Pub Date : 2024-08-12DOI: 10.1016/j.apsb.2024.07.008
Yi Zhang, Junyu Shi, Jie Zhu, Xinxin Ding, Jianxu Wei, Xue Jiang, Yijie Yang, Xiaomeng Zhang, Yongzhuo Huang, Hongchang Lai
Periodontitis is a chronic inflammatory disease marked by a dysregulated immune microenvironment, posing formidable challenges for effective treatment. The disease is characterized by an altered glucose metabolism in macrophages, specifically an increase in aerobic glycolysis, which is linked to heightened inflammatory responses. This suggests that targeting macrophage metabolism could offer a new therapeutic avenue. In this study, we develop an immunometabolic intervention using quercetin (Q) encapsulated in bioadhesive mesoporous polydopamine (Q@MPDA) to treat periodontitis. Our results demonstrate that Q@MPDA can reprogram inflammatory macrophages to an anti-inflammatory phenotype (, from-M1-to-M2 repolarization). In a murine periodontitis model, locally administered Q@MPDA reduced the presence of inflammatory macrophages, and decreased the levels of inflammatory cytokines (IL-1 and TNF-) and reactive oxygen species (ROS) in the periodontium. Consequently, it alleviated periodontitis symptoms, reduced alveolar bone loss, and promoted tissue repair. Furthermore, our study revealed that Q@MPDA could inhibit the glycolysis of inflammatory macrophages while enhancing oxidative phosphorylation (OXPHOS), facilitating the shift from M1 to M2 macrophage subtype. Our findings suggest that Q@MPDA is a promising treatment for periodontitis immunometabolic rewiring.
{"title":"Immunometabolic rewiring in macrophages for periodontitis treatment via nanoquercetin-mediated leverage of glycolysis and OXPHOS","authors":"Yi Zhang, Junyu Shi, Jie Zhu, Xinxin Ding, Jianxu Wei, Xue Jiang, Yijie Yang, Xiaomeng Zhang, Yongzhuo Huang, Hongchang Lai","doi":"10.1016/j.apsb.2024.07.008","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.07.008","url":null,"abstract":"Periodontitis is a chronic inflammatory disease marked by a dysregulated immune microenvironment, posing formidable challenges for effective treatment. The disease is characterized by an altered glucose metabolism in macrophages, specifically an increase in aerobic glycolysis, which is linked to heightened inflammatory responses. This suggests that targeting macrophage metabolism could offer a new therapeutic avenue. In this study, we develop an immunometabolic intervention using quercetin (Q) encapsulated in bioadhesive mesoporous polydopamine (Q@MPDA) to treat periodontitis. Our results demonstrate that Q@MPDA can reprogram inflammatory macrophages to an anti-inflammatory phenotype (, from-M1-to-M2 repolarization). In a murine periodontitis model, locally administered Q@MPDA reduced the presence of inflammatory macrophages, and decreased the levels of inflammatory cytokines (IL-1 and TNF-) and reactive oxygen species (ROS) in the periodontium. Consequently, it alleviated periodontitis symptoms, reduced alveolar bone loss, and promoted tissue repair. Furthermore, our study revealed that Q@MPDA could inhibit the glycolysis of inflammatory macrophages while enhancing oxidative phosphorylation (OXPHOS), facilitating the shift from M1 to M2 macrophage subtype. Our findings suggest that Q@MPDA is a promising treatment for periodontitis immunometabolic rewiring.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anxiety disorders are one of the most epidemic and chronic psychiatric disorders. An incomplete understanding of anxiety pathophysiology has limited the development of highly effective drugs against these disorders. GPR17 has been shown to be involved in multiple sclerosis and some acute brain injury disorders. However, no study has investigated the role of GPR17 in psychiatric disorders. In a well-established chronic restraint stress (CRS) mouse model, using a combination of pharmacological and molecular biology techniques, viral tracing, electrophysiology recordings, fiber photometry, chemogenetic manipulations and behavioral tests, we demonstrated that CRS induced anxiety-like behaviors and increased the expression of GPR17 in basolateral amygdala (BLA) glutamatergic neurons. Inhibition of GPR17 by cangrelor or knockdown of GPR17 by adeno-associated virus in BLA glutamatergic neurons effectively improved anxiety-like behaviors. Overexpression of GPR17 in BLA glutamatergic neurons increased the susceptibility to anxiety-like behaviors. What's more, BLA glutamatergic neuronal activity was required for anxiolytic-like effects of GPR17 antagonist and GPR17 modulated anxiety-like behaviors BLA to ventral hippocampal CA1 glutamatergic projection. Our study finds for the first and highlights the new role of GPR17 in regulating anxiety-like behaviors and it might be a novel potential target for therapy of anxiety disorders.
