检索结果-南通市图书馆

Journal of Pharmaceutical Analysis 2021年第5期11卷 580-587页

作者： Shuning Li Zhenyao Lu Li Jiao Ran Zhang Yu Hong Jiye Aa Guangji Wang Jiangsu Province key laboratory of drug metabolism and pharmacokinetics China Pharmaceutical UniversityNanjingJiangsu210009China

Cystine is the primary source material for the synthesis of ***,the pharmacokinetics and tissue distribution of cystine are largely unknown.A surrogate analyte D_(4)-cystine was employed to generate calibration curves for the determination of levels of D_(4)-cystine and endogenous cystine in mice by liquid chromatography-tandem mass spectrometry(LC-MS/MS).Validation assessments proved the sensitivity,specificity and reproducibility of the method with a lower limit of quantification(LLOQ)of 5 ng/mL over 5e5000 ng/mL in *** pharmacokinetics of D_(4)-cystine were evaluated after administering injections and oral solutions,both of which minimally impacted endogenous cystine *** absolute bioavailability of cystine was 18.6%,15.1%and 25.6%at doses of 25,50 and 100 mg/kg,*** injected D_(4)-cystine resulted in dramatically high plasma levels with reduced levels in the brain and *** administered D_(4)-cystine resulted in high levels in the plasma and stomach with relatively low levels in the lung,kidney,heart and brain.

关键词： Cystine LC-MS/MS pharmacokinetics Distribution Absolute bioavailability

SIRT1 activation synergizes with FXR agonism in hepatoprotection via governing nucleocytoplasmic shuttling and degradation of FXR

在线全文

学校读者我要写书评

暂无评论

Acta Pharmaceutica Sinica B 2023年第2期13卷 559-576页

作者： Shuang Cui Huijian Hu An Chen Ming Cui Xiaojie Pan Pengfei Zhang Guangji Wang Hong Wang Haiping Hao State key laboratory of Natural Medicines Key Laboratory of Drug Metabolism&PharmacokineticsChina Pharmaceutical UniversityNanjing 210009China

Farnesoid X receptor(FXR)is widely accepted as a promising target for various liver diseases;however,panels of ligands in drug development show limited clinical benefits,without a clear ***,we reveal that acetylation initiates and orchestrates FXR nucleocytoplasmic shuttling and then enhances degradation by the cytosolic E3 ligase CHIP under conditions of liver injury,which represents the major culprit that limits the clinical benefits of FXR agonists against liver *** inflammatory and apoptotic stimulation,enhanced FXR acetylation at K217,closed to the nuclear location signal,blocks its recognition by importin KPNA3,thereby preventing its nuclear ***,reduced phosphorylation at T442 within the nuclear export signals promotes its recognition by exportin CRM1,and thereby facilitating FXR export to the *** governs nucleocytoplasmic shuttling of FXR,resulting in enhanced cytosolic retention of FXR that is amenable to degradation by ***1 activators reduce FXR acetylation and prevent its cytosolic *** importantly,SIRT1 activators synergize with FXR agonists in combating acute and chronic liver *** conclusion,these findings innovate a promising strategy to develop therapeutics against liver diseases by combining SIRT1 activators and FXR agonists.

关键词： FXR Nuclear receptor Acetylation Phosphorylation Nucleocytoplasmic shuttling Degradation Nonalcoholic steatohepatitis Combinatorial drugs

A hepatoprotection study of Radix Bupleuri on acetaminophen-induced liver injury based on CYP450 inhibition

在线全文

学校读者我要写书评

暂无评论

Chinese Journal of Natural Medicines 2019年第7期17卷 517-524页

作者： WANG Yu-Xin DU Yi LIU Xia-Fei YANG Fang-Xiu WU Xiao TAN Li LU Yi-Hong ZHANG Jing-Wei ZHOU Fang WANG Guang-Ji key lab of drug metabolism and pharmacokinetics China Pharmaceutical University Nanjing 210009 China key laboratory of New drug Research and Clinical Pharmacy Xuzhou Medical University Xuzhou 221004 China Jiangsu Institute for Food and drug Control Nanjing 210019 China

We investigated the potential hepatoprotective effect of Radix Bupleuri(RB) by inducing acute liver injury(ALI) in an animal model using acetaminophen(APAP) after pretreatment with RB aqueous extract for three consecutive days. Compared to those of the APAP group, the biochemical and histological results of the RB pretreatment group showed lower serum aspartate transaminase(AST) and alanine transaminase(ALT) levels as well as less liver damage. Pharmacokinetic study of the toxicity related marker acetaminophen-cysteine(APC) revealed a lower exposure level in rats, suggesting that RB alleviated APAP-induced liver damage by preventing glutathione(GSH) depletion. The results of cocktail approach showed significant inhibition of CYP2 E1 and CYP3 A activity. Further investigation revealed the increasing of CYP2 E1 and CYP3 A protein was significantly inhibited in pretreatment group,while no obvious effect on gene expression was found. Therefore, this study clearly demonstrates that RB exhibited significant protective action against APAP-induced acute live injury via pretreatment, and which is partly through inhibiting the increase of activity and translation of cytochrome P450 enzymes, rather than gene transcription.

