Abstract: Niclosamide (NIC), an anthelmintic drug, has garnered recent attention for its potential as an antiviral, antibacterial, and chemotherapeutic agent, among other applications. Repurposing NIC presents a current trend, offering significant time and cost savings compared to developing entirely new therapeutic chemical entities. However, its drawback lies in poor solubility, resulting in notably low oral bioavailability. This review consolidates efforts to overcome this limitation by summarizing twelve categories of formulations, spanning derivatives, amorphous solid dispersions, co-crystals, nanocrystals, micelles, nanohybrids, lipid nanoparticles and emulsions, cyclodextrins, polymeric nanoparticles, dry powders for inhalation, 3D printlets, and nanofibers. These formulations cover oral, injectable, inhalable and potentially (trans)dermal routes of administration. Additionally, we present a comprehensive overview of NIC characteristics, including physico-chemical properties, metabolism, safety, and pharmacokinetics. Moreover, we identify gaps in formulation and administration pathways that warrant further investigation to address NIC poor bioavailability.
Keywords: niclosamide, drug repurposing, solubility, formulations, administration pathways, pharmaco-kinetics
摘要：尼克洛沙胺（NIC）是一种抗蠕虫药物，最近因其作为抗病毒、抗菌和化疗药物等应用的潜力而备受关注。与开发全新的治疗化学实体相比，重新利用 NIC 可大大节省时间和成本，是当前的一种趋势。然而，其缺点在于溶解性差，导致口服生物利用度明显偏低。本综述总结了 12 类制剂，包括衍生物、无定形固体分散体、共晶体、纳米晶体、胶束、纳米混合物、脂质纳米颗粒和乳剂、环糊精、聚合物纳米颗粒、吸入用干粉、3D 打印小剂和纳米纤维，以此来克服这一局限性。这些制剂涵盖口服、注射、吸入以及潜在的（经）皮肤给药途径。此外，我们还全面概述了 NIC 的特性，包括物理化学特性、新陈代谢、安全性和药代动力学。此外，我们还指出了在制剂和给药途径方面存在的差距，这些差距值得进一步研究，以解决 NIC 生物利用率低的问题。 关键词：尼氯沙坦；药物再利用；溶解度；制剂；给药途径；药代动力学
{"title":"Revisiting Niclosamide Formulation Approaches – a Pathway Toward Drug Repositioning","authors":"Mario Jug, Flavia Laffleur, Gioconda Millotti","doi":"10.2147/dddt.s473178","DOIUrl":"https://doi.org/10.2147/dddt.s473178","url":null,"abstract":"<strong>Abstract:</strong> Niclosamide (NIC), an anthelmintic drug, has garnered recent attention for its potential as an antiviral, antibacterial, and chemotherapeutic agent, among other applications. Repurposing NIC presents a current trend, offering significant time and cost savings compared to developing entirely new therapeutic chemical entities. However, its drawback lies in poor solubility, resulting in notably low oral bioavailability. This review consolidates efforts to overcome this limitation by summarizing twelve categories of formulations, spanning derivatives, amorphous solid dispersions, co-crystals, nanocrystals, micelles, nanohybrids, lipid nanoparticles and emulsions, cyclodextrins, polymeric nanoparticles, dry powders for inhalation, 3D printlets, and nanofibers. These formulations cover oral, injectable, inhalable and potentially (trans)dermal routes of administration. Additionally, we present a comprehensive overview of NIC characteristics, including physico-chemical properties, metabolism, safety, and pharmacokinetics. Moreover, we identify gaps in formulation and administration pathways that warrant further investigation to address NIC poor bioavailability.<br/><br/><strong>Keywords:</strong> niclosamide, drug repurposing, solubility, formulations, administration pathways, pharmaco-kinetics<br/>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"16 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142269605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ming Bai, Wei-Xue Wang, Ting Deng, Jing-Jing Duan, Yi Ba
Objective: This study aimed to identify the effectiveness and safety of PD-1 blockades among elderly patients with metastatic esophageal squamous cell carcinoma (ESCC) clinically. Methods: A total of 78 elderly patients with previously treated metastatic ESCC aged ≥ 65 years who received PD-1 blockades monotherapy were included retrospectively. Demographic characteristics, therapeutic effectiveness and adverse reactions of the elderly patients who underwent PD-1 blockade therapy were recorded. Regular follow-up was conducted for all patients. The analysis aimed to identify potential risk factors for OS by examining the correlation between prognosis and subgroups based on baseline characteristics. Results: The median age of the 78 elderly patients was 73 years, ranging from 65 to 87 years. Among the 78 patients, 18 cases showed partial response, 26 cases had stable disease, 29 cases experienced progressive disease and 5 cases were not assessable for response, yielding an ORR of 23.1%, a DCR of 56.4%. The prognostic outcomes indicated that among the 78 patients with metastatic ESCC who received PD-1 blockades, the median PFS was 3.1 months [95% confidence interval (CI): 1.64– 4.56], and the median OS was 10.9 months (95% CI: 6.02– 15.78), 24-month OS rate was 22.7% (95% CI: 12.8– 34.2%). In terms of the safety profile, among the 78 patients with metastatic ESCC during PD-1 blockades single-agent treatment, a total of 61 patients (78.2%) experienced any grade adverse reactions and the incidence of grade ≥ 3 adverse reactions were 20.5%. Briefly, the common adverse reactions manifested as fatigue (32.1%), gastrointestinal reaction (24.4%), diarrhea (19.2%), anemia (17.9%) and rash (16.7%). Overall tolerability of PD-1 blockade monotherapy in elderly patients with metastatic ESCC was acceptable and manageable. Conclusion: PD-1 blockades single agent demonstrated encouraging effectiveness and acceptable safety profile for elderly patients with previously treated metastatic ESCC in clinical practice. Prospective study should be performed to elucidate the conclusion in this study subsequently.
