Esterases participate in the metabolism of^10%of the clinical drugs that contain ester or amide bonds,but the esterases mediated drug/herb-drug interactions(DDIs or HDIs)have not been reviewed in depth.Carboxylesteras...Esterases participate in the metabolism of^10%of the clinical drugs that contain ester or amide bonds,but the esterases mediated drug/herb-drug interactions(DDIs or HDIs)have not been reviewed in depth.Carboxylesterases(CEs),the most abundant esterases expressed in the metabolic organ of mammals,play a pivotal role in hydrolysis of a variety of endogenous and xenobiotic esters.In the human body,two predominant carboxylesterases including hCE1 and hCE2 have been identified and extensively studied over the past decade.These two enzymes have been found with hydrolytic activity towards a variety of endogenous esters and ester-containing drugs.Recent studies have demonstrated that strong inhibition on hCEs may slow down the hydrolysis of CEs substrates,which may affect their pharmacokinetic properties and thus trigger potential DDIs or HDIs.Over the past decade,many herbal extracts and herbal constitutes have been found with strong inhibitory effects against CEs,and their potential risks on herb-drug interactions(HDIs)have also attracted much attention.This review focused on recent progress in hCEs mediated herb-drug interactions.The roles of hCEs in drug metabolism,the inhibitory capacities and inhibition mechanism of a variety of herbal extract and herbal constitutes against hCEs have been well summarized.Furthermore,the challenges and future perspectives in this field are highlighted by the authors.All information and knowledge presented in this review will be very helpful for the pharmacologists to deeper understand the metabolic interactions between herbal constituents and hCEs,as well as for clinical clinicians to reasonable use herbal medicines for alleviating hCEs-associated drug toxicity or avoiding the occurrence of clinically relevant hCEs-mediated HDIs.展开更多
Household CO2 emissions were increasing due to rapid economic growth and different household lifestyle. We assessed per capita household CO2 emissions（PHCEs） based on different household consuming demands（including...Household CO2 emissions were increasing due to rapid economic growth and different household lifestyle. We assessed per capita household CO2 emissions（PHCEs） based on different household consuming demands（including clothing, food, residence, transportation and service） by using provincial capital city level survey data in China. The results showed that：（1） there was a declining trend moving from eastward to westward as well as moving from northward to southward in the distribution of PHCEs.（2） PHCEs from residence demand were the largest which accounted for 44% of the total.（3） Correlation analysis and spatial analysis（Spatial Lag Model（SLM） and Spatial Error Model（SEM）） were used to evaluate the complex determinants of PHCEs. Per capita income（PI） and household size（HS） were analyzed as the key influencing factors. We concluded that PHCEs would increase by 0.2951% and decrease by 0.5114% for every 1% increase in PI and HS, respectively. According to the results, policy-makers should consider household consuming demand, income disparity and household size on the variations of PHCEs. The urgency was to improve technology and change household consuming lifestyle to reduce PHCEs.展开更多
Human carboxylesterase 2A(hCES2A)plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals.Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irino...Human carboxylesterase 2A(hCES2A)plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals.Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity(ITGT),but the orally active,selective,and efficacious hCES2A inhibitors are rarely reported.Here,a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design(SBDD)and structural optimization.Initially,donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration(FDA)-approved drugs.Following two rounds of SBDD and structural optimization,a donepezil derivative(B7)was identified as a strong reversible hCES2A inhibitor.Subsequently,nine B7 carbamates were rationally designed,synthesized and biologically assayed.Among all synthesized carbamates,C3 showed the most potent time-dependent inhibition on hCES2A(IC50=0.56 nmol/L),excellent specificity and favorable drug-like properties.C3 could covalently modify the catalytic serine of hCES2A with high selectivity,while this agent also showed favorable safety profiles,high intestinal exposure,and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice.Collectively,this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s),while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.展开更多
The serine hydrolase(SH)superfamily,one of the largest enzyme groups in mammals with over 200 members,is characterized by a serine-containing catalytic triad within its active site1.These enzymes hydrolyze amide and/o...The serine hydrolase(SH)superfamily,one of the largest enzyme groups in mammals with over 200 members,is characterized by a serine-containing catalytic triad within its active site1.These enzymes hydrolyze amide and/or ester bonds through a nucleophilic attack mediated by the catalytic serine residue.SHs are expressed across various mammalian tissues and play critical roles in diverse physiological and pathological processes.展开更多
基金the National Key Research and Development Program of China(2017YFC1700200,2017YFC1702000)the National Scientific and Technological Major Projects of China(2017ZX09101004)+3 种基金the National Natural Science Foundation of China(81703604,81773687 and 81573501)Program of Shanghai Academic/Technology Research Leader(18XD1403600)Shuguang Program(No.18SG40)Shanghai Education Development Foundation and Shanghai Municipal Education Commission,Project funded by China Postdoctoral Science Foundation(2017M621520,and 2018T110406).
