Pharmacological perturbation studies based on protein-level signatures are fundamental for drug discovery. In the present study, we used a mass spectrometry (MS)-based proteomic platform to profile the whole proteome ...Pharmacological perturbation studies based on protein-level signatures are fundamental for drug discovery. In the present study, we used a mass spectrometry (MS)-based proteomic platform to profile the whole proteome of the breast cancer MCF7 cell line under stress induced by 78 bioactive compounds. The integrated analysis of perturbed signal abundance revealed the connectivity between phenotypic behaviors and molecular features in cancer cells. Our data showed functional relevance in exploring the novel pharmacological activity of phenolic xanthohumol, as well as the noncanonical targets of clinically approved tamoxifen, lovastatin, and their derivatives. Furthermore, the rational design of synergistic inhibition using a combination of histone methyltransferase and topoisomerase was identified based on their complementary drug fingerprints. This study provides rich resources for the proteomic landscape of drug responses for precision therapeutic medicine.展开更多
Liquid chromatography tandem mass spectrometry(LC-MS/MS)has gradually become a promising alternative to ligand binding assay for the bioanalysis of biotherapeutic molecules,due to its rapid method development and high...Liquid chromatography tandem mass spectrometry(LC-MS/MS)has gradually become a promising alternative to ligand binding assay for the bioanalysis of biotherapeutic molecules,due to its rapid method development and high accuracy.In this study,we established a new LC-MS/MS method for the determination of the anti-sclerostin monoclonal antibody(SHR-1222)in cynomolgus monkey serum,and compared it to a previous electrochemiluminescence method.The antibody was quantified by detecting the surrogate peptide obtained by trypsin digestion.The surrogate peptide was carefully selected by investigating its uniqueness,stability and MS response.The quantitative range of the proposed method was 2.00-500μg/mL,and this verified method was successfully applied to the toxicokinetic assessment of SHR-1222 in cynomolgus monkey serum.It was found that the concentrations of SHR-1222 in cynomolgus monkeys displayed an excellent agreement between the LC-MS/MS and electrochemiluminescence methods(ratios of drug exposure,0.8-1.0).Notably,two monkeys in the60 mg/kg dose group had abnormal profiles with a low detection value of SHR-1222 in their individual sample.Combining the high-level anti-drug antibodies(ADAs)in these samples and the consistent quantitative results of the two methods,we found that the decreased concentration of SHR-1222 was due to the accelerated clearance mediated by ADAs rather than the interference of ADAs to the detection platform.Taken together,we successfully developed an accurate,efficient and cost-effective LC-MS/MS method for the quantification of SHR-1222 in serum samples,which could serve as a powerful tool to improve the preclinical development of antibody drugs.展开更多
A series of novel L-amino acid esters prodrugs of acyclic nucleoside phosphonates was synthesized and their anti-HBV activity was evaluated in HepG2 2.2.15 cells. Compound 1d exhibited more potent anti-HBV activity an...A series of novel L-amino acid esters prodrugs of acyclic nucleoside phosphonates was synthesized and their anti-HBV activity was evaluated in HepG2 2.2.15 cells. Compound 1d exhibited more potent anti-HBV activity and lower cytotoxicity than those of adefovir dipivoxil with EC50 and CC50 values of 0.207 μmol/L and 2530 μmol/L, respectively.展开更多
The National Medical Products Administration has authorized sodium oligomannate for treating mild-to-moderate Alzheimer’s disease.In this study,an LC-MS/MS method was developed and validated to quantitate sodium olig...The National Medical Products Administration has authorized sodium oligomannate for treating mild-to-moderate Alzheimer’s disease.In this study,an LC-MS/MS method was developed and validated to quantitate sodium oligomannate in different biomatrices.The plasma pharmacokinetics,tissue distribution,and excretion of sodium oligomannate in Sprague-Dawley rats and beagle dogs were systematically investigated.Despite its complicated structural composition,the absorption,distribution,metabolism,and excretion profiles of the oligosaccharides in sodium oligomannate of different sizes and terminal derivatives were indiscriminate.Sodium oligomannate mainly crossed the gastrointestinal epithelium through paracellular