Qing-Qing Xu, Wen Yang, Mei Zhong, Zhi-xiu Lin, Nora E. Gray, Yan-Fang Xian
Alzheimer’s disease (AD), an irreversible neurodegenerative disease that progressively impairs memory and cognitive judgment, severely affects the quality of life and imposes a heavy burden on the healthcare system. No cure is currently available for AD, in part because the pathogenesis of this disease has not been established. Animal models are essential for investigating AD pathogenesis and evaluating potential therapeutic strategies for AD. Some phenotypic and neuropathologic changes in AD patients can be recapitulated with genetic and pharmacologic approaches in animals. This article systematically reviews the animal models available for AD research, including transgenic, chemical- or drug-induced, and spontaneous animal models, and the characteristics of these animal models. In this review we also discuss the challenges and constraints when using AD animal models. Although no single animal model can reproduce all pathologic aspects and behavioral features in AD patients, the currently available AD models are valuable tools for deciphering the pathogenic mechanisms underlying AD and developing new anti-AD therapeutics.
{"title":"Animal models of Alzheimer’s disease: preclinical insights and challenges","authors":"Qing-Qing Xu, Wen Yang, Mei Zhong, Zhi-xiu Lin, Nora E. Gray, Yan-Fang Xian","doi":"10.15212/amm-2023-0001","DOIUrl":"https://doi.org/10.15212/amm-2023-0001","url":null,"abstract":"Alzheimer’s disease (AD), an irreversible neurodegenerative disease that progressively impairs memory and cognitive judgment, severely affects the quality of life and imposes a heavy burden on the healthcare system. No cure is currently available for AD, in part because the pathogenesis of this disease has not been established. Animal models are essential for investigating AD pathogenesis and evaluating potential therapeutic strategies for AD. Some phenotypic and neuropathologic changes in AD patients can be recapitulated with genetic and pharmacologic approaches in animals. This article systematically reviews the animal models available for AD research, including transgenic, chemical- or drug-induced, and spontaneous animal models, and the characteristics of these animal models. In this review we also discuss the challenges and constraints when using AD animal models. Although no single animal model can reproduce all pathologic aspects and behavioral features in AD patients, the currently available AD models are valuable tools for deciphering the pathogenic mechanisms underlying AD and developing new anti-AD therapeutics.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67303321","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}
Junjie Li, Shuoyi Ma, Yantao Zheng, Mengchen Qin, Hui Jia, Chang Liu, Yunjia Li, Guanghui Deng, Min Cai, Bin Liu, Lei Gao
The role of cuproptosis, a newly discovered form of programmed cell death, remains poorly understood in hepatocellular carcinoma (HCC). This study was aimed at constructing a novel cuproptosis model for analyzing the clinical features, mutation characteristics and immune profile of HCC associated with cuproptosis-related genes (CRG), and to analyze the prognostic value of CRGs in HCC. We comprehensively evaluated HCC datasets containing clinicopathological information from The Cancer Genome Atlas and GEO, on the basis of 19 CRGs. The prognostic value of the cuproptosis-related risk score was established. Our results revealed two clusters associated with cuproptosis. Cluster B exhibited pronounced isolated innate immune cell infiltration and poor prognosis, and significant differences in prognosis and immune infiltration were observed between the groups with high and low cuproptosis risk. High copper mortality risk scores were associated with an elevated tumor mutational burden (TMB) and poor prognosis. Our findings suggest that evaluating copper-death subtypes provides insights into CRGs. Moreover, the copper mortality risk score model aids in characterizing prognosis and immune infiltration independently of the TMB.
