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Facile engineered macrophages-derived exosomes-functionalized PLGA nanocarrier for targeted delivery of dual drug formulation against neuroinflammation by modulation of microglial polarization in a post-stroke depression rat model. 在中风后抑郁大鼠模型中通过调节小胶质细胞极化靶向递送抗神经炎症的双重药物配方
Pub Date : 2024-10-01 Epub Date: 2024-09-08 DOI: 10.1016/j.biopha.2024.117263
Zhongyue Lv, Cui Zhao, Xiping Wu, Yinqi Chen, Cheng Zheng, Xiaoling Zhang, Yifei Xu, Lujia Zhu, Haifeng Wang, Guomin Xie, Wu Zheng

Post-stroke depression (POSD) is a common difficulty and most predominant emotional syndrome after stroke often consequences in poor outcomes. In the present investigation, we have designed and studied the neurologically active celastrol/minocycline encapsulated with macrophages-derived exosomes functionalized PLGA nanoformulations (CMC-EXPL) to achieve enhanced anti-inflammatory behaviour and anti-depressant like activity in a Rat model of POSD. The animal model of POSD was established through stimulating process with chronic unpredictable mild stress (CUM) stimulations after procedure of middle cerebral artery occlusion (MCAO). Neuronal functions and Anti-inflammation behaviours were observed by histopathological (H&E) examination and Elisa analyses, respectively. The anti-depressive activity of the nanoformulations treated Rat models were evaluated by open-field and sucrose preference test methods. Microglial polarization was evaluated via flow-cytometry and qRT-PCR observations. The observed results exhibited that prepared nanoformulations reduced the POSD-stimulated depressive-like activities in rat models as well alleviated the neuronal damages and inflammatory responses in the cerebral hippocampus. Importantly, prepared CMC-EXPL nanoformulation effectively prevented the M1 pro-inflammatory polarization and indorsed M2 anti-inflammatory polarization, which indicates iNOS and CD86 levels significantly decreased and upsurged Arg-1 and CD206 levels. CMC-EXPL nanoformulation suggestively augmented anti-depressive activities and functional capability and also alleviated brain inflammation in POSD rats, demonstrating its therapeutic potential for POSD therapy.

脑卒中后抑郁(POSD)是脑卒中后常见的一种困难和最主要的情绪综合征,往往会导致不良后果。在本研究中,我们设计并研究了具有神经活性的塞拉司琼/三环素与巨噬细胞衍生的外泌体功能化聚乳酸(PLGA)纳米制剂(CMC-EXPL),以在大鼠 POSD 模型中实现增强的抗炎行为和类似抗抑郁剂的活性。POSD动物模型是在大脑中动脉闭塞(MCAO)术后通过慢性不可预知轻度应激(CUM)刺激过程建立的。通过组织病理学(H&E)检查和 Elisa 分析分别观察了神经元功能和抗炎行为。纳米制剂处理大鼠模型的抗抑郁活性通过开场和蔗糖偏好试验方法进行评估。通过流式细胞仪和 qRT-PCR 观察评估了微神经胶质细胞的极化。观察结果表明,制备的纳米制剂降低了 POSD 刺激大鼠模型的抑郁样活动,并减轻了大脑海马的神经元损伤和炎症反应。重要的是,制备的CMC-EXPL纳米制剂能有效阻止M1促炎极化,支持M2抗炎极化,这表明iNOS和CD86水平显著下降,Arg-1和CD206水平上升。CMC-EXPL纳米制剂可增强POSD大鼠的抗抑郁活性和功能能力,缓解脑部炎症,显示了其治疗POSD的潜力。
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引用次数: 0
Glucose oxidase and MnO2 functionalized liposome for catalytic radiosensitization enhanced synergistic breast cancer therapy. 用于催化放射增敏的葡萄糖氧化酶和 MnO2 功能化脂质体增强了乳腺癌的协同治疗。
