Epigenetics, a field that investigates alterations in gene function that can be inherited without changes in DNA sequence, encompasses molecular pathways such as histone variants, posttranslational modifications of amino acids, and covalent modifications of DNA bases. These pathways modulate the transformation of genotypes into specific phenotypes. Epigenetics plays a substantial role in cell growth, development, and differentiation by dynamically regulating gene transcription and ensuring genomic stability. This regulation is carried out by three key players: writers, readers, and erasers. In recent years, epigenetic proteins have played a crucial role in epigenetic regulation and have gradually become important targets in drug research and development. Targeted therapy is an essential strategy; however, the effectiveness of targeted drugs is often limited by drug resistance, posing a significant dilemma in clinical practice. Targeted protein degradation technologies, including proteolysis-targeting chimeras (PROTACs), have great potential in overcoming drug resistance and targeting undruggable targets. These areas of research are gaining increasing attention to various epigenetic related disease. In this review, we have provided a summary of the recently developed degraders targeting epigenetic readers, writers, and erasers. Additionally, we have outlined new applications for epigenetic protein degraders. Finally, we have addressed several unresolved challenges within the PROTAC field and offered potential solutions from our perspective. As the field continues to advance, the integration of these innovative methodologies holds great promise for addressing the challenges associated with PROTAC development.
表观遗传学（Epigenetics）是一个研究基因功能改变的领域，这种改变可以在不改变 DNA 序列的情况下遗传，它包括组蛋白变异、氨基酸翻译后修饰和 DNA 碱基共价修饰等分子途径。这些途径可调节基因型向特定表型的转化。表观遗传学通过动态调节基因转录和确保基因组稳定性，在细胞生长、发育和分化过程中发挥着重要作用。这种调控由三个关键角色完成：书写者、阅读者和擦除者。近年来，表观遗传蛋白在表观遗传调控中发挥了重要作用，并逐渐成为药物研发的重要靶点。靶向治疗是一种必不可少的策略，然而，靶向药物的疗效往往受到耐药性的限制，给临床实践带来了极大的困境。靶向蛋白降解技术，包括蛋白水解靶向嵌合体（PROTACs），在克服耐药性和靶向不可药靶点方面具有巨大潜力。这些研究领域正日益受到各种表观遗传相关疾病的关注。在这篇综述中，我们总结了最近开发的针对表观遗传阅读器、写入器和擦除器的降解器。此外，我们还概述了表观遗传蛋白质降解剂的新应用。最后，我们探讨了 PROTAC 领域几个尚未解决的难题，并从我们的角度提出了潜在的解决方案。随着该领域的不断进步，整合这些创新方法有望解决与 PROTAC 开发相关的挑战。
{"title":"PROTACs Targeting Epigenetic Proteins.","authors":"Chao Zhang, Yuna He, Xiuyun Sun, Wenyi Wei, Yanlong Liu, Yu Rao","doi":"10.15212/amm-2023-0039","DOIUrl":"10.15212/amm-2023-0039","url":null,"abstract":"<p><p>Epigenetics, a field that investigates alterations in gene function that can be inherited without changes in DNA sequence, encompasses molecular pathways such as histone variants, posttranslational modifications of amino acids, and covalent modifications of DNA bases. These pathways modulate the transformation of genotypes into specific phenotypes. Epigenetics plays a substantial role in cell growth, development, and differentiation by dynamically regulating gene transcription and ensuring genomic stability. This regulation is carried out by three key players: writers, readers, and erasers. In recent years, epigenetic proteins have played a crucial role in epigenetic regulation and have gradually become important targets in drug research and development. Targeted therapy is an essential strategy; however, the effectiveness of targeted drugs is often limited by drug resistance, posing a significant dilemma in clinical practice. Targeted protein degradation technologies, including proteolysis-targeting chimeras (PROTACs), have great potential in overcoming drug resistance and targeting undruggable targets. These areas of research are gaining increasing attention to various epigenetic related disease. In this review, we have provided a summary of the recently developed degraders targeting epigenetic readers, writers, and erasers. Additionally, we have outlined new applications for epigenetic protein degraders. Finally, we have addressed several unresolved challenges within the PROTAC field and offered potential solutions from our perspective. As the field continues to advance, the integration of these innovative methodologies holds great promise for addressing the challenges associated with PROTAC development.</p>","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11364368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jie Guo, Meng Wang, Yong Zhu, F. Watari, Yonghong Xu, Xiao Chen
Platelets are blood components traditionally believed to have fundamental roles in vascular hemostasis and thrombosis. In recent years, platelets have received new attention for their roles in tumorigenesis and progression. On the one hand, platelets are actively recruited by various tumors and comprise a crucial part of the tumor microenvironment (TME), thus inspiring the use of platelets for tumor-targeted drug delivery. To this end, various platelet-based devices have been proposed, such as natural platelets, engineered platelets, platelet membranes, and platelet-derived microparticles. On the other hand, platelets are involved in tumor immunosuppression mechanisms, by directing and/or assisting various tumor-associated immune cells. However, in the context of inflammation and autoimmune diseases, platelets can amplify immune responses by promoting immune cell mobilization and activation, thereby exacerbating tissue damage. Thus, interest is growing in the use of tumor-associated platelets as targets for therapeutic modulation of the TME and augmenting anti-tumor immune responses. In this review, we summarize current advances in exploiting platelets for both antitumor drug delivery and immune modulation of the TME.