{"title":"Feasibility and Safety of PD-1 Blockades Among Elderly Patients with Metastatic Esophageal Squamous Cell Carcinoma: A Real-World Study","authors":"Ming Bai, Wei-Xue Wang, Ting Deng, Jing-Jing Duan, Yi Ba","doi":"10.2147/dddt.s476457","DOIUrl":"https://doi.org/10.2147/dddt.s476457","url":null,"abstract":"<strong>Objective:</strong> This study aimed to identify the effectiveness and safety of PD-1 blockades among elderly patients with metastatic esophageal squamous cell carcinoma (ESCC) clinically.<br/><strong>Methods:</strong> A total of 78 elderly patients with previously treated metastatic ESCC aged ≥ 65 years who received PD-1 blockades monotherapy were included retrospectively. Demographic characteristics, therapeutic effectiveness and adverse reactions of the elderly patients who underwent PD-1 blockade therapy were recorded. Regular follow-up was conducted for all patients. The analysis aimed to identify potential risk factors for OS by examining the correlation between prognosis and subgroups based on baseline characteristics.<br/><strong>Results:</strong> The median age of the 78 elderly patients was 73 years, ranging from 65 to 87 years. Among the 78 patients, 18 cases showed partial response, 26 cases had stable disease, 29 cases experienced progressive disease and 5 cases were not assessable for response, yielding an ORR of 23.1%, a DCR of 56.4%. The prognostic outcomes indicated that among the 78 patients with metastatic ESCC who received PD-1 blockades, the median PFS was 3.1 months [95% confidence interval (CI): 1.64– 4.56], and the median OS was 10.9 months (95% CI: 6.02– 15.78), 24-month OS rate was 22.7% (95% CI: 12.8– 34.2%). In terms of the safety profile, among the 78 patients with metastatic ESCC during PD-1 blockades single-agent treatment, a total of 61 patients (78.2%) experienced any grade adverse reactions and the incidence of grade ≥ 3 adverse reactions were 20.5%. Briefly, the common adverse reactions manifested as fatigue (32.1%), gastrointestinal reaction (24.4%), diarrhea (19.2%), anemia (17.9%) and rash (16.7%). Overall tolerability of PD-1 blockade monotherapy in elderly patients with metastatic ESCC was acceptable and manageable.<br/><strong>Conclusion:</strong> PD-1 blockades single agent demonstrated encouraging effectiveness and acceptable safety profile for elderly patients with previously treated metastatic ESCC in clinical practice. Prospective study should be performed to elucidate the conclusion in this study subsequently.<br/><br/><strong>Keywords:</strong> elderly patients, esophageal squamous cell carcinoma, PD-1 blockades, effectiveness, safety<br/>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"26 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142260267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xi Huang, Yu Peng, Lingfei Lu, Liwen Gao, Shanshan Wu, Jiandong Lu, Xinhui Liu
Background: Huangqi-Danshen decoction (HDD) is a Chinese medicinal herb pair with good efficacy in treating chronic kidney disease, but its mechanism needs to be clarified. Aim: To uncover the underlying mechanism of HDD antagonizing renal fibrosis through network pharmacology (NP) analysis and experimental validation. Materials and Methods: The chemical components of water extract of HDD were analyzed by combining the ultra-high performance liquid chromatography coupled with Q-Exactive mass spectrum analysis (UHPLC-QE-MS) and HERB database. NP was used to identify core common targets of HDD components and renal fibrosis. Subsequently, male C57BL/6 mice were divided into Sham, unilateral ureteral obstruction (UUO) and UUO+HDD groups. Renal function, histopathology, Western blotting, and immunohistochemistry analyses were used to evaluate the protective effect of HDD on UUO mice. The effects of HDD on signaling pathways were validated in both UUO mice and transforming growth factor-β 1 (TGF-β 1)-induced HK-2 cells. Results: By combining UHPLC-QE-MS analysis and HERB database, 25 components were screened in HDD extract. There were 270 intersection targets of the 25 components and renal fibrosis. Based on their scores in protein-protein interaction analysis and degree values in component-pathway-target triadic network, 6 core common targets of the 25 components and renal fibrosis were identified, namely phosphoinositide 3-kinase (PI3K), signal transducer and activator of transcription 3 (Stat3), non-receptor tyrosine kinase Src (Src), epidermal growth factor receptor (EGFR), matrix metalloproteinase 9 (MMP9), and MMP2. HDD ameliorated renal tubular damage and collagen deposition and downregulated fibrosis-related proteins expression in UUO mice. Furthermore, HDD was demonstrated to reduce PI3K, Stat3, Src, EGFR, and MMP2 expressions, and enhance MMP9 expression in the kidney of UUO mice and in TGF-β 1-induced HK-2 cells. Conclusion: HDD can alleviate renal fibrosis which may be related to regulating the expression of essential proteins in the epithelial-mesenchymal transition and extracellular matrix production/degradation signaling pathways.