{"title":"Prognostic value and immune infiltration analyses of cuproptosis-related genes in hepatocellular carcinoma","authors":"Junjie Li, Shuoyi Ma, Yantao Zheng, Mengchen Qin, Hui Jia, Chang Liu, Yunjia Li, Guanghui Deng, Min Cai, Bin Liu, Lei Gao","doi":"10.15212/amm-2023-0035","DOIUrl":"https://doi.org/10.15212/amm-2023-0035","url":null,"abstract":"The role of cuproptosis, a newly discovered form of programmed cell death, remains poorly understood in hepatocellular carcinoma (HCC). This study was aimed at constructing a novel cuproptosis model for analyzing the clinical features, mutation characteristics and immune profile of HCC associated with cuproptosis-related genes (CRG), and to analyze the prognostic value of CRGs in HCC. We comprehensively evaluated HCC datasets containing clinicopathological information from The Cancer Genome Atlas and GEO, on the basis of 19 CRGs. The prognostic value of the cuproptosis-related risk score was established. Our results revealed two clusters associated with cuproptosis. Cluster B exhibited pronounced isolated innate immune cell infiltration and poor prognosis, and significant differences in prognosis and immune infiltration were observed between the groups with high and low cuproptosis risk. High copper mortality risk scores were associated with an elevated tumor mutational burden (TMB) and poor prognosis. Our findings suggest that evaluating copper-death subtypes provides insights into CRGs. Moreover, the copper mortality risk score model aids in characterizing prognosis and immune infiltration independently of the TMB.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":"30 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134884305","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}
A significant proportion of patients who survive coronavirus disease of 2019 (COVID-19) develop a constellation of life-altering symptoms that persist long after the initial infection has resolved. This post-COVID-19 syndrome may result from the development of autoreactive IgG antibodies that cause inflammation and tissue injury. In this commentary, we suggest that efgartigimod, a drug approved for the treatment of generalized myasthenia gravis, be tested for use in patients with post-COVID-19. Efgartigimod is a humanized IgG Fc fragment containing five point mutations that significantly increase affinity for the Fc region of the neonatal crystallizable fragment receptor (FcRn). FcRn is involved in the pathogenesis of autoimmune diseases via the IgG recycling pathway because FcRN binds to autoreactive IgG antibodies and prevents the antibodies from being catabolized. Efgartigimod is a modified immunoglobulin that competitively displaces endogenous IgG from FcRn, thus increasing the level of unbound IgG, which is then catabolized and leads to decreased circulating levels of autoreactive as well as normal IgG. We suggest that efgartigimod be evaluated in a random, double-blind placebo-control trial in adults with post-COVID-19 for at least 2 months. If re-purposing this myasthenia gravis-approved drug for post - COVID-19 is successful, additional bioengineered FcRn antagonists should be tested for efficacy in patients with post-COVID-19.
{"title":"Efgartigimod, an FcRn antagonist, as a potential treatment for post COVID-19 syndrome","authors":"S. Reznik, A. Tiwari, C. Ashby","doi":"10.15212/amm-2023-0004","DOIUrl":"https://doi.org/10.15212/amm-2023-0004","url":null,"abstract":"A significant proportion of patients who survive coronavirus disease of 2019 (COVID-19) develop a constellation of life-altering symptoms that persist long after the initial infection has resolved. This post-COVID-19 syndrome may result from the development of autoreactive IgG antibodies that cause inflammation and tissue injury. In this commentary, we suggest that efgartigimod, a drug approved for the treatment of generalized myasthenia gravis, be tested for use in patients with post-COVID-19. Efgartigimod is a humanized IgG Fc fragment containing five point mutations that significantly increase affinity for the Fc region of the neonatal crystallizable fragment receptor (FcRn). FcRn is involved in the pathogenesis of autoimmune diseases via the IgG recycling pathway because FcRN binds to autoreactive IgG antibodies and prevents the antibodies from being catabolized. Efgartigimod is a modified immunoglobulin that competitively displaces endogenous IgG from FcRn, thus increasing the level of unbound IgG, which is then catabolized and leads to decreased circulating levels of autoreactive as well as normal IgG. We suggest that efgartigimod be evaluated in a random, double-blind placebo-control trial in adults with post-COVID-19 for at least 2 months. If re-purposing this myasthenia gravis-approved drug for post - COVID-19 is successful, additional bioengineered FcRn antagonists should be tested for efficacy in patients with post-COVID-19.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67303138","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}
Peng Wu, Xiaoning Liu, Yuheng Duan, Liping Pan, Zhaogang Sun, Hong-qian Chu, Chuanzhi Zhu, Bei Liu
The development of novel antimicrobial agents is highly desirable for treating bacterial infections. Here, a smart photodynamic therapy (PDT) system based on a combination of peony-shaped ferroselite FeSe2 particles and zinc (II) phthalocyanine (ZnPc) photosensitizers was constructed. Effective energy transfer occurred from ZnPc to FeSe2, because of their proximity, thus eliciting the OFF state of ZnPc photosensitizers. Under 808 nm NIR light irradiation, the photothermal effect of FeSe2 promoted the release of ZnPc, thus turning on the photodynamic effect of the photosensitizers (ON state). In vitro, FeSe2-ZnPc exhibited high photo-to-thermal conversion efficiency (26.4%) and effective generation of reactive oxygen species for combined photothermal/photodynamic therapy. Therefore, the FeSe2-ZnPc hybrids have great potential to serve as alternatives to antibiotics for eradication of pathogenic bacteria.