Pub Date : 2024-10-01 Epub Date: 2024-09-08 DOI: 10.1016/j.biopha.2024.117402
Lihua Shao, Dun Liu, Xuexue Liu, Xueyuan Wang, Xian Yang, Runyan Niu, Shaoping Yin, Peipei Xu, Yonghuan Mao, Xiao Du, Lin Yang

In recent years, the integration of radiotherapy and nanocatalytic medicine has gained widespread attention in the treatment of breast cancer. Herein, the glucose oxidase (GOx) and MnO2 nanoparticles co-modified multifunctional liposome of GOx-MnO2@Lip was constructed for enhanced radiotherapy. Introduction of GOx would not only elevate the glucose consumption to starve the cancer cells, but also increased the endogenous H2O2 level. Meanwhile, high intracellular GSH concentration facilitated the release of Mn2+ to amplify the cytotoxic ·OH through cascade catalytic reactions within the tumor microenvironment, resulting in a favorable tumor suppression rate of 74.45 %. Furthermore, the blood biochemical and blood routine demonstrated that GOx-MnO2@Lip had no obvious toxic side effects. Therefore, this work provided a potential vehicle for synergistic cancer starving therapy, chemodynamic therapy and radiotherapy for improving therapeutic efficacy of breast cancer.

近年来,放疗与纳米催化医学的结合在乳腺癌治疗中受到广泛关注。本文构建了葡萄糖氧化酶(GOx)和二氧化锰(MnO2)纳米颗粒共同修饰的多功能脂质体GOx-MnO2@Lip,用于增强放射治疗。引入 GOx 不仅会增加葡萄糖的消耗,使癌细胞处于饥饿状态,还会提高内源性 H2O2 的水平。同时,高浓度的细胞内 GSH 可促进 Mn2+ 的释放,通过肿瘤微环境中的级联催化反应放大细胞毒性-OH,使肿瘤抑制率达到 74.45%。此外,血液生化和血常规表明,GOx-MnO2@Lip 没有明显的毒副作用。因此,这项工作为协同癌症饥饿疗法、化学动力学疗法和放射疗法提高乳腺癌疗效提供了潜在的载体。
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引用次数: 0
Corrigendum to ''Spinosad blocks CHRNA5 mediated EGFR signaling pathway activation to inhibit lung adenocarcinoma proliferation'' [Biomed. Pharma. 177 (2024) 117105]. 对 "Spinosad 阻断 CHRNA5 介导的表皮生长因子受体信号通路激活以抑制肺腺癌增殖"[Biomed. Pharma. 177 (2024) 117105]的更正。
Pub Date : 2024-10-01 Epub Date: 2024-08-19 DOI: 10.1016/j.biopha.2024.117213
Hongling Zou, Yan Chen, Xinping Zhu, Xinyun Zhao, Jili Cao, Yuxin Chen, Ziru Zhang, Yongqiang Zhu, Qun Li, Mingqian Li
{"title":"Corrigendum to ''Spinosad blocks CHRNA5 mediated EGFR signaling pathway activation to inhibit lung adenocarcinoma proliferation'' [Biomed. Pharma. 177 (2024) 117105].","authors":"Hongling Zou, Yan Chen, Xinping Zhu, Xinyun Zhao, Jili Cao, Yuxin Chen, Ziru Zhang, Yongqiang Zhu, Qun Li, Mingqian Li","doi":"10.1016/j.biopha.2024.117213","DOIUrl":"10.1016/j.biopha.2024.117213","url":null,"abstract":"","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":" ","pages":"117213"},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142010112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Corrigendum to "Prenylated xanthones from mangosteen (Garcinia mangostana) target oxidative mitochondrial respiration in cancer cells" Biomed. Pharmacother. 179 (2024) 117365. 更正:"山竹果(Garcinia mangostana)中的异戊烯基黄酮具有靶向癌细胞氧化线粒体呼吸的作用" Biomed.Pharmacother.179 (2024) 117365.
