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Recent developments of topoisomerase inhibitors: Clinical trials, emerging indications, novel molecules and global sales 拓扑异构酶抑制剂的最新进展:临床试验、新兴适应症、新型分子和全球销售额
IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-20 DOI: 10.1016/j.phrs.2024.107431
Andrey D. Bondarev , Jörgen Jonsson , Vladimir N. Chubarev , Vadim V. Tarasov , Francisco Alejandro Lagunas-Rangel , Helgi B. Schiöth

The nucleic acid topoisomerases (TOP) are an evolutionary conserved mechanism to solve topological problems within DNA and RNA that have been historically well-established as a chemotherapeutic target. During investigation of trends within clinical trials, we have identified a very high number of clinical trials involving TOP inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 233 unique molecules with TOP-inhibiting activity. In this review, we provide an overview of the clinical drug development highlighting advances in current clinical uses and discussing novel drugs and indications under development. A wide range of bacterial infections, along with solid and hematologic neoplasms, represent the bulk of clinically approved indications. Negative ADR profile and drug resistance among the antibacterial TOP inhibitors and anthracycline-mediated cardiotoxicity in the antineoplastic TOP inhibitors are major points of concern, subject to continuous research efforts. Ongoing development continues to focus on bacterial infections and cancer; however, there is a degree of diversification in terms of novel drug classes and previously uncovered indications, such as glioblastoma multiforme or Clostridium difficile infections. Preclinical studies show potential in viral, protozoal, parasitic and fungal infections as well and suggest the emergence of a novel target, TOP IIIβ. We predict further growth and diversification of the field thanks to the large number of experimental TOP inhibitors emerging.

核酸拓扑异构酶(TOP)是一种解决 DNA 和 RNA 拓扑问题的进化保守机制,历来被公认为化疗靶点。在调查临床试验趋势的过程中,我们发现了大量涉及拓扑抑制剂的临床试验,这促使我们进一步评估这类治疗药物的现状。我们总共发现了 233 种具有 TOP 抑制活性的独特分子。在这篇综述中,我们概述了临床药物的开发情况,重点介绍了当前临床应用的进展,并讨论了正在开发的新型药物和适应症。各种细菌感染以及实体肿瘤和血液肿瘤占临床批准适应症的绝大部分。抗菌 TOP 抑制剂的不良 ADR 和耐药性,以及抗肿瘤 TOP 抑制剂中蒽环类药物介导的心脏毒性,都是值得关注的主要问题,需要不断进行研究。正在进行的开发工作仍然以细菌感染和癌症为重点;不过,在新药类别和以前未发现的适应症(如多形性胶质母细胞瘤或艰难梭菌感染)方面也有一定程度的多样化。临床前研究显示,TOP IIIβ 在病毒、原生动物、寄生虫和真菌感染方面也具有潜力,并表明新靶点的出现。我们预测,随着大量实验性 TOP 抑制剂的出现,该领域将进一步发展和多样化。
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引用次数: 0
Insight of neonicotinoid insecticides: Exploring exposure, mechanisms in non-target organisms, and removal technologies 透视新烟碱类杀虫剂:探索非目标生物的接触、机理和清除技术。
IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-19 DOI: 10.1016/j.phrs.2024.107415
Yuanyuan Zhang , Wanxuan Zhu , Ying Wang , Xueli Li , Jianxin Lv , Jiaoyang Luo , Meihua Yang
Neonicotinoid insecticides (NEOs) have garnered global attention due to their selective toxicity to insects and minimal impact on mammals. However, growing concerns about their extensive use and potential adverse effects on the ecological environment and non-target organisms necessitate further investigation. This study utilized bibliometric tools to analyze Web of Science data from 2003 to 2024, elucidating the current research landscape, identifying key research areas, and forecasting future trends related to NEOs. This paper provides an in-depth analysis of NEO exposure in non-target organisms, including risk assessments for various samples and maximum residue limits established by different countries. Additionally, it examines the impacts and mechanisms of NEOs on non-target organisms. Finally, it reviews the current methods for NEO removal and degradation. This comprehensive analysis provides valuable insights for regulating NEO usage and addressing associated exposure challenges.
