Cancer is a consequence of uncontrolled cell proliferation that is associated with cell-cycle disruption. It is a multifactorial disease that depends on the modulation of numerous oncogenic signaling pathways and targets. Although a battle against cancer has been waged for centuries, this disease remains a major cause of death worldwide. Because of the development of resistance to current anticancer drugs, substantial effort has been focused on discovering more effective agents for tumor therapy. Natural products have powerful prospects as anticancer drugs. Brusatol, a component isolated from the plant Brucea javanica, has been demonstrated to efficiently combat a wide variety of tumors. Extensive studies have indicated that brusatol exhibits anticancer effects by arresting the cell cycle; promoting apoptosis; inducing autophagy; attenuating epithelial-mesenchymal transition; inhibiting migration, invasion and angiogenesis; and increasing chemosensitivity and radiosensitivity. These effects involve various oncogenic signaling pathways, including the MAPK, NF-κB, PI3K/AKT/mTOR, JAK/STAT and Keap1/Nrf2/ARE signaling pathways. This review describes the evidence suggesting that brusatol is a promising drug candidate for cancer therapeutics.
{"title":"Brusatol modulates diverse cancer hallmarks and signaling pathways as a potential cancer therapeutic","authors":"Song-Bin Guo, Wei-Juan Huang, X. Tian","doi":"10.15212/amm-2022-0014","DOIUrl":"https://doi.org/10.15212/amm-2022-0014","url":null,"abstract":"Cancer is a consequence of uncontrolled cell proliferation that is associated with cell-cycle disruption. It is a multifactorial disease that depends on the modulation of numerous oncogenic signaling pathways and targets. Although a battle against cancer has been waged for centuries, this disease remains a major cause of death worldwide. Because of the development of resistance to current anticancer drugs, substantial effort has been focused on discovering more effective agents for tumor therapy. Natural products have powerful prospects as anticancer drugs. Brusatol, a component isolated from the plant Brucea javanica, has been demonstrated to efficiently combat a wide variety of tumors. Extensive studies have indicated that brusatol exhibits anticancer effects by arresting the cell cycle; promoting apoptosis; inducing autophagy; attenuating epithelial-mesenchymal transition; inhibiting migration, invasion and angiogenesis; and increasing chemosensitivity and radiosensitivity. These effects involve various oncogenic signaling pathways, including the MAPK, NF-κB, PI3K/AKT/mTOR, JAK/STAT and Keap1/Nrf2/ARE signaling pathways. This review describes the evidence suggesting that brusatol is a promising drug candidate for cancer therapeutics.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42802855","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}
Peijin Wang, Sarah Peskoe, Rebecca Byrd, Patrick Smith, Rachel Breslin, Shein-Chung Chow
In clinical trials, the primary analysis is often either a test of absolute/relative change in a measured outcome or a corresponding responder analysis. Though each of these tests may be reasonable, determining which test is most suitable for a particular research study is still an open question. These tests may require different sample sizes, define different clinically meaningful differences, and most importantly, lead to different study conclusions. This paper aims to compare a typical non-inferiority test using absolute change as the study endpoint to the corresponding responder analysis in terms of sample size requirements, statistical power, and hypothesis testing results. From numerical analysis, using absolute change as an endpoint generally requires a larger sample size; therefore, when the sample size is the same, the responder analysis has higher power. The cut-off value and non-inferiority margin are critical which can meaningfully impact whether the two types of endpoints yield conflicting conclusions. Specifically, an extreme cut-off value is more likely to cause different conclusions. However, this impact decreases as population variance increases. One important reason for conflicting conclusions is that the population distribution is not normal. To eliminate conflicting results, researchers should pay attention to the population distribution and cut-off value selection.
