European journal of pharmacology最新文献_第3页

Low molecular weight fucoidan induces M2 macrophage polarization to attenuate inflammation through activation of the AMPK/mTOR autophagy pathway. 低分子量褐藻糖胶通过激活AMPK/mTOR自噬途径诱导M2巨噬细胞极化，从而减轻炎症反应。

IF 4.2 3区医学

European journal of pharmacology Pub Date : 2024-11-14 DOI: 10.1016/j.ejphar.2024.177134

Mingyu Chen, Jiahao Wang, Pengfei Zhang, Zichao Jiang, Sijie Chen, Shuailong Liang, Tianliang Ma, Haiqin Liao, Wanlin Tan, Chengcheng Niu, Long Wang

{"title":"Low molecular weight fucoidan induces M2 macrophage polarization to attenuate inflammation through activation of the AMPK/mTOR autophagy pathway.","authors":"Mingyu Chen, Jiahao Wang, Pengfei Zhang, Zichao Jiang, Sijie Chen, Shuailong Liang, Tianliang Ma, Haiqin Liao, Wanlin Tan, Chengcheng Niu, Long Wang","doi":"10.1016/j.ejphar.2024.177134","DOIUrl":"10.1016/j.ejphar.2024.177134","url":null,"abstract":"<p><p>Fucoidan, a sulfated polysaccharide with a complex structure, has gradually become the focus of biomedical research due to its remarkable biological activity and low toxicity. In this research, it was noted that low molecular weight fucoidan (LMWF) exhibited significant antimicrobial effects on Methicillin-resistant Staphylococcus aureus (MRSA) and promoted polarization towards M2 macrophages, leading to a substantial reduction in inflammatory responses within the lipopolysaccharide (LPS)-activated macrophages. We further explored the mechanism underlying the anti-inflammation activity. Our findings indicated that LMWF significantly enhanced the phosphorylation level of AMP-activated protein kinase (AMPK), inhibited the phosphorylation of the mammalian target of rapamycin (mTOR), and enhanced the expression of LC3II. Meanwhile, Compound C (CC) substantially reversed the anti-inflammation effect of LMWF, indicating that the AMPK pathway plays a pivotal role in this effect. In in vivo research, LMWF revealed impressive anti-inflammatory potential. LMWF treatment significantly eliminated MRSA and ameliorated inflammatory symptoms in mice's MRSA-infected skin wound model. Further analysis using Western Blot (WB) indicated significant AMPK/mTOR signaling pathway activation in mice treated with LMWF, which led to accelerated polarization of macrophages from the M1 to the M2 phenotype. In summary, we systematically explored the mechanism by which LMWF exerts anti-inflammatory effects through in vitro and in vivo experiments. It was confirmed that LMWF effectively induced the conversion of macrophages to an anti-inflammatory M2 phenotype by activating the AMPK/mTOR pathway. Simultaneously, LMWF effectively eradicated MRSA and accelerated wound healing in mice. This finding provides an important theoretical basis for further research on fucoidan.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177134"},"PeriodicalIF":4.2,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638689","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}

引用次数: 0

Melittin suppresses aerobic glycolysis by regulating HSF1/PDK3 to increase chemosensitivity of NSCLC. Melittin 通过调节 HSF1/PDK3 来抑制有氧糖酵解，从而提高 NSCLC 的化疗敏感性。

IF 4.2 3区医学

European journal of pharmacology Pub Date : 2024-11-14 DOI: 10.1016/j.ejphar.2024.177084

Yuhan Wang, Jiaying Yuan, Jiao Liu, Xiaodan Li, Chuanqiang Zhou, Minxuan Qian, Zhangyan Zou, Changlian Lu, Gang Huang, Mingming Jin