{"title":"Exploitation of platelets for antitumor drug delivery and modulation of the tumor immune microenvironment","authors":"Jie Guo, Meng Wang, Yong Zhu, F. Watari, Yonghong Xu, Xiao Chen","doi":"10.15212/amm-2023-0005","DOIUrl":"https://doi.org/10.15212/amm-2023-0005","url":null,"abstract":"Platelets are blood components traditionally believed to have fundamental roles in vascular hemostasis and thrombosis. In recent years, platelets have received new attention for their roles in tumorigenesis and progression. On the one hand, platelets are actively recruited by various tumors and comprise a crucial part of the tumor microenvironment (TME), thus inspiring the use of platelets for tumor-targeted drug delivery. To this end, various platelet-based devices have been proposed, such as natural platelets, engineered platelets, platelet membranes, and platelet-derived microparticles. On the other hand, platelets are involved in tumor immunosuppression mechanisms, by directing and/or assisting various tumor-associated immune cells. However, in the context of inflammation and autoimmune diseases, platelets can amplify immune responses by promoting immune cell mobilization and activation, thereby exacerbating tissue damage. Thus, interest is growing in the use of tumor-associated platelets as targets for therapeutic modulation of the TME and augmenting anti-tumor immune responses. In this review, we summarize current advances in exploiting platelets for both antitumor drug delivery and immune modulation of the TME.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41947171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jiaqi Tan, Lertnimitphun Peeraphong, Chattarin Ruchawapol, Juan Zhang, Juan Zhao, Wenwei Fu, Li Zhang, Hongxi Xu
Holliday junction recognition protein (HJURP) is a key molecular chaperone for centromere protein A (CENP-A), which is essential for chromosome separation during mitosis and cell cycle regulation. Recent studies have identified the essential role of HJURP in carcinogenesis. Abnormal upregulation of HJURP expression has been observed in various human cancers, such as non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), bladder cancer, and breast cancer, and is associated with poor pathologic development and prognosis. In vitro and in vivo studies have shown that HJURP mainly exerts oncogenic functions by regulating the cell cycle, cellular senescence, and epithelial-mesenchymal transition (EMT). The purpose of this review was to evaluate the prognostic significance of HJURP in human cancers and summarize anti-tumor studies targeting HJURP. The factors regulating HJURP in carcinogenesis and the corresponding effects are also discussed to provide new insight into targeting HJURP as a promising strategy for cancer treatment.