{"title":"Huangqi-Danshen Decoction Against Renal Fibrosis in UUO Mice via TGF-β1 Induced Downstream Signaling Pathway","authors":"Xi Huang, Yu Peng, Lingfei Lu, Liwen Gao, Shanshan Wu, Jiandong Lu, Xinhui Liu","doi":"10.2147/dddt.s457100","DOIUrl":"https://doi.org/10.2147/dddt.s457100","url":null,"abstract":"<strong>Background:</strong> Huangqi-Danshen decoction (HDD) is a Chinese medicinal herb pair with good efficacy in treating chronic kidney disease, but its mechanism needs to be clarified.<br/><strong>Aim:</strong> To uncover the underlying mechanism of HDD antagonizing renal fibrosis through network pharmacology (NP) analysis and experimental validation.<br/><strong>Materials and Methods:</strong> The chemical components of water extract of HDD were analyzed by combining the ultra-high performance liquid chromatography coupled with Q-Exactive mass spectrum analysis (UHPLC-QE-MS) and HERB database. NP was used to identify core common targets of HDD components and renal fibrosis. Subsequently, male C57BL/6 mice were divided into Sham, unilateral ureteral obstruction (UUO) and UUO+HDD groups. Renal function, histopathology, Western blotting, and immunohistochemistry analyses were used to evaluate the protective effect of HDD on UUO mice. The effects of HDD on signaling pathways were validated in both UUO mice and transforming growth factor-β 1 (TGF-β 1)-induced HK-2 cells.<br/><strong>Results:</strong> By combining UHPLC-QE-MS analysis and HERB database, 25 components were screened in HDD extract. There were 270 intersection targets of the 25 components and renal fibrosis. Based on their scores in protein-protein interaction analysis and degree values in component-pathway-target triadic network, 6 core common targets of the 25 components and renal fibrosis were identified, namely phosphoinositide 3-kinase (PI3K), signal transducer and activator of transcription 3 (Stat3), non-receptor tyrosine kinase Src (Src), epidermal growth factor receptor (EGFR), matrix metalloproteinase 9 (MMP9), and MMP2. HDD ameliorated renal tubular damage and collagen deposition and downregulated fibrosis-related proteins expression in UUO mice. Furthermore, HDD was demonstrated to reduce PI3K, Stat3, Src, EGFR, and MMP2 expressions, and enhance MMP9 expression in the kidney of UUO mice and in TGF-β 1-induced HK-2 cells.<br/><strong>Conclusion:</strong> HDD can alleviate renal fibrosis which may be related to regulating the expression of essential proteins in the epithelial-mesenchymal transition and extracellular matrix production/degradation signaling pathways. <br/><br/>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"17 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142260268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Response to Letter in regards to Comparison Between Esketamine and Alfentanil for Hysteroscopy: A Prospective, Double-Blind, Randomized Controlled Trial [Letter]
{"title":"Comparison Between Esketamine and Alfentanil for Hysteroscopy: A Prospective, Double-Blind, Randomized Controlled Trial [Response to Letter]","authors":"Mengcao Weng, Yue Jin","doi":"10.2147/dddt.s492879","DOIUrl":"https://doi.org/10.2147/dddt.s492879","url":null,"abstract":"Response to Letter in regards to Comparison Between Esketamine and Alfentanil for Hysteroscopy: A Prospective, Double-Blind, Randomized Controlled Trial [Letter]","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"4 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142223741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wei Lu, Zhenyu Yang, Mengjie Wang, Ye Zhang, Zuoliang Qi, Xiaonan Yang
Introduction: Infantile Hemangioma (IH) is a prevalent benign vascular tumor affecting approximately 5– 10% of infants. Its underlying pathogenesis remains enigmatic, and current therapeutic approaches show limited effectiveness. Our study aimed to discover potential IH-associated therapeutics through a transcriptomic, computational drug repurposing methodology. Methods: Utilizing the IH-specific dataset GSE127487 from the Gene Expression Omnibus, we identified differentially expressed genes (DEGs) and conducted weighted gene coexpression network analysis (WGCNA). Subsequently, a protein-protein interaction (PPI) network was constructed to obtain the top 100 hub genes. Drug candidates were sourced from the Connectivity Map (CMap) and Comparative Toxicogenomics Database (CTD). Results: Our analysis revealed 1203 DEGs and a significant module of 1780 mRNAs strongly correlated with IH. These genes were primarily enriched in the PI3K/AKT/MTOR, RAS/MAPK, and CGMP/PKG signaling pathway. After creating a PPI network of overlapping genes, we filtered out the top 100 hub genes. Ultimately, 44 non-toxic drugs were identified through the CMap and CTD databases. Twelve molecular-targeting agents (belinostat, chir 99021, dasatinib, entinostat, panobinostat, sirolimus, sorafenib, sunitinib, thalidomide, U 0126, vorinostat, and wortmannin) may be potential candidates for IH therapy. Moreover, in vitro experiments demonstrated that entinostat, sorafenib, dasatinib, and sirolimus restricted the proliferation and migration and initiated apoptosis in HemEC cells, thereby underscoring their potential therapeutic value. Conclusion: Our investigation revealed that the pathogenic mechanism underlying IH might be closely associated with the PI3K/AKT/MTOR, RAS/MAPK, and CGMP/PKG signaling pathways. Furthermore, we identified twelve molecular-targeting agents among the predicted drugs that show promise as therapeutic candidates for IH.