{"title":"Melittin suppresses aerobic glycolysis by regulating HSF1/PDK3 to increase chemosensitivity of NSCLC.","authors":"Yuhan Wang, Jiaying Yuan, Jiao Liu, Xiaodan Li, Chuanqiang Zhou, Minxuan Qian, Zhangyan Zou, Changlian Lu, Gang Huang, Mingming Jin","doi":"10.1016/j.ejphar.2024.177084","DOIUrl":"10.1016/j.ejphar.2024.177084","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC), although considered non-immunogenic, is often resistant to chemotherapy agents during the course of treatment in clinical patients. Melittin (C<sub>131</sub>H<sub>229</sub>N<sub>39</sub>O<sub>31</sub>, CAS: 20449-79-0), the major component of honey bee venom, is a promising anticancer drug. However, the mechanism employed by melittin to reverse chemotherapy resistance of NSCLC cells remains unknown. In this study, the Cell Counting Kit 8, ethynyl deoxyuridine assay, and other assays were utilized to elucidate the melittin effects upon cell proliferation. Proteomics, lung cancer (LC) tissue chip, and Western blot analysis were used to identify potential targets of melittin. A549/DDP cells were employed to investigate the melittin effects against cisplatin resistance. Also, an in vivo animal experiment was conducted to further clarify the regulatory function of melittin towards cisplatin resistance of A549/DDP cells. Results showed that melittin inhibited malignant progression of A549/DDP cells by down-regulation of pyruvate dehydrogenase kinase 3 (PDK3)-mediated aerobic glycolysis and inhibition of heat shock factor 1 (HSF1) expression. The therapeutic effect of melittin was increased by combination with KNK437 and impaired chemotherapy resistance regarding A549/DDP cells via reversing aerobic glycolysis. The in vivo experiments confirmed that melittin incremented A549/DDP cell cisplatin sensitivities. Collectively, the data suggested that melittin suppressed aerobic glycolysis by regulating HSF1/PDK3, which incremented cisplatin sensitivity of A549/DDP cells. It may provide a new treatment method for chemotherapy resistance in clinical NSCLC patients.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177084"},"PeriodicalIF":4.2,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638692","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}

引用次数: 0

Insight into the molecular mechanism of anti-breast cancer therapeutic potential of substituted salicylidene-based compounds using cell-based assays and molecular docking studies 利用细胞分析和分子对接研究，深入了解取代的水杨醛基化合物抗乳腺癌治疗潜力的分子机制。

IF 4.2 3区医学

European journal of pharmacology Pub Date : 2024-11-13 DOI: 10.1016/j.ejphar.2024.177129

Emmanuel Mfotie Njoya , Hannah van Dyk , Jennifer Nambooze , Chika I. Chukwuma , Alice Brink , Tshepiso Jan Makhafola

{"title":"Insight into the molecular mechanism of anti-breast cancer therapeutic potential of substituted salicylidene-based compounds using cell-based assays and molecular docking studies","authors":"Emmanuel Mfotie Njoya , Hannah van Dyk , Jennifer Nambooze , Chika I. Chukwuma , Alice Brink , Tshepiso Jan Makhafola","doi":"10.1016/j.ejphar.2024.177129","DOIUrl":"10.1016/j.ejphar.2024.177129","url":null,"abstract":"<div><div>Targeting oxidative stress and inflammatory signaling pathways is an effective cancer prevention and therapy approach. The mechanism of action of synthesized salicylidene-based compounds was investigated in regulating key molecular targets of breast cancer development. Compounds (<strong>1</strong>), (<strong>4</strong>), (<strong>5</strong>), and (<strong>7</strong>) were found to be more cytotoxic to MCF-7 and 4T1 cells compared to non-cancerous Chang liver cells, while these compounds were cytotoxic to MDA-MB-231 cells, but with poor selectivity. The colony formation assay indicated that bioactive compounds induced significant damage to breast cancer cells, as observed by a reduction in the number of colonies compared to control cells. By inducing a concentration and time-dependent increase of luminescence and fluorescence of phosphatidylserine, and activating the expression of caspases-3, -7, -8, -9 in breast cancer cells, (<strong>1</strong>) and (<strong>7</strong>) have shown to induce caspase-dependent apoptosis. The downregulation of NF-kB-p65 and an upregulation of TP53 expression after exposure to bioactive compounds, demonstrated the suppression of two key targets of breast cancer development. Molecular docking studies revealed that selected protein targets strongly interact with bioactive compounds, and the estimated inhibition constants (Ki) of JAK2, STAT3, COX-2, HPV31 E6, EGFR1, TP53, and PARP1 were significantly decreased compared to acetylsalicylic acid. This could be a clear indication that these protein targets are implicated with antiproliferative efficacy, thereby warranting the potential of (<strong>1</strong>) and (<strong>7</strong>) to be used as anti-breast cancer drug candidates.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177129"},"PeriodicalIF":4.2,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617490","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}