新烟碱类杀虫剂(NEOs)因其对昆虫的选择性毒性和对哺乳动物的最小影响而备受全球关注。然而,人们越来越关注其广泛使用及其对生态环境和非目标生物的潜在不利影响,因此有必要对其进行进一步调查。本研究利用文献计量学工具分析了 2003 年至 2024 年的 Web of Science 数据,阐明了当前的研究状况,确定了关键研究领域,并预测了与近地天体有关的未来趋势。本文深入分析了非目标生物接触近地天体的情况,包括各种样本的风险评估和不同国家规定的最大残留限量。此外,本文还研究了近地天体对非目标生物的影响和机制。最后,报告回顾了目前去除和降解近地物体的方法。这一全面分析为规范近地天体的使用和应对相关的暴露挑战提供了宝贵的见解。
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引用次数: 0
TRP channels in cancer: Therapeutic opportunities and research strategies 癌症中的 TRP 通道:治疗机会与研究策略
IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-19 DOI: 10.1016/j.phrs.2024.107412
Jiahui Xu , Ziming Wang , Yuqing Niu , Yuping Tang , Yuwei Wang , Jumin Huang , Elaine Lai-Han Leung

The influence of gut microbiota on transient receptor potential (TRP) channels has been identified as an important element in the development of gastrointestinal conditions, yet its involvement in cancer progression is not as thoroughly understood. This review explores the multifaceted roles of TRP channels in oncogenesis and emphasizes their significance in cancer progression and therapeutic outcomes. Critical focus was placed on the influence of traditional medicines, such as traditional Chinese medicine (TCM) related aromatic medicines, on TRP channel functions. Moreover, we explored the interplay between the gut microbiota and TRP channels in cancer signaling, highlighting the therapeutic potential of targeting this axis in cancer treatment. The impact of current therapies on TRP channel function was examined, demonstrating the need for a comprehensive understanding of how different modalities affect TRP channels in cancer. Technological advancements, including artificial intelligence (AI) tools and computer-aided drug development (CADD), have been discussed in the context of leveraging TRP channels for innovative cancer therapies. Future directions emphasize the potential applications of TRP channel research in advancing cancer treatment and enhancing patients' well-being.

肠道微生物群对瞬时受体电位(TRP)通道的影响已被确定为胃肠道疾病发展中的一个重要因素,但对其在癌症进展中的参与却了解得不那么透彻。本综述探讨了 TRP 通道在肿瘤发生中的多方面作用,并强调了它们在癌症进展和治疗结果中的重要意义。重点关注传统药物,如与中药相关的芳香类药物对 TRP 通道功能的影响。此外,我们还探讨了肠道微生物群与 TRP 通道在癌症信号转导中的相互作用,强调了在癌症治疗中针对这一轴心的治疗潜力。我们还研究了当前疗法对TRP通道功能的影响,表明有必要全面了解不同疗法如何影响癌症中的TRP通道。在利用 TRP 通道创新癌症疗法的背景下,还讨论了技术进步,包括人工智能(AI)工具和计算机辅助药物开发(CADD)。未来发展方向强调了 TRP 通道研究在推进癌症治疗和提高患者福祉方面的潜在应用。
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引用次数: 0
The ZDHHC13/ZDHHC17 subfamily: From biological functions to therapeutic targets of diseases ZDHHC13/ZDHHC17 亚家族:从生物功能到疾病治疗靶点。
IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-19 DOI: 10.1016/j.phrs.2024.107418
Ying Zhang , Sisi Fan , Lu He , Lanfang Li
The ZDHHC13/ZDHHC17 subfamily belongs to the zinc finger DHHC-domain containing (ZDHHC) family, including ZDHHC13 and ZDHHC17. Recent studies have shown that the ZDHHC13/ZDHHC17 subfamily is involved in various pathological and physiological processes, including S-palmitoylation, Mg2+ transport, and CALCOCO1-mediated Golgiphagy. Moreover, the ZDHHC13/ZDHHC17 subfamily plays a crucial role in the occurrence and development of many diseases, including Huntington disease (HD), osteoporosis, atopic dermatitis, diabetes, and cancer. In the present review, we describe the distribution, structure, and post-translational modifications (PTMs) of the ZDHHC13/ZDHHC17 subfamily. Moreover, we effectively summarize the biological functions and associated diseases of this subfamily. Given the pleiotropy of the ZDHHC13/ZDHHC17 subfamily, it is imperative to conduct further research on its members to comprehend the pertinent pathophysiological mechanisms and to devise tactics for managing and controlling various diseases.