Plain Language Summary: Transcriptomic analysis used to discover potential therapeutics for Infantile Hemangioma (IH). Key IH-related pathways: PI3K/AKT/MTOR, RAS/MAPK, and CGMP/PKG signaling identified. Identified 44 non-toxic drugs as potential IH therapies via CMap and CTD. Twelve molecular agents show potential as IH therapy candidates. In vitro studies confirmed entinostat, sorafenib, dasatinib, and sirolimus inhibit HemEC cell proliferation and induce apoptosis.
{"title":"Identification of Potential Therapeutics for Infantile Hemangioma via in silico Investigation and in vitro Validation","authors":"Wei Lu, Zhenyu Yang, Mengjie Wang, Ye Zhang, Zuoliang Qi, Xiaonan Yang","doi":"10.2147/dddt.s460575","DOIUrl":"https://doi.org/10.2147/dddt.s460575","url":null,"abstract":"<strong>Introduction:</strong> Infantile Hemangioma (IH) is a prevalent benign vascular tumor affecting approximately 5– 10% of infants. Its underlying pathogenesis remains enigmatic, and current therapeutic approaches show limited effectiveness. Our study aimed to discover potential IH-associated therapeutics through a transcriptomic, computational drug repurposing methodology.<br/><strong>Methods:</strong> Utilizing the IH-specific dataset GSE127487 from the Gene Expression Omnibus, we identified differentially expressed genes (DEGs) and conducted weighted gene coexpression network analysis (WGCNA). Subsequently, a protein-protein interaction (PPI) network was constructed to obtain the top 100 hub genes. Drug candidates were sourced from the Connectivity Map (CMap) and Comparative Toxicogenomics Database (CTD).<br/><strong>Results:</strong> Our analysis revealed 1203 DEGs and a significant module of 1780 mRNAs strongly correlated with IH. These genes were primarily enriched in the <em>PI3K/AKT/MTOR, RAS/MAPK</em>, and <em>CGMP/PKG</em> signaling pathway. After creating a PPI network of overlapping genes, we filtered out the top 100 hub genes. Ultimately, 44 non-toxic drugs were identified through the CMap and CTD databases. Twelve molecular-targeting agents (belinostat, chir 99021, dasatinib, entinostat, panobinostat, sirolimus, sorafenib, sunitinib, thalidomide, U 0126, vorinostat, and wortmannin) may be potential candidates for IH therapy. Moreover, in vitro experiments demonstrated that entinostat, sorafenib, dasatinib, and sirolimus restricted the proliferation and migration and initiated apoptosis in HemEC cells, thereby underscoring their potential therapeutic value.<br/><strong>Conclusion:</strong> Our investigation revealed that the pathogenic mechanism underlying IH might be closely associated with the <em>PI3K/AKT/MTOR, RAS/MAPK</em>, and <em>CGMP/PKG</em> signaling pathways. Furthermore, we identified twelve molecular-targeting agents among the predicted drugs that show promise as therapeutic candidates for IH.<br/><br/><strong>Plain Language Summary:</strong> Transcriptomic analysis used to discover potential therapeutics for Infantile Hemangioma (IH).<br/>Key IH-related pathways: PI3K/AKT/MTOR, RAS/MAPK, and CGMP/PKG signaling identified.<br/>Identified 44 non-toxic drugs as potential IH therapies via CMap and CTD.<br/>Twelve molecular agents show potential as IH therapy candidates.<br/>In vitro studies confirmed entinostat, sorafenib, dasatinib, and sirolimus inhibit HemEC cell proliferation and induce apoptosis. <br/><br/><strong>Keywords:</strong> infantile hemangioma, entinostat, sirolimus, hub gene, transcriptome, bioinformatics<br/>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"51 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142178578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Feiyu Gao, Tao Xu, Fangnan Zang, Yuanyuan Luo, Defeng Pan
Abstract: With the continuous refinement of therapeutic measures, the survival rate of tumor patients has been improving year by year, while cardiovascular complications related to cancer therapy have become increasingly prominent. Exploring the mechanism and prevention strategy of cancer therapy-related cardiovascular toxicity (CTR-CVT) remains one of the research hotspots in the field of Cardio-Oncology in recent years. Cardiotoxicity of anticancer drugs involves heart failure, myocarditis, hypertension, arrhythmias and vascular toxicity, mechanistically related to vascular endothelial dysfunction, ferroptosis, mitochondrial dysfunction and oxidative stress. To address the cardiotoxicity induced by different anticancer drugs, various therapeutic measures have been put in place, such as reducing the accumulation of anticancer drugs, shifting to drugs with less cardiotoxicity, using cardioprotective drugs, and early detection. Due to the very limited treatments available to ameliorate anticancer drugs-induced cardiotoxicity, a few innovations are being shifted from animal studies to human studies. Examples include mitochondrial transplantation. Mitochondrial transplantation has been proven to be effective in in vivo and in vitro experiments. Several recent studies have demonstrated that intercellular mitochondrial transfer can ameliorate doxorubicin(DOX)-induced cardiotoxicity, laying the foundation for innovative therapies in anticancer drugs-induced cardiotoxicity. In this review, we will discuss the current status of anticancer drugs-induced cardiotoxicity in terms of the pathogenesis and treatment, with a focus on mitochondrial transplantation, and we hope that this review will bring some inspiration to you.