{"title":"Statistical Evaluation of Absolute Change versus Responder Analysis in Clinical Trials.","authors":"Peijin Wang, Sarah Peskoe, Rebecca Byrd, Patrick Smith, Rachel Breslin, Shein-Chung Chow","doi":"10.15212/amm-2022-0020","DOIUrl":"https://doi.org/10.15212/amm-2022-0020","url":null,"abstract":"<p><p>In clinical trials, the primary analysis is often either a test of absolute/relative change in a measured outcome or a corresponding responder analysis. Though each of these tests may be reasonable, determining which test is most suitable for a particular research study is still an open question. These tests may require different sample sizes, define different clinically meaningful differences, and most importantly, lead to different study conclusions. This paper aims to compare a typical non-inferiority test using absolute change as the study endpoint to the corresponding responder analysis in terms of sample size requirements, statistical power, and hypothesis testing results. From numerical analysis, using absolute change as an endpoint generally requires a larger sample size; therefore, when the sample size is the same, the responder analysis has higher power. The cut-off value and non-inferiority margin are critical which can meaningfully impact whether the two types of endpoints yield conflicting conclusions. Specifically, an extreme cut-off value is more likely to cause different conclusions. However, this impact decreases as population variance increases. One important reason for conflicting conclusions is that the population distribution is not normal. To eliminate conflicting results, researchers should pay attention to the population distribution and cut-off value selection.</p>","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":"1 3","pages":"320-332"},"PeriodicalIF":0.0,"publicationDate":"2022-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10237148/pdf/nihms-1833344.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9636823","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}
Ye Zhang, Yuhang Zhao, Linhui Yang, Yuanxuan Cai, Xiaofang Shangguan, R. Huang
The consequences of medication errors are more severe for high-alert medications than general drugs. Improving pharmacists’ knowledge regarding high-alert medications is important to increase drug safety and maintain patient health. This study was aimed at understanding Chinese hospital pharmacists’ knowledge regarding high-alert medications and exploring associated factors, to provide suggestions for management of high-alert medications. A total of 380 pharmacists from four hospitals in southern, northern and central China were selected through a convenience sampling method. Through a questionnaire survey, the pharmacists’ demographic sociology characteristics and knowledge regarding high-alert medications were investigated. Chi-square tests and binary logistic regression were used to analyze the factors associated with pharmacists’ knowledge regarding high-alert medications. A total of 336 valid questionnaires were returned, with an effective recovery rate of 88.4%. Among the respondents, 79.2% had high knowledge regarding high-alert medications. The analysis results show that the main factors significantly associated with pharmacists’ knowledge levels of high-alert medication were work experience and professional title, whether high alert-medication knowledge was obtained through the network channel, whether high-alert-medication knowledge was obtained through daily work practice and whether high-alert medications were double independent checked before use. Increase the sharing of work cases and knowledge cooperation among different pharmacists and departments in high-alert medications, rationally adjust and arrange the responsibilities of pharmacists, and improve the internal circulation of hospital high-alert medications are helpful to improve pharmacists’ cognitive level of high-alert medication and improve the hospital’s ability to control the risk of high-alert medication.
{"title":"Factors associated with pharmacists’ knowledge regarding high-alert medications: a convenience sample survey in China","authors":"Ye Zhang, Yuhang Zhao, Linhui Yang, Yuanxuan Cai, Xiaofang Shangguan, R. Huang","doi":"10.15212/amm-2022-0012","DOIUrl":"https://doi.org/10.15212/amm-2022-0012","url":null,"abstract":"The consequences of medication errors are more severe for high-alert medications than general drugs. Improving pharmacists’ knowledge regarding high-alert medications is important to increase drug safety and maintain patient health. This study was aimed at understanding Chinese hospital pharmacists’ knowledge regarding high-alert medications and exploring associated factors, to provide suggestions for management of high-alert medications. A total of 380 pharmacists from four hospitals in southern, northern and central China were selected through a convenience sampling method. Through a questionnaire survey, the pharmacists’ demographic sociology characteristics and knowledge regarding high-alert medications were investigated. Chi-square tests and binary logistic regression were used to analyze the factors associated with pharmacists’ knowledge regarding high-alert medications. A total of 336 valid questionnaires were returned, with an effective recovery rate of 88.4%. Among the respondents, 79.2% had high knowledge regarding high-alert medications. The analysis results show that the main factors significantly associated with pharmacists’ knowledge levels of high-alert medication were work experience and professional title, whether high alert-medication knowledge was obtained through the network channel, whether high-alert-medication knowledge was obtained through daily work practice and whether high-alert medications were double independent checked before use. Increase the sharing of work cases and knowledge cooperation among different pharmacists and departments in high-alert medications, rationally adjust and arrange the responsibilities of pharmacists, and improve the internal circulation of hospital high-alert medications are helpful to improve pharmacists’ cognitive level of high-alert medication and improve the hospital’s ability to control the risk of high-alert medication.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49064864","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}
Liangzhen Zheng, Jintao Meng, Ming-cheng Lin, Rui Lv, Hongjun Cheng, Lixin Zou, Jinyuan Sun, Linxian Li, R. Ren, Sheng Wang
Recently, the monkeypox virus has begun to spread in many countries worldwide [1]. The genome sequence of the monkeypox virus variant responsible for the current outbreak has been reported, thus providing an important resource for better understanding the new variant and accelerating vaccine and drug development. Here, we report structure predictions of the whole proteomes of three monkeypox variants, with annotation of potential small-molecule-binding regions of the proteins. Experimentally determined structures with high similarity to monkeypox proteins were vetted through a structure-alignment algorithm. Our work should help accelerate the development of vaccines and drugs.