{"title":"ZnPc photosensitizer-loaded peony-shaped FeSe2 remotely controlled by near-infrared light for antimycobacterial therapy","authors":"Peng Wu, Xiaoning Liu, Yuheng Duan, Liping Pan, Zhaogang Sun, Hong-qian Chu, Chuanzhi Zhu, Bei Liu","doi":"10.15212/amm-2023-0012","DOIUrl":"https://doi.org/10.15212/amm-2023-0012","url":null,"abstract":"The development of novel antimicrobial agents is highly desirable for treating bacterial infections. Here, a smart photodynamic therapy (PDT) system based on a combination of peony-shaped ferroselite FeSe2 particles and zinc (II) phthalocyanine (ZnPc) photosensitizers was constructed. Effective energy transfer occurred from ZnPc to FeSe2, because of their proximity, thus eliciting the OFF state of ZnPc photosensitizers. Under 808 nm NIR light irradiation, the photothermal effect of FeSe2 promoted the release of ZnPc, thus turning on the photodynamic effect of the photosensitizers (ON state). In vitro, FeSe2-ZnPc exhibited high photo-to-thermal conversion efficiency (26.4%) and effective generation of reactive oxygen species for combined photothermal/photodynamic therapy. Therefore, the FeSe2-ZnPc hybrids have great potential to serve as alternatives to antibiotics for eradication of pathogenic bacteria.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67303434","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}
Yang Liu, Kuiru Sa, Wei-Na Xu, Yong-Quan Chen, Jing Liang, Peng Zou, Lixia Chen
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally since 2020. The nucleocapsid (N) protein plays a crucial role in the life cycle of SARS-CoV-2. Here, we established a method to screen inhibitors of N protein by using microscale thermophoresis assays to obtain potential anti-SARS-CoV-2 agents. We identified 1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one (N-17, a diphenylheptane) as a compound with outstanding inhibitory activity. We further validated the binding of N-17 to the N-terminal domain of N protein (N-NTD) by using drug affinity responsive target stability assays. We evaluated the ability of N-17 to bind N protein and predicted the affinity of N-17 to the N-NTD with molecular docking and molecular dynamics simulation. N-17 exhibited excellent anti-viral activity against HCoV-OC43 and SARS-CoV-2, with EC50 values of 0.16 ± 0.01 μM and 0.17 ± 0.07 μM, respectively. Thus, we discovered a novel SARS-CoV-2 inhibitor targeting the N protein and validated its anti-viral activity in vitro. Our results may contribute to the development of promising therapeutic agents for COVID-19.
{"title":"1,7-Bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one inhibits SARS-CoV-2 by targeting the nucleocapsid protein","authors":"Yang Liu, Kuiru Sa, Wei-Na Xu, Yong-Quan Chen, Jing Liang, Peng Zou, Lixia Chen","doi":"10.15212/amm-2023-0021","DOIUrl":"https://doi.org/10.15212/amm-2023-0021","url":null,"abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally since 2020. The nucleocapsid (N) protein plays a crucial role in the life cycle of SARS-CoV-2. Here, we established a method to screen inhibitors of N protein by using microscale thermophoresis assays to obtain potential anti-SARS-CoV-2 agents. We identified 1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one (N-17, a diphenylheptane) as a compound with outstanding inhibitory activity. We further validated the binding of N-17 to the N-terminal domain of N protein (N-NTD) by using drug affinity responsive target stability assays. We evaluated the ability of N-17 to bind N protein and predicted the affinity of N-17 to the N-NTD with molecular docking and molecular dynamics simulation. N-17 exhibited excellent anti-viral activity against HCoV-OC43 and SARS-CoV-2, with EC50 values of 0.16 ± 0.01 μM and 0.17 ± 0.07 μM, respectively. Thus, we discovered a novel SARS-CoV-2 inhibitor targeting the N protein and validated its anti-viral activity in vitro. Our results may contribute to the development of promising therapeutic agents for COVID-19.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67303795","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 Chen, Zheling Feng, Jovana Petrović, Marina Soković, Yang Ye, Ligen Lin
Inflammation is an essential part of the immune response to injury and infection. Emerging evidence indicates that long-term low-grade inflammation is positively correlated with many diseases, such as cancer, metabolic disorders, and cardiovascular diseases. Due to common anti-inflammatory drugs are suitable for treating acute inflammation and cause severe adverse effects, new safe and effective drug candidates are urgently needed for treating chronic inflammation. Plants of the Asteraceae family have been widely used in traditional medicines for relieving fever symptoms and killing pathogens. The anti-inflammatory properties of sesquiterpenoids from plants in the Asteraceae family have attracted increasing attention in recent decades because of their structural complexity and potent bioactivities. Herein, we provide a comprehensive and up-to-date summary of sesquiterpenoids from the Asteraceae family with anti-inflammatory properties, including their drug likeness and druggability, as analyzed with the SwissADME and ADMETlab online tools. In the future, some sesquiterpenoids might serve as therapeutic agents to treat inflammation-associated diseases.