{"title":"GPR17 modulates anxiety-like behaviors via basolateral amygdala to ventral hippocampal CA1 glutamatergic projection","authors":"Ruizhe Nie, Xinting Zhou, Jiaru Fu, Shanshan Hu, Qilu Zhang, Weikai Jiang, Yizi Yan, Xian Cao, Danhua Yuan, Yan Long, Hao Hong, Susu Tang","doi":"10.1016/j.apsb.2024.08.005","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.005","url":null,"abstract":"Anxiety disorders are one of the most epidemic and chronic psychiatric disorders. An incomplete understanding of anxiety pathophysiology has limited the development of highly effective drugs against these disorders. GPR17 has been shown to be involved in multiple sclerosis and some acute brain injury disorders. However, no study has investigated the role of GPR17 in psychiatric disorders. In a well-established chronic restraint stress (CRS) mouse model, using a combination of pharmacological and molecular biology techniques, viral tracing, electrophysiology recordings, fiber photometry, chemogenetic manipulations and behavioral tests, we demonstrated that CRS induced anxiety-like behaviors and increased the expression of GPR17 in basolateral amygdala (BLA) glutamatergic neurons. Inhibition of GPR17 by cangrelor or knockdown of GPR17 by adeno-associated virus in BLA glutamatergic neurons effectively improved anxiety-like behaviors. Overexpression of GPR17 in BLA glutamatergic neurons increased the susceptibility to anxiety-like behaviors. What's more, BLA glutamatergic neuronal activity was required for anxiolytic-like effects of GPR17 antagonist and GPR17 modulated anxiety-like behaviors BLA to ventral hippocampal CA1 glutamatergic projection. Our study finds for the first and highlights the new role of GPR17 in regulating anxiety-like behaviors and it might be a novel potential target for therapy of anxiety disorders.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-08DOI: 10.1016/j.apsb.2024.08.002
Jun Liu, Wenfu Wu, Jiayi Hu, Siyu Zhao, Yiqun Chang, Qiuxian Chen, Yujie Li, Jie Tang, Zhenmeng Zhang, Xiao Wu, Shumeng Jiao, Haichuan Xiao, Qiang Zhang, Jiarui Du, Jianfu Zhao, Kaihe Ye, Meiyan Huang, Jun Xu, Haibo Zhou, Junxia Zheng, Pinghua Sun
The management of antibiotic-resistant, bacterial biofilm infections in skin wounds poses an increasingly challenging clinical scenario. infection is difficult to eradicate because of biofilm formation and antibiotic resistance. In this study, we identified a new benzothiazole derivative compound, (IC = 43.3 nmol/L), demonstrating remarkable biofilm inhibition at nanomolar concentrations . In further activity assays and mechanistic studies, we formulated an unconventional strategy for combating -derived infections by targeting the two-component (Gac/Rsm) system. Furthermore, slowed the development of ciprofloxacin and tobramycin resistance. By using murine skin wound infection models, we observed that significantly augmented the antibacterial effects of three widely used antibiotics—tobramycin (100-fold), vancomycin (200-fold), and ciprofloxacin (1000-fold)—compared with single-dose antibiotic treatments for infection . The findings of this study suggest the potential of as a promising antibacterial synergist, highlighting the effectiveness of targeting the two-component system in treating challenging bacterial biofilm infections in humans.