{"title":"Structure prediction of the entire proteome of monkeypox variants","authors":"Liangzhen Zheng, Jintao Meng, Ming-cheng Lin, Rui Lv, Hongjun Cheng, Lixin Zou, Jinyuan Sun, Linxian Li, R. Ren, Sheng Wang","doi":"10.15212/amm-2022-0017","DOIUrl":"https://doi.org/10.15212/amm-2022-0017","url":null,"abstract":"Recently, the monkeypox virus has begun to spread in many countries worldwide [1]. The genome sequence of the monkeypox virus variant responsible for the current outbreak has been reported, thus providing an important resource for better understanding the new variant and accelerating vaccine and drug development. Here, we report structure predictions of the whole proteomes of three monkeypox variants, with annotation of potential small-molecule-binding regions of the proteins. Experimentally determined structures with high similarity to monkeypox proteins were vetted through a structure-alignment algorithm. Our work should help accelerate the development of vaccines and drugs.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43338015","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}
In our ongoing work on the identification of potent anti-inflammatory agents, we designed and synthesized three series of lathyrane diterpenoid hybrids in which the lathyrane diterpenoid skeleton was hybridized with other anti-inflammatory pharmacophores. Unexpectedly, lathyrane diterpenoid/3-hydroxyflavone hybrids showed more potent anti-inflammatory activity in RAW264.7 cells than did the corresponding parent compounds. Compound 8d1 exhibited potent anti-inflammatory activity with low cytotoxicity (IC50 = 1.55 ± 0.68 μM), and downregulated LPS-induced expression of iNOS and COX-2, as well as IκBα phosphorylation. This compound also inhibited the expression and nuclear translocation of NF-κB, and stimulated autophagy induction. Thus, 8d1’s anti-inflammatory mechanism is associated with inhibition of the NF-κB signaling pathway and increasing autophagy. This compound may serve as a promising anti-inflammatory agent.