{"title":"Sesquiterpenoids from the sunflower family as potential anti-inflammatory candidates: a review","authors":"Cheng Chen, Zheling Feng, Jovana Petrović, Marina Soković, Yang Ye, Ligen Lin","doi":"10.15212/amm-2023-0026","DOIUrl":"https://doi.org/10.15212/amm-2023-0026","url":null,"abstract":"Inflammation is an essential part of the immune response to injury and infection. Emerging evidence indicates that long-term low-grade inflammation is positively correlated with many diseases, such as cancer, metabolic disorders, and cardiovascular diseases. Due to common anti-inflammatory drugs are suitable for treating acute inflammation and cause severe adverse effects, new safe and effective drug candidates are urgently needed for treating chronic inflammation. Plants of the Asteraceae family have been widely used in traditional medicines for relieving fever symptoms and killing pathogens. The anti-inflammatory properties of sesquiterpenoids from plants in the Asteraceae family have attracted increasing attention in recent decades because of their structural complexity and potent bioactivities. Herein, we provide a comprehensive and up-to-date summary of sesquiterpenoids from the Asteraceae family with anti-inflammatory properties, including their drug likeness and druggability, as analyzed with the SwissADME and ADMETlab online tools. In the future, some sesquiterpenoids might serve as therapeutic agents to treat inflammation-associated diseases.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":"23 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135846122","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}
Dechao Feng, Dengxiong Li, Jie Wang, Rui-cheng Wu, Chi Zhang
Cellular senescence has been considered as a hallmark of aging. In this study, we aimed to establish two novel prognostic subtypes for prostate cancer patients using senescence-related lncRNAs. Nonnegative matrix factorization algorithm was used to identify molecular subtypes. We completed analyses using software R 3.6.3 and its suitable packages. Using SNHG1, MIAT and SNHG3, 430 patients in TCGA database were classified into two subtypes associated with biochemical recurrence (BCR)-free survival and subtype 2 was prone to BCR (HR: 19.62, p < 0.001). The similar results were observed in the GSE46602 and GSE116918. For hallmark gene set enrichment, we found that protein secretion and androgen response were highly enriched in subtype 1 and G2M checkpoint was highly enriched in subtype 2. For tumor heterogeneity and stemness, homologous recombination deficiency and tumor mutation burden were significantly higher in subtype 2 than subtype 1. The top ten genes between subtype 2 and subtype 1 were CUBN, DNAH9, PTCHD4, NOD1, ARFGEF1, HRAS, PYHIN1, ARHGEF2, MYOM1 and ITGB6 with statistical significance. In terms of immune checkpoints, only CD47 was significantly higher in subtype 1 than that in subtype 2. For the overall assessment, no significant difference was detected between two subtypes, while B cells score was significantly higher in subtype 1 than subtype 2. Overall, we found two distinct subtypes closely associated with BCR-free survival and androgen response for prostate cancer. These subtypes might facilitate future research in the field of prostate cancer.