ZDHHC13/ZDHHC17 亚家族属于含锌手指 DHHC-domain(ZDHHC)家族,包括 ZDHHC13 和 ZDHHC17。最近的研究表明,ZDHHC13/ZDHHC17 亚家族参与了多种病理和生理过程,包括 S-棕榈酰化、Mg2+ 转运和 CALCOCO1 介导的 Golgiphagy。此外,ZDHHC13/ZDHHC17 亚家族在亨廷顿病(HD)、骨质疏松症、特应性皮炎、糖尿病和癌症等多种疾病的发生和发展中起着至关重要的作用。在本综述中,我们描述了 ZDHHC13/ZDHHC17 亚家族的分布、结构和翻译后修饰(PTMs)。此外,我们还有效总结了该亚家族的生物学功能和相关疾病。鉴于 ZDHHC13/ZDHHC17 亚家族的多变性,我们有必要对其成员进行进一步的研究,以了解相关的病理生理学机制,并制定管理和控制各种疾病的策略。
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引用次数: 0
Astrocyte-derived lactoferrin inhibits neuronal ferroptosis by reducing iron content and GPX4 degradation in APP/PS1 transgenic mice 在 APP/PS1 转基因小鼠体内,源自星形胶质细胞的乳铁蛋白通过降低铁含量和 GPX4 降解抑制神经元铁突变
IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-19 DOI: 10.1016/j.phrs.2024.107404
Yong-Gang Fan , Ri-Le Ge , Hang Ren , Rong-Jun Jia , Ting-Yao Wu , Xian-Fang Lei , Zheng Wu , Xiao-Bei Zhou , Zhan-You Wang

Increased astrocytic lactoferrin (Lf) expression was observed in the brains of elderly individuals and Alzheimer's disease (AD) patients. Our previous study revealed that astrocytic Lf overexpression improved cognitive capacity by facilitating Lf secretion to neurons to inhibit β-amyloid protein (Aβ) production in APP/PS1 mice. Here, we further discovered that astrocytic Lf overexpression inhibited neuronal loss by decreasing iron accumulation and increasing glutathione peroxidase 4 (GPX4) expression in neurons within APP/PS1 mice. Furthermore, human Lf (hLf) treatment inhibited ammonium ferric citrate (FAC)-induced ferroptosis by chelating intracellular iron. Additionally, machine learning analysis uncovered a correlation between Lf and GPX4. hLf treatment boosted low-density lipoprotein receptor-related protein 1 (LRP1) internalization and facilitated its interaction with heat shock cognate 70 (HSC70), thereby inhibiting HSC70 binds to GPX4, and eventually attenuating GPX4 degradation and FAC-induced ferroptosis. Overall, astrocytic Lf overexpression inhibited neuronal ferroptosis through two pathways: reducing intracellular iron accumulation and promoting GPX4 expression via inhibiting chaperone-mediated autophagy (CMA)-mediated GPX4 degradation. Hence, upregulating astrocytic Lf expression is a promising strategy for combating AD.