transport following oral administration,with very low oral bioavailability in rats(0.6%-1.6%)and dogs(4.5%-9.3%).Absorbed sodium oligomannate mainly resided in circulating body fluids in free form with minimal distribution into erythrocytes and major tissues.Sodium oligomannate could penetrate the blood-cerebrospinal fluid(CSF)barrier of rats,showing a constant area under the concentration-time curve ratio(CSF/plasma)of approximately 5%.The cumulative urinary excretion of sodium oligomannate was commensurate with its oral bioavailability,supporting that excretion was predominantly renal,whereas no obvious biliary secretion was observed following a single oral dose to bile duct-cannulated rats.Moreover,only 33.7%(male)and 26.3%(female)of the oral dose were recovered in the rat excreta within 96 h following a single oral administration,suggesting that the intestinal flora may have ingested a portion of unabsorbed sodium oligomannate as a nutrient.展开更多
Diabetes,characterized by hyperglycemia,is a major cause of death and disability worldwide.Peptides,such as insulin and glucagon-like peptide-1(GLP-1)analogs,have shown promise as treatments for diabetes due to their ...Diabetes,characterized by hyperglycemia,is a major cause of death and disability worldwide.Peptides,such as insulin and glucagon-like peptide-1(GLP-1)analogs,have shown promise as treatments for diabetes due to their ability to mimic or enhance insulin's actions in the body.Compared to subcutaneous injection,oral administration of anti-diabetic peptides is a preferred approach.However,biological barriers significantly reduce the efficacy of oral peptide therapeutics.Recent advancements in drug delivery systems and formulation techniques have greatly improved the oral delivery of peptide therapeutics and their efficacy in treating diabetes.This review will highlight(1)the benefits of oral anti-diabetic peptide therapeutics;(2)the biological barriers for oral peptide delivery,including pH and enzyme degradation,intestinal mucosa barrier,and biodistribution barrier;(3)the delivery platforms to overcome these biological barriers.Additionally,the review will discuss the prospects in this field.The information provided in this review will serve as a valuable guide for future developments in oral anti-diabetic peptide therapeutics.展开更多
Prostate cancer(PCa)is the second most prevalent malignancy in males across the world.A greater knowledge of the relationship between protein abundance and drug responses would benefit precision treatment for PCa.Here...Prostate cancer(PCa)is the second most prevalent malignancy in males across the world.A greater knowledge of the relationship between protein abundance and drug responses would benefit precision treatment for PCa.Herein,we establish 35 Chinese PCa primary cell models to capture specific characteristics among PCa patients,including gene mutations,mRNA/protein/surface protein distributions,and pharmaceutical responses.The multi-omics analyses identify Anterior Gradient 2(AGR2)as a pre-operative prognostic biomarker in PCa.Through the drug library screening,we describe crizotinib as a selective compound for malignant PCa primary cells.We further perform the pharmacoproteome analysis and identify 14,372 significant protein-drug correlations.Surprisingly,the diminished AGR2 enhances the inhibition activity of crizotinib via ALK/c-MET-AKT axis activation which is validated by PC3 and xenograft model.Our integrated multi-omics approach yields a comprehensive understanding of PCa biomarkers and pharmacological responses,allowing for more precise diagnosis and therapies.展开更多
Self-nanoemulsifying systems(SNEs) have excellent ability to improve the solubility ofpoorly water-soluble drugs(PWSD). However, SNEs are likely to be degraded in gastroin-testinal(GIT) when their surface is recognize...Self-nanoemulsifying systems(SNEs) have excellent ability to improve the solubility ofpoorly water-soluble drugs(PWSD). However, SNEs are likely to be degraded in gastroin-testinal(GIT) when their surface is recognized by lipase/co-lipase enzyme complex, result-ing in rapid release and precipitation of encapsulated drugs. The precipitates are then cap-tured and removed by intestinal mucus, reducing the delivery efficacy of SNEs. Herein, theamphiphilic polymer Pluronic? F127 was incorporated into long and short-chain triglyc-erides(LCT, SCT) based SNEs to diminish the recognition and therefore minimized theirdegradation by enzymes and clearance by mucus. The SNEs were characterized in termsof particle size, zeta potential and stability. Ex vivo