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Chinese Journal of Natural Medicines 2023年第9期21卷 658-669页

作者： DONG Zhaomin wang Hong wang guangji Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical SciencesChina Pharmaceutical UniversityNanjing 210009China

Pien Tze Huang(PTH)was documented as an imperial prescription composed of Notoginseng Radix,Calculus Bovis,Snake Gallbladder,and *** is famous in China and Asian countries due to its excellent effects in heat clearing,detoxifying,swelling reduction,and pain *** pharmacological studies demonstrate that PTH shows excellent effects against various inflammatory diseases,liver diseases,and *** review summaries the pharmacological effects,clinical applications,and mainchemical components of *** importantly,its potential quality markers(Q-markers)were then analyzed based on the“five principles”of Q-markers under the guidance of Traditional Chinese Medicine theory,including transfer and traceability,specificity,efficacy,compatibility,and *** a result,ginsenosides Rb1,ginsenoside Rg1,ginsenoside Rd,ginsenoside Re,notoginsenoside R1,dencichine,bilirubin,biliverdin,taurocholic acid,and muscone are considered as the Q-markers of *** findings will provide guidance and assistance for the construction of a quality control system for PTH.

关键词： Pien Tze Huang(PTH) Quality marker(Q-marker) Chemical components Pharmacological effects Clinical application Qualitycontrol

Research on Condenser Deterioration Evolution Trend Based on ANP-EWM Fusion Health Degree

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Computer Modeling in Engineering & Sciences 2024年第4期139卷 679-698页

作者： Hong Qian Haixin wang guangji wang Qingyun Yan College of Automation Engineering Shanghai University of Electric PowerShanghai200090China Shanghai Key Laboratory of Power Station Automation Technology Shanghai200072China Empower Information Technology(Shanghai)Co. Ltd.Shanghai201508China China Nuclear Power Engineering Design Co. Ltd.Shenzhen518052China

This study presents a proposed method for assessing the condition and predicting the future status of condensers operating in seawater over an extended *** aim is to address the problems of scaling and corrosion,which lead to increased loss of cold *** method involves utilising a set of multivariate feature parameters associated with the condenser as input for evaluation and trend *** methodology offers a precise means of determining the optimal timing for condenser cleaning,with the ultimate goal of improving its overall *** proposed approach involves the integration of the analytic network process with subjective expert experience and the entropy weightmethod with objective big data analysis to develop a fusion health *** mathematical model is constructed quantitatively using the improved Mahalanobis ***,a comprehensive prediction model is developed by integrating the improved Informer model and Markov error *** model takes into account the health status of the equipment and several influencing factors,includingmultivariate feature *** model facilitates the objective examination and prediction of the progression of equipment deterioration *** present study involves the computation and verification of the field time series data,which serves to demonstrate the accuracy of the condenser health-related models proposed in this *** models effectively depict the real condition and temporal variations of the equipment,thus offering a valuable method for determining the precise cleaning time required for the condenser.

关键词： Condenser health degree improved Mahalanobis distance GC-Informer model Markov error correction

Reliability of dermatomal somatosensory-evoked potential in the evaluation of lumbosacral nerve root injury A concurrent case-control study

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Neural Regeneration Research 2008年第1期3卷 57-60页

作者： Ningjiang Shen Jian Chen guangji wang Xiaoli Wu Yutian wang Department of Orthopaedic Surgery Hainan Provincial People＇s Hospital Haikou 570311 Hainan Province China

BACKGROUND： It has been reported that dermatomal somatosensory evoked potential （DSEP） can be used for diagnosing nerve root injury in patients with lumbar disc herniation （LDH）, and that 83% 95% of patients suffer from the disease. Body height correction is not performed prior to determinations of latency and latency difference between the healthy and affected sides. However, latency noticeably correlates to body height. OBJECTIVE： This study aims to determine the lumbosacral nerve root injury in patients with LDH by DSEP, and to evaluate the sensitivity of the DSEP difference between the healthy and affected sides using a diagnostic index following body height correction. DESIGN： A case-control observation. SETTING： Department of Orthopedic Surgery, Hainan Provincial People＇s Hospital. PARTICIPANTS： Ninety-six patients, comprised of 67 males and 29 females, with an average age of 43 years and a mean body height of 1.65 m （range 1.48-1.81 m）, were recruited for this study. These patients suffered from unilateral lower limb radiation pain and received treatment at the Department of Orthopedic Surgery, Hainan Provincial People＇s Hospital between January 2004 and December 2006. All patients were confirmed to suffer from LDH at the L3-4, L-5, and/or Ls-SI by CT and/or MRI examinations. Central nervous system diseases were excluded. In order to obtain a normal reference value, DSEP was determined for a group of 50 subjects, who concurrently received health examinations in the same department. The subjects had no previous history of back leg pain or nervous system disease. The group of healthy controls included 26 males and 24 females, with an average age of 37 years and a mean body height of 1.63 m （range 1.50-1.80 m）. Written informed consent was obtained from all subjects for laboratory samples. The protocol was approved by the Hospital＇s Ethics Committees. DSEP was determined with myoelectricity-evoked potential equipment （Keypoint, Batch No. 9020A0042591, Dantec Com

关键词： dermatomal somatosensory evoked potential lumbar disc herniation nerve root injury

Herbal drug discovery for the treatment of nonalcoholic fatty liver disease

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Acta Pharmaceutica Sinica B 2020年第1期10卷 3-18页

作者： Tingting Yan Nana Yan Ping wang Yangliu Xia Haiping Hao guangji wang Frank JGonzalez Laboratory of Metabolism Center for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMD 20892USA State Key Laboratory of Natural Medicines Key Laboratory of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityNanjing 210009China Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese MedicineShanghai 201203China School of Life Science and Medicine Dalian University of TechnologyPanjin 124221China