关键词： Hepatoprotection Radix Bupleuri Acetaminophen Acute liver injury Cytochrome P450 enzymes

Discovery of proqodine A derivatives with antitumor activity targeting NAD(P)H:quinone oxidoreductase 1 and nicotinamide phosphoribosyltransferase

在线全文

学校读者我要写书评

暂无评论

Chinese Journal of Natural Medicines 2024年第1期22卷 75-88页

作者： SONG Jiangzhou ZOU Guiqing ZHAO Zhou ZHU Ya XUE Jiayu AO Lanjia SUN Huiyong HAO Haiping ZHANG Bo XU Xiaowei State key laboratory of Natural Medicines Key Lab of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityNanjing 210009China State key laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China

NAD(P)H:quinone oxidoreductase 1(NQO1)is a flavin protease highly expressed in various cancer ***1 catalyzes a futile redox cycle in substrates,leading to substantial reactive oxygen species(ROS)*** ROS generation results in extensive DNA damage and elevated poly(ADP-ribose)polymerase 1(PARP1)-mediated consumption of nicotinamide adenine dinucleotide(NAD^(+)),ultimately causing cell *** phosphoribosyltransferase(NAMPT),the rate-limiting enzyme in the NAD^(+)salvage synthesis pathway,emerges as a critical target in cancer *** concurrent inhibition of NQO1 and NAMPT triggers hyperactivation of PARP1 and intensive NAD+*** this study,we designed,synthesized,and assessed a novel series of proqodine A derivatives targeting both NQO1 and *** these,compound T8 demonstrated potent antitumor ***,T8 selectively inhibited the proliferation of MCF-7 cells and induced apoptosis through mechanisms dependent on both NQO1 and *** discovery offers a promising new molecular entity for advancing anticancer research.

关键词： NQO1 ROS NAMPT NAD^(+) T8

Isochlorogenic acid A affects P450 and UGT enzymes in vitro and in vivo

在线全文

学校读者我要写书评

暂无评论

Chinese Journal of Natural Medicines 2016年第11期14卷 865-870页

作者： WANG Jing WANG Hong PENG Ying WANG Guang-Ji HAO Hai-Ping key lab of drug metabolism & pharmacokinetics State Key Laboratory of Natural Medicines China Pharmaceutical University

Isochlorogenic acid A(ICQA), which has anti-inflammatory, hepatoprotective, and antiviral properties, is commonly presented in fruits, vegetables, coffee, plant-based food products, and herbal medicines. These herbal medicines are usually used in combination with other medicines in the clinic. However, little is known about the regulatory effects of ICQA on drug-metabolizing enzymes and the herb-drug interactions. In the present study, we evaluated the inhibitory potentials of ICQA on CYP1A2, CYP2C9,CYP2C19, CYP3A4, CYP2D6, and CYP2E1 in vitro based on a cocktail approach. The P450 and UGT activities in mice treated with ICQA for a prolonged period were also determined. Our results demonstrated that ICQA exhibited a weak inhibitory effect on CYP2C9 in human liver microsomes with IC_(50) being 57.25 μmol·L^(-1) and Ki being 26.77 μmol·L^(-1). In addition, ICQA inhibited UGT1A6 activity by 25%, in the mice treated with ICQA(i.p.) at 30 mg·kg^(-1)for 14 d, compared with the control group. Moreover, ICQA showed no mechanism-based inhibition on CYP2C9 or UGT1A6. In conclusion, our results further confirm a safe use of ICQA in clinical practice.

