>, has demonstrated anti-inflammatory activity; however, its toxic nature limits its application. We proposed modifications of parthenin to enhance its efficacy while reducing toxicity<strong>.</strong> In this context, we screened parthenin derivatives for anti-inflammatory efficacy and identified dispiro-indanedione hybrid of parthenin (DIHP) as a potent anti-inflammatory agent. Macrophages were pre-treated with DIHP followed by LPS stimulation to evaluate the <em>in-vitro</em> anti-inflammatory and anti-oxidant activity. We assessed <em>in-vivo</em> anti-inflammatory effect of DIHP in carrageenan-induced paw edema and LPS-induced sepsis model. Our findings showed that DIHP exerts negligible effect on cell viability, effectively attenuates the production of inflammatory markers (NO, TNF-α, IL-6 &amp;IL-1β) and down-regulates NF-κB, MAPK pathways in <em>in-vitro</em> and <em>in-vivo</em> system. Additionally, DIHP inhibited LPS-induced generation of prostaglandin E2, leukotriene B4, ROS and upregulated the expression of superoxide dismutase, catalase, nuclear factor-E2-related factor 2 and peroxisome proliferator-activated receptor gamma. Furthermore, DIHP effectively reduced carrageenan-induced paw edema and curtailed the levels of liver, and kidney damage markers (AST, ALT, CRE, and BUN), protected the lung, liver and kidney against pathological damage and enhanced the survival rate in LPS-challenged mice. DIHP demonstrated comparable efficacy to dexamethasone in reducing inflammatory markers. In conclusion, our study strongly suggests that DIHP curtailed inflammation and oxidative stress by down regulating NF-κB and MAPK pathways and enhanced anti-oxidant response.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177547"},"PeriodicalIF":4.2,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug-associated hyperprolactinemia: A comprehensive disproportionality analysis based on the FAERS database","authors":"Jinhua Liu ,&nbsp;Liping Xue ,&nbsp;Xinyi Fang ,&nbsp;Cuixian Zheng ,&nbsp;Fanxiang Zeng ,&nbsp;Ying Liu ,&nbsp;Jinhua Zhang ,&nbsp;Huajiao Chen","doi":"10.1016/j.ejphar.2025.177551","DOIUrl":"10.1016/j.ejphar.2025.177551","url":null,"abstract":"<div><div>Hyperprolactinemia (HPRL) is a clinically significant adverse event that requires careful monitoring. This study aims to identify the medications associated with HPRL using data from the FDA Adverse Event Reporting System (FAERS) between 2004Q1 and 2024Q1. Disproportionality analysis was performed to identify potential drug signals. Sensitivity analysis was conducted to assess the stability and strength of HPRL signals associated with these medications, as well as to examine signal differences by age and gender through stratification. Time-to-onset (TTO) analysis was performed to investigate the factors affecting the onset of HPRL. Disproportionality analyses identified 39 drugs related to HPRL across six main anatomical systems, with the majority (N = 29) affecting the nervous system. Notably, most of these medications belong to psychotropic categories, including atypical antipsychotics (AAPs, N = 13), typical antipsychotics (TAPs, N = 5) and selective serotonin reuptake inhibitors (SSRIs, N = 5). Sensitivity analysis indicated that most signals remained robust, with risperidone exhibiting the strongest signal for HPRL, followed by amisulpride, paliperidone, fluphenazine, and thioridazine. Stratified analysis showed that females had stronger signals for HPRL. Compared to individuals aged 18–44, those aged ≥45 exhibited weaker signals, while the signals in minors varied by drug. TTO analysis revealed that AAP-related HPRL manifested earlier in females, with earlier onset observed in minors using AAPs or SSRIs. In conclusion, we identified and ranked drugs associated with HPRL, primarily psychotropic medications, and observed variations in signal strength and onset time across gender and age. These findings emphasize the importance of individualized HPRL screening based on specific medications, gender, and age.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177551"},"PeriodicalIF":4.2,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of CYP2C19 genotype on outcomes of treatment with ticagrelor versus clopidogrel in acute coronary syndrome patients with diabetes mellitus: A analysis in a large-scale, real-world study","authors":"Haofu Tian ,&nbsp;Miaohan Qiu ,&nbsp;Kun Na ,&nbsp;Zizhao Qi ,&nbsp;Kai Xu ,&nbsp;Haiwei Liu ,&nbsp;Xiaozeng Wang ,&nbsp;Jing Li ,&nbsp;Yi Li ,&nbsp;Yaling Han","doi":"10.1016/j.ejphar.2025.177546","DOIUrl":"10.1016/j.ejphar.2025.177546","url":null,"abstract":"<div><h3>Purpose</h3><div>This study evaluates the impact of CYP2C19 genotype on the outcomes of ticagrelor versus clopidogrel-based dual antiplatelet therapy (DAPT) in acute coronary syndrome (ACS) patients with diabetes mellitus (DM).</div></div><div><h3>Methods</h3><div>A total of 10,376 ACS patients with DM treated with ticagrelor (N = 2931) or clopidogrel (N = 7445) following percutaneous coronary intervention (PCI) were included. Patients were categorized by CYP2C19 genotype into non-carriers (N = 4326) and loss-of-function (LOF) allele carriers (N = 6050). The primary outcome was a composite of fatal or irreversible ischemic and bleeding events at 12 months, including cardiac death, myocardial infarction, stroke, and Bleeding Academic Research Consortium (BARC) types 3 or 5 bleeding.