Pub Date : 2024-10-01 Epub Date: 2024-09-14 DOI: 10.1016/j.biopha.2024.117441
Menna El Gaafary, Passent M Abdel-Baki, Ali M El-Halawany, Heba M Mohamed, Amira Duweb, Hossam M Abdallah, Gamal A Mohamed, Sabrin R M Ibrahim, Thomas Simmet, Tatiana Syrovets
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引用次数: 0
Corrigendum to "Salvianolic acid A improve mitochondrial respiration and cardiac function via inhibiting apoptosis pathway through CRYAB in diabetic cardiomyopathy" [Biomed. Pharmacother. (2023) 160 114382]. 丹酚酸 A 在糖尿病心肌病中通过 CRYAB 抑制细胞凋亡途径改善线粒体呼吸和心脏功能》[Biomed. Pharmacother. (2023) 160 114382]的更正。
Pub Date : 2024-10-01 Epub Date: 2024-09-10 DOI: 10.1016/j.biopha.2024.117435
Di-Fei Gong, Shu-Chan Sun, Ran-Ran Wang, Awaguli Dawuti, De-Wen Kong, Rui-Qi Liu, Li-da Du, Shou-Bao Wang, Yang Lu, Tian-Yi Yuan, Guan-Hua Du, Lian-Hua Fang
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引用次数: 0
Preparation of photo-controlled release ROS-responsive Ce6/elemene co-loaded liposomes and study on the effect on enhancing apoptosis of NMIBC. 制备光控释放 ROS 响应的 Ce6/elemene 共载脂质体并研究其对增强 NMIBC 细胞凋亡的作用。
Pub Date : 2024-10-01 Epub Date: 2024-09-08 DOI: 10.1016/j.biopha.2024.117398
Xiulin Zhang, Wei Mei, Dongyan Guo, Jing Sun, Yajun Shi, Xiaofei Zhang, Junbo Zou, Jiangxue Cheng, Fei Luan, Bingtao Zhai, Huan Tian

At present, chemotherapy combined with photodynamic therapy is exerting satisfactory therapeutic effects in the treatment of tumors. Chlorin e6 (Ce6) is a photosensitizer with high efficiency and low dark toxicity. At the same time, elemene (ELE) contains high-efficiency and low-toxicity anti-cancer active ingredients, which can effectively penetrate tumor tissue and inhibit its recovery and proliferation. Due to the poor water solubility of these two drugs, we prepared ELE/Ce6 co-loaded liposomes (Lipo-ELE/Ce6) to improve their water solubility, thereby enhancing the anti-tumor effect. The characterization of Lipo-ELE/Ce6 showed that Lipo-ELE/Ce6 had suitable encapsulation efficiency (EE), particle size, polydispersity (PDI), zeta potential, and good photo-controlled release properties. In vitro, Lipo-ELE/Ce6 effectively inhibited the growth of T24 cells and induced apoptosis, and more importantly, in vivo experiments showed that Lipo-ELE/Ce6 had significant anti-tumor effects, which was significantly better than free drugs. The above results suggest that Lipo-ELE/Ce6 can significantly enhance the induction of apoptosis of non-muscle invasive bladder cancer (NMIBC) by light-controlled release and ROS response.

