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| 1 | Human carboxylesterases:a comprehensive review显示文摘Mammalian carboxylesterases(CEs) are key enzymes from the serine hydrolase superfamily.In the human body, two predominant carboxylesterases(CES1 and CES2) have been identified and extensively studied over the past decade. These two enzymes play crucial roles in the metabolism of a wide variety of endogenous esters, ester-containing drugs and environmental toxicants. The key roles of CES in both human health and xenobiotic metabolism arouse great interest in the discovery of potent CES modulators to regulate endobiotic metabolism or to improve the efficacy of ester drugs. This review covers the structural and catalytic features of CES, tissue distributions, biological functions, genetic polymorphisms, substrate specificities and inhibitor properties of CES1 and CES2, as well as the significance and recent progress on the discovery of CES modulators. The information presented here will help pharmacologists explore the relevance of CES to human diseases or to assign the contribution of certain CES in xenobiotic metabolism. It will also facilitate medicinal chemistry efforts to design prodrugs activated by a given CES isoform, or to develop potent and selective modulators of CES for potential biomedical applications. | Dandan Wang Liwei Zou Qiang Jin Jie Hou Guangbo Ge Ling Yang | 2018 | Acta Pharmaceutica Sinica B2018，8，5： | 14 |
| 2 | Recent progress and challenges in screening and characterization of UGT1A1 inhibitors显示文摘Uridine-diphosphate glucuronosyltransferase 1 A1(UGT1 A1) is an important conjugative enzyme in mammals that is responsible for the conjugation and detoxification of both endogenous and xenobiotic compounds. Strong inhibition of UGT1 A1 may trigger adverse drug/herb–drug interactions, or result in metabolic disorders of endobiotic metabolism. Therefore, both the US Food and Drug Administration(FDA)and the European Medicines Agency(EMA) have recommended assaying the inhibitory potential of drugs under development on the human UGT1 A1 prior to approval. This review focuses on the significance,progress and challenges in discovery and characterization of UGT1 A1 inhibitors. Recent advances in the development of UGT1 A1 probes and their application for screening UGT1 A1 inhibitors are summarized and discussed in this review for the first time. Furthermore, a long list of UGT1 A1 inhibitors, including information on their inhibition potency, inhibition mode, and affinity, has been prepared and analyzed. Challenges and future directions in this field are highlighted in the final section. The information and knowledge that are presented in this review provide guidance for rational use of drugs/herbs in order to avoid the occurrence of adverse effects via UGT1 A1 inhibition, as well as presenting methods for rapid screening and characterization of UGT1 A1 inhibitors and for facilitating investigations on UGT1 A1–ligand interactions. | Xia Lv Yangliu Xia Moshe Finel Jingjing Wu Guangbo Ge Ling Yang | 2019 | Acta Pharmaceutica Sinica B2019，9，2： | 14 |
| 3 | Comparison of the inhibition potentials of icotinib and erlotinib against human UDP-glucuronosyltransferase 1A1显示文摘UDP-glucuronosyltransferase 1A1(UGT1A1) plays a key role in detoxification of many potentially harmful compounds and drugs. UGT1A1 inhibition may bring risks of drug–drug interactions(DDIs), hyperbilirubinemia and drug-induced liver injury. This study aimed to investigate and compare the inhibitory effects of icotinib and erlotinib against UGT1A1, as well as to evaluate their potential DDI risks via UGT1A1 inhibition. The results demonstrated that both icotinib and erlotinib are UGT1A1 inhibitors, but the inhibitory effect of icotinib on UGT1A1 is weaker than that of erlotinib. The IC_(50) values of icotinib and erlotinib against UGT1A1-mediated NCHN-O-glucuronidation in human liver microsomes(HLMs) were 5.15 