{"title":"Emerging role of HJURP as a therapeutic target in cancers","authors":"Jiaqi Tan, Lertnimitphun Peeraphong, Chattarin Ruchawapol, Juan Zhang, Juan Zhao, Wenwei Fu, Li Zhang, Hongxi Xu","doi":"10.15212/amm-2023-0008","DOIUrl":"https://doi.org/10.15212/amm-2023-0008","url":null,"abstract":"Holliday junction recognition protein (HJURP) is a key molecular chaperone for centromere protein A (CENP-A), which is essential for chromosome separation during mitosis and cell cycle regulation. Recent studies have identified the essential role of HJURP in carcinogenesis. Abnormal upregulation of HJURP expression has been observed in various human cancers, such as non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), bladder cancer, and breast cancer, and is associated with poor pathologic development and prognosis. In vitro and in vivo studies have shown that HJURP mainly exerts oncogenic functions by regulating the cell cycle, cellular senescence, and epithelial-mesenchymal transition (EMT). The purpose of this review was to evaluate the prognostic significance of HJURP in human cancers and summarize anti-tumor studies targeting HJURP. The factors regulating HJURP in carcinogenesis and the corresponding effects are also discussed to provide new insight into targeting HJURP as a promising strategy for cancer treatment.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45854186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The current study focused on the formulation, physicochemical characterization, and antibacterial susceptibility testing of inhalable spray dried powders containing ciprofloxacin (CIP) and polymyxin B sulfate (PMB). CIP nanosuspensions with an average particle diameter of 435.9 ± 9.3 nm were initially obtained using the wet-milling protocol and subsequently co-spray dried with PMB solutions to yield inhalable dry powders. The Powder X-Ray Diffraction (P-XRD) results showed that the wet-milled CIP nanoparticles were in a 4.8 hydrate state, which were transformed to 3.7 hydrates and amorphous materials after co-spray drying. The PMB remained in an amorphous state in the dry powders. Differential Scanning Calorimetry (DSC) analyses revealed that the glass transition temperatures (Tgs) of the co–spray dried formulations were higher than the Tg of CIP, but lower than the Tg of PMB. Fourier Transform Infrared Spectrometer (FTIR) studies suggested the existence of π - π interactions between CIP and PMB in the co-spray dried powders. These powders also retained antimicrobial effects against Pseudomonas aeruginosa strain PAO1. In addition, the spray-dried powder formulations exhibited satisfactory solid-state stability and aerodynamic characteristics when stored under 3% relative humidity and 20 ± 5 °C for 4 months. Overall, the newly developed inhalable CIP/PMB dry powders are a promising therapeutic strategy for respiratory tract infections.
{"title":"Inhalable ciprofloxacin/polymyxin B dry powders in respiratory infection therapy","authors":"Zhengqi Xu, Hriday Bera, Hengzhuang Wang, Junwei Wang, Dongmei Cun, Yu Feng, Mingshi Yang","doi":"10.15212/amm-2022-0050","DOIUrl":"https://doi.org/10.15212/amm-2022-0050","url":null,"abstract":"The current study focused on the formulation, physicochemical characterization, and antibacterial susceptibility testing of inhalable spray dried powders containing ciprofloxacin (CIP) and polymyxin B sulfate (PMB). CIP nanosuspensions with an average particle diameter of 435.9 ± 9.3 nm were initially obtained using the wet-milling protocol and subsequently co-spray dried with PMB solutions to yield inhalable dry powders. The Powder X-Ray Diffraction (P-XRD) results showed that the wet-milled CIP nanoparticles were in a 4.8 hydrate state, which were transformed to 3.7 hydrates and amorphous materials after co-spray drying. The PMB remained in an amorphous state in the dry powders. Differential Scanning Calorimetry (DSC) analyses revealed that the glass transition temperatures (Tgs) of the co–spray dried formulations were higher than the Tg of CIP, but lower than the Tg of PMB. Fourier Transform Infrared Spectrometer (FTIR) studies suggested the existence of π - π interactions between CIP and PMB in the co-spray dried powders. These powders also retained antimicrobial effects against Pseudomonas aeruginosa strain PAO1. In addition, the spray-dried powder formulations exhibited satisfactory solid-state stability and aerodynamic characteristics when stored under 3% relative humidity and 20 ± 5 °C for 4 months. Overall, the newly developed inhalable CIP/PMB dry powders are a promising therapeutic strategy for respiratory tract infections.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44299684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The rapid development of bioinformatics tools has recently broken through the bottleneck in natural products research. These advances have enabled natural products researchers to rapidly separate and efficiently target and discover previously undescribed molecules. Among these advances, tandem mass spectrometry molecular networking is a promising method for rapidly de-replicating complex natural mixtures, thus leading to an accelerated revolution in the “art of natural products isolation” field. In this review we describe the current molecular networking-based metabolite analysis methods that are widely applied or implementable in natural products discovery research, metabolomics, and related fields. The main objective of this review was to summarize strategies that can be rapidly implemented as alternative de-replication approaches for efficient natural products discovery and to list examples of successful applications that combine networking with other techniques.