在老年人和阿尔茨海默病(AD)患者的大脑中观察到星形胶质细胞乳铁蛋白(Lf)表达增加。我们之前的研究发现,星形胶质细胞过量表达 Lf 能促进 Lf 分泌到神经元,从而抑制 APP/PS1 小鼠体内 β 淀粉样蛋白(Aβ)的生成,从而提高认知能力。在这里,我们进一步发现,星形胶质细胞过量表达 Lf 可减少 APP/PS1 小鼠神经元中铁的积累并增加谷胱甘肽过氧化物酶 4 (GPX4) 的表达,从而抑制神经元的损失。此外,人Lf(hLf)处理通过螯合细胞内的铁,抑制了柠檬酸铁铵(FAC)诱导的铁变态反应。hLf处理可促进低密度脂蛋白受体相关蛋白1(LRP1)的内化,并促进其与热休克同源物70(HSC70)的相互作用,从而抑制HSC70与GPX4的结合,最终减轻GPX4的降解和FAC诱导的铁变态反应。总之,星形胶质细胞 Lf 的过表达可通过两种途径抑制神经元的铁突变:减少细胞内铁的积累和通过抑制伴侣介导的自噬(CMA)来促进 GPX4 的表达。因此,上调星形胶质细胞 Lf 的表达是一种很有希望的抗击 AD 的策略。
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引用次数: 0
Melatonin increases Olaparib sensitivity and suppresses cancer-associated fibroblast infiltration via suppressing the LAMB3-CXCL2 axis in TNBC 褪黑素通过抑制 TNBC 中的 LAMB3-CXCL2 轴,增加奥拉帕尼的敏感性并抑制癌症相关成纤维细胞的活化。
IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-19 DOI: 10.1016/j.phrs.2024.107429
Yi-Wen Lai , Zei-Wei Liu , Mei-Hsiang Lin , Ching-Chieh Yang , Cheng-Ying Chu , Chu-Hung Chung , Cheng-Wei Lin
Triple-negative breast cancer (TNBC) is the most malignant breast cancer subtype, characterized with high aggressiveness and a high recurrence rate. Olaparib is the first US Food and Drug Administration-approved poly(ADP ribose) polymerase (PARP) inhibitor (PARPi) to treat breast cancer patients with a germline BRCA1 or BRCA2 mutation. However, resistance to Olaparib treatment restricts the therapeutic effects, and thus novel therapeutics are urgently required. In the present study, we identified that the combination of melatonin and Olaparib synergistically enhanced the sensitivity of TNBC cells. Moreover, melatonin exerted promising antitumor activities in Olaparib-resistant cells, implying the potential for its clinical application. An RNA-sequencing analysis revealed that melatonin treatment downregulated laminin subunit beta 3 (LAMB3) expression. Genetic ablation of LAMB3 significantly increased Olaparib sensitivity, and subsequently suppressed proliferation, epithelial-to-mesenchymal transition (EMT)-related gene expressions, and aggressiveness of breast cancer cells. Accordingly, LAMB3 expression was positively correlated with C-X-C motif chemokine ligand 2 (CXCL2), and they collaboratively promoted cancer-associated fibroblast (CAF) infiltration. An in vivo study demonstrated that combined treatment with melatonin and Olaparib showed enhanced inhibitory efficacy against tumor growth, LAMB3 expression, CXCL2 levels, and CAF infiltration compared to single treatment groups, and combined treatment with melatonin and Olaparib significantly ameliorated the immunosuppressive tumor microenvironment. These findings illustrate a promising therapeutic strategy using melatonin to overcome Olaparib resistance and activate antitumor immunity via attenuating the LAMB3-CXCL2 axis in breast cancer patients.