{"title":"Cardiotoxicity of Anticancer Drugs: Molecular Mechanisms, Clinical Management and Innovative Treatment","authors":"Feiyu Gao, Tao Xu, Fangnan Zang, Yuanyuan Luo, Defeng Pan","doi":"10.2147/dddt.s469331","DOIUrl":"https://doi.org/10.2147/dddt.s469331","url":null,"abstract":"<strong>Abstract:</strong> With the continuous refinement of therapeutic measures, the survival rate of tumor patients has been improving year by year, while cardiovascular complications related to cancer therapy have become increasingly prominent. Exploring the mechanism and prevention strategy of cancer therapy-related cardiovascular toxicity (CTR-CVT) remains one of the research hotspots in the field of Cardio-Oncology in recent years. Cardiotoxicity of anticancer drugs involves heart failure, myocarditis, hypertension, arrhythmias and vascular toxicity, mechanistically related to vascular endothelial dysfunction, ferroptosis, mitochondrial dysfunction and oxidative stress. To address the cardiotoxicity induced by different anticancer drugs, various therapeutic measures have been put in place, such as reducing the accumulation of anticancer drugs, shifting to drugs with less cardiotoxicity, using cardioprotective drugs, and early detection. Due to the very limited treatments available to ameliorate anticancer drugs-induced cardiotoxicity, a few innovations are being shifted from animal studies to human studies. Examples include mitochondrial transplantation. Mitochondrial transplantation has been proven to be effective in in vivo and in vitro experiments. Several recent studies have demonstrated that intercellular mitochondrial transfer can ameliorate doxorubicin(DOX)-induced cardiotoxicity, laying the foundation for innovative therapies in anticancer drugs-induced cardiotoxicity. In this review, we will discuss the current status of anticancer drugs-induced cardiotoxicity in terms of the pathogenesis and treatment, with a focus on mitochondrial transplantation, and we hope that this review will bring some inspiration to you. <br/><br/><strong>Keywords:</strong> cancer therapy-related cardiovascular toxicity, CTR-CVT, mitochondrial dysfunction, oxidative stress, ferroptosis, mitochondrial transplantation<br/>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"3 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142178577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Purpose: Acute kidney injury (AKI) is a common clinical critical condition that has become a significant healthcare burden. In recent years, the relationship between AKI and mitochondria has attracted increasing attention. Protecting mitochondria or restoring their function has emerged as a novel therapeutic strategy for alleviating AKI. This study aims to analyze and summarize the current status, research trends, and hotspots in this field, providing references and directions for future research. Methods: AKI and mitochondria-related literature from the Web of Science core collection were retrieved and collected. Bibliometric and visualization analyses were conducted using Microsoft Excel 2021, bibliometric tools (VosViewer, Citespace 6.3.R1, and the bibliometrix R package), R 4.3.2, and SCImagoGraphica software. Results: A total of 2433 publications were included in this study. The number of annual publications in this field has increased year by year. China and the United States are the two most productive countries. Central South University is the most influential research institution in terms of research output, and Parikh SM, Schnellmann RG, and Dong Z are the most influential authors in this field. KIDNEY INTERNATIONAL, JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, and AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY are the most influential journals. Initially, the research focused on keywords such as oxidative stress, ischemia-reperfusion injury, apoptosis, inflammation, and autophagy. In recent years, new research hotspots have emerged, including ferroptosis, aging, mitochondrial quality control, messenger RNA, mitochondrial-targeted antioxidants, extracellular vesicles, and nanodrug delivery. Conclusion: Research on the relationship between mitochondria and AKI has broad developing prospects, and targeting mitochondrial regulation will become a focus of future AKI prevention and treatment research.