引用次数: 0

Taxifolin attenuates hepatic ischemia-reperfusion injury by enhancing PINK1/Parkin-mediated mitophagy 紫杉叶素通过增强PINK1/Parkin介导的有丝分裂来减轻肝缺血再灌注损伤

IF 4.2 3区医学

European journal of pharmacology Pub Date : 2024-11-13 DOI: 10.1016/j.ejphar.2024.177100

Ruixin Zhang , Qi Fang , Lei Yao , Xiaolan Yu , Xingyun Liu , Mengting Zhan , Deng Liu , Qi Yan , Jian Du , Lijian Chen

{"title":"Taxifolin attenuates hepatic ischemia-reperfusion injury by enhancing PINK1/Parkin-mediated mitophagy","authors":"Ruixin Zhang , Qi Fang , Lei Yao , Xiaolan Yu , Xingyun Liu , Mengting Zhan , Deng Liu , Qi Yan , Jian Du , Lijian Chen","doi":"10.1016/j.ejphar.2024.177100","DOIUrl":"10.1016/j.ejphar.2024.177100","url":null,"abstract":"<div><h3>Background</h3><div>Hepatic ischemia-reperfusion (I/R) injury stands as a recurring clinical challenge in liver transplantation, leading to mitochondrial dysfunction and cellular imbalance. Mitochondria, crucial for hepatocyte metabolism, are significantly damaged during hepatic I/R and the extent of mitochondrial damage correlates with hepatocyte injury. PINK1/Parkin-mediated mitophagy, is a specialized form of cellular autophagy, that maintains mitochondrial quality by identifying and removing damaged mitochondria, thereby restoring cellular homeostasis. Taxifolin (TAX), a natural flavonoid, possesses antioxidant, anti-inflammatory and anticancer properties. This study aimed at investigating the effects of TAX on hepatic I/R and the underlying mechanisms.</div></div><div><h3>Methods</h3><div>C57BL/6 mice were pretreated with TAX or vehicle control, followed by 60 min of 70% hepatic ischemia. After 6 h of reperfusion, the mice were euthanized. In vitro, TAX-pretreated primary hepatocytes were subjected to oxygen glucose deprivation/reperfusion (OGD/R).</div></div><div><h3>Results</h3><div>Hepatic I/R caused mitochondrial damage and apoptosis in hepatocytes, but TAX pretreatment mitigated these effects by normalizing mitochondrial membrane potential and inhibiting reducing apoptotic protein expression. TAX exerted its protective effects by enhancing mitophagy via the PINK1/Parkin pathway. Moreover, silencing the PINK1 gene in primary hepatocytes reversed the beneficial effects of TAX.</div></div><div><h3>Conclusion</h3><div>The results of the study demonstrate that promoting mitophagy through the PINK1/Parkin pathway restores mitochondrial function and protects the liver from I/R, suggesting that it may have therapeutic potential for the treatment of hepatic I/R.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177100"},"PeriodicalIF":4.2,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615402","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}

引用次数: 0

Ellagic acid(EA) ameliorates Alzheimer's disease by reducing Aβ levels, oxidative stress and attenuating inflammation. 鞣花酸（EA）可通过降低 Aβ 水平、氧化应激和减轻炎症来改善阿尔茨海默病。