细胞衰老被认为是衰老的标志。在这项研究中，我们旨在利用衰老相关的lncrna建立前列腺癌患者的两种新的预后亚型。采用非负矩阵分解算法识别分子亚型。我们使用R 3.6.3软件及其配套软件包完成分析。使用SNHG1、MIAT和SNHG3将TCGA数据库中的430例患者分为与生化复发(BCR)无生存相关的两种亚型，亚型2易发生BCR (HR: 19.62, p < 0.001)。在GSE46602和GSE116918中观察到类似的结果。对于标记基因集富集，我们发现蛋白分泌和雄激素反应在亚型1中高度富集，而G2M检查点在亚型2中高度富集。在肿瘤异质性和干性方面，亚型2的同源重组缺失和肿瘤突变负担显著高于亚型1。2亚型与1亚型之间的前10位基因分别为CUBN、DNAH9、PTCHD4、NOD1、ARFGEF1、HRAS、PYHIN1、ARHGEF2、MYOM1、ITGB6，差异均有统计学意义。在免疫检查点方面，只有CD47在亚型1中明显高于亚型2。对于总体评估，两种亚型之间没有明显差异，而亚型1的B细胞评分明显高于亚型2。总的来说，我们发现两种不同的亚型与前列腺癌无bcr生存和雄激素反应密切相关。这些亚型可能有助于未来在前列腺癌领域的研究。
{"title":"Senescence-associated lncRNAs indicate distinct molecular subtypes associated with prognosis and androgen response in patients with patients with prostate cancer","authors":"Dechao Feng, Dengxiong Li, Jie Wang, Rui-cheng Wu, Chi Zhang","doi":"10.15212/amm-2023-0025","DOIUrl":"https://doi.org/10.15212/amm-2023-0025","url":null,"abstract":"Cellular senescence has been considered as a hallmark of aging. In this study, we aimed to establish two novel prognostic subtypes for prostate cancer patients using senescence-related lncRNAs. Nonnegative matrix factorization algorithm was used to identify molecular subtypes. We completed analyses using software R 3.6.3 and its suitable packages. Using SNHG1, MIAT and SNHG3, 430 patients in TCGA database were classified into two subtypes associated with biochemical recurrence (BCR)-free survival and subtype 2 was prone to BCR (HR: 19.62, p < 0.001). The similar results were observed in the GSE46602 and GSE116918. For hallmark gene set enrichment, we found that protein secretion and androgen response were highly enriched in subtype 1 and G2M checkpoint was highly enriched in subtype 2. For tumor heterogeneity and stemness, homologous recombination deficiency and tumor mutation burden were significantly higher in subtype 2 than subtype 1. The top ten genes between subtype 2 and subtype 1 were CUBN, DNAH9, PTCHD4, NOD1, ARFGEF1, HRAS, PYHIN1, ARHGEF2, MYOM1 and ITGB6 with statistical significance. In terms of immune checkpoints, only CD47 was significantly higher in subtype 1 than that in subtype 2. For the overall assessment, no significant difference was detected between two subtypes, while B cells score was significantly higher in subtype 1 than subtype 2. Overall, we found two distinct subtypes closely associated with BCR-free survival and androgen response for prostate cancer. These subtypes might facilitate future research in the field of prostate cancer.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67303509","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}
Mitogen-activated protein kinases (MAPKs) are a group of serine-threonine protein kinases that can be activated by extracellular stimuli. MAPK14 (p38α) affects major disease processes, while inhibition of p38α has been shown to have potential therapeutic effects. Many inhibitors targeting p38α have entered clinical trials but have a long development cycle and severe side effects. We developed a multi-step receptor structure-based virtual screening method to screen potential bioactive molecules from SPECS and our MCDB libraries. Compound 10 was identified as a promising p38α inhibitor that may be used in the treatment of p38αMAPK pathway-related diseases, but corollary studies are warranted.
{"title":"Structure-based virtual screening for novel p38 MAPK inhibitors and a biological evaluation","authors":"Qinwen Zheng, Yumeng Zhu, Aoxue Wang, Panpan Yang, Xin Wang, Wen Shuai, Liang Ouyang, Guan Wang","doi":"10.15212/amm-2023-0028","DOIUrl":"https://doi.org/10.15212/amm-2023-0028","url":null,"abstract":"Mitogen-activated protein kinases (MAPKs) are a group of serine-threonine protein kinases that can be activated by extracellular stimuli. MAPK14 (p38α) affects major disease processes, while inhibition of p38α has been shown to have potential therapeutic effects. Many inhibitors targeting p38α have entered clinical trials but have a long development cycle and severe side effects. We developed a multi-step receptor structure-based virtual screening method to screen potential bioactive molecules from SPECS and our MCDB libraries. Compound 10 was identified as a promising p38α inhibitor that may be used in the treatment of p38αMAPK pathway-related diseases, but corollary studies are warranted.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":"309 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134882494","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}
Tylophorine has diverse biological activities; however, the stability, solubility, and central nervous system toxicity have severely limited use of tylophorine. The gem -dimethyl group is an organic chemistry functional group that consists of two methyl groups bonded to the same carbon atom. This feature has gained significant attention in medicinal chemistry due to its unique properties and potential applications in drug design. We applied a new photoredox methodology to tylophorine modification, resulting in a series of gem-dimethyl tylophorine analogues. Among the analogues, compound 4b demonstrated promising activity against a wide range of tumor cell lines and exhibited significantly improved drug-like properties, including enhanced solubility and stability. Compound 4b showed an exceptional inhibitory effect (7.8 nM) against a C481S mutation-induced ibrutinib-resistant non-Hodgkin’s lymphoma cell line, as well as primary tumor cell lines obtained from patients. Importantly, compound 4b exhibited significantly reduced anti-proliferative activity against the normal cell line tested, indicating the potential for an enhanced therapeutic window for compound 4b . Based on these early-stage data, we believe that our study provides a solid foundation for the development of new therapeutic agents for potential drug-resistant cancer treatment in the near future.