{"title":"New lathyrane diterpenoid hybrids have anti-inflammatory activity through the NF-κB signaling pathway and autophagy","authors":"Wang Wang, Lian-Ming Xiong, Yanli Wu, Yirong Zhou, Yutong Li, Meng-zhu Zheng, Zhuorui Song, De-juan Sun, Lixia Chen","doi":"10.15212/amm-2022-0008","DOIUrl":"https://doi.org/10.15212/amm-2022-0008","url":null,"abstract":"In our ongoing work on the identification of potent anti-inflammatory agents, we designed and synthesized three series of lathyrane diterpenoid hybrids in which the lathyrane diterpenoid skeleton was hybridized with other anti-inflammatory pharmacophores. Unexpectedly, lathyrane diterpenoid/3-hydroxyflavone hybrids showed more potent anti-inflammatory activity in RAW264.7 cells than did the corresponding parent compounds. Compound 8d1 exhibited potent anti-inflammatory activity with low cytotoxicity (IC50 = 1.55 ± 0.68 μM), and downregulated LPS-induced expression of iNOS and COX-2, as well as IκBα phosphorylation. This compound also inhibited the expression and nuclear translocation of NF-κB, and stimulated autophagy induction. Thus, 8d1’s anti-inflammatory mechanism is associated with inhibition of the NF-κB signaling pathway and increasing autophagy. This compound may serve as a promising anti-inflammatory agent.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45651202","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}
Manjiong Wang, Tongke Tang, Zhenghui Huang, Ruoxi Li, Dazheng Ling, Jin Zhu, Lubing Jiang, Jian Li, Xiaokang Li
In our previous work, the clinical phase II HDAC inhibitor quisinostat was identified as a promising antimalarial agent through a drug repurposing strategy, but its safety was a matter of concern. Herein, further medicinal chemistry methods were used to identify new chemical entities with greater effectiveness and safety than quisinostat. In total, 38 novel hydroxamic acid derivatives were designed and synthesized, and their in vitro antimalarial activities were systematically investigated. These compounds at nanomolar concentrations showed inhibitory effects on wild-type and drug-resistant Plasmodium falciparum strains in the erythrocyte stage. Among them, compound 30, after oral administration, resulted in complete elimination of parasites in mice infected with Plasmodium yoelii, and also exhibited better safety and metabolic properties than observed in our previous work. Mechanistically, compound 30 upregulated plasmodium histone acetylation, according to western blotting, thus suggesting that it exerts antimalarial effects through inhibition of Plasmodium falciparum HDAC enzymes.
{"title":"Design and synthesis of novel hydroxamic acid derivatives based on quisinostat as promising antimalarial agents with improved safety","authors":"Manjiong Wang, Tongke Tang, Zhenghui Huang, Ruoxi Li, Dazheng Ling, Jin Zhu, Lubing Jiang, Jian Li, Xiaokang Li","doi":"10.15212/amm-2022-0007","DOIUrl":"https://doi.org/10.15212/amm-2022-0007","url":null,"abstract":"In our previous work, the clinical phase II HDAC inhibitor quisinostat was identified as a promising antimalarial agent through a drug repurposing strategy, but its safety was a matter of concern. Herein, further medicinal chemistry methods were used to identify new chemical entities with greater effectiveness and safety than quisinostat. In total, 38 novel hydroxamic acid derivatives were designed and synthesized, and their in vitro antimalarial activities were systematically investigated. These compounds at nanomolar concentrations showed inhibitory effects on wild-type and drug-resistant Plasmodium falciparum strains in the erythrocyte stage. Among them, compound 30, after oral administration, resulted in complete elimination of parasites in mice infected with Plasmodium yoelii, and also exhibited better safety and metabolic properties than observed in our previous work. Mechanistically, compound 30 upregulated plasmodium histone acetylation, according to western blotting, thus suggesting that it exerts antimalarial effects through inhibition of Plasmodium falciparum HDAC enzymes.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42357011","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}
Enhancer of zeste homolog 2 (EZH2) is activated in breast cancer, particularly in triple-negative breast cancer (TNBC), and is critical for cell invasion. It interacts with embryonic ectoderm development (EED) in maintaining cancer stem cells (CSC) and epithelial-mesenchymal transition (EMT) properties, hence promoting CSC metastasis. Because the association of EZH2 with EED promotes the catalytic activity of EZH2, inhibiting the EED-EZH2 interaction is a potential therapeutic strategy for treating EZH2-dependent cancer. Although several EED-EZH2 protein-protein interaction (PPI) inhibitors have been developed, few target EED. Here, we identified that a cytisine derivative compound (1) potently binds EED, thus blocking the EED-EZH2 PPI. Compound 1 was found to inhibit cell proliferation and suppress the growth of 3D tumor spheres of TNBC cells. Moreover, by reversing EMT and decreasing the ratio of CSCs, the compound inhibited TNBC metastasis and invasion ability. Therefore, targeting EED to disrupt the EED-EZH2 PPI may provide a new approach for treating TNBC metastasis. To our knowledge, compound 1 is the first cytisine-based EED-EZH2 PPI inhibitor preventing metastasis in TNBC cells. This study may provide a new avenue for the development of more efficacious EED-EZH2 PPI inhibitors in TNBC treatment.