目前,化疗结合光动力疗法在治疗肿瘤方面取得了令人满意的疗效。氯素 e6(Ce6)是一种高效、低暗毒性的光敏剂。同时,榄香烯(ELE)含有高效低毒的抗癌活性成分,能有效渗透肿瘤组织,抑制肿瘤的恢复和增殖。由于这两种药物的水溶性较差,我们制备了ELE/Ce6共载脂质体(Lipo-ELE/Ce6),以提高其水溶性,从而增强抗肿瘤效果。Lipo-ELE/Ce6的表征结果表明,Lipo-ELE/Ce6具有合适的包封效率(EE)、粒度、多分散性(PDI)、Zeta电位和良好的光控释放特性。体外实验表明,Lipo-ELE/Ce6能有效抑制T24细胞的生长并诱导细胞凋亡,更重要的是,体内实验表明,Lipo-ELE/Ce6具有显著的抗肿瘤作用,明显优于游离药物。上述结果表明,Lipo-ELE/Ce6 可通过光控释放和 ROS 反应显著增强非肌层浸润性膀胱癌(NMIBC)的细胞凋亡诱导作用。
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引用次数: 0
Intrathecal administration of MCRT produced potent antinociception in chronic inflammatory pain models via μ-δ heterodimer with limited side effects. 在慢性炎症性疼痛模型中,鞘内给药 MCRT 可通过 μ-δ 异二聚体产生强效抗镇痛作用,且副作用有限。
Pub Date : 2024-10-01 Epub Date: 2024-09-08 DOI: 10.1016/j.biopha.2024.117389
Yaofeng Zhao, Zhonghua Zhang, Dingnian Gou, Pengtao Li, Tong Yang, Zhanyu Niu, Jerine Peter Simon, Xuyan Guan, Xinyu Li, Chunbo He, Shouliang Dong

An important goal in the opioid field is to discover effective analgesic drugs with minimal side effects. MCRT demonstrated potent antinociceptive effects with limited side effects, making it a promising candidate. However, its pharmacological properties and how it minimizes side effects remain unknown. Various mouse pain and opioid side effect models were used to evaluate the antinociceptive properties and safety at the spinal level. The targets of MCRT were identified through cAMP measurement, isolated tissue assays, and pharmacological experiments. Immunofluorescence was employed to visualize protein expression. MCRT displayed distinct antinociceptive effects between acute and chronic inflammatory pain models due to its multifunctional properties at the μ opioid receptor (MOR), µ-δ heterodimer (MDOR), and neuropeptide FF receptor 2 (NPFFR2). Activation of NPFFR2 reduced MOR-mediated antinociception, leading to bell-shaped response curves in acute pain models. However, activation of MDOR produced more effective antinociception in chronic inflammatory pain models. MCRT showed limited tolerance and opioid-induced hyperalgesia in both acute and chronic pain models and did not develop cross-tolerance to morphine. Additionally, MCRT did not exhibit addictive properties, gastrointestinal inhibition, and effects on motor coordination. Mechanistically, peripheral chronic inflammation or repeated administration of morphine and MCRT induced an increase in MDOR in the spinal cord. Chronic administration of MCRT had no apparent effect on microglial activation in the spinal cord. These findings suggest that MCRT is a versatile compound that provides potent antinociception with minimal opioid-related side effects. MDOR could be a promising target for managing chronic inflammatory pain and addressing the opioid crisis.