and 0.68 μmol/L, respectively. Inhibition kinetic analyses demonstrated that both icotinib and erlotinib were non-competitive inhibitors against UGT1A1-mediated glucuronidation of NCHN in HLMs, with the Kivalues of 8.55 and 1.23 μmol/L, respectively. Furthermore, their potential DDI risks via UGT1A1 inhibition were quantitatively predicted by the ratio of the areas under the concentration–time curve(AUC) of NCHN. These findings are helpful for the medicinal chemists todesign and develop next generation tyrosine kinase inhibitors with improved safety, as well as to guide reasonable applications of icotinib and erlotinib in clinic, especially for avoiding their potential DDI risks via UGT1A1 inhibition. | Xuewei Cheng Xia Lv Hengyan Qu Dandan Li Mengmeng Hu Wenzhi Guo Guangbo Ge Ruihua Dong | 2017 | Acta Pharmaceutica Sinica B2017，7，6： | 7 |
| 4 | Arenobufagin is a novel isoform-specific probe for sensing human sulfotransferase 2A1显示文摘Human cytosolic sulfotransferase 2 A1(SULT2A1) is an important phase II metabolic enzyme. The detection of SULT2A1 is helpful for the functional characterization of SULT2A1 and diagnosis of its related diseases. However, due to the overlapping substrate specificity among members of the sulfotransferase family, it is difficult to develop a probe substrate for selective detection of SULT2A1. In the present study, through characterization of the sulfation of series of bufadienolides, arenobufagin(AB) was proved as a potential probe substrate for SULT2A1 with high sensitivity and specificity. Subsequently, the sulfation of AB was characterized by experimental and molecular docking studies. The sulfate-conjugated metabolite was identified as AB-3-sulfate.The sulfation of AB displayed a high selectivity for SULT2A1 which was confirmed by in vitro reaction phenotyping assays. The sulfation of AB by human liver cytosols and recombinant SULT2A1 both obeyed Michaelis-Menten kinetics, with similar kinetic parameters. Molecular docking was performed to understand the interaction between AB and SULT2A1, in which the lack of interaction with Met-137 and Tyr-238 of SULT2A1 made it possible to eliminate substrate inhibition of AB sulfation. Finally, the probe was successfully used to determine the activity of SULT2A1 and its isoenzymes in tissue preparations of human and laboratory animals. | Xiangge Tian Chao Wang Peipei Dong Yue An Xinyu Zhao Weiru Jiang Gang Wang Jie Hou Lei Feng Yan Wang Guangbo Ge Xiaokui Huo Jing Ning Xiaochi Ma | 2018 | Acta Pharmaceutica Sinica B2018，8，5： | 2 |
| 5 | Synthesis and Biological Evaluation of Hydroxylcoumarin Derivatives as Antioxidant Agents显示文摘In this study, esculetin(1) was chosen as a lead compound and some structural modifications weredesigned to explore the antioxidant activities of esculetin derivatives. Meanwhile, a convenient method for selectivemethylation of catechol cournarins with different bases was developed. Furthermore, a few 5,7-dihydroxylcoumarinswere synthesized and 7-hydroxylcoumarins were employed in order to explore the potential structure-antioxidantactivity relationships. The antioxidant activities of these compounds were evaluated and compared with standardantioxidant Trolox by the 22'-diphenyl-l-picrylhydrazyl(DPPH) assay, 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulfonate)cation(ABTS+) assay and ferric reducing antioxidant power(FRAP) assay. The results show that the catechol group isthe key pharmacophore. Meanwhile, introducing electronegative groups at the C4 position of esculetin(1) mayenhance the antioxidative capacity, while introducing a group containing nitrogen as a hydrogen bond acceptor at theC8 position may slightly reduce the antioxidative capacity, Among them, the most powerful antioxidants are com-pounds 5 and 7, which exhibit higher antioxidant activity than esculetin(1) in all assays. | CHEN Chen WANG Ping ZOU Liwei YANG Ling FAN Yiming HU Wenzhong GE Guangbo | 2017 | Chemical Research in Chinese Universities2017，33，2： | 2 |