{"title":"Molecular networking as a natural products discovery strategy","authors":"Mi Zhang, Kouharu Otsuki, Wei Li","doi":"10.15212/amm-2023-0007","DOIUrl":"https://doi.org/10.15212/amm-2023-0007","url":null,"abstract":"The rapid development of bioinformatics tools has recently broken through the bottleneck in natural products research. These advances have enabled natural products researchers to rapidly separate and efficiently target and discover previously undescribed molecules. Among these advances, tandem mass spectrometry molecular networking is a promising method for rapidly de-replicating complex natural mixtures, thus leading to an accelerated revolution in the “art of natural products isolation” field. In this review we describe the current molecular networking-based metabolite analysis methods that are widely applied or implementable in natural products discovery research, metabolomics, and related fields. The main objective of this review was to summarize strategies that can be rapidly implemented as alternative de-replication approaches for efficient natural products discovery and to list examples of successful applications that combine networking with other techniques.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46125839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cheng Zhang, Guoming Chen, Guoyi Tang, Xiaoyu Xu, Z. Feng, Yuanjun Lu, Y. Chan, Junyu Wu, Yuanyuan Chen, Lin Xu, Qing-li Ren, Hongchao Yuan, Dong Yang, Zhe-Sheng Chen, Ning Wang, Yibin Feng
For hundreds of years, the drug discovery and development industry has aimed at identifying single components with a clear mechanism of action as desirable candidates for potential drugs. However, this conventional strategy of drug discovery and development has faced challenges including a low success rate and high development costs. Herein, we critically review state-of-the-art drug discovery and development based on multi-component Chinese medicine formulas. We review the policies and application status of new drugs based on multi-component Chinese medicines in the US, China, and the European Union. Moreover, we illustrate several excellent cases of ongoing applications. Biomedical technologies that may facilitate drug discovery and development based on multi-component Chinese medicine formulas are discussed, including network pharmacology, integrative omics, CRISPR gene editing, and chemometrics. Finally, we discuss potential problems and solutions in pre-clinical and clinical research in drug discovery and development based on multi-component Chinese medicine formulas. We hope that this review will promote discussion of the roles of multi-component Chinese medicine formulas in the discovery and development of new drugs for the treatment of human diseases.
{"title":"Multi-component Chinese medicine formulas for drug discovery: State of the art and future perspectives","authors":"Cheng Zhang, Guoming Chen, Guoyi Tang, Xiaoyu Xu, Z. Feng, Yuanjun Lu, Y. Chan, Junyu Wu, Yuanyuan Chen, Lin Xu, Qing-li Ren, Hongchao Yuan, Dong Yang, Zhe-Sheng Chen, Ning Wang, Yibin Feng","doi":"10.15212/amm-2022-0049","DOIUrl":"https://doi.org/10.15212/amm-2022-0049","url":null,"abstract":"For hundreds of years, the drug discovery and development industry has aimed at identifying single components with a clear mechanism of action as desirable candidates for potential drugs. However, this conventional strategy of drug discovery and development has faced challenges including a low success rate and high development costs. Herein, we critically review state-of-the-art drug discovery and development based on multi-component Chinese medicine formulas. We review the policies and application status of new drugs based on multi-component Chinese medicines in the US, China, and the European Union. Moreover, we illustrate several excellent cases of ongoing applications. Biomedical technologies that may facilitate drug discovery and development based on multi-component Chinese medicine formulas are discussed, including network pharmacology, integrative omics, CRISPR gene editing, and chemometrics. Finally, we discuss potential problems and solutions in pre-clinical and clinical research in drug discovery and development based on multi-component Chinese medicine formulas. We hope that this review will promote discussion of the roles of multi-component Chinese medicine formulas in the discovery and development of new drugs for the treatment of human diseases.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43989988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Development of efficient photosensitizers with minimal side effects is highly desirable for photodynamic therapy. Reported herein is the discovery of a novel pyridophenoselenazinium-based NIR-I photosensitizer, termed PPSe, that efficiently generated both type I and II reactive oxygen species (ROS) upon appropriate light irradiation. PPSe exhibited potent phototoxicity as well as excellent phototherapeutic indices against several breast cancer cell lines. PPSe induced DNA damage and breast cancer cell apoptosis via photo-triggered intracellular ROS generation.