目的：急性肾损伤（AKI）是一种常见的临床危重症，已成为医疗保健的重要负担。近年来，急性肾损伤与线粒体之间的关系引起了越来越多的关注。保护线粒体或恢复其功能已成为缓解 AKI 的一种新型治疗策略。本研究旨在分析和总结该领域的研究现状、研究趋势和热点，为未来研究提供参考和方向：方法：检索并收集了 Web of Science 核心数据库中与 AKI 和线粒体相关的文献。使用 Microsoft Excel 2021、文献计量工具（VosViewer、Citespace 6.3.R1 和 bibliometrix R 软件包）、R 4.3.2 和 SCImagoGraphica 软件进行文献计量和可视化分析：本研究共收录了 2433 篇出版物。该领域的年度出版物数量逐年增加。中国和美国是发表论文最多的两个国家。就研究成果而言，中南大学是最有影响力的研究机构，Parikh SM、Schnellmann RG 和 Dong Z 是该领域最有影响力的作者。KIDNEY INTERNATIONAL》、《JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY》和《American JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY》是最有影响力的期刊。最初的研究主要集中在氧化应激、缺血再灌注损伤、细胞凋亡、炎症和自噬等关键词上。近年来，新的研究热点不断涌现，包括铁变态反应、衰老、线粒体质量控制、信使 RNA、线粒体靶向抗氧化剂、细胞外囊泡和纳米药物递送等：线粒体与 AKI 关系的研究具有广阔的发展前景，针对线粒体的调控将成为未来 AKI 预防和治疗研究的重点。
{"title":"Research Hotspots in Mitochondria-Related Studies for AKI Treatment: A Bibliometric Study","authors":"Mengfan Yang, Youqun Huang, Anqi Tang, Yu Zhang, Yu Liu, Zhenliang Fan, Mingquan Li","doi":"10.2147/dddt.s473426","DOIUrl":"https://doi.org/10.2147/dddt.s473426","url":null,"abstract":"<strong>Purpose:</strong> Acute kidney injury (AKI) is a common clinical critical condition that has become a significant healthcare burden. In recent years, the relationship between AKI and mitochondria has attracted increasing attention. Protecting mitochondria or restoring their function has emerged as a novel therapeutic strategy for alleviating AKI. This study aims to analyze and summarize the current status, research trends, and hotspots in this field, providing references and directions for future research.<br/><strong>Methods:</strong> AKI and mitochondria-related literature from the Web of Science core collection were retrieved and collected. Bibliometric and visualization analyses were conducted using Microsoft Excel 2021, bibliometric tools (VosViewer, Citespace 6.3.R1, and the bibliometrix R package), R 4.3.2, and SCImagoGraphica software.<br/><strong>Results:</strong> A total of 2433 publications were included in this study. The number of annual publications in this field has increased year by year. China and the United States are the two most productive countries. Central South University is the most influential research institution in terms of research output, and Parikh SM, Schnellmann RG, and Dong Z are the most influential authors in this field. KIDNEY INTERNATIONAL, JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, and AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY are the most influential journals. Initially, the research focused on keywords such as oxidative stress, ischemia-reperfusion injury, apoptosis, inflammation, and autophagy. In recent years, new research hotspots have emerged, including ferroptosis, aging, mitochondrial quality control, messenger RNA, mitochondrial-targeted antioxidants, extracellular vesicles, and nanodrug delivery.<br/><strong>Conclusion:</strong> Research on the relationship between mitochondria and AKI has broad developing prospects, and targeting mitochondrial regulation will become a focus of future AKI prevention and treatment research.<br/><br/><strong>Keywords:</strong> acute kidney injury, mitochondria, bibliometric analysis, visualization, VOSviewer, citespace<br/>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"13 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142178576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chunxia Yin, Taohua Lan, Yunshan Wu, Jing Cai, Haoxiang Li, Xiaolan Kuang, Lin Jiao, Xiaomin Ou, Hua Yang, Bo Liu, Weihui Lu
Purpose: This study was designed to evaluate the effect and mechanism of the Qushi Huatan (QSHT) decoction against coronary heart disease (CHD) through network pharmacology and experimental verification. Methods: In the present study, the active ingredients of the QSHT decoction were identified by ultra performance liquid chromatography/tandem mass spectrometry (UPLC/MS), then the potential ingredients and coronary heart disease targets were predicted using the SwissTarget Prediction database and the database of Genecards and OMIM database, respectively. A herb-compound-target network was constructed using Cytoscape. GO and KEGG enrichment analysis were performed using the ClusterProfiler data package of R software. Molecular docking was used to predict the core targets of QSHT against CHD. In addition, we used a myocardial infarction (MI) and high-fat diet ApoE−/− mice model to investigate the cardioprotective effects of QSHT. Western blotting and immunochemistry were used to verify the core targets and the signaling pathway. Results: A total of 68 active ingredients were found in the QSHT decoction. Network pharmacology indicated 28 targets and 147 signal pathways, including AKT1, HIF-1α, GSK-3β, TLR4 and NF-κB, those key targets were also verified by molecular docking. The results of GO and KEGG enrichment analysis showed that the targets of QSHT against CHD were largely associated with inflammatory and oxidative stress, and AKT/HIF-1α and TLR4/NF-κB pathways might be key functional pathways. In vivo, QSHT significantly improved cardiac function and attenuated fibrosis and inflammation. Furthermore, QSHT could significantly inhibit the expression of HIF-1α, TLR4, phosphorylation of AKT1, GSK-3β and NF-κB after MI in ApoE−/− mice. Conclusion: Based on network pharmacology, molecular docking and experimental verification, this study demonstrated that QSHT could improve cardiac function and attenuate cardiac fibrosis by regulating TLR4/NF-κB and AKT/HIF-1α signaling pathway in post- MI and high-fat diet ApoE−/− mice.