{"title":"Identification of a cytisine-based EED-EZH2 protein-protein interaction inhibitor preventing metastasis in triple-negative breast cancer cells","authors":"Shasha Cheng, Guan-Jun Yang, Wanhe Wang, Ying-Qi Song, Chung-Nga Ko, Quan-Bing Han, Diklung Ma, Chung-Hang Leung","doi":"10.15212/amm-2022-0006","DOIUrl":"https://doi.org/10.15212/amm-2022-0006","url":null,"abstract":"Enhancer of zeste homolog 2 (EZH2) is activated in breast cancer, particularly in triple-negative breast cancer (TNBC), and is critical for cell invasion. It interacts with embryonic ectoderm development (EED) in maintaining cancer stem cells (CSC) and epithelial-mesenchymal transition (EMT) properties, hence promoting CSC metastasis. Because the association of EZH2 with EED promotes the catalytic activity of EZH2, inhibiting the EED-EZH2 interaction is a potential therapeutic strategy for treating EZH2-dependent cancer. Although several EED-EZH2 protein-protein interaction (PPI) inhibitors have been developed, few target EED. Here, we identified that a cytisine derivative compound (1) potently binds EED, thus blocking the EED-EZH2 PPI. Compound 1 was found to inhibit cell proliferation and suppress the growth of 3D tumor spheres of TNBC cells. Moreover, by reversing EMT and decreasing the ratio of CSCs, the compound inhibited TNBC metastasis and invasion ability. Therefore, targeting EED to disrupt the EED-EZH2 PPI may provide a new approach for treating TNBC metastasis. To our knowledge, compound 1 is the first cytisine-based EED-EZH2 PPI inhibitor preventing metastasis in TNBC cells. This study may provide a new avenue for the development of more efficacious EED-EZH2 PPI inhibitors in TNBC treatment.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48926079","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}
Tielan Wei, Sachin S. Thakur, Mengyang Liu, Jingyuan Wen
Glutathione (GSH) is a tripeptide with potent antioxidant activity, which is involved in numerous basic biological processes and has been used for interventions in various degenerative diseases. However, oral delivery of GSH remains challenging, similarly to that of other protein and peptide drugs, because the physicochemical barriers in the gastrointestinal (GI) tract lead to low oral bioavailability. Although several approaches have been explored to improve delivery, such as co-administration with penetration enhancers and enzymatic inhibitors, or encapsulation into nanoparticles, microemulsions and liposomes, appropriate formulations with clinical therapeutic effects remain to be developed. This review discusses approaches explored to developing an oral GSH delivery system that could provide protection against proteolytic degradation in the GI tract and enhance molecular absorption across the epithelial membrane. This system may be beneficial for the design and development of an oral formulation of GSH in the future.
{"title":"Oral delivery of glutathione: antioxidant function, barriers and strategies","authors":"Tielan Wei, Sachin S. Thakur, Mengyang Liu, Jingyuan Wen","doi":"10.15212/amm-2022-0005","DOIUrl":"https://doi.org/10.15212/amm-2022-0005","url":null,"abstract":"Glutathione (GSH) is a tripeptide with potent antioxidant activity, which is involved in numerous basic biological processes and has been used for interventions in various degenerative diseases. However, oral delivery of GSH remains challenging, similarly to that of other protein and peptide drugs, because the physicochemical barriers in the gastrointestinal (GI) tract lead to low oral bioavailability. Although several approaches have been explored to improve delivery, such as co-administration with penetration enhancers and enzymatic inhibitors, or encapsulation into nanoparticles, microemulsions and liposomes, appropriate formulations with clinical therapeutic effects remain to be developed. This review discusses approaches explored to developing an oral GSH delivery system that could provide protection against proteolytic degradation in the GI tract and enhance molecular absorption across the epithelial membrane. This system may be beneficial for the design and development of an oral formulation of GSH in the future.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43715691","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}
Chun Xing Li, Hao-Nan Wang, Guanghao Zhu, Li-Lin Song, Xu-Dong Hou, Peng-Chao Huo, J. Hou, Guangbo Ge
Bile salt hydrolases (BSHs) play crucial roles in the deconjugation of conjugated bile acids and therefore are key targets for modulating bile acid metabolism. This study aimed to identify efficacious BSH inhibitors from a natural compound library and to characterize their inhibitory mechanisms. The inhibitory potential of more than 100 natural compounds against BSH produced by Lactobacillus salivarius (lsBSH) was assayed, and several chalcones with strong or moderate lsBSH inhibitory activity were identified. Of all tested chalcones, licochalcone C and isobavachalcone showed the most potent lsBSH inhibitory activity (IC50 < 1 μM). Inhibition kinetic analyses demonstrated that both licochalcone C and isobavachalcone reversibly inhibited lsBSH-catalyzed CA-AMCA hydrolysis via a mixed manner. Docking simulations suggested that they bind lsBSH at two distinct sites mainly via hydrogen bonding and hydrophobic interactions. Additionally, licochalcone C and isobavachalcone were found to inhibit various BSHs and decrease the total BSH activity in mouse feces, thus suggesting that these agents are broad-spectrum BSH inhibitors. Collectively, our findings revealed that licochalcone C and isobavachalcone are naturally occurring inhibitors of BSH, which may serve as promising lead compounds in the development of more efficacious BSH inhibitors for modulating bile acid metabolism.