{"title":"Novel benzothiazole derivatives target the Gac/Rsm two-component system as antibacterial synergists against Pseudomonas aeruginosa infections","authors":"Jun Liu, Wenfu Wu, Jiayi Hu, Siyu Zhao, Yiqun Chang, Qiuxian Chen, Yujie Li, Jie Tang, Zhenmeng Zhang, Xiao Wu, Shumeng Jiao, Haichuan Xiao, Qiang Zhang, Jiarui Du, Jianfu Zhao, Kaihe Ye, Meiyan Huang, Jun Xu, Haibo Zhou, Junxia Zheng, Pinghua Sun","doi":"10.1016/j.apsb.2024.08.002","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.002","url":null,"abstract":"The management of antibiotic-resistant, bacterial biofilm infections in skin wounds poses an increasingly challenging clinical scenario. infection is difficult to eradicate because of biofilm formation and antibiotic resistance. In this study, we identified a new benzothiazole derivative compound, (IC = 43.3 nmol/L), demonstrating remarkable biofilm inhibition at nanomolar concentrations . In further activity assays and mechanistic studies, we formulated an unconventional strategy for combating -derived infections by targeting the two-component (Gac/Rsm) system. Furthermore, slowed the development of ciprofloxacin and tobramycin resistance. By using murine skin wound infection models, we observed that significantly augmented the antibacterial effects of three widely used antibiotics—tobramycin (100-fold), vancomycin (200-fold), and ciprofloxacin (1000-fold)—compared with single-dose antibiotic treatments for infection . The findings of this study suggest the potential of as a promising antibacterial synergist, highlighting the effectiveness of targeting the two-component system in treating challenging bacterial biofilm infections in humans.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Programmed cell death ligand-1 (PD-L1) is a T cell inhibitory immune checkpoint molecule that interacts with programmed cell death-1 (PD-1) to promote immune escape of tumor cells. Compared with antibody therapies, small molecule drugs show better prospects due to their advantages such as higher bioavailability, better tissue penetration, and reduced risk of immunogenicity. Here, we found that the small molecule demethylzeylasteral (Dem) can significantly downregulate the expression of PD-L1 in colorectal cancer cells and enhance the killing effect of T cells on tumor cells. Mechanistically, Dem binds to the deubiquitinating enzyme USP22 and promotes its degradation, resulting in increased ubiquitination and degradation of PD-L1 through the proteasome pathway. In addition, Dem increased the activity of cytotoxic T cells and reduced the number of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in tumor-infiltrating lymphocytes (TILs), thereby activating the tumor immune microenvironment and inhibiting the growth of subcutaneous MC38 tumors in C57BL/6 mice. Moreover, we also found that the combination of Dem and CTLA4 antibodies can further improve the efficacy of antitumor therapy. Our study reveals the mechanism by which Dem promotes PD-L1 degradation and suggests that the combination of Dem and CTLA4 antibodies may improve the efficacy of immunotherapy.
{"title":"Demethylzeylasteral induces PD-L1 ubiquitin–proteasome degradation and promotes antitumor immunity via targeting USP22","authors":"Yanyan Zhang, Yun Huang, Dianping Yu, Mengting Xu, Hongmei Hu, Qing Zhang, Minchen Cai, Xiangxin Geng, Hongwei Zhang, Jianhua Xia, Mengmeng Guo, Dong Lu, Hanchi Xu, Linyang Li, Xing Zhang, Qun Wang, Sanhong Liu, Weidong Zhang","doi":"10.1016/j.apsb.2024.08.004","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.004","url":null,"abstract":"Programmed cell death ligand-1 (PD-L1) is a T cell inhibitory immune checkpoint molecule that interacts with programmed cell death-1 (PD-1) to promote immune escape of tumor cells. Compared with antibody therapies, small molecule drugs show better prospects due to their advantages such as higher bioavailability, better tissue penetration, and reduced risk of immunogenicity. Here, we found that the small molecule demethylzeylasteral (Dem) can significantly downregulate the expression of PD-L1 in colorectal cancer cells and enhance the killing effect of T cells on tumor cells. Mechanistically, Dem binds to the deubiquitinating enzyme USP22 and promotes its degradation, resulting in increased ubiquitination and degradation of PD-L1 through the proteasome pathway. In addition, Dem increased the activity of cytotoxic T cells and reduced the number of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in tumor-infiltrating lymphocytes (TILs), thereby activating the tumor immune microenvironment and inhibiting the growth of subcutaneous MC38 tumors in C57BL/6 mice. Moreover, we also found that the combination of Dem and CTLA4 antibodies can further improve the efficacy of antitumor therapy. Our study reveals the mechanism by which Dem promotes PD-L1 degradation and suggests that the combination of Dem and CTLA4 antibodies may improve the efficacy of immunotherapy.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Protein kinase C (PKC) regulates diverse biological functions of cancer cells and is a promising therapeutic target. However, clinical trials of PKC-targeted therapies have not yielded satisfactory results. Recent studies have also indicated a tumor-suppressive role of PKCs unclear molecular mechanisms. In this study, we found that PKC inhibition enhances CD8 T-cell-mediated tumor evasion and abolishes antitumor activity in immunocompetent mice. We further identified PKC as a critical regulator of programmed cell death-ligand 1 (PD-L1) and found that it enhances T-cell-dependent antitumor immunity in breast cancer by interacting with PD-L1 and suppressing PD-L1 expression. We demonstrated that PKC-mediated PD-L1 phosphorylation promotes PD-L1 degradation through transducin repeat-containing protein. Notably, the efficacy of PKC inhibitors was intensified by synergizing with anti-PD-L1 mAb therapy to boost antitumor T-cell immunity . Clinical analysis revealed that PKC expression is positively correlated with T-cell function and the interferon-gamma signature in patients with breast cancer. This study demonstrated the antitumor capability of PKC, identified potential therapeutic strategies to avoid tumor evasion PKC-targeted therapies, and provided a proof of concept for targeting PKC in combination with anti-PD-L1 mAb therapy as a potential therapeutic approach against breast cancer, especially TNBC.