目的：本研究旨在通过网络药理学和实验验证，评价曲石花潭煎膏对冠心病（CHD）的作用和机制：本研究采用超高效液相色谱/串联质谱法（UPLC/MS）对曲氏化潭煎膏的有效成分进行了鉴定，然后分别利用SwissTarget Prediction数据库、Genecards数据库和OMIM数据库预测了曲氏化潭煎膏的潜在成分和冠心病靶点。利用Cytoscape构建了草药-化合物-靶标网络。使用R软件的ClusterProfiler数据包进行了GO和KEGG富集分析。分子对接被用来预测QSHT抗心肌梗死的核心靶点。此外，我们还利用心肌梗死（MI）和高脂饮食载脂蛋白E-/-小鼠模型研究了QSHT的心脏保护作用。我们使用了 Western 印迹和免疫化学方法来验证核心靶点和信号通路：结果：在羌活水煎剂中发现了68种有效成分。网络药理学显示了28个靶点和147条信号通路，包括AKT1、HIF-1α、GSK-3β、TLR4和NF-κB。GO和KEGG富集分析结果表明，QSHT防治冠心病的靶点主要与炎症和氧化应激有关，而AKT/HIF-1α和TLR4/NF-κB通路可能是关键的功能通路。在体内，QSHT 能明显改善心脏功能，减轻纤维化和炎症反应。此外，QSHT还能明显抑制载脂蛋白E-/-小鼠心肌梗死后HIF-1α、TLR4、AKT1磷酸化、GSK-3β和NF-κB的表达：基于网络药理学、分子对接和实验验证，本研究证实瞿氏化瘀汤可通过调节TLR4/NF-κB和AKT/HIF-1α信号通路，改善心肌梗死后和高脂饮食载脂蛋白E-/-小鼠的心功能，减轻心脏纤维化。
{"title":"Integrating Network Pharmacology and Experimental Validation to Investigate the Mechanism of Qushi Huatan Decoction Against Coronary Heart Disease","authors":"Chunxia Yin, Taohua Lan, Yunshan Wu, Jing Cai, Haoxiang Li, Xiaolan Kuang, Lin Jiao, Xiaomin Ou, Hua Yang, Bo Liu, Weihui Lu","doi":"10.2147/dddt.s463054","DOIUrl":"https://doi.org/10.2147/dddt.s463054","url":null,"abstract":"<strong>Purpose:</strong> This study was designed to evaluate the effect and mechanism of the Qushi Huatan (QSHT) decoction against coronary heart disease (CHD) through network pharmacology and experimental verification.<br/><strong>Methods:</strong> In the present study, the active ingredients of the QSHT decoction were identified by ultra performance liquid chromatography/tandem mass spectrometry (UPLC/MS), then the potential ingredients and coronary heart disease targets were predicted using the SwissTarget Prediction database and the database of Genecards and OMIM database, respectively. A herb-compound-target network was constructed using Cytoscape. GO and KEGG enrichment analysis were performed using the ClusterProfiler data package of R software. Molecular docking was used to predict the core targets of QSHT against CHD. In addition, we used a myocardial infarction (MI) and high-fat diet ApoE<sup>−/−</sup> mice model to investigate the cardioprotective effects of QSHT. Western blotting and immunochemistry were used to verify the core targets and the signaling pathway.<br/><strong>Results:</strong> A total of 68 active ingredients were found in the QSHT decoction. Network pharmacology indicated 28 targets and 147 signal pathways, including AKT1, HIF-1α, GSK-3β, TLR4 and NF-κB, those key targets were also verified by molecular docking. The results of GO and KEGG enrichment analysis showed that the targets of QSHT against CHD were largely associated with inflammatory and oxidative stress, and AKT/HIF-1α and TLR4/NF-κB pathways might be key functional pathways. In vivo, QSHT significantly improved cardiac function and attenuated fibrosis and inflammation. Furthermore, QSHT could significantly inhibit the expression of HIF-1α, TLR4, phosphorylation of AKT1, GSK-3β and NF-κB after MI in ApoE<sup>−/−</sup> mice.<br/><strong>Conclusion:</strong> Based on network pharmacology, molecular docking and experimental verification, this study demonstrated that QSHT could improve cardiac function and attenuate cardiac fibrosis by regulating TLR4/NF-κB and AKT/HIF-1α signaling pathway in post- MI and high-fat diet ApoE<sup>−/−</sup> mice.<br/><br/><strong>Keywords:</strong> network pharmacology, molecular docking, Qushi Huatan decoction, coronary heart disease<br/>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"11 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142178579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Siddhartha Dutta, Rima B Shah, Shubha Singhal, Sudeshna Banerjee Dutta, Sumit Bansal, Susmita Sinha, Mainul Haque
Response to Letter in regards to Metformin’s Enigma: Bridging Gaps in Research on Potential Benefits & Associated Risks - A Critical Plea for Comprehensive Investigation [Letter]
{"title":"Metformin’s Enigma: Bridging Gaps in Research on Potential Benefits & Associated Risks - A Critical Plea for Comprehensive Investigation [Response to Letter]","authors":"Siddhartha Dutta, Rima B Shah, Shubha Singhal, Sudeshna Banerjee Dutta, Sumit Bansal, Susmita Sinha, Mainul Haque","doi":"10.2147/dddt.s491638","DOIUrl":"https://doi.org/10.2147/dddt.s491638","url":null,"abstract":"Response to Letter in regards to Metformin’s Enigma: Bridging Gaps in Research on Potential Benefits & Associated Risks - A Critical Plea for Comprehensive Investigation [Letter]","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"6 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142178581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Liang Wu, Yunxia Zhu, Shengcai Zhu, Deng Zhang, Xiuping Wang, Zhen Xiao, Yanping Tan, Xiaoliang Ouyang, Chunming Li