{"title":"Discovery and characterization of naturally occurring chalcones as potent inhibitors of bile salt hydrolases","authors":"Chun Xing Li, Hao-Nan Wang, Guanghao Zhu, Li-Lin Song, Xu-Dong Hou, Peng-Chao Huo, J. Hou, Guangbo Ge","doi":"10.15212/amm-2022-0003","DOIUrl":"https://doi.org/10.15212/amm-2022-0003","url":null,"abstract":"Bile salt hydrolases (BSHs) play crucial roles in the deconjugation of conjugated bile acids and therefore are key targets for modulating bile acid metabolism. This study aimed to identify efficacious BSH inhibitors from a natural compound library and to characterize their inhibitory mechanisms. The inhibitory potential of more than 100 natural compounds against BSH produced by Lactobacillus salivarius (lsBSH) was assayed, and several chalcones with strong or moderate lsBSH inhibitory activity were identified. Of all tested chalcones, licochalcone C and isobavachalcone showed the most potent lsBSH inhibitory activity (IC50 < 1 μM). Inhibition kinetic analyses demonstrated that both licochalcone C and isobavachalcone reversibly inhibited lsBSH-catalyzed CA-AMCA hydrolysis via a mixed manner. Docking simulations suggested that they bind lsBSH at two distinct sites mainly via hydrogen bonding and hydrophobic interactions. Additionally, licochalcone C and isobavachalcone were found to inhibit various BSHs and decrease the total BSH activity in mouse feces, thus suggesting that these agents are broad-spectrum BSH inhibitors. Collectively, our findings revealed that licochalcone C and isobavachalcone are naturally occurring inhibitors of BSH, which may serve as promising lead compounds in the development of more efficacious BSH inhibitors for modulating bile acid metabolism.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41643882","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}
Three-dimensional printing (3DP) is a rapid-prototyping technology that uses a digital model file to construct an object through layer printing. This novel technology is widely used in aerospace, medicine, architecture and industrial applications. However, the pharmaceutical applications of 3DP technology remain in early stages, and the pharmaceutical industry is expected to experience a revolution in 3DP. Herein, recent research progress in 3D-printed medicinal tablets is reviewed, to provide a reference for future studies and applications of 3DP technology in pharmaceutics.
{"title":"Research progress in 3D-printed medicinal tablets","authors":"Naijun Dong, Hongqian Lv, Cheng Liu, P. Zhang","doi":"10.15212/amm-2021-0010","DOIUrl":"https://doi.org/10.15212/amm-2021-0010","url":null,"abstract":"Three-dimensional printing (3DP) is a rapid-prototyping technology that uses a digital model file to construct an object through layer printing. This novel technology is widely used in aerospace, medicine, architecture and industrial applications. However, the pharmaceutical applications of 3DP technology remain in early stages, and the pharmaceutical industry is expected to experience a revolution in 3DP. Herein, recent research progress in 3D-printed medicinal tablets is reviewed, to provide a reference for future studies and applications of 3DP technology in pharmaceutics.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44659228","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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