Pub Date : 2024-09-20DOI: 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。
{"title":"Recent developments of topoisomerase inhibitors: Clinical trials, emerging indications, novel molecules and global sales","authors":"Andrey D. Bondarev , Jörgen Jonsson , Vladimir N. Chubarev , Vadim V. Tarasov , Francisco Alejandro Lagunas-Rangel , Helgi B. Schiöth","doi":"10.1016/j.phrs.2024.107431","DOIUrl":"10.1016/j.phrs.2024.107431","url":null,"abstract":"<div><p>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 <em>Clostridium difficile</em> 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.</p></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107431"},"PeriodicalIF":9.1,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003761/pdfft?md5=df08da2321b9fa2fc00df15b7f52a32c&pid=1-s2.0-S1043661824003761-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142271907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-19DOI: 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。
{"title":"Insight of neonicotinoid insecticides: Exploring exposure, mechanisms in non-target organisms, and removal technologies","authors":"Yuanyuan Zhang , Wanxuan Zhu , Ying Wang , Xueli Li , Jianxin Lv , Jiaoyang Luo , Meihua Yang","doi":"10.1016/j.phrs.2024.107415","DOIUrl":"10.1016/j.phrs.2024.107415","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107415"},"PeriodicalIF":9.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142293011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"TRP channels in cancer: Therapeutic opportunities and research strategies","authors":"Jiahui Xu , Ziming Wang , Yuqing Niu , Yuping Tang , Yuwei Wang , Jumin Huang , Elaine Lai-Han Leung","doi":"10.1016/j.phrs.2024.107412","DOIUrl":"10.1016/j.phrs.2024.107412","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107412"},"PeriodicalIF":9.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003578/pdfft?md5=46248b88c7beaa74fe4643d2e77feaf7&pid=1-s2.0-S1043661824003578-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142271906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-19DOI: 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.
{"title":"The ZDHHC13/ZDHHC17 subfamily: From biological functions to therapeutic targets of diseases","authors":"Ying Zhang , Sisi Fan , Lu He , Lanfang Li","doi":"10.1016/j.phrs.2024.107418","DOIUrl":"10.1016/j.phrs.2024.107418","url":null,"abstract":"<div><div>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, Mg<sup>2+</sup> 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.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107418"},"PeriodicalIF":9.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142293014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-19DOI: 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.
{"title":"Astrocyte-derived lactoferrin inhibits neuronal ferroptosis by reducing iron content and GPX4 degradation in APP/PS1 transgenic mice","authors":"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","doi":"10.1016/j.phrs.2024.107404","DOIUrl":"10.1016/j.phrs.2024.107404","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107404"},"PeriodicalIF":9.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003499/pdfft?md5=f4bacab0e0cb1852dc9c6eb5368dfb4e&pid=1-s2.0-S1043661824003499-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142271959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-19DOI: 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.
{"title":"Melatonin increases Olaparib sensitivity and suppresses cancer-associated fibroblast infiltration via suppressing the LAMB3-CXCL2 axis in TNBC","authors":"Yi-Wen Lai , Zei-Wei Liu , Mei-Hsiang Lin , Ching-Chieh Yang , Cheng-Ying Chu , Chu-Hung Chung , Cheng-Wei Lin","doi":"10.1016/j.phrs.2024.107429","DOIUrl":"10.1016/j.phrs.2024.107429","url":null,"abstract":"<div><div>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 <em>in vivo</em> 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.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107429"},"PeriodicalIF":9.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142293012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-19DOI: 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.
{"title":"Human F-ATP synthase as a drug target","authors":"Christoph Gerle , Chimari Jiko , Atsuki Nakano , Ken Yokoyama , Chai C. Gopalasingam , Hideki Shigematsu , Kazuhiro Abe","doi":"10.1016/j.phrs.2024.107423","DOIUrl":"10.1016/j.phrs.2024.107423","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107423"},"PeriodicalIF":9.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003682/pdfft?md5=0e47dcd3b2e458dd98aae8915ea9ad9f&pid=1-s2.0-S1043661824003682-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142293010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18DOI: 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.
{"title":"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","authors":"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","doi":"10.1016/j.phrs.2024.107428","DOIUrl":"10.1016/j.phrs.2024.107428","url":null,"abstract":"<div><p>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 (H<sub>2</sub>S) is an important player in the liver, regulating lipid metabolism and mitochondrial function. However, direct delivery of H<sub>2</sub>S 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 <em>de novo</em> 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 (<em>Il1b, Il6, Tnf</em>, <em>Mcp1</em>), 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.</p></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107428"},"PeriodicalIF":9.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003736/pdfft?md5=e56c7e6ddc9bd5790b953902f032656d&pid=1-s2.0-S1043661824003736-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 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.
{"title":"Molecular mechanisms underlying hepatoprotective activity of lutein in the context of intestinal failure-associated liver disease","authors":"Izabela Żółnowska , Aleksandra Gostyńska-Stawna , Maciej Stawny","doi":"10.1016/j.phrs.2024.107421","DOIUrl":"10.1016/j.phrs.2024.107421","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107421"},"PeriodicalIF":9.1,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003669/pdfft?md5=92dde2611e7fee5d8ed114874628986c&pid=1-s2.0-S1043661824003669-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142238765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Alternative splicing of Mff regulates AMPK-mediated phosphorylation, mitochondrial fission and antiviral response","authors":"Yuki Hanada , Risa Maeda , Takaya Ishihara , Masaki Nakahashi , Yuichi Matsushima , Emi Ogasawara , Toshihiko Oka , Naotada Ishihara","doi":"10.1016/j.phrs.2024.107414","DOIUrl":"10.1016/j.phrs.2024.107414","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107414"},"PeriodicalIF":9.1,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003591/pdfft?md5=3733cacbdfdeed08e6c84579793571fd&pid=1-s2.0-S1043661824003591-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}