multiple particles tracking studies wereperformed by adding particle solution into fresh rat mucus. Cellular uptake of SNEs wereconducted by using E12 cells, the absorption and distribution in small intestine were alsostudied after oral administration in male Sprague-Dawley(SD) rats. The in vitro digestionrate of SNEs were found to be in following order SCT-SNE > SCT-F127-SNE > LCT-SNE > LCT-F127-SNE. Moreover, the LCT-F127-SNE was found to be most effective in enhancing cellularuptake, resulting in 3.5-fold, 2.1-fold and 1.7-fold higher than that of SCT-SNE, LCT-SNE andSCT-F127-SNE, respectively. After incubating the SNE with E12 cells, the LCT-F127-SNE ex-hibited the highest amount regarding both mucus penetration and cellular uptake, with anuptake amount number(via bicinchoninic acid(BCA) analysis) of 3.5-fold, 2.1-fold and 1.7-fold higher than that of SCT-SNE, LCT-SNE and SCT-F127-SNE, respectively. The in vivo results revealed that orally administered LCT-F127-SNE could significantly increase the bioavailability of Cyclosporine A(CsA), which was approximately 2.43-fold, 1.33-fold and 1.80-fold higher than that of SCT-SNE, SCT-F127-SNE and LCT-SNE, respectively. We address in this work that F127-modified SNEs have potentials to improve oral drug absorption by significantly reducing gastrointestinal enzymatic degradation and simultaneously enhancing mucus penetration.展开更多
Objective:Fluzoparib(SHR3162)is a novel,potent poly(ADP-ribose)polymerases(PARP)1,2 inhibitor that showed anti-tumor activity in xenograft models.We conducted a phaseⅠ,first-in-human,dose-escalation and expansion(D-E...Objective:Fluzoparib(SHR3162)is a novel,potent poly(ADP-ribose)polymerases(PARP)1,2 inhibitor that showed anti-tumor activity in xenograft models.We conducted a phaseⅠ,first-in-human,dose-escalation and expansion(D-Esc and D-Ex)trial in patients with advanced solid cancer.Methods:This was a 3+3 phaseⅠD-Esc trial with a 3-level D-Ex at 5 hospitals in China.Eligible patients for DEsc had advanced solid tumors refractory to standard therapies,and D-Ex enrolled patients with ovarian cancer(OC).Fluzoparib was administered orally once or twice daily(bid)at 11 dose levels from 10 to 400 mg/d.Endpoints included dose-finding,safety,pharmacokinetics,and antitumor activity.Results:Seventy-nine patients were enrolled from March,2015 to January,2018[OC(47,59.5%);breast cancer(BC)(16,20.3%);colorectal cancer(8,10.1%),other tumors(8,10.1%)];48 patients were treated in the D-Esc arm and 31 in the D-Ex arm.The maximum tolerated dose(MTD)was 150 mg bid,with a half-life of 9.14 h.Grade 3/4 adverse events included anemia(7.6%)and neutropenia(5.1%).The objective response rate(ORR)was 30%(3/10)in patients with platinum-sensitive OC and 7.7%(1/13)in patients with BC.Among patients treated with fluzoparib≥120 mg/d,median progression-free survival(m PFS)was 7.2[95%confidence interval(95%CI),1.8-9.3]months in OC,9.3(95%CI,7.2-9.3)months in platinum-sensitive OC,and 3.5(range,2.0-28.0)months in BC.In patients with germline BC susceptibility gene mutation(g BRCAMut)(11/43 OC;2/16 BC),m PFS was 8.9 months for OC(range,1.0-23.2;95%CI,1.0-16.8)and 14 and 28 months for BC(those two patients both also had somatic BRCAMut).Conclusions:The MTD of fluzoparib was 150 mg bid in advanced solid malignancies.Fluzoparib demonstrated single-agent antitumor activity in BC and OC,particularly in BRCAMut and platinum-sensitive OC.展开更多
XueBiJing is an intravenous five-herb injection used to treat sepsis in China.The study aimed to develop a liquid chromatography-tandem mass spectrometry(LC-MS/MS)-or liquid chromatography-ultraviolet(LC-UV)-based ass...XueBiJing is an intravenous five-herb injection used to treat sepsis in China.The study aimed to develop a liquid chromatography-tandem mass spectrometry(LC-MS/MS)-or liquid chromatography-ultraviolet(LC-UV)-based assay for quality evaluation of XueBiJing.Assay development involved identifying marker constituents to make the assay therapeutically relevant and building a reliable one-point calibrator for monitoring the various analytes in parallel.Nine marker constituents from the five herbs were selected based on XueBiJing's chemical composition,pharmacokinetics,and pharmacodynamics.A selectivity test(for“similarity of response”)was developed to identify and minimize interference by nontarget constituents.Then,an intercept test was developed to fulfill“linearity through zero”for each analyte(absolute ratio of intercept to C response,<2%).Using the newly developed assays,we analyzed samples from 33 batches of XueBiJing,manufactured over three years,and found small batch-to-batch variability in contents of the marker constituents(4.1%-14.8%),except for senkyunolide I(26.5%).展开更多