IF 4.2 3区医学

European journal of pharmacology Pub Date : 2024-11-13 DOI: 10.1016/j.ejphar.2024.177099

Yongbiao Li, Jie Zhang, Lan Zhang, Chengwei Hu, Linning Zhou, Yong Cheng, Qingshan Liu

{"title":"Ellagic acid(EA) ameliorates Alzheimer's disease by reducing Aβ levels, oxidative stress and attenuating inflammation.","authors":"Yongbiao Li, Jie Zhang, Lan Zhang, Chengwei Hu, Linning Zhou, Yong Cheng, Qingshan Liu","doi":"10.1016/j.ejphar.2024.177099","DOIUrl":"10.1016/j.ejphar.2024.177099","url":null,"abstract":"<p><strong>Background: </strong>Ellagic acid (EA) serves as a pivotal coenzyme for various dehydrogenases, influencing diverse biological processes. Recognized for its potential in impeding disease progression, EA's effectiveness and mechanism in treating 5xFAD remain elusive.</p><p><strong>Aim of the study: </strong>This study aims to investigate EA's potential roles and underlying mechanisms in mitigating symptoms associated with 5xFAD.</p><p><strong>Materials and methods: </strong>5 × FAD mice underwent a 12-week EA treatment regimen. The efficacy of EA against 5 × FAD was assessed through in vivo experiments, including Morris water maze and contextual fear conditioning tests for learning and memory abilities. Immunofluorescence (IF) and thioflavin staining examined changes in Aβ/neurons in brain tissue. RT‒qPCR evaluated inflammatory cytokine expression, while Bcl2/Bax protein levels were analyzed via Western blot (WB).</p><p><strong>Results: </strong>EA demonstrates promise in alleviating symptoms associated with 5xFAD. It significantly reduced the mice's escape latency in the Morris water maze, increased the frequency of crossings in the target quadrant, and prolonged freezing time in the contextual fear memory test. EA also improved neuronal pathology in the hippocampus and cortex, decreased neuronal loss, and reduced Aβ levels. Moreover, EA significantly increased MDA and SOD levels, effectively modulated the Bcl2/Bax ratio, and decreased the production of proinflammatory factors in brain tissue of 5xFAD model mice.</p><p><strong>In conclusion: </strong>Our findings highlight the potential therapeutic efficacy of EA in addressing 5xFAD-related nervous system disorders by targeting Aβ levels, oxidative stress, and inflammation.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177099"},"PeriodicalIF":4.2,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617473","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}

引用次数: 0

Tanshinone I inhibits the functions of T lymphocytes and exerts therapeutic effects on delayed-type hypersensitivity reaction via blocking STATs signaling pathways 丹参酮 I 可抑制 T 淋巴细胞的功能，并通过阻断 STATs 信号通路对迟发型超敏反应产生治疗效果。

IF 4.2 3区医学

European journal of pharmacology Pub Date : 2024-11-12 DOI: 10.1016/j.ejphar.2024.177128

Zihan Lu , Hanjing Liao , Mingliang Zhang , Manjing Huang , Meng Du , Yaqin Wang , Zongjie Zhao , Shepo Shi , Zhixiang Zhu