| 6 | Sensing carboxylesterase 1 in living systems by a practical and isoformspecific fluorescent probe显示文摘Carboxylesterase 1(CES1), one of the most abundant serine hydrolases in mammals, has drawn much attentions in recent years, owing to this enzyme involves in many physiological processes via hydrolysis of both endogenous esters and xenobiotic esters. Herein, to real-time monitor the activities of CES1 in various biological systems, a practical and iso form-specific fluorescent probe was developed on the basis of the substrate preference of CES1, as well as the structural and optical properties of BODIPY dyes. After screening of a panel of BODIPY ester derivatives, probe 1 displayed the best combination of specificity,sensitivity, enzymatic kinetics and applicability for monitoring CES1 activities in real samples. This probe was successfully used to detect CESl activities in several biological systems including tissue preparations,living cells, tissue slices and zebrafish. Furthermore, the biomedical applications of probe 1 for screening of CES1 inhibitors were also demonstrated using tissue preparations or living cells as enzyme sources. In summary, a practical and broadly applicable tool for real-time monitoring CES1 in biological systems was developed and well-characterized, which held great promise for further investigations on CES1-associated drug discovery, clinical practice and fundamental research. | Lele Ding Zhenhao Tian Jie Hou Tongyi Dou Qiang Jin Dandan Wang Liwei Zou Yadi Zhu Yunqing Song Jingnan Cui Guangbo Ge | 2019 | Chinese Chemical Letters2019，30，3： | 2 |
| 7 | Sensing cytochrome P4501A1 activity by a resorufin-based isoform-specific fluorescent probe显示文摘Cytochrome P4501 A1(CYP1A1),a heme-containing monooxygenase,is of particular importance for human health because of its vital roles in the metabolic activation of pro-carcinogenic compounds to the carcinogens.Deciphering the relevance of CYP1A1 to human diseases and screening of CYP1A1 modulators require reliable tool(s)for probing this key enzyme in complex biological matrices.Herein,a practical and ultrasensitive fluorescence-based assay for real-time sensing CYP1A1 activities in biological systems has been developed,via designing an isoform-specific fluorogenic sensor for CYP1A1(CHPO).The newly developed fluorogenic substrate for CYP1A1 has been carefully investigated in terms of specificity,sensitivity,precision,quantitative linear range and the anti-interference ability.The excellent selectivity,strong anti-interference ability and fast response kinetics,making the practicability of CHPObased CYP1A1 activity assay is better than that of most reported CYP1A1 activity assays.Furthermore,CHPO has been successfully used for imaging CYP1A1 activities in living cells and human tissues,as well as for high-throughput screening of CYP1A1 inhibitors using tissue preparations as enzyme sources.Collectively,this study provided a practical fluorogenic sensor for real-time sensing CYP1A1 in complex biological systems,which would strongly facilitate the investigations on the relevance of CYP1A1 to human diseases and promote high-throughput screening of CYP1A1 modulators for biomedical applications. | Qiang Jin Hongying Ma Lei Feng Ping Wang Rongjing He Jing Ning Ling Yang Guangbo Ge | 2020 | Chinese Chemical Letters2020，31，11： | 2 |
| 8 | An Expedient Method for Regioselective Methylation of Catechol Coumarins显示文摘 | LU Junxia WANG Ping HOU Jie ZOU Liwei CUI Pan YANG Ling GE Guangbo GONG Xiaojie | 2016 | Chemical Research in Chinese Universities2016，32，5： | 1 |
| 9 | Rapid profiling and target analysis of principal components in Fuling De- coctions by UFLC-DAD-ESI-MS 显示文摘 | Wang Aoxue Ge Guangbo Qi Xiaoyi | 2010 | Fitoterapia2010，81，6： | 1 |
| 10 | Determi- nation of propofol UDP-glucuronosyltransferase (UGT) activities in hepatic microsomes from different species by UFLC-ESI-MS 显示文摘 | Liang Sicheng Ge Guangbo Liu Huixin | 2011 | J Pharm Biomed Anal2011，54，： | 1 |