{"title":"PKCα inhibitors promote breast cancer immune evasion by maintaining PD-L1 stability","authors":"Jiaojiao Yu, Yujin Xiang, Yuzhen Gao, Shan Chang, Ren Kong, Xiaoxi Lv, Jinmei Yu, Yunjie Jin, Chenxi Li, Yiran Ma, Zhenhe Wang, Jichao Zhou, Hongyu Yuan, Shuang Shang, Fang Hua, Xiaowei Zhang, Bing Cui, Pingping Li","doi":"10.1016/j.apsb.2024.08.003","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.003","url":null,"abstract":"Protein kinase C (PKC) regulates diverse biological functions of cancer cells and is a promising therapeutic target. However, clinical trials of PKC-targeted therapies have not yielded satisfactory results. Recent studies have also indicated a tumor-suppressive role of PKCs unclear molecular mechanisms. In this study, we found that PKC inhibition enhances CD8 T-cell-mediated tumor evasion and abolishes antitumor activity in immunocompetent mice. We further identified PKC as a critical regulator of programmed cell death-ligand 1 (PD-L1) and found that it enhances T-cell-dependent antitumor immunity in breast cancer by interacting with PD-L1 and suppressing PD-L1 expression. We demonstrated that PKC-mediated PD-L1 phosphorylation promotes PD-L1 degradation through transducin repeat-containing protein. Notably, the efficacy of PKC inhibitors was intensified by synergizing with anti-PD-L1 mAb therapy to boost antitumor T-cell immunity . Clinical analysis revealed that PKC expression is positively correlated with T-cell function and the interferon-gamma signature in patients with breast cancer. This study demonstrated the antitumor capability of PKC, identified potential therapeutic strategies to avoid tumor evasion PKC-targeted therapies, and provided a proof of concept for targeting PKC in combination with anti-PD-L1 mAb therapy as a potential therapeutic approach against breast cancer, especially TNBC.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-05DOI: 10.1016/j.apsb.2024.07.026
Xiabing Huang, Jianping Ye
{"title":"Inhibition of liver cholesterol synthesis by a diet-induced gut hormone","authors":"Xiabing Huang, Jianping Ye","doi":"10.1016/j.apsb.2024.07.026","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.07.026","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-05DOI: 10.1016/j.apsb.2024.07.009
Ercan Wu, Juan Guan, Yifei Yu, Shiqi Lin, Tianhao Ding, Yuxiu Chu, Feng Pan, Mengyuan Liu, Yang Yang, Zui Zhang, Jian Zhang, Changyou Zhan, Jun Qian
The different fate of liposomes among species has been discovered and mentioned in many studies, but the underlying mechanisms have not been explored. In the present work, we concentrated on the fate of PEGylated liposomes (sLip) in three commonly used species (mice, rats, and dogs). It was exhibited that the accelerated blood clearance (ABC) phenomenon and hypersensitivity in large animals (beagle dogs) was much more significant than that in rodents. We demonstrated that anti-PEG IgM (partially) and complement (mostly) determined the elimination of sLip and linked the distinct interspecies performances with the diverse complement capacity among species. Based on the data from animals and clinical patients, it was revealed that the fate of sLip in large animals was closer to that in humans, for the sufficient complement capacity could expose the potential adverse reactions caused by antiPEG antibodies. Our results suggested that the distinctive interspecies performances of sLip were highly related to the physiological variabilities among species, which should not be overlooked in the innovation and translation of nanomedicines.