关键词： Isochlorogenic acid A P450 UGT Herb-drug interaction

Appropriate choice of collision-induced dissociation energy for qualitative analysis of notoginsenosides based on liquid chromatography hybrid ion trap time-of-flight mass spectrometry

在线全文

学校读者我要写书评

暂无评论

Chinese Journal of Natural Medicines 2016年第4期14卷 278-285页

作者： WANG Guang-Ji FU Han-Xu XIAO Jing-Cheng YE Wei RAO Tai SHAO Yu-Hao KANG Dian XIE Lin LIANG Yan key lab of drug metabolism & pharmacokinetics State Key Laboratory of Natural Medicines China Pharmaceutical University

Liquid chromatography hybrid ion trap/time-of-flight mass spectrometry possesses both the MS^n ability of ion trap and the excellent resolution of a time-of-flight and has been widely used to identify drug metabolites and determine trace multi-components in natural products. Collision energy, one of the most important factors in acquiring MS^n information, could be set freely in the range of 10%–400%. Herein, notoginsenosides were chosen as model compounds to build a novel methodology for the collision energy optimization. Firstly, the fragmental patterns of the representatives for the authentic standards of protopanaxadiol-type and protopanaxatriol-type notoginsenosides were obtained based on accurate MS^2 and MS^3 measurements via liquid chromatography hybrid ion trap/time-of-flight mass spectrometry. The extracted ion chromatograms of characteristic product ions of notoginsenosides in Panax Notoginseng Extract were produced under a series of collision energies and compared to screen the optimum collision energies values for MS^2 and MS^3. The results demonstrated that the qualitative capability of liquid chromatography hybrid ion trap/time-of-flight mass spectrometry was greatly influenced by collision energies, and 50% of MS^2 collision energy was found to produce the highest collision-induced dissociation efficiency for notoginsenosides. Addtionally, the highest collision-induced dissociation efficiency appeared when the collision energy was set at 75% in the MS^3 stage.

关键词： Collision energy Collision-induced dissociation Notoginsenosides Qualitative analysis

Evaluation of the metabolism of PEP06,an endostatin-RGDRGD 30-amino-acid polypeptide and a promising novel drug for targeting tumor cells

在线全文

学校读者我要写书评

暂无评论

Journal of Pharmaceutical Analysis 2022年第5期12卷 766-773页

作者： Liyun Niu Huiyu Zhou Yueru Lian Ya Gao Yulu Liu Ruolan Gu Zhuona Wu Xiaoxia Zhu Hui Gan Zhiyun Meng Guifang Dou State key laboratory of drug metabolism and pharmacokinetics Department of Pharmaceutical SciencesBeijing Institute of Radiation MedicineBeijing100850China Henan University KaifengHenan475004China

PEP06 is a novel endostatin-Arg-Gly-Asp-Arg-Gly-Asp(RGDRGD)30-amino-acid polypeptide featuring a terminally fused RGDRGD hexapeptide at the N *** active endostatin fragment of PEP06 directly targets tumor cells and exerts an antitumoral ***,little is known about the kinetics and degradation products of PEP06 in vitro or in *** this study,we investigated the in vitro metabolic stability of PEP06 after it was incubated with living cells obtained from animals of different species;we further identified the degradation characteristics of its cleavage ***06 underwent rapid enzymatic degradation in multiple types of living cells,and the liver,kidney,and blood play important roles in the metabolism and clearance of the peptides resulting from the molecular degradation of *** identified metabolites of PEP06 using full-scan mass spectrometry(MS)and tandem MS(MS2),wherein 43 metabolites were characterized and identified as the degradation metabolites from the parent peptide,formed by successive losses of amino *** metabolites were C and N terminal truncated products of *** structures of 11 metabolites(M6,M7,M16,M17,M21,M25,M33,M34,M39,M40,and M42)were further confirmed by comparing the retention times of similar full MS spectrum and MS2 spectrum information with reference standards for the synthesized *** have demonstrated the metabolic stability of PEP06 in vitro and identified a series of potentially bioactive downstream metabolites of PEP06,which can support further drug research.

关键词： PEP06 HRMS Metabolic stability Metabolites identification

Combined obeticholic acid and apoptosis inhibitor treatment alleviates liver fibrosis

维普期刊数据库评论

在线全文

维普期刊数据库

学校读者我要写书评

暂无评论

Acta Pharmaceutica Sinica B 2019年第3期9卷 526-536页

作者： Jiyu Zhou Ningning Huang Yitong Guo Shuang Cui Chaoliang Ge Qingxian He Xiaojie Pan Guangji Wang Hong Wang Haiping Hao State key laboratory of Natural Medicines Key Laboratory of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityNanjing210009China First Affiliated Hospital of Anhui Medical University Hefei230022China