{"title":"Discovery of a pyridophenoselenazinium-based photosensitizer with high photodynamic efficacy against breast cancer cells","authors":"Guiling Li, Peixia Li, Qiaoyun Jiang, Qianqian Zhang, Jingru Qiu, Donghai Li, Gang Shan","doi":"10.15212/amm-2023-0002","DOIUrl":"https://doi.org/10.15212/amm-2023-0002","url":null,"abstract":"Development of efficient photosensitizers with minimal side effects is highly desirable for photodynamic therapy. Reported herein is the discovery of a novel pyridophenoselenazinium-based NIR-I photosensitizer, termed PPSe, that efficiently generated both type I and II reactive oxygen species (ROS) upon appropriate light irradiation. PPSe exhibited potent phototoxicity as well as excellent phototherapeutic indices against several breast cancer cell lines. PPSe induced DNA damage and breast cancer cell apoptosis via photo-triggered intracellular ROS generation.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43118388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Huitao Gao, Hongzhong Liu, Xin Zheng, X. Cui, S. Bricout-Hennel, A. Lucien, Pauline Lauruol, Yaqin Wang, Xue Wang, Hongyun Wang, Chen Rui
S05590 is a fixed-dose combination of perindopril tert-butylamine 4 mg/indapamide 1.25 mg, and S06593 is a fixed-dose combination of perindopril arginine 5 mg/indapamide 1.25 mg/amlodipine 5 mg. The purpose of this study was to determine whether pharmacokinetic interactions exist among the components of S06593, compared with S05590 and amlodipine as reference drugs, in healthy Chinese male volunteers after a single oral administration under fasting conditions. A single-center, open-label, randomized, three-period, six-way crossover study was conducted. A total of 42 participants were enrolled and randomized to receive S05590 plus amlodipine, or S06593. The doses of perindopril were 3.34 mg in both S05590 and S06593, calculated as free acid. Blood samples were collected in each treatment period to determine the plasma concentrations of perindopril, indapamide and amlodipine, as well as perindoprilat, the main metabolite of perindopril. A total of 39 participants completed this study. The 90% confidence intervals of the geometric mean ratios of Cmax, AUC0-t and AUC0-∞ for perindopril, perindoprilat, indapamide and amlodipine were all within 80.00–125.00%, thus indicating that S05590 plus amlodipine and S06593 were pharmacokinetically equivalent. During the study, only one serious emergent adverse event was reported, which was deemed not to be associated with the study drug. No serious treatment-associated adverse events were observed.
{"title":"Potential pharmacokinetic interactions in fixed-dose combinations of perindopril/indapamide/amlodipine compared with perindopril/indapamide and amlodipine in healthy Chinese volunteers","authors":"Huitao Gao, Hongzhong Liu, Xin Zheng, X. Cui, S. Bricout-Hennel, A. Lucien, Pauline Lauruol, Yaqin Wang, Xue Wang, Hongyun Wang, Chen Rui","doi":"10.15212/amm-2022-0045","DOIUrl":"https://doi.org/10.15212/amm-2022-0045","url":null,"abstract":"S05590 is a fixed-dose combination of perindopril tert-butylamine 4 mg/indapamide 1.25 mg, and S06593 is a fixed-dose combination of perindopril arginine 5 mg/indapamide 1.25 mg/amlodipine 5 mg. The purpose of this study was to determine whether pharmacokinetic interactions exist among the components of S06593, compared with S05590 and amlodipine as reference drugs, in healthy Chinese male volunteers after a single oral administration under fasting conditions. A single-center, open-label, randomized, three-period, six-way crossover study was conducted. A total of 42 participants were enrolled and randomized to receive S05590 plus amlodipine, or S06593. The doses of perindopril were 3.34 mg in both S05590 and S06593, calculated as free acid. Blood samples were collected in each treatment period to determine the plasma concentrations of perindopril, indapamide and amlodipine, as well as perindoprilat, the main metabolite of perindopril. A total of 39 participants completed this study. The 90% confidence intervals of the geometric mean ratios of Cmax, AUC0-t and AUC0-∞ for perindopril, perindoprilat, indapamide and amlodipine were all within 80.00–125.00%, thus indicating that S05590 plus amlodipine and S06593 were pharmacokinetically equivalent. During the study, only one serious emergent adverse event was reported, which was deemed not to be associated with the study drug. No serious treatment-associated adverse events were observed.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43836076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
XIN-YAN Chen, Min Shi, Le-tian Yang, F. Guo, Yan Liang, Liang Ma, P. Fu
Diabetic kidney disease (DKD) is one of the leading causes of end-stage renal disease. Verbascoside is a ubiquitous phenylethanoid glycoside with potent anti-inflammatory, antioxidant, and hypoglycemic properties. This study determined the renoprotective effect of verbascoside against DKD, as well as the underlying mechanism. After administration of verbascoside for 4 consecutive weeks, the fasting blood glucose level, albumin:creatinine ratio, and podocyte damage in diabetic mice were alleviated, especially at a dose of 150 mg/kg/d. Moreover, the inflammatory response, cell apoptosis, and autophagy were improved in a dose-dependent fashion in the kidneys of diabetic mice and high glucose-stimulated podocytes. Verbascoside reversed the elevated NR4A1 expression and suppressed LKB1 to inhibit AMPKα phosphorylation. Silencing NR4A1 inhibited LKB1 and phospho-AMPKα expression, and relieved the stress response in injured podocytes. Taken together, our results indicated that verbascoside alleviates DKD-associated podocyte injury by regulating NR4A1-LKB1-AMPK signaling.