三阴性乳腺癌(TNBC)是恶性程度最高的乳腺癌亚型,具有高侵袭性和高复发率的特点。奥拉帕利是美国食品和药物管理局批准的第一种聚(ADP核糖)聚合酶(PARP)抑制剂(PARPi),用于治疗具有种系BRCA1或BRCA2突变的乳腺癌患者。然而,奥拉帕利的耐药性限制了治疗效果,因此迫切需要新型疗法。在本研究中,我们发现褪黑素与奥拉帕利联合使用可协同增强 TNBC 细胞的敏感性。此外,褪黑素在奥拉帕尼耐药细胞中发挥了良好的抗肿瘤活性,这意味着其具有临床应用的潜力。RNA序列分析表明,褪黑激素处理会下调层粘连蛋白亚基β3(LAMB3)的表达。基因消减LAMB3可显著提高奥拉帕尼的敏感性,并随后抑制乳腺癌细胞的增殖、上皮细胞向间质转化(EMT)相关基因的表达和侵袭性。相应地,LAMB3 的表达与 C-X-C motif 趋化因子配体 2(CXCL2)呈正相关,它们共同促进了癌症相关成纤维细胞(CAF)的浸润。一项体内研究表明,与单一治疗组相比,褪黑素和奥拉帕利联合治疗对肿瘤生长、LAMB3表达、CXCL2水平和CAF浸润的抑制效果更强,而且褪黑素和奥拉帕利联合治疗能显著改善免疫抑制性肿瘤微环境。这些研究结果表明,利用褪黑激素克服奥拉帕尼耐药性并通过减弱乳腺癌患者的LAMB3-CXCL2轴激活抗肿瘤免疫是一种很有前景的治疗策略。
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引用次数: 0
Human F-ATP synthase as a drug target 作为药物靶点的人类 F-ATP 合酶
IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-19 DOI: 10.1016/j.phrs.2024.107423
Christoph Gerle , Chimari Jiko , Atsuki Nakano , Ken Yokoyama , Chai C. Gopalasingam , Hideki Shigematsu , Kazuhiro Abe
Practical and conceptual barriers have kept human F-ATP synthase out of reach as a target for the treatment of human diseases. Although this situation has persisted for decades, it may change in the near future. In this review the principal functionalities of human F-ATP synthase--proton motive force / ATP interconversion, membrane bending and mitochondrial permeability transition--are surveyed in the context of their respective potential for pharmaceutical intervention. Further, the technical requirements necessary to allow drug designs that are effective at the multiple levels of functionality and modality of human F-ATP synthase are discussed. The structure-based development of gastric proton pump inhibitors is used to exemplify what might be feasible for human F-ATP synthase. And finally, four structural regions of the human F-ATP synthase are examined as potential sites for the development of structure based drug development.
由于实际操作和概念上的障碍,人类 F-ATP 合成酶一直未能成为治疗人类疾病的靶点。虽然这种情况已经持续了几十年,但在不久的将来可能会改变。在这篇综述中,我们结合人类 F-ATP 合成酶的主要功能--质子动力/ATP 相互转化、膜弯曲和线粒体通透性转换--对它们各自的药物干预潜力进行了研究。此外,还讨论了在人类 F-ATP 合成酶的多层次功能和模式下进行有效药物设计所需的技术要求。以基于结构的胃质子泵抑制剂的开发为例,说明人类 F-ATP 合成酶的可行性。最后,对人类 F-ATP 合成酶的四个结构区域进行了研究,将其作为开发基于结构的药物的潜在部位。
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引用次数: 0
Mitochondria-targeted hydrogen sulfide donor reduces fatty liver and obesity in mice fed a high fat diet by inhibiting de novo lipogenesis and inflammation via mTOR/SREBP-1 and NF-κB signaling pathways 线粒体靶向硫化氢供体通过 mTOR/SREBP-1 和 NF-κB 信号通路抑制新生脂肪生成和炎症,从而减少高脂饮食小鼠的脂肪肝和肥胖症
IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-18 DOI: 10.1016/j.phrs.2024.107428
Aneta Stachowicz , Klaudia Czepiel , Anna Wiśniewska , Kamila Stachyra , Magdalena Ulatowska-Białas , Beata Kuśnierz-Cabala , Marcin Surmiak , Grzegorz Majka , Katarzyna Kuś , Mark E. Wood , Roberta Torregrossa , Matthew Whiteman , Rafał Olszanecki

Metabolic diseases that include obesity and metabolic-associated fatty liver disease (MAFLD) are a rapidly growing worldwide public health problem. The pathogenesis of MAFLD includes abnormally increased lipogenesis, chronic inflammation, and mitochondrial dysfunction. Mounting evidence suggests that hydrogen sulfide (H2S) is an important player in the liver, regulating lipid metabolism and mitochondrial function. However, direct delivery of H2S to mitochondria has not been investigated as a therapeutic strategy in obesity-related metabolic disorders. Therefore, our aim was to comprehensively evaluate the influence of prolonged treatment with a mitochondria sulfide delivery molecule (AP39) on the development of fatty liver and obesity in a high fat diet (HFD) fed mice. Our results demonstrated that AP39 reduced hepatic steatosis in HFD-fed mice, which was corresponded with decreased triglyceride content. Furthermore, treatment with AP39 downregulated pathways related to biosynthesis of unsaturated fatty acids, lipoprotein assembly and PPAR signaling. It also led to a decrease in hepatic de novo lipogenesis by downregulating mTOR/SREBP-1/SCD1 pathway. Moreover, AP39 administration alleviated obesity in HFD-fed mice, which was reflected by reduced weight of mice and adipose tissue, decreased leptin levels in the plasma and upregulated expression of adipose triglyceride lipase in epididymal white adipose tissue (eWAT). Finally, AP39 reduced inflammation in the liver and eWAT measured as the expression of proinflammatory markers (Il1b, Il6, Tnf, Mcp1), which was due to downregulated mTOR/NF-κB pathway. Taken together, mitochondria-targeted sulfide delivery molecules could potentially provide a novel therapeutic approach to the treatment/prevention of obesity-related metabolic disorders.