Obeticholic acid(OCA), the first FXR-targeting drug, has been claimed effective in the therapy of liver fibrosis. However, recent clinical trials indicated that OCA might not be effective against liver fibrosis, possibly due to the lower dosage to reduce the incidence of the side-effect of pruritus. Here we propose a combinatory therapeutic strategy of OCA and apoptosis inhibitor for combating against liver fibrosis. CCl4-injured mice, D-galactosamine/LPS(GalN/LPS)-treated mice and cycloheximide/TNFα(CHX/TNFα)-treated HepG2 cells were employed to assess the effects of OCA, or together with IDN-6556, an apoptosis inhibitor. OCA treatment significantly inhibited hepatic stellate cell(HSC)activation/proliferation and prevented fibrosis. Elevated bile acid(BA) levels and hepatocyte apoptosis triggered the activation and proliferation of HSCs. OCA treatment reduced BA levels but could not inhibit hepatocellular apoptosis. An enhanced anti-fibrotic effect was observed when OCA was co-administrated with IDN-6556. Our study demonstrated that OCA inhibits HSCs activation/proliferation partially by regulating BA homeostasis and thereby inhibiting activation of HSCs. The findings in this study suggest that combined use of apoptosis inhibitor and OCA at lower dosage represents a novel therapeutic strategy for liver fibrosis.

关键词： Obeticholic acid Liver fibrosis Bile acid Hepatocellular apoptosis IDN-6556 Farnesoid X receptor Hepatic stellate cell

Target-responsive subcellular catabolism analysis for early-stage antibody-drug conjugates screening and assessment

在线全文

学校读者我要写书评

暂无评论

Acta Pharmaceutica Sinica B 2021年第12期11卷 4020-4031页

作者： Hua Sang Jiali Liu Fang Zhou Xiaofang Zhang Jingwei Zhang Yazhong Liu Guangji Wang Hui Ye Jiangsu Provincial key laboratory of drug metabolism and pharmacokinetics State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China Department of Pharmacy the Affiliated Hospital of Nantong UniversityNantong 226001China

Events including antibody-antigen affinity,internalization,trafficking and lysosomal proteolysis combinatorially determine the efficiency of antibody-drug conjugate(ADC) catabolism and hence the ***,an approach that conveniently identifies proteins requisite for payload release and the ensuing toxicity for mechanistic studies and quality assessment is *** the plethora of ADC candidates under development,we developed a target-responsive subcellular catabolism(TARSC) approach that examines ADC catabolism and probes changes in response to targeted interferences of proteins of *** firstly applied TARSC to study the commercial T-DM1 and the *** recorded unequivocal catabolic behaviors regardless of the absence and presence of the targeted *** negligible differences in TARSC profiles agreed with their undifferentiated anti-tumoral efficacy according to further in vitro viability and in vivo tumor growth assays,highlighting TARSC analysis as a useful tool for biosimilarity assessment and functional dissection of proteins requisite for ADC ***,we employed TARSC to investigate the catabolic behavior of a new trastuzumab-toxin ***,TARSC can not only characterize ADC catabolism at(sub)cellular level but also comprehensively determine which protein targets affect payload release and therapeutic *** use of TARSC is thus anticipated in early-stage screening,quality assessment and mechanistic investigations of ADCs.

关键词： ADC Target-responsive subcellular catabolism(TARSC) T-DM1 Therapeutic efficacy Screening Biosimilarity

Emerging mechanisms of non-alcoholic steatohepatitis and novel drug therapies

在线全文

学校读者我要写书评

暂无评论

Chinese Journal of Natural Medicines 2024年第8期22卷 724-745页

作者： CHEN Hao ZHOU Yang HAO Haiping XIONG Jing Department of Pharmacology School of PharmacyChina Pharmaceutical UniversityNanjing 210009China Jiangsu Provincial key laboratory of drug metabolism and pharmacokinetics State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China

Non-alcoholic fatty liver disease(NAFLD)has become a leading cause of chronic liver disease *** initiates with simple steatosis(NAFL)and can progress to the more severe condition of non-alcoholic steatohepatitis(NASH).NASH often advances to end-stage liver diseases such as liver fibrosis,cirrhosis,and hepatocellular carcinoma(HCC).Notably,the transition from NASH to end-stage liver diseases is irreversible,and the precise mechanisms driving this progression are not yet fully ***,there is a critical need for the development of effective therapies to arrest or reverse this *** review provides a comprehensive overview of the pathogenesis of NASH,examines the current therapeutic targets and pharmacological treatments,and offers insights for future drug discovery and development strategies for NASH therapy.

关键词： Metabolic dysfunction drug development Bile acids Liver-gut axis Inflammation Fibrosis