文摘Esterases participate in the metabolism of^10%of the clinical drugs that contain ester or amide bonds,but the esterases mediated drug/herb-drug interactions(DDIs or HDIs)have not been reviewed in depth.Carboxylesterases(CEs),the most abundant esterases expressed in the metabolic organ of mammals,play a pivotal role in hydrolysis of a variety of endogenous and xenobiotic esters.In the human body,two predominant carboxylesterases including hCE1 and hCE2 have been identified and extensively studied over the past decade.These two enzymes have been found with hydrolytic activity towards a variety of endogenous esters and ester-containing drugs.Recent studies have demonstrated that strong inhibition on hCEs may slow down the hydrolysis of CEs substrates,which may affect their pharmacokinetic properties and thus trigger potential DDIs or HDIs.Over the past decade,many herbal extracts and herbal constitutes have been found with strong inhibitory effects against CEs,and their potential risks on herb-drug interactions(HDIs)have also attracted much attention.This review focused on recent progress in hCEs mediated herb-drug interactions.The roles of hCEs in drug metabolism,the inhibitory capacities and inhibition mechanism of a variety of herbal extract and herbal constitutes against hCEs have been well summarized.Furthermore,the challenges and future perspectives in this field are highlighted by the authors.All information and knowledge presented in this review will be very helpful for the pharmacologists to deeper understand the metabolic interactions between herbal constituents and hCEs,as well as for clinical clinicians to reasonable use herbal medicines for alleviating hCEs-associated drug toxicity or avoiding the occurrence of clinically relevant hCEs-mediated HDIs.
基金National Key Research and Development Program,No.2016YFA0602803National Natural Science Foundation of China,No.41371537+1 种基金The Fundamental Research Funds for the Central Universities,No.lzujbky-2016-257The Fundamental Research Funds for the Central Universities,No.lzu-jbky-2017-it106
文摘Household CO2 emissions were increasing due to rapid economic growth and different household lifestyle. We assessed per capita household CO2 emissions（PHCEs） based on different household consuming demands（including clothing, food, residence, transportation and service） by using provincial capital city level survey data in China. The results showed that：（1） there was a declining trend moving from eastward to westward as well as moving from northward to southward in the distribution of PHCEs.（2） PHCEs from residence demand were the largest which accounted for 44% of the total.（3） Correlation analysis and spatial analysis（Spatial Lag Model（SLM） and Spatial Error Model（SEM）） were used to evaluate the complex determinants of PHCEs. Per capita income（PI） and household size（HS） were analyzed as the key influencing factors. We concluded that PHCEs would increase by 0.2951% and decrease by 0.5114% for every 1% increase in PI and HS, respectively. According to the results, policy-makers should consider household consuming demand, income disparity and household size on the variations of PHCEs. The urgency was to improve technology and change household consuming lifestyle to reduce PHCEs.
基金supported by the National Natural Science Foundation of China(Nos.82104281,82273897,and 22367007)China Postdoctoral Science Foundation(Nos.2022M712153,and 2023M742380)+3 种基金The Fundamental Research Funds for Hainan University(KYQD(ZR)23002,China)Hainan Provincial Natural Science Foundation of China(824RC500)PhD Program in Key Fields at Shanghai University of Traditional Chinese Medicine(GJ2023004,China)Liaoning Province Science and Technology Plan Alliance Fund project(2024-BSLH-041,China).
文摘Human carboxylesterase 2A(hCES2A)plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals.Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity(ITGT),but the orally active,selective,and efficacious hCES2A inhibitors are rarely reported.Here,a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design(SBDD)and structural optimization.Initially,donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration(FDA)-approved drugs.Following two rounds of SBDD and structural optimization,a donepezil derivative(B7)was identified as a strong reversible hCES2A inhibitor.Subsequently,nine B7 carbamates were rationally designed,synthesized and biologically assayed.Among all synthesized carbamates,C3 showed the most potent time-dependent inhibition on hCES2A(IC50=0.56 nmol/L),excellent specificity and favorable drug-like properties.C3 could covalently modify the catalytic serine of hCES2A with high selectivity,while this agent also showed favorable safety profiles,high intestinal exposure,and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice.Collectively,this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s),while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.
文摘The serine hydrolase(SH)superfamily,one of the largest enzyme groups in mammals with over 200 members,is characterized by a serine-containing catalytic triad within its active site1.These enzymes hydrolyze amide and/or ester bonds through a nucleophilic attack mediated by the catalytic serine residue.SHs are expressed across various mammalian tissues and play critical roles in diverse physiological and pathological processes.