Mevinolin is one of the earlier statin drugs which is effective for the treatment of hypercholesterolemia, as an inhibitor of the HMG-CoA reductase. The transformations of mevinolin in acidic alcohol( such as ethanol...Mevinolin is one of the earlier statin drugs which is effective for the treatment of hypercholesterolemia, as an inhibitor of the HMG-CoA reductase. The transformations of mevinolin in acidic alcohol( such as ethanol, methanol and isopropanol) solutions caused by solvent effects were revealed in the present article. The solvates, that is, mevinolinic methyl ester, mevinolinic ethyl ester and mevinolinic isopropyl ester, were identified by LC/PDA and LC/MS. The kinetics parameters of the transformations caused by solvent effects, such as the observed rate constant of mevinolin (kobs), the maximum concentration( Cmax ), and its corresponding maximum time( t time for the acid form to reach the maximum concentration) of mevinolinic acid, are discussed. The influencing factors, such as the kind of solvents, the acidic concentration, the initial mevinolin concentration, and the water content as well as temperature were investigated. Two kinds of comparative reactions, hydrolysis and alcoholysis, of mevinolin in solution were studied. This detailed study on the kinetics of mevinolin transformations is valuable and meaningful for the purification, preparation, injection manufacturing, extraction, storage, etc. , of mevinolin or other similar compounds. This work provides useful information for the quality control of mevinolin and mevinolin-like drugs as well.展开更多
Objective:Drug repurposing,the application of existing therapeutics to new indications,holds promise in achieving rapid clinical effects at a much lower cost than that of de novo drug development.The aim of our study ...Objective:Drug repurposing,the application of existing therapeutics to new indications,holds promise in achieving rapid clinical effects at a much lower cost than that of de novo drug development.The aim of our study was to perform a more comprehensive drug repurposing prediction of diseases,particularly cancers.Methods:Here,by targeting 4,096 human diseases,including 384 cancers,we propose a greedy computational model based on a heterogeneous multilayer network for the repurposing of 1,419 existing drugs in Drug Bank.We performed additional experimental validation for the dominant repurposed drugs in cancer.Results:The overall performance of the model was well supported by cross-validation and literature mining.Focusing on the top-ranked repurposed drugs in cancers,we verified the anticancer effects of 5 repurposed drugs widely used clinically in drug sensitivity experiments.Because of the distinctive antitumor effects of nifedipine(an antihypertensive agent)and nortriptyline(an antidepressant drug)in prostate cancer,we further explored their underlying mechanisms by using quantitative proteomics.Our analysis revealed that both nifedipine and nortriptyline affected the cancer-related pathways of DNA replication,the cell cycle,and RNA transport.Moreover,in vivo experiments demonstrated that nifedipine and nortriptyline significantly inhibited the growth of prostate tumors in a xenograft model.Conclusions:Our predicted results,which have been released in a public database named The Predictive Database for Drug Repurposing(PAD),provide an informative resource for discovering and ranking drugs that may potentially be repurposed for cancer treatment and determining new therapeutic effects of existing drugs.展开更多
A new trijugin-type limonoid,cipatrijugin G(1),together with the related known cipatrijugin A(2),were isolated from the aerial parts of Cipadessa cinerascens.The structure of the new compound was determined by extensi...A new trijugin-type limonoid,cipatrijugin G(1),together with the related known cipatrijugin A(2),were isolated from the aerial parts of Cipadessa cinerascens.The structure of the new compound was determined by extensive analysis of its spectroscopic data and by comparison of its NMR data with those reported in the literature.Compound 1 showed cytotoxicity against tumor cell line A549 with an IC_(50) value of 9.78μM.This is the first report of a trijugin-type limonoid bearing aγ-hydroxybutenolide unit,in comparison to the common furan unit as ring E.展开更多