Few medications are available for meeting the increasing disease burden of nonalcoholic fatty liver disease(NAFLD)and its progressive stage,nonalcoholic steatohepatitis(NASH).Traditional herbal medicines(THM)have been used for centuries to treat indigenous people with various symptoms but without clarified modern-defined disease types and *** modern times,NAFLD was defined as a common chronic disease leading to more studies to understand NAFLD/NASH pathology and *** have garnered increased attention for providing therapeutic candidates for treating *** this review,a new model called"multiple organs-multiple hits"is proposed to explain mechanisms of NASH *** this proposed model,the effects and mechanisms of the frequentlystudied THM-yielded single anti-NAFLD drug candidates and multiple herb medicines are reviewed,among which silymarin and berberine are already under ***-sanctioned phase 4 clinical ***,experimental designs for anti-NAFLD drug discovery from THM in treating NAFLD are *** opportunities and challenges of reverse pharmacology and reverse pharmacokinetic concepts-guided strategies for THM modernization and its global recognition to treat NAFLD are *** mechanistic evidence is being generated to support the beneficial role of THM in treating NAFLD and anti-NAFLD drug discovery.

关键词： Natural products Fatty liver Metabolic syndrome TCM NAFLD

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

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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

Quantitative determination of D_(4)-cystine in mice using LC-MS/MS and its application to the assessment of pharmacokinetics and bioavailability

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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

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

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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

Pharmacokinetic characteristics of mesenchymal stem cells in translational challenges

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Signal Transduction and Targeted Therapy 2024年第10期9卷 4314-4340页

作者： Yunlong Shan Mengying Zhang Enxiang Tao Jing wang Ning Wei Yi Lu Qing Liu Kun Hao Fang Zhou guangji wang Key Laboratory of Drug Metabolism and Pharmacokinetics Haihe Laboratory of Cell EcosystemState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina Jiangsu Renocell Biotech Co.Ltd. NanjingChina

Over the past two decades,mesenchymal stem/stromal cell(MSC)therapy has made substantial strides,transitioning from experimental clinical applications to commercial *** therapies hold considerable promise for treating refractory and critical conditions such as acute graft-versus-host disease,amyotrophic lateral sclerosis,and acute respiratory distress *** recent successes in clinical and commercial applications,MSC therapy still faces challenges when used as a commercial *** detection methods have limitations,leaving the dynamic biodistribution,persistence in injured tissues,and ultimate fate of MSCs in patients *** the relationship between the pharmacokinetic characteristics of MSCs and their therapeutic effects is crucial for patient stratification and the formulation of precise therapeutic ***,the development of advanced imaging and tracking technologies is essential to address these clinical *** review provides a comprehensive analysis of the kinetic properties,key regulatory molecules,different fates,and detection methods relevant to MSCs and discusses concerns in evaluating MSC druggability from the perspective of integrating pharmacokinetics and efficacy.A better understanding of these challenges could improve MSC clinical efficacy and speed up the introduction of MSC therapy products to the market.

关键词： characteristics translational precise

Dual-function natural products:Farnesoid X receptor agonist/inflammation inhibitor for metabolic dysfunction-associated steatotic liver disease therapy

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Chinese Journal of Natural Medicines 2024年第11期22卷 965-976页

作者： wang Kang ZHANG Pengfei SUN Huiyong CUI Shuang AO Lanjia CUI Ming XU Xiaowei wang Lin XU Yuanyuan wang guangji wang Hong HAO Haiping State Key Laboratory of Natural Medicines Key Laboratory of Drug Metabolism&PharmacokineticsChina Pharmaceutical UniversityNanjing 210009China Basic Science Research Center Base(Pharmaceutical Science) Shandong provinceYantai UniversityYantai 264005China Jiangsu Tasly Diyi Pharmaceutical Co. LtdHuaian 223002China

Metabolic dysfunction-associated steatotic liver disease(MASLD)is the most prevalent chronic liver disease globally,with only one Food and Drug Administration(FDA)-approved drug for its *** MASLD's complex pathophysiology,ther-apies that simultaneously target multiple pathways are highly *** promising approach is dual-modulation of the famesoid X receptor(FXR),which regulates lipid and bile acid ***,FXR agonists alone are insufficient due to their limited anti-inflammatory *** study aimed to dto identify natural products capable of both FXR activation and inflammation inhibition to provide a comprehensive therapeutic approach for *** FXR ligands from the Natural Product Library were predicted via virtual screening using the Protein Preparation Wizard module in Schrodinger(2018)for molecular *** binding and regulation of candidate compounds on FXR were analyzed using surface plasmon resonance(SPR)binding assay,reporter gene ana-lysis,and reverse transcription-polymerase chain reaction(RT-PCR).The anti-inflammatory properties of these compounds were eval-uated in AML12 cells treated with tumor necrosis factor-alpha(TNF-α).Dual-function compounds with FXR agonism and inflamma-tion inhibition were further identified in cells transfected with Fxr siRNA and treated with TNF-α.The effects of these dual-function compounds on lipid accumulation and inflammation were evaluated in cells treated with palmitic *** revealed that 17 natural products were predicted via computational molecular docking as potential FXR agonists,with 15 exhibiting a strong affinity for FXR recombinant *** isoflavone compounds significantly enhanced FXR reporter luciferase activity and the mRNA expressions of Shp and ***-activity relationship analysis indicated that introducing isopropyl or methoxy groups at the C7 position or a methoxy group at the C6 position could enhance the agonistic efficacy of isofl

关键词： FXR agonist Inflammation Dual modulator Natural products MASLD

Combined obeticholic acid and apoptosis inhibitor treatment alleviates liver fibrosis

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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