{"title":"Tanshinone I inhibits the functions of T lymphocytes and exerts therapeutic effects on delayed-type hypersensitivity reaction via blocking STATs signaling pathways","authors":"Zihan Lu , Hanjing Liao , Mingliang Zhang , Manjing Huang , Meng Du , Yaqin Wang , Zongjie Zhao , Shepo Shi , Zhixiang Zhu","doi":"10.1016/j.ejphar.2024.177128","DOIUrl":"10.1016/j.ejphar.2024.177128","url":null,"abstract":"<div><div>Delayed-type hypersensitivity (DTH) reactions are a kind of chronic inflammatory diseases initiated by antigens and antigen-specific T cells. Currently, the therapy of DTH reactions is limited by the poor curative effects and serious adverse reactions of existing agents. In this study, we investigated the regulatory effects of tanshinone Ⅰ, a natural compound isolated from <em>Salvia miltiorrhiza</em>, on the functions of multiple immune cells and its therapeutic effects on DNFB-induced DTH reaction, and then explored its immunosuppressive mechanisms. The results showed that tanshinone Ⅰ at 5–20 μM moderately inhibited the activation of macrophages and dendritic cells, but did not weaken the activation of neutrophils. Tanshinone Ⅰ at 1–4 μM intensively suppressed the activation, proliferation, and differentiation of CD4<sup>+</sup> and CD8<sup>+</sup> T cells, and slightly affected the functions of B cells. Tanshinone Ⅰ administration markedly alleviated the edema, inflammatory response, and the infiltrations of CD4<sup>+</sup> T cells, CD8<sup>+</sup> T cells, and CD11b<sup>+</sup> cells in ear tissues of mice which were induced DTH reactions by DNFB. Transcriptome analysis revealed that tanshinone Ⅰ strongly inhibited CD4<sup>+</sup> T cells to express genes involving in cell proliferation, metabolism, activation, and differentiation. Furthermore, immunoblotting analysis showed that tanshinone Ⅰ selectively inhibited the phosphorylation of STAT3 and STAT5 in CD4<sup>+</sup> T cells stimulated by anti-CD3e and anti-CD28 antibodies or IL-2. Collectively, tanshinone Ⅰ can strongly inhibit the functions of T lymphocytes, exert therapeutic effects on DTH reaction by blocking STATs signaling pathways, and has potential to be developed into therapeutic drug for DTH reactions.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177128"},"PeriodicalIF":4.2,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617515","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}

引用次数: 0

Neuroprotective potential of Epigenetic modulators, its regulation and therapeutic approaches for the management of Parkinson's disease 表观遗传调节剂的神经保护潜力、对帕金森病的调控和治疗方法。

IF 4.2 3区医学

European journal of pharmacology Pub Date : 2024-11-12 DOI: 10.1016/j.ejphar.2024.177123

Shobha Kumari , Sakshi Gupta , Rajesh Sukhija , Shaifali Gurjar , Sunil Kumar Dubey , Rajeev Taliyan

{"title":"Neuroprotective potential of Epigenetic modulators, its regulation and therapeutic approaches for the management of Parkinson's disease","authors":"Shobha Kumari , Sakshi Gupta , Rajesh Sukhija , Shaifali Gurjar , Sunil Kumar Dubey , Rajeev Taliyan","doi":"10.1016/j.ejphar.2024.177123","DOIUrl":"10.1016/j.ejphar.2024.177123","url":null,"abstract":"<div><div>The progressive degeneration of dopaminergic neurons in the substantia nigra region of the brain leads to a deficiency of dopamine and, ultimately, the onset of Parkinson's disease (PD). Since there is currently no cure for PD, patients all around the world are dealing with symptomatic management. PD progression is influenced by multiple elements, such as environmental, biological, chemical, genetic, and epigenetic factors. Epigenetics is gaining increased attention due to its role in controlling the expression of genes that contribute to PD. Recent advancements in our understanding of the brain network and its related conditions have shown that alterations in gene expression may occur independently of genetic abnormalities. Therefore, a thorough investigation has been carried out to explore the significance of epigenetics in all degenerative disorders. Epigenetic modifications are essential for regulating cellular homeostasis. Therefore, a deeper understanding of these modifications might provide valuable insights into many diseases and potentially serve as targets for therapeutic interventions. This review article focuses on diverse epigenetic alterations linked to the progression of PD. These abnormalities are supported by numerous research on the control of gene expression and encompass all the epigenetic processes. The beginning of PD is intricately associated with aberrant DNA methylation mechanisms. DNA methyltransferases are the enzymes that create and preserve various DNA methylation patterns. Integrating epigenetic data with existing clinical methods for diagnosing PD may aid in discovering potential curative medicines and novel drug development approaches. This article solely addresses the importance of epigenetic modulators in PD, primarily the mechanisms of DNMTs, their roles in the development of PD, and their therapeutic approaches; it bypasses other PD therapies.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177123"},"PeriodicalIF":4.2,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616704","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}