| 11 | Rapid bioluminescence assay for monitoring rat CES1 activity and its alteration by traditional Chinese medicines显示文摘In traditional Chinese medicine herbs(TCM),including Radix Salviae Miltiorrhizae(Danshen),Radix Puerariae Lobatae(Gegen),Radix Angelicae Sinensis(Danggui),and Rhizoma Chuanxiong(Chuanxiong)are widely used for the prevention and treatment of cardiovascular diseases and also often co-administered with Western drugs as a part of integrative medicine practice.Carboxylesterase 1(CES1)plays a pivotal role in the metabolisms of pro-drugs,Since(S)-2-(2-(6-dimethylamino)-benzothiazole)-4,5-dihydrothiazole-4-carboxylate(NLMe)has recently been identified by us as a selective CES1 bioluminescent sensor,we developed a rapid method using this substrate for the direct measurement of CES1 activity in rats.This bioluminescence assay was applied to determine CES1 activity in rat tissues after a two-week oral administration of each of the four herbs noted above.The results demonstrated the presence of CES1 enzyme in rat blood and all tested tissues with much higher enzyme activity in the blood,liver,kidney and heart than that in the small intestine,spleen,lung,pancreas,brain and stomach.In addition,the four herbs showed tissue-specific effects on rat CES1 expression.Based on the CES1 biodistribution and its changes after treatment in rats,the possibility that Danshen,Gegen and Danggui might alter CES1 activities in human blood and kidney should be considered.In summary,a selective and sensitive bioluminescence assay was developed to rapidly evaluate CES1 activity and the effects of orally administered TCMs in rats. | Jun Zhang Dandan Wang Liwei Zou Min Xiao Yufeng Zhang Ziwei Li Ling Yang Guangbo Ge Zhong Zuo | 2020 | Journal of Pharmaceutical Analysis2020，10，3： | 1 |
| 12 | A novel TICT-based near-infrared fluorescent probe for light-up sensing and imaging of human serum albumin in real samples显示文摘Human serum albumin(HSA) has emerged as a pivotal biomarker and prognostic indicator for various human diseases. Real-time sensing and visual tracking of HSA in plasma or other biological systems will immensely facilitate the basic researchers and clinicians to better understand HSA-associated biological processes. Herein, a novel near-infrared(NIR) fluorescent probe(7-HTCF) was rationally constructed for light-up sensing and in-situ imaging of HSA in real samples, based on the principle of twisted intramolecular charge transfer(TICT). Under physiological conditions, 7-HTCF could be efficiently trapped by HSA to form a stable complex via binding on a non-drug binding site, while the complex emitted strong fluoresce signals around 670 nm. Further investigations demonstrated that 7-HTCF displayed a great combination of excellent selectivity and good chemical stability, as well as rapid fluorescent response and ultra-high sensitivity for HSA detection. Particularly, the newly developed light-up probe has been successfully utilized for quantitative detection of HSA in diluted plasma samples, while its readouts are hardly affected by the addition of therapeutic agents and herbal medicines. 7-HTCF is also successfully used for in-situ imaging of the reabsorbed HSA in living renal cells, while this dye exhibits good cell permeability and high resolution for in-situ imaging in living cells. Collectively, a novel TICT-based near-infrared fluorescent probe was devised for highly selective and ultra-sensitive sensing of HSA in plasma samples or imaging HSA in living cells, which offered a practical tool for clinical tests and for exploring HSA-associated biological processes. | Yufan Fan Fangyuan Wang Fanbin Hou Lai Wei Guanghao Zhu Dongfang Zhao Qing Hu Tao Lei Ling Yang Ping Wang Guangbo Ge | 2023 | Chinese Chemical Letters2023，34，2： | 0 |