{"title":"Photoredox-catalyzed reaction as a powerful tool for rapid natural product Gem-dimethylation modification: discovery of potent anti-cancer agents with improved druggability","authors":"Chao Zhang, Yugang Song, Xiuyun Sun, Qianlong Liu, Zhen Li, Shenyi Yin, Jianzhong Jeff Xi, Xin Zhai, Yu Rao","doi":"10.15212/amm-2023-0032","DOIUrl":"https://doi.org/10.15212/amm-2023-0032","url":null,"abstract":"Tylophorine has diverse biological activities; however, the stability, solubility, and central nervous system toxicity have severely limited use of tylophorine. The gem -dimethyl group is an organic chemistry functional group that consists of two methyl groups bonded to the same carbon atom. This feature has gained significant attention in medicinal chemistry due to its unique properties and potential applications in drug design. We applied a new photoredox methodology to tylophorine modification, resulting in a series of gem-dimethyl tylophorine analogues. Among the analogues, compound 4b demonstrated promising activity against a wide range of tumor cell lines and exhibited significantly improved drug-like properties, including enhanced solubility and stability. Compound 4b showed an exceptional inhibitory effect (7.8 nM) against a C481S mutation-induced ibrutinib-resistant non-Hodgkin’s lymphoma cell line, as well as primary tumor cell lines obtained from patients. Importantly, compound 4b exhibited significantly reduced anti-proliferative activity against the normal cell line tested, indicating the potential for an enhanced therapeutic window for compound 4b . Based on these early-stage data, we believe that our study provides a solid foundation for the development of new therapeutic agents for potential drug-resistant cancer treatment in the near future.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":"25 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135261277","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}
Activation of simulator of interferon genes (STING), which induces the production of proinflammatory factors and immune effector cell activation, is considered a promising strategy for enhanced anti-cancer intervention. However, several obstacles prevent STING signaling in solid tumors, such as delivered molecules’ rapid degradation, restriction to tumor sites, insufficient intracellular concentrations, and low responsivity. Well-designed, multifunctional nano-formulations have emerged as optimized platforms for STING activation. Recently, a variety of nano-formulations have been developed and used in STING activation, thus facilitating immunotherapy in preclinical and clinical stages. Herein, we summarize recent advances in nanotechnology-based delivery, activation, and application strategies, which have advanced various aspects of immunotherapy. Novel STING agonists and their mechanisms in STING-activation-mediated tumor interventions are highlighted herein, to provide a comprehensive overview and discuss future directions for boosting immunotherapy via STING regulation.
{"title":"Novel emerging nano-assisted anti-cancer strategies based on the STING pathway","authors":"Xianghui Li, Haoran Wang, Yuanyuan Chen, Zhiyan Li, Song Liu, Wenxian Guan, Youkun Lin, Cunwei Cao, Wenjun Zheng, Jinhui Wu","doi":"10.15212/amm-2023-0023","DOIUrl":"https://doi.org/10.15212/amm-2023-0023","url":null,"abstract":"Activation of simulator of interferon genes (STING), which induces the production of proinflammatory factors and immune effector cell activation, is considered a promising strategy for enhanced anti-cancer intervention. However, several obstacles prevent STING signaling in solid tumors, such as delivered molecules’ rapid degradation, restriction to tumor sites, insufficient intracellular concentrations, and low responsivity. Well-designed, multifunctional nano-formulations have emerged as optimized platforms for STING activation. Recently, a variety of nano-formulations have been developed and used in STING activation, thus facilitating immunotherapy in preclinical and clinical stages. Herein, we summarize recent advances in nanotechnology-based delivery, activation, and application strategies, which have advanced various aspects of immunotherapy. Novel STING agonists and their mechanisms in STING-activation-mediated tumor interventions are highlighted herein, to provide a comprehensive overview and discuss future directions for boosting immunotherapy via STING regulation.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":"11 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135402137","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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