阿片类药物领域的一个重要目标是发现副作用最小的有效镇痛药物。MCRT 具有强效镇痛作用,但副作用有限,因此是一种很有前途的候选药物。然而,它的药理特性以及如何将副作用降至最低仍是未知数。我们使用了各种小鼠疼痛和阿片类药物副作用模型来评估脊髓水平的抗痛特性和安全性。通过 cAMP 测量、分离组织测定和药理实验确定了 MCRT 的靶点。免疫荧光技术用于观察蛋白质的表达。由于 MCRT 在μ 阿片受体(MOR)、μ-δ 杂二聚体(MDOR)和神经肽 FF 受体 2(NPFFR2)上的多功能特性,它在急性和慢性炎症性疼痛模型中显示出不同的抗痛觉作用。激活 NPFFR2 会降低 MOR 介导的抗痛作用,从而导致急性疼痛模型出现钟形反应曲线。然而,在慢性炎症性疼痛模型中,激活 MDOR 能产生更有效的抗痛作用。在急性和慢性疼痛模型中,MCRT 表现出有限的耐受性和阿片类药物诱导的痛觉减退,并且不会对吗啡产生交叉耐受。此外,MCRT 不表现出成瘾性、胃肠道抑制和对运动协调的影响。从机理上讲,外周慢性炎症或反复给予吗啡和 MCRT 会诱导脊髓中 MDOR 的增加。长期服用 MCRT 对脊髓中的小胶质细胞活化没有明显影响。这些研究结果表明,MCRT 是一种多功能化合物,可提供强效抗痛作用,而与阿片类药物相关的副作用却很小。MDOR可能是治疗慢性炎症性疼痛和解决阿片类药物危机的一个很有前景的靶点。
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引用次数: 0
Transcriptome analysis reveals the anti-Parkinson's activity of Mangiferin in zebrafish. 转录组分析揭示了芒果苷在斑马鱼体内的抗帕金森病活性。
Pub Date : 2024-10-01 Epub Date: 2024-09-08 DOI: 10.1016/j.biopha.2024.117387
Fengqing Qin, Ming Zhang, Pei Wang, Ziru Dai, Xi Li, Dongliang Li, Lijun Jing, Cen Qi, Heliang Fan, Mei Qin, Ying Li, Likun Huang, Tianci Wang

As the global population ages, the incidence of Parkinson's Disease (PD) continues to rise, imposing significant social and economic burdens. Mangiferin (MGF), a polyphenolic, bioactive compound has been shown to play a role in the prevention and treatment of PD. This study investigates the neuroprotective effects of MGF in an MPTP-induced zebrafish model of PD through transcriptome analysis. Initially, optimal concentrations for modeling were determined using various MPTP and MGF combinations. The zebrafish were then divided into control, MPTP-treated, and MGF co-treated groups. Subsequent evaluations included hatching rates, mortality rates, growth and development conditions, spontaneous motor abilities, as well as measurements of enzymatic activities of SOD, CAT, and levels of GSH. Ultimately, the therapeutic efficacy of MGF on the PD model in zebrafish was assessed through transcriptome sequencing. The results demonstrated that MPTP treatment induced PD-associated symptoms in zebrafish, while MGF treatment significantly improved the motor abilities and survival rates of the PD model zebrafish, effectively reducing oxidative stress and ameliorating PD symptoms. Transcriptome sequencing further revealed that MGF may mitigate mitochondrial-related oxidative stress in PD zebrafish by modulating the expression of critical genes including lrrk2, vps35, atp13a, dnajc6, and uchl1. Differential gene expression analysis indicated that these genes are primarily involved in vital signaling pathways, such as neuroactive ligand-receptor interaction, and the calcium signaling pathway. In summary, our study provides robust scientific evidence supporting MGF as a potential therapeutic candidate for PD by preserving mitochondrial homeostasis and elucidating its mechanisms of action.