引用次数: 0

Intracellular delivery of a phospholamban-targeting aptamer using cardiomyocyte-internalizing aptamers 使用心肌细胞内化适配体在细胞内输送磷脂酰胆碱靶向适配体。

IF 4.2 3区医学

European journal of pharmacology Pub Date : 2024-11-12 DOI: 10.1016/j.ejphar.2024.177130

Takeshi Honda , Hiroki Sakai , Makoto Inui

{"title":"Intracellular delivery of a phospholamban-targeting aptamer using cardiomyocyte-internalizing aptamers","authors":"Takeshi Honda , Hiroki Sakai , Makoto Inui","doi":"10.1016/j.ejphar.2024.177130","DOIUrl":"10.1016/j.ejphar.2024.177130","url":null,"abstract":"<div><div>The sarco (endo)plasmic reticulum Ca<sup>2+</sup>-ATPase 2a (SERCA2a)–phospholamban (PLN) system within the sarcoplasmic reticulum is crucial for regulating intracellular Ca<sup>2+</sup> cycling in ventricular cardiomyocytes. Given that impaired Ca<sup>2+</sup> cycling is associated with heart failure, modulating SERCA2a activity represents a promising therapeutic strategy. Previously, we engineered an RNA aptamer (Apt30) that binds to PLN, thereby activating SERCA2a by alleviating PLN's inhibitory effect. However, Apt30 alone cannot reach intracellular PLN, necessitating the development of a mechanism for its specific internalization into cardiomyocytes.</div><div>Using the systematic evolution of ligands by exponential enrichment (SELEX) method, we isolated RNA aptamers capable of internalizing into cardiomyocytes. These aptamers demonstrated sub-micromolar EC<sub>50</sub> values for cardiomyocyte internalization and exhibited significantly reduced activity against various non-myocardial cells, highlighting their specificity for cardiomyocytes. Moreover, some of these cardiomyocyte-internalizing aptamers could be linked to Apt30 as a single RNA strand without compromising their internalization efficacy. Supplementing the culture medium with these hybrid aptamers enhanced Ca<sup>2+</sup> transients and contractile function in rat cardiomyocytes. These findings provide critical insights for developing novel therapeutics directly acting on PLN in cardiomyocytes, potentially compensating for the disadvantages of conventional methods that involve viral vector-mediated intracellular transduction or alterations in endogenous protein expression.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177130"},"PeriodicalIF":4.2,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617497","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}

引用次数: 0

Biochanin A inhibits excitotoxicity-triggered ferroptosis in hippocampal neurons 生物变色素 A 可抑制兴奋毒性触发的海马神经元铁突变。

IF 4.2 3区医学

European journal of pharmacology Pub Date : 2024-11-10 DOI: 10.1016/j.ejphar.2024.177104