A phytochemical investigation of the EtOH extract of the flowers of Lagerstroemia indica L.led to the isolation and char-acterization of a new pyrrole alkaloid,named lagerindicine(1),along with four known compounds(2-...A phytochemical investigation of the EtOH extract of the flowers of Lagerstroemia indica L.led to the isolation and char-acterization of a new pyrrole alkaloid,named lagerindicine(1),along with four known compounds(2-5).Their structures were elucidated by the detailed spectroscopic analysis and comparison with literature data,whereas the structure,in par-ticularly,the absolute configuration(AC)of 1,was firmly determined by total synthesis.All the isolates were evaluated for their cytotoxic effects against human colon cancer cell(HCT-116),and compound 3 exhibited weak cytotoxicity with IC50 value of 28.4μM.展开更多
The N-terminal domain of heat shock protein 90(Hsp90~N) is responsible for the catalytic activity of Hsp90.The reported inhibitors of Hsp90 bind to this domain and would inhibit tumor growth and progression. Here,we s...The N-terminal domain of heat shock protein 90(Hsp90~N) is responsible for the catalytic activity of Hsp90.The reported inhibitors of Hsp90 bind to this domain and would inhibit tumor growth and progression. Here,we synthesized FS23, a small molecule inhibitor of hsp90 and collected X-ray diffraction data of the complex crystal of Hsp90-FS23. High resolution X-ray crystallography shows that FS23 interacted with Hsp90 Nat the nucleotide binding cleft, and this suggests that FS23 may complete with nucleotides to bind to Hsp90~N. The crystal structure and the interaction between Hsp90 Nand FS23 suggest a rational basis for the design of novel antitumor drugs.展开更多
A mild and efficient procedure to build up various chromone-2-carboxylates was developed. Condensation of diverse 2-hydroxyacetophones with tetr-butyl oxalate in the presence of sodium ethoxide could be accomplished r...A mild and efficient procedure to build up various chromone-2-carboxylates was developed. Condensation of diverse 2-hydroxyacetophones with tetr-butyl oxalate in the presence of sodium ethoxide could be accomplished rapidly under mild condition. Cyclodehydration was carried out to achieve chromone-2-carboxylates in one-pot with impressive yield. Advantages over conventional methods with diethyl oxalate were observed in yield and reaction time.展开更多
As a part of the ongoing search for new constituents of Stemona species in China, chemical investigation of Stemona sessilifolia, a plant used in the traditional Chinese medicine to treat respiratory disorders, was ca...As a part of the ongoing search for new constituents of Stemona species in China, chemical investigation of Stemona sessilifolia, a plant used in the traditional Chinese medicine to treat respiratory disorders, was carried out. To identify the chemical components rapidly, a selected sample of S. sessilifolia containing bibenzyls was tested using LC-ESIMS and analyzed further using stop-flow LC-UV-NMR, which was sensitive for the detection of the main constituents. LC microfractions were collected using the LC-UV-NMR technique and HR-EIMS off-line analysis was cartied out on the collected fractions. This chemical screening strategy allowed for the on-line identification of the main constituents of S. sessilifolia and provided information that was useful for a further peak-guided isolation procedure. Using these methods, four bibenzyls were isolated: two known compounds, 3,5-dihydroxy-4-methyl bibenzyl(1) and 3, 5-dihydroxy-2'-methoxy-4-methyl bibenzyl ( 2 ), and two novel compounds, 3,3'-dihydroxy-5, 6'-dimethoxy bibenzyl(3) and 3,5-dihydroxy-2', 5'-dimethoxy bibenzyl (4).展开更多
A series of novel bis(trifluoroethyl)phosphonomethyl ether derivatives of acyclovir was synthesized and their in vitro anti-HBV activity was evaluated in HepG2 2.2.15 cells. In contrast to acyclovir, most of the des...A series of novel bis(trifluoroethyl)phosphonomethyl ether derivatives of acyclovir was synthesized and their in vitro anti-HBV activity was evaluated in HepG2 2.2.15 cells. In contrast to acyclovir, most of the described phosphonates emerged as potent inhibitors of HBV replication. Especially, the most active compound 11 with IC50 value of 2.92 μmol/L was 33 times more potent than acyclovir with ICso value of 100 μmol/L.展开更多
基金supported by the Natural Science Foundation of China(Grant Nos.:22225702 and 32322048)the National Key R&D Program of China(Grant No.:2020YFE0202200)+8 种基金the Shanghai Academic/Technology Research Leader Program,China(Grant No.:22XD1420900)Guangdong High-level New R&D Institute,China(Grant No.:2019B090904008)Guangdong High-level Innovative Research Institute,China(Grant No.:2021B0909050