包括肥胖症和代谢相关性脂肪肝(MAFLD)在内的代谢性疾病是一个迅速增长的全球性公共健康问题。代谢相关性脂肪肝的发病机制包括脂肪生成异常增加、慢性炎症和线粒体功能障碍。越来越多的证据表明,硫化氢(H2S)在肝脏中发挥着重要作用,可调节脂质代谢和线粒体功能。然而,将 H2S 直接输送到线粒体作为肥胖相关代谢紊乱的治疗策略还没有进行过研究。因此,我们的目的是全面评估线粒体硫化物递送分子(AP39)长期治疗对高脂饮食(HFD)喂养的小鼠脂肪肝和肥胖症发展的影响。我们的研究结果表明,AP39 能减轻高脂饮食喂养小鼠的肝脏脂肪变性,这与甘油三酯含量的降低是相对应的。此外,用 AP39 治疗会降低与不饱和脂肪酸的生物合成、脂蛋白组装和 PPAR 信号转导相关的通路。它还通过下调 mTOR/SREBP-1/SCD1 通路,导致肝脏新生脂肪生成减少。此外,服用 AP39 还能缓解高氟酸饲料喂养小鼠的肥胖问题,具体表现为小鼠和脂肪组织的体重减轻、血浆中瘦素水平降低以及附睾白色脂肪组织(eWAT)中脂肪甘油三酯脂酶的表达上调。最后,AP39 降低了肝脏和 eWAT 中的炎症反应,其表现为促炎标志物(Il1b、Il6、Tnf、Mcp1)的表达,这是由于 mTOR/NF-κB 通路的下调所致。综上所述,线粒体靶向硫化物递送分子有可能为治疗/预防肥胖相关代谢紊乱提供一种新的治疗方法。
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引用次数: 0
Molecular mechanisms underlying hepatoprotective activity of lutein in the context of intestinal failure-associated liver disease 肠功能衰竭相关肝病中叶黄素保肝活性的分子机制
IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-16 DOI: 10.1016/j.phrs.2024.107421
Izabela Żółnowska , Aleksandra Gostyńska-Stawna , Maciej Stawny

Intestinal failure-associated liver disease (IFALD) is a spectrum of liver diseases occurring in patients not exposed to liver-damaging factors other than those linked to intestinal dysfunction. The pathogenesis of this disease is multifactorial. It is estimated that up to 90 % of people taking long-term parenteral nutrition may develop IFALD, with particular risk for premature neonates and infants due to their immature antioxidant protection and bile acid metabolism. The lack of effective prevention and treatment methods for IFALD encourages scientists to search for new therapeutic solutions. The use of lutein as a substance with antioxidant and anti-inflammatory effects seems to be of great potential in such indication, especially since patients on parenteral nutrition are at risk of deficits in various plant-based nutrients, including lutein. In this review, we explain the pathogenesis of IFALD and summarize knowledge of the hepatoprotective properties of lutein, underscoring its potential as a treatment option. The hepatoprotective effects of lutein and their proposed mechanisms of action are supported by studies on cells and animals exposed to various liver-damaging factors, such as lipopolysaccharide, high-fat diet, alcohol, and more. Finally, we provide perspectives on the future application of lutein in therapy.