Jun Pil Won, Han Jun Yoon, Hyuk Gyoon Lee, Han Geuk Seo

{"title":"Biochanin A inhibits excitotoxicity-triggered ferroptosis in hippocampal neurons","authors":"Jun Pil Won, Han Jun Yoon, Hyuk Gyoon Lee, Han Geuk Seo","doi":"10.1016/j.ejphar.2024.177104","DOIUrl":"10.1016/j.ejphar.2024.177104","url":null,"abstract":"<div><div>Excitatory neurotransmitter-induced neuronal ferroptosis has been implicated in multiple neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Although there are several reports pertaining to the pharmacological activities of biochanin A, the effects of this isoflavone on excitotoxicity-triggered neuronal ferroptosis remain unclear. In this study, we demonstrate that biochanin A inhibits ferroptosis of mouse hippocampal neurons induced by glutamate or the glutamate analog, kainic acid. Biochanin A significantly inhibited accumulation of intracellular iron and lipid peroxidation in glutamate- or kainic acid-treated mouse hippocampal neurons. Furthermore, biochanin A regulated the level of glutathione peroxidase 4, a master regulator of ferroptosis, by modulating its autophagy-dependent degradation. We observed that biochanin A reduced the glutamate-induced accumulation of intracellular iron by regulating expression of iron metabolism-related proteins including ferroportin-1, divalent metal transferase 1, and transferrin receptor 1. Taken together, these results indicate that biochanin A effectively inhibits hippocampal neuronal death triggered by glutamate or kainic acid. Our study is the first to report that biochanin A has therapeutic potential for the treatment of diseases associated with hippocampal neuronal death, particularly ferroptosis induced by excitatory neurotransmitter.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177104"},"PeriodicalIF":4.2,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617456","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}

引用次数: 0

4-Octyl itaconate inhibits vascular calcification partially via modulation of HMOX-1 signaling 衣康酸 4-辛酯部分通过调节 HMOX-1 信号抑制血管钙化。

IF 4.2 3区医学

European journal of pharmacology Pub Date : 2024-11-10 DOI: 10.1016/j.ejphar.2024.177122

Qianqian Dong , Fang Liu , Jiahui Zhu , Mingxi Li , An Chen , Liyun Feng , Zirong Lan , Yuanzhi Ye , Lihe Lu , Qingchun Liang , Jianyun Yan

{"title":"4-Octyl itaconate inhibits vascular calcification partially via modulation of HMOX-1 signaling","authors":"Qianqian Dong , Fang Liu , Jiahui Zhu , Mingxi Li , An Chen , Liyun Feng , Zirong Lan , Yuanzhi Ye , Lihe Lu , Qingchun Liang , Jianyun Yan","doi":"10.1016/j.ejphar.2024.177122","DOIUrl":"10.1016/j.ejphar.2024.177122","url":null,"abstract":"<div><div>Vascular calcification frequently occurs in patients with chronic conditions such as chronic kidney disease (CKD), diabetes, and hypertension and represents a significant cause of cardiovascular events. Thus, identifying effective therapeutic targets to inhibit the progression of vascular calcification is essential. 4-Octyl itaconate (4-OI), a derivative of itaconate, exhibits anti-inflammatory and antioxidant activity, both of which play an essential role in the progression of vascular calcification. However, the role and molecular mechanisms of 4-OI in vascular calcification have not yet been elucidated. In this study, we investigated the effects of exogenous 4-OI on vascular calcification using vascular smooth muscle cells (VSMCs), arterial rings, and mice. Alizarin red staining and western blot revealed that 4-OI inhibited calcification and osteogenic differentiation of human VSMCs. Similarly, 4-OI inhibited calcification of rat and human arterial rings and VitD<sub>3</sub>-overloaded mouse aortas. Mechanistically, RNA sequencing analysis revealed that 4-OI treatment is most likely to affect heme oxygenase 1 (HMOX-1) mRNA expression. The study demonstrated that 4-OI treatment increased HMOX-1 mRNA and protein levels, but suppressed inflammation and oxidative stress in VSMCs under osteogenic conditions. Moreover, HMOX-1 knockdown by siRNA or treatment with the HMOX-1 inhibitor ZnPP9 significantly reversed the suppression effect on calcification of VSMCs and aortas of VitD<sub>3</sub>-overloaded mice by 4-OI. Furthermore, HMOX-1 knockdown by siRNA markedly abrogated the inhibitory effect of 4-OI on inflammation in VSMCs. These findings suggest that 4-OI alleviates vascular calcification and inhibits oxidative stress and inflammation through modulation of HMOX-1, indicating its potential as a therapeutic target for vascular calcification.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177122"},"PeriodicalIF":4.2,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617396","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}

引用次数: 0