| 13 | Sustainable utilization of precious Chinese medicines:challenges and the road ahead显示文摘Traditional Chinese medicine(TCM)is considered as a unique treasure of Chinese civilization for its profound theoretical system and extensive experience in clinical practice for more than two thousand years.As one of the most commonly used folk medicines,Chinese medicines have made indelible contributions to well-being maintenance and disease treatment,as well as the progress of human civilization[1]. | GONG Jiahao LI Haiying XU Jianguang CHEN Hongzhuan GE Guangbo | 2022 | Chinese Journal of Natural Medicines2022，20，11： | 0 |
| 14 | Preface for special issue on new analytical techniques and methods in drug metabolism and pharmacokinetics显示文摘Analytical technologies and approaches for drug metabolism and pharmacokinetics(DMPK)research in the pharmaceutical industry and academic research institutes have evolved rapidly over the past decade.On one hand,the discovery and development of small molecule drug candidates requires earlier and better understanding of their absorption,distribution,metabolism and excretion(ADME)in human as well as their interactions with metabolizing enzymes. | Guangbo Ge Mingshe Zhu | 2020 | Journal of Pharmaceutical Analysis2020，10，3： | 0 |
| 15 | Optical substrates for drug-metabolizing enzymes: Recent advances and future perspectives显示文摘Drug-metabolizing enzymes(DMEs),a diverse group of enzymes responsible for the metabolic elimination of drugs and other xenobiotics,have been recognized as the critical determinants to drug safety and efficacy.Deciphering and understanding the key roles of individual DMEs in drug metabolism and toxicity,as well as characterizing the interactions of central DMEs with xenobiotics require reliable,practical and highly specific tools for sensing the activities of these enzymes in biological systems.In the last few decades,the scientists have developed a variety of optical substrates for sensing human DMEs,parts of them have been successfully used for studying target enzyme(s)in tissue preparations and living systems.Herein,molecular design principals and recent advances in the development and applications of optical substrates for human DMEs have been reviewed systematically.Furthermore,the challenges and future perspectives in this field are also highlighted.The presented information offers a group of practical approaches and imaging tools for sensing DMEs activities in complex biological systems,which strongly facilitates high-throughput screening the modulators of target DMEs and studies on drug/herb-drug interactions,as well as promotes the fundamental researches for exploring the relevance of DMEs to human diseases and drug treatment outcomes. | Qiang Jin Jing Jing Wu Yue Wu Hongxin Li Moshe Finel Dandan Wang Guangbo Ge | 2022 | Acta Pharmaceutica Sinica B2022，12，3： | 0 |
| 16 | Clinical efficacy of low-dose emetine for patients with COVID-19:a real-world study显示文摘Objective:Emetine,an isoquinoline alkaloid that is enriched at high concentrations in the lung,has shown potent in vitro activity against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).The aim of this study was to better understand the effectiveness of low-dose emetine for patients with coronavirus disease 2019(COVID-19).Methods:In this real-world study,63 patients with mild or common COVID-19 were recruited from Wuhan Fangcang Shelter Hospital and five COVID-19-designated hospitals in Anhui Province,China from February to March 2020.Thirty-nine patients from Wuhan Fangcang Shelter Hospital were assigned to a pragmatic randomized controlled clinical trial,and 24 patients from the 5 COVID-19-designated hospitals in Anhui Province underwent a real-world study.The medication course of emetine was less than 10 days.The main symptoms and adverse reactions of all patients were observed and recorded.The primary outcome measure was the time required for a negative SARS-CoV-2 RNA result or the negative result rate on day 10.Secondary outcomes included