{"title":"Exemplifying interspecies variation of liposome in vivo fat e by the effects of anti-PEG antibodies","authors":"Ercan Wu, Juan Guan, Yifei Yu, Shiqi Lin, Tianhao Ding, Yuxiu Chu, Feng Pan, Mengyuan Liu, Yang Yang, Zui Zhang, Jian Zhang, Changyou Zhan, Jun Qian","doi":"10.1016/j.apsb.2024.07.009","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.07.009","url":null,"abstract":"The different fate of liposomes among species has been discovered and mentioned in many studies, but the underlying mechanisms have not been explored. In the present work, we concentrated on the fate of PEGylated liposomes (sLip) in three commonly used species (mice, rats, and dogs). It was exhibited that the accelerated blood clearance (ABC) phenomenon and hypersensitivity in large animals (beagle dogs) was much more significant than that in rodents. We demonstrated that anti-PEG IgM (partially) and complement (mostly) determined the elimination of sLip and linked the distinct interspecies performances with the diverse complement capacity among species. Based on the data from animals and clinical patients, it was revealed that the fate of sLip in large animals was closer to that in humans, for the sufficient complement capacity could expose the potential adverse reactions caused by antiPEG antibodies. Our results suggested that the distinctive interspecies performances of sLip were highly related to the physiological variabilities among species, which should not be overlooked in the innovation and translation of nanomedicines.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141945623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-03DOI: 10.1016/j.apsb.2024.07.022
Jing Zhang, Qiong Wu, Yifei Xie, Feng Li, Huifang Wei, Yanan Jiang, Yan Qiao, Yinhua Li, Yanan Sun, Han Huang, Mengmeng Ge, Dengyun Zhao, Zigang Dong, Kangdong Liu
Esophageal squamous cell carcinoma (ESCC), a malignancy of the digestive system, is highly prevalent and the primary cause of cancer-related deaths worldwide due to the lack of early diagnostic biomarkers and effective therapeutic targets. Dysregulated ribonucleotide reductase (RNR) expression has been confirmed to be causally linked to tumorigenesis. This study demonstrated that ribonucleotide reductase small subunit M2 (RRM2) is significantly upregulated in ESCC tissue and that its expression is negatively correlated with clinical outcomes. Mechanistically, HuR promotes mRNA stabilization by binding to the adenine/uridine (AU)-rich elements (AREs) within the 3′UTR, resulting in persistent overexpression of RRM2. Furthermore, bifonazole is identified as an inhibitor of HuR computational screening and molecular docking analysis. Bifonazole disrupts HuR-ARE interactions by competitively binding to HuR at F65, R97, I103, and R153 residues, resulting in reduced RRM2 expression. Furthermore, bifonazole exhibited antitumor effects on ESCC patient-derived xenograft (PDX) models by decreasing RRM2 expression and the dNTP pool. In summary, this study reveals the interaction network among HuR, RRM2, and bifonazole and demonstrated that bifonazole is a potential therapeutic compound for ESCC through inhibition of the HuR/RRM2 axis.
食管鳞状细胞癌（ESCC）是一种消化系统恶性肿瘤，由于缺乏早期诊断生物标志物和有效的治疗靶点，其发病率很高，是全球癌症相关死亡的主要原因。核糖核苷酸还原酶（RNR）表达失调已被证实与肿瘤发生有因果关系。本研究表明，核糖核苷酸还原酶小亚基M2（RRM2）在ESCC组织中显著上调，其表达与临床预后呈负相关。从机理上讲，HuR通过与3′UTR内富含腺嘌呤/尿苷元素（AU）结合促进mRNA稳定，从而导致RRM2持续过表达。此外，通过计算筛选和分子对接分析，确定联苯苄唑是 HuR 的抑制剂。联苯苄唑通过在 F65、R97、I103 和 R153 残基与 HuR 竞争性结合，破坏了 HuR 与ARE 的相互作用，导致 RRM2 表达量减少。此外，联苯苄唑通过降低 RRM2 的表达和 dNTP 池，对 ESCC 患者衍生异种移植（PDX）模型产生抗肿瘤作用。总之，本研究揭示了 HuR、RRM2 和联苯苄唑之间的相互作用网络，并证明联苯苄唑是一种通过抑制 HuR/RRM2 轴治疗 ESCC 的潜在化合物。
{"title":"Ribonucleotide reductase small subunit M2 promotes the proliferation of esophageal squamous cell carcinoma cells via HuR-mediated mRNA stabilization","authors":"Jing Zhang, Qiong Wu, Yifei Xie, Feng Li, Huifang Wei, Yanan Jiang, Yan Qiao, Yinhua Li, Yanan Sun, Han Huang, Mengmeng Ge, Dengyun Zhao, Zigang Dong, Kangdong Liu","doi":"10.1016/j.apsb.2024.07.022","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.07.022","url":null,"abstract":"Esophageal squamous cell carcinoma (ESCC), a malignancy of the digestive system, is highly prevalent and the primary cause of cancer-related deaths worldwide due to the lack of early diagnostic