{"title":"Phenylethanoid glycoside verbascoside ameliorates podocyte injury of diabetic kidney disease by regulating NR4A1-LKB1-AMPK signaling","authors":"XIN-YAN Chen, Min Shi, Le-tian Yang, F. Guo, Yan Liang, Liang Ma, P. Fu","doi":"10.15212/amm-2022-0044","DOIUrl":"https://doi.org/10.15212/amm-2022-0044","url":null,"abstract":"Diabetic kidney disease (DKD) is one of the leading causes of end-stage renal disease. Verbascoside is a ubiquitous phenylethanoid glycoside with potent anti-inflammatory, antioxidant, and hypoglycemic properties. This study determined the renoprotective effect of verbascoside against DKD, as well as the underlying mechanism. After administration of verbascoside for 4 consecutive weeks, the fasting blood glucose level, albumin:creatinine ratio, and podocyte damage in diabetic mice were alleviated, especially at a dose of 150 mg/kg/d. Moreover, the inflammatory response, cell apoptosis, and autophagy were improved in a dose-dependent fashion in the kidneys of diabetic mice and high glucose-stimulated podocytes. Verbascoside reversed the elevated NR4A1 expression and suppressed LKB1 to inhibit AMPKα phosphorylation. Silencing NR4A1 inhibited LKB1 and phospho-AMPKα expression, and relieved the stress response in injured podocytes. Taken together, our results indicated that verbascoside alleviates DKD-associated podocyte injury by regulating NR4A1-LKB1-AMPK signaling.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46782759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xuanting Mou, Aolin Zhang, Tao He, Renjie Chen, Fanfan Zhou, Tsz Ching Yeung, C. Wang, Chao Tang, Xiaoyan Lu, Lu Li, Xiaohui Fan
Organoids are three-dimensional cell accusations generated from pluripotent stem cells or adult stem cells in vitro. With many advantages over cell and animal models, organoids have been increasingly used in drug and clinical medical research in recent years. Chinese herbal medicine (CHM) is characterized by multi-target and multi-pathway treatment methods; however, there is no commonly accepted study method regarding efficacy and underlying mechanisms. In this review we summarized the important applications of organoid models in pharmacodynamic mechanism studies, efficacy and safety evaluations, and CHM personalized medicine, thus providing the theoretical basis for its development and innovation.
{"title":"Organoid models for Chinese herbal medicine studies","authors":"Xuanting Mou, Aolin Zhang, Tao He, Renjie Chen, Fanfan Zhou, Tsz Ching Yeung, C. Wang, Chao Tang, Xiaoyan Lu, Lu Li, Xiaohui Fan","doi":"10.15212/amm-2022-0047","DOIUrl":"https://doi.org/10.15212/amm-2022-0047","url":null,"abstract":"Organoids are three-dimensional cell accusations generated from pluripotent stem cells or adult stem cells in vitro. With many advantages over cell and animal models, organoids have been increasingly used in drug and clinical medical research in recent years. Chinese herbal medicine (CHM) is characterized by multi-target and multi-pathway treatment methods; however, there is no commonly accepted study method regarding efficacy and underlying mechanisms. In this review we summarized the important applications of organoid models in pharmacodynamic mechanism studies, efficacy and safety evaluations, and CHM personalized medicine, thus providing the theoretical basis for its development and innovation.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49062452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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