</div></div><div><h3>Results</h3><div>Among patients with normal CYP2C19 enzyme function, ticagrelor use compared with clopidogrel was not associated with a reduction of fatal or irreversible ischemic and bleeding events (hazard ratio [HR], 1.04; 95 % confidence interval [CI], 0.70 to 1.55; <em>p</em> = 0.85) with excessive risk of BARC type 2 bleeding (HR, 1.72; 95 % CI, 1.13 to 2.63; <em>p</em> = 0.01). Among patients carried CYP2C19 loss-of-function (LOF) alleles, those treated with ticagrelor were associated with a lower risk of fatal or irreversible ischemic and bleeding events (HR, 0.69; 95 % CI, 0.50 to 0.95; <em>p</em> = 0.02) and all-cause death (HR, 0.58; 95 % CI, 0.34 to 0.97; <em>p</em> = 0.04), albeit with a higher incidence of BARC type 2 bleeding (HR, 1.86; 95 % CI, 1.38 to 2.51; <em>p</em> = 0.0001).</div></div><div><h3>Conclusions</h3><div>The CYP2C19 genotype could be used to identify potential patients who would derive benefit from the ticagrelor-based antiplatelet strategy. Further research is warranted to trade off in bleeding complications from potent P2Y12 inhibitors.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177546"},"PeriodicalIF":4.2,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Iguratimod, a promising therapeutic agent for COVID-19 that attenuates excessive inflammation in mouse models","authors":"Seiya Oba ,&nbsp;Tadashi Hosoya ,&nbsp;Daisuke Kawata ,&nbsp;Yoji Komiya ,&nbsp;Hideyuki Iwai ,&nbsp;Ryuji Koike ,&nbsp;Sho Miyamoto ,&nbsp;Takayuki Kanno ,&nbsp;Akira Ainai ,&nbsp;Tadaki Suzuki ,&nbsp;Hideki Hasegawa ,&nbsp;Shinsuke Yasuda","doi":"10.1016/j.ejphar.2025.177537","DOIUrl":"10.1016/j.ejphar.2025.177537","url":null,"abstract":"<div><div>In severe COVID-19 patients, excessive inflammation can lead to multiorgan dysfunction. Current anti-inflammatory treatments like glucocorticoids partially improve the outcomes, while immune systems are compromised. We have identified that SARS-CoV-2-infected obese mice were a good model of the cytokine storm seen in COVID-19. Here, we revealed that iguratimod (IGU), an approved agent for rheumatoid arthritis, improved survival by attenuating inflammation with minimal immune suppression.</div><div>In this study, C57BL/6 mice were fed a high-fat diet (HFD) or a normal-fat diet (NFD) for ten weeks before being infected with a mouse-adapted SARS-CoV-2. IGU significantly improved survival rates and reduced lung inflammation in HFD-fed mice, with minimal impact on interferon-induced genes and viral load. Meanwhile, dexamethasone (DEX) did not improve survival, while it suppressed various immune reactions with different mechanisms to IGU. Interestingly, IGU-treated mice had fewer SARS-CoV-2 positive cells in the lung, although viral replication was comparable to the control mice. Neither IGU nor DEX inhibited the SARS-CoV-2 infection in Vero-E6 cells, unlike the antiviral agent, remdesivir. Of note, IGU was effective prophylactically and therapeutically in HFD mice, and showed beneficial effects in NFD-fed mice with a lethal dose exposure of SARS-CoV-2.</div><div>We demonstrated that IGU could be a promising treatment for severe COVID-19, especially in obese patients, by fine-tuning inflammation without compromising antiviral immunity. This study supports the possibility of drug repositioning for IGU COVID-19 beyond autoimmune diseases.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177537"},"PeriodicalIF":4.2,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into the itaconate family: Immunomodulatory mechanisms and therapeutic potentials","authors":"Chunlin Qian,&nbsp;Yueying Wang,&nbsp;Quan Yuan,&nbsp;Yuchen Guo,&nbsp;Yuan Wang","doi":"10.1016/j.ejphar.2025.177542","DOIUrl":"10.1016/j.ejphar.2025.177542","url":null,"abstract":"<div><div>The itaconate family, comprising itaconate derivatives, endogenous isomers, and other related compounds, has demonstrated substantial immunoregulatory properties. These compounds exhibit significant therapeutic potential in various disease models by modulating metabolic pathways, signal transduction cascades, and post-translational modifications. In this review, we delineate the structural characteristics and biological functions of the members of the itaconate family and elucidate their immunomodulatory mechanisms. Additionally, we summarize the immunomodulatory effects of the itaconate family across various disease categories, including cardiovascular, liver, respiratory, bone and cartilage, neurological, and autoimmune diseases. This review aims to deepen our understanding of the itaconate family and its potential applications, providing new perspectives and therapeutic strategies for inflammatory disorders and autoimmune diseases.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"997 ","pages":"Article 177542"},"PeriodicalIF":4.2,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}