biomarkers and effective therapeutic targets. Dysregulated ribonucleotide reductase (RNR) expression has been confirmed to be causally linked to tumorigenesis. This study demonstrated that ribonucleotide reductase small subunit M2 (RRM2) is significantly upregulated in ESCC tissue and that its expression is negatively correlated with clinical outcomes. Mechanistically, HuR promotes mRNA stabilization by binding to the adenine/uridine (AU)-rich elements (AREs) within the 3′UTR, resulting in persistent overexpression of RRM2. Furthermore, bifonazole is identified as an inhibitor of HuR computational screening and molecular docking analysis. Bifonazole disrupts HuR-ARE interactions by competitively binding to HuR at F65, R97, I103, and R153 residues, resulting in reduced RRM2 expression. Furthermore, bifonazole exhibited antitumor effects on ESCC patient-derived xenograft (PDX) models by decreasing RRM2 expression and the dNTP pool. In summary, this study reveals the interaction network among HuR, RRM2, and bifonazole and demonstrated that bifonazole is a potential therapeutic compound for ESCC through inhibition of the HuR/RRM2 axis.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141945626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Due to the limitations of current anti-HBV therapies, the HBV core (HBc) protein assembly modulators (CpAMs) are believed to be potential anti-HBV agents. Therefore, discovering safe and efficient CpAMs is of great value. In this study, we established a HiBiT-based high-throughput screening system targeting HBc and screened novel CpAMs from an in-house marine chemicals library. A novel lead compound , a derivative of the marine natural product naamidine J, has been successfully screened for potential anti-HBV activity. Bioactivity-driven synthesis was then conducted, and the structure‒activity relationship was analyzed, resulting in the discovery of the most effective compound (IC = 0.24 μmol/L. Furthermore, was found to significantly inhibit HBV replication in multiple cell models and exhibit a synergistic effect with tenofovir disoproxil fumarate (TDF) and IFNa2 for anti-HBV activity. Treatment with in a hydrodynamic-injection mouse model demonstrated significant anti-HBV activity without apparent hepatotoxicity. These findings suggest that the naamidine J derivative could be used as the HBV core protein assembly modulator to develop safe and effective anti-HBV therapies.
{"title":"Discovery of novel small molecules targeting hepatitis B virus core protein from marine natural products with HiBiT-based high-throughput screening","authors":"Chao Huang, Yang Jin, Panpan Fu, Kongying Hu, Mengxue Wang, Wenjing Zai, Ting Hua, Xinluo Song, Jianyu Ye, Yiqing Zhang, Gan Luo, Haiyu wang, Jiangxia Liu, Jieliang Chen, Xuwen Li, Zhenghong Yuan","doi":"10.1016/j.apsb.2024.07.019","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.07.019","url":null,"abstract":"Due to the limitations of current anti-HBV therapies, the HBV core (HBc) protein assembly modulators (CpAMs) are believed to be potential anti-HBV agents. Therefore, discovering safe and efficient CpAMs is of great value. In this study, we established a HiBiT-based high-throughput screening system targeting HBc and screened novel CpAMs from an in-house marine chemicals library. A novel lead compound , a derivative of the marine natural product naamidine J, has been successfully screened for potential anti-HBV activity. Bioactivity-driven synthesis was then conducted, and the structure‒activity relationship was analyzed, resulting in the discovery of the most effective compound (IC = 0.24 μmol/L. Furthermore, was found to significantly inhibit HBV replication in multiple cell models and exhibit a synergistic effect with tenofovir disoproxil fumarate (TDF) and IFNa2 for anti-HBV activity. Treatment with in a hydrodynamic-injection mouse model demonstrated significant anti-HBV activity without apparent hepatotoxicity. These findings suggest that the naamidine J derivative could be used as the HBV core protein assembly modulator to develop safe and effective anti-HBV therapies.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141945670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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