axillary temperature,transcutaneous oxygen saturation,and respiratory frequency recovery.The study was approved by the Ethics Committee of The First Affiliated Hospital of Anhui Medical University on February 20,2019(approval No.PJ2020-03-19)and was registered with the Chinese Clinical Trial Registry on February 20,2019(registration number:ChiCTR2000030022).Results:The oxygen saturation values were higher in the treatment group than in the control group on the first day after enrollment for patients treated at Fangcang Shelter Hospital.The axillary body temperature,respiratory rate,and oxygen saturation among patients in Fangcang Shelter Hospital were related to the time effect but not to the intervention measures.The respiratory rate and oxygen saturation of patients in the Anhui designated hospitals were related to the intervention measures but not to the time effect.The axillary body temperature of patients in Anhui designated hospitals was related to the time effect but not to the intervention measures.Conclusion:Our preliminary study shows that low-dose emetine combined with basic conventional antiviral drugs improves clinical symptoms in patients with mild and common COVID-19 without apparent adverse effects,suggesting that moderately increased doses of emetine may have good potential for treatment and prevention of COVID-19. | Song Fan Qi Zhen Cheng Chen Wenjun Wang Qibing Wu Huihui Ma Chengyuan Zhang Li Zhang Baojing Lu Huiyao Ge Liang Yong Bao Li Yafen Yu Weiwei Chen Yiwen Mao Guangbo Qu Li Su Aoli Wang Zhen Ding Haiwen Li Jin Zhang Yonglian Wang Yufeng Gao Xihai Xu Zhongming Zhu Jun Chen Long Zhang Hongqiang Liang Song Wu Meng Huang Quan Xia Ping Li Yehuan Sun Chaozhao Liang Wei Wei Qingsong Liu Liangdan Sun | 2021 | Journal of Bio-X Research2021，4，2： | 0 |
| 17 | Preventive and therapeutic benefits of nelfinavir in rhesus macaques and human beings infected with SARS-CoV-2显示文摘Effective drugs with broad spectrum safety profile to all people are highly expected to combat COVID-19 caused by SARS-CoV-2.Here we report that nelfinavir,an FDA approved drug for the treatment of HIV infection,is effective against SARS-CoV-2 and COVID-19.Preincubation of nelfinavir could inhibit the activity of the main protease of the SARS-CoV-2(IC50=8.26μM),while its antiviral activity in Vero E6 cells against a clinical isolate of SARS-CoV-2 was determined to be 2.93μM(EC50).In comparison with vehicle-treated animals,rhesus macaque prophylactically treated with nelfinavir had significantly lower temperature and significantly reduced virus loads in the nasal and anal swabs of the animals.At necropsy,nelfinavir-treated animals had a significant reduction of the viral replication in the lungs by nearly three orders of magnitude.A prospective clinic study with 37 enrolled treatment-naive patients at Shanghai Public Health Clinical Center,which were randomized(1:1)to nelfinavir and control groups,showed that the nelfinavir treatment could shorten the duration of viral shedding by 5.5 days(9.0 vs.14.5 days,P=0.055)and the duration of fever time by 3.8 days(2.8 vs.6.6 days,P=0.014)in mild/moderate COVID-19 patients.The antiviral efficiency and clinical benefits in rhesus macaque model and in COVID-19 patients,together with its well-established good safety profile in almost all ages and during pregnancy,indicated that nelfinavir is a highly promising medication with the potential of preventative effect for the treatment of COVID-19. | Zhijian Xu Danrong Shi Jian-Bao Han Yun Ling Xiangrui Jiang Xiangyun Lu Chuan Li Likun Gong Guangbo Ge Yani Zhang Yi Zang Tian-Zhang Song Xiao-Li Feng Ren-Rong Tian Jia Ji Miaojin Zhu Nanping Wu Chunhui Wu Zhen Wang Yechun Xu Cheng Peng Min Zheng Junling Yang Feifei Du Junliang Wu Peipei Wang Jingshan Shen Jianliang Zhang Yong-Tang Zheng Hangping Yao Weiliang Zhu | 2023 | Signal Transduction and Targeted Therapy2023，8，5： | 0 |
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