随着全球人口的老龄化,帕金森病(PD)的发病率持续上升,给社会和经济造成了巨大负担。多酚类生物活性化合物芒果苷(Mangiferin,MGF)已被证明在帕金森病的预防和治疗中发挥作用。本研究通过转录组分析,研究了 MGF 在 MPTP 诱导的斑马鱼脑退化症模型中的神经保护作用。首先,使用不同的 MPTP 和 MGF 组合确定了建模的最佳浓度。然后将斑马鱼分为对照组、MPTP 处理组和 MGF 联合处理组。随后的评估包括孵化率、死亡率、生长发育状况、自发运动能力以及 SOD、CAT 酶活性和 GSH 水平的测量。最后,通过转录组测序评估了 MGF 对斑马鱼帕金森病模型的疗效。结果表明,MPTP 治疗可诱导斑马鱼出现与帕金森病相关的症状,而 MGF 治疗可显著提高帕金森病模型斑马鱼的运动能力和存活率,有效降低氧化应激,改善帕金森病症状。转录组测序进一步发现,MGF可通过调节包括lrrk2、vps35、atp13a、dnajc6和uchl1在内的关键基因的表达,减轻帕金森病斑马鱼体内与线粒体相关的氧化应激。差异基因表达分析表明,这些基因主要参与重要的信号通路,如神经活性配体-受体相互作用和钙信号通路。总之,我们的研究提供了有力的科学证据,支持 MGF 通过保护线粒体稳态和阐明其作用机制成为治疗帕金森病的潜在候选药物。
{"title":"Transcriptome analysis reveals the anti-Parkinson's activity of Mangiferin in zebrafish.","authors":"Fengqing Qin, Ming Zhang, Pei Wang, Ziru Dai, Xi Li, Dongliang Li, Lijun Jing, Cen Qi, Heliang Fan, Mei Qin, Ying Li, Likun Huang, Tianci Wang","doi":"10.1016/j.biopha.2024.117387","DOIUrl":"10.1016/j.biopha.2024.117387","url":null,"abstract":"<p><p>As the global population ages, the incidence of Parkinson's Disease (PD) continues to rise, imposing significant social and economic burdens. Mangiferin (MGF), a polyphenolic, bioactive compound has been shown to play a role in the prevention and treatment of PD. This study investigates the neuroprotective effects of MGF in an MPTP-induced zebrafish model of PD through transcriptome analysis. Initially, optimal concentrations for modeling were determined using various MPTP and MGF combinations. The zebrafish were then divided into control, MPTP-treated, and MGF co-treated groups. Subsequent evaluations included hatching rates, mortality rates, growth and development conditions, spontaneous motor abilities, as well as measurements of enzymatic activities of SOD, CAT, and levels of GSH. Ultimately, the therapeutic efficacy of MGF on the PD model in zebrafish was assessed through transcriptome sequencing. The results demonstrated that MPTP treatment induced PD-associated symptoms in zebrafish, while MGF treatment significantly improved the motor abilities and survival rates of the PD model zebrafish, effectively reducing oxidative stress and ameliorating PD symptoms. Transcriptome sequencing further revealed that MGF may mitigate mitochondrial-related oxidative stress in PD zebrafish by modulating the expression of critical genes including lrrk2, vps35, atp13a, dnajc6, and uchl1. Differential gene expression analysis indicated that these genes are primarily involved in vital signaling pathways, such as neuroactive ligand-receptor interaction, and the calcium signaling pathway. In summary, our study provides robust scientific evidence supporting MGF as a potential therapeutic candidate for PD by preserving mitochondrial homeostasis and elucidating its mechanisms of action.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"179 ","pages":"117387"},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142156940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Corrigendum to "Blocking 5-LO pathway alleviates renal fibrosis by inhibiting the epithelial-mesenchymal transition" [Biomed. Pharmacother. 138 (2021) 1-11]. 对 "通过抑制上皮-间质转化阻断 5-LO 通路减轻肾脏纤维化 "的更正 [Biomed. Pharmacother. 138 (2021) 1-11].