肠功能衰竭相关性肝病(IFALD)是一种肝脏疾病,发生在未暴露于除与肠功能障碍有关的因素之外的其他肝脏损伤因素的患者身上。这种疾病的发病机制是多因素的。据估计,多达 90% 的长期肠外营养患者可能会患上 IFALD,早产新生儿和婴儿由于抗氧化保护和胆汁酸代谢功能尚未成熟,患上 IFALD 的风险尤其高。IFALD 缺乏有效的预防和治疗方法,这促使科学家们寻找新的治疗方案。叶黄素作为一种具有抗氧化和抗炎作用的物质,似乎在此类适应症中具有很大的潜力,特别是因为接受肠外营养的患者有可能缺乏包括叶黄素在内的各种植物营养素。在这篇综述中,我们解释了 IFALD 的发病机制,并总结了叶黄素的保肝特性,强调了叶黄素作为一种治疗选择的潜力。叶黄素的保肝作用及其拟议的作用机制得到了暴露于各种肝损伤因素(如脂多糖、高脂饮食、酒精等)的细胞和动物的研究的支持。最后,我们对叶黄素未来在治疗中的应用进行了展望。
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引用次数: 0
Alternative splicing of Mff regulates AMPK-mediated phosphorylation, mitochondrial fission and antiviral response Mff 的交替剪接调节 AMPK 介导的磷酸化、线粒体分裂和抗病毒反应。
IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-16 DOI: 10.1016/j.phrs.2024.107414
Yuki Hanada , Risa Maeda , Takaya Ishihara , Masaki Nakahashi , Yuichi Matsushima , Emi Ogasawara , Toshihiko Oka , Naotada Ishihara

Mitochondrial morphology and function change dynamically in response to intracellular signaling and the surrounding environment. The mitochondrial fission factor Mff, which localizes to the outer mitochondrial membrane, mediates not only mitochondrial fission by recruiting the dynamin-related GTPase Drp1 to mitochondrial fission sites but also the double-stranded RNA-induced antiviral response on mitochondria through mitochondrial antiviral signaling (MAVS). Mff is reported to be regulated by AMP-activated protein kinase (AMPK)-mediated protein phosphorylation and alternative pre-mRNA splicing; however, the relationships among RNA splicing, phosphorylation, and multiple functions of Mff have not been fully understood. Here, we showed that mouse Mff has a tissue-specific splicing pattern, and at least eight Mff splice isoforms were expressed in mouse embryonic fibroblasts (MEFs). We introduced single Mff isoforms into Mff knockout MEFs and found that insertion of exon 6 just after the phosphorylation site, by the alternative splicing, reduced its phosphorylation by AMPK and its functions in mitochondrial fission and the antiviral response. In addition, the underlying mechanism repressing these functions was independent of phosphorylation. These results indicate that multiple functions of Mff on mitochondria are regulated by AMPK-mediated phosphorylation and alternative splicing, under the control of energy metabolism and cellular differentiation.

线粒体的形态和功能会随着细胞内信号和周围环境的变化而发生动态变化。线粒体裂变因子 Mff 定位于线粒体外膜,它不仅通过招募与达能相关的 GTPase Drp1 到线粒体裂变位点来介导线粒体裂变,还通过线粒体抗病毒信号转导(MAVS)介导线粒体上的双链 RNA 诱导的抗病毒反应。据报道,Mff受AMP激活的蛋白激酶(AMPK)介导的蛋白磷酸化和前mRNA的替代剪接调控;然而,RNA剪接、磷酸化和Mff的多种功能之间的关系尚未完全明了。在这里,我们发现小鼠 Mff 具有组织特异性剪接模式,至少有八种 Mff 剪接异构体在小鼠胚胎成纤维细胞(MEFs)中表达。我们将单个 Mff 异构体导入 Mff 基因敲除的 MEFs 中,发现通过替代剪接插入磷酸化位点后的第 6 号外显子,会降低其被 AMPK 磷酸化的程度,并降低其在线粒体裂变和抗病毒反应中的功能。此外,抑制这些功能的潜在机制与磷酸化无关。这些结果表明,Mff 在线粒体上的多种功能受 AMPK 介导的磷酸化和替代剪接的调控,受能量代谢和细胞分化的控制。
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Pharmacological research
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