Background: Acne vulgaris (AV), a chronic inflammatory pilosebaceous disorder, affects 80– 90% of teenagers. This study aimed to discover lipid profiles and biomarkers of the rabbit ear acne model, and investigate the mechanism of isotretinoin in treating acne at the lipid level. Methods: Untargeted lipidomic analysis using ultra-high performance liquid chromatography system (UHPLC) coupled to q-extraction plus was performed to identify skin lipid metabolites in blank control (groups C), model group (group M) and isotretinoin group (group T). Multivariate statistical analysis was used to process the lipidomics data. Results: A total of 43 lipid classes comprising 6989 lipid species were identified from the mass spectrometry data. The orthogonal partial least squares discriminant analysis (OPLS-DA) model demonstrated significant separation in skin lipidomic profiles between group M and group C. With variable influence on projection (VIP) > 1.0 and P-value < 0.05, 299 significantly different lipid metabolites were identified. These lipid metabolites consisted mainly of ceramides (Cer) (53.85%), phosphatidylethanolamines (PE) (9.03%), phosphatidylcholines (PC)(5.35%), and sphingomyelin (SM)(4.01%). Combining with AUC ≥ 0.9 as the elected criteria, Cer (d18;1_24:0), zymosterol (ZyE)(33:5), Cer (t43:1), ZyE (33:6), ZyE (24:7), and ZyE (35:6) have “high” accuracy. Isotretinoin treatment normalized 25 lipid metabolites in the acne model. Conclusion: Our findings provide new insights into the role of lipid metabolism in the pathogenesis of acne and the action mechanism of isotretinoin.
{"title":"Untargeted Lipidomics Analysis to Discover Lipid Profiles and Biomarkers of Rabbit Acne Model and Reveal Action Mechanism of Isotretinoin","authors":"Liang Wu, Yunxia Zhu, Shengcai Zhu, Deng Zhang, Xiuping Wang, Zhen Xiao, Yanping Tan, Xiaoliang Ouyang, Chunming Li","doi":"10.2147/dddt.s476649","DOIUrl":"https://doi.org/10.2147/dddt.s476649","url":null,"abstract":"<strong>Background:</strong> Acne vulgaris (AV), a chronic inflammatory pilosebaceous disorder, affects 80– 90% of teenagers. This study aimed to discover lipid profiles and biomarkers of the rabbit ear acne model, and investigate the mechanism of isotretinoin in treating acne at the lipid level.<br/><strong>Methods:</strong> Untargeted lipidomic analysis using ultra-high performance liquid chromatography system (UHPLC) coupled to q-extraction plus was performed to identify skin lipid metabolites in blank control (groups C), model group (group M) and isotretinoin group (group T). Multivariate statistical analysis was used to process the lipidomics data.<br/><strong>Results:</strong> A total of 43 lipid classes comprising 6989 lipid species were identified from the mass spectrometry data. The orthogonal partial least squares discriminant analysis (OPLS-DA) model demonstrated significant separation in skin lipidomic profiles between group M and group C. With variable influence on projection (VIP) > 1.0 and P-value < 0.05, 299 significantly different lipid metabolites were identified. These lipid metabolites consisted mainly of ceramides (Cer) (53.85%), phosphatidylethanolamines (PE) (9.03%), phosphatidylcholines (PC)(5.35%), and sphingomyelin (SM)(4.01%). Combining with AUC ≥ 0.9 as the elected criteria, Cer (d18;1_24:0), zymosterol (ZyE)(33:5), Cer (t43:1), ZyE (33:6), ZyE (24:7), and ZyE (35:6) have “high” accuracy. Isotretinoin treatment normalized 25 lipid metabolites in the acne model.<br/><strong>Conclusion:</strong> Our findings provide new insights into the role of lipid metabolism in the pathogenesis of acne and the action mechanism of isotretinoin.<br/><br/>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"60 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142178453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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