Pub Date : 2024-10-01 Epub Date: 2024-08-27 DOI: 10.1016/j.biopha.2024.117318
Jian Zhou, Rui Li, Qinhui Liu, Jinhang Zhang, Hui Huang, Cuiyuan Huang, Guorong Zhang, Yingnan Zhao, Tong Wu, Qin Tang, Ya Huang, Zijing Zhang, Yanping Li, Jinhan He
{"title":"Corrigendum to \"Blocking 5-LO pathway alleviates renal fibrosis by inhibiting the epithelial-mesenchymal transition\" [Biomed. Pharmacother. 138 (2021) 1-11].","authors":"Jian Zhou, Rui Li, Qinhui Liu, Jinhang Zhang, Hui Huang, Cuiyuan Huang, Guorong Zhang, Yingnan Zhao, Tong Wu, Qin Tang, Ya Huang, Zijing Zhang, Yanping Li, Jinhan He","doi":"10.1016/j.biopha.2024.117318","DOIUrl":"10.1016/j.biopha.2024.117318","url":null,"abstract":"","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":" ","pages":"117318"},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142082833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Metformin inhibits OCT3-mediated serotonin transport in the placenta. 二甲双胍可抑制胎盘中由 OCT3 介导的血清素转运。
Pub Date : 2024-10-01 Epub Date: 2024-09-08 DOI: 10.1016/j.biopha.2024.117399
Veronika Vachalova, Fiona Kumnova, Tetiana Synova, Kasin Yadunandam Anandam, Cilia Abad, Rona Karahoda, Frantisek Staud

Proper fetal development requires tight regulation of serotonin concentrations within the fetoplacental unit. This homeostasis is partly maintained by the placental transporter OCT3/SLC22A3, which takes up serotonin from the fetal circulation. Metformin, an antidiabetic drug commonly used to treat gestational diabetes mellitus, was shown to inhibit OCT3. We, therefore, hypothesized that its use during pregnancy could disrupt placental serotonin homeostasis. This hypothesis was tested using three experimental model systems: primary trophoblast cells isolated from the human term placenta, fresh villous human term placenta fragments, and rat term placenta perfusions. Inhibition of serotonin transport by metformin at three concentrations (1 μM, 10 μM, and 100 μM) was assessed in all three models. The OCT3 inhibitor decynium-22 (100 μM) and paroxetine (100 μM), a dual inhibitor of SERT and OCT3, were used as controls. In primary trophoblasts, paroxetine exhibited the strongest inhibition of serotonin uptake, followed by decynium-22. Metformin showed a concentration-dependent effect, reducing serotonin uptake by up to 57 % at the highest concentration. Its inhibitory effect was less pronounced in fresh villous fragments but remained statistically significant at all concentrations. In the perfused rat placenta, metformin demonstrated a concentration-dependent effect, reducing placental serotonin uptake by 44 % at the highest concentration tested. Our findings across all experimental models show inhibition of placental OCT3 by metformin, resulting in reduced serotonin uptake by the trophoblast. This sheds light on mechanisms that may underpin metformin-mediated effects on fetal development.

胎儿的正常发育需要胎盘内血清素浓度的严格调节。这种平衡部分由胎盘转运体 OCT3/SLC22A3 维持,它从胎儿血液循环中摄取血清素。二甲双胍是一种常用于治疗妊娠糖尿病的抗糖尿病药物,已被证实能抑制 OCT3。因此,我们推测孕期使用二甲双胍可能会破坏胎盘血清素的平衡。我们使用三种实验模型系统对该假设进行了验证:从人类足月胎盘分离的原发性滋养层细胞、新鲜绒毛人类足月胎盘片段和大鼠足月胎盘灌注。在这三种模型中,评估了二甲双胍在三种浓度(1 μM、10 μM 和 100 μM)下对血清素转运的抑制作用。OCT3 抑制剂 Decynium-22(100 μM)和帕罗西汀(100 μM)(SERT 和 OCT3 的双重抑制剂)被用作对照组。在原代滋养细胞中,帕罗西汀对血清素摄取的抑制作用最强,其次是癸炔诺酮-22。二甲双胍显示出浓度依赖性效应,在最高浓度下可减少血清素摄取达 57%。在新鲜绒毛片中,二甲双胍的抑制作用并不明显,但在所有浓度下仍具有显著的统计学意义。在灌注的大鼠胎盘中,二甲双胍显示出浓度依赖性效应,在测试的最高浓度下,胎盘对血清素的摄取减少了44%。我们对所有实验模型的研究结果表明,二甲双胍抑制了胎盘 OCT3,导致滋养细胞对血清素的摄取减少。这揭示了二甲双胍可能对胎儿发育产生影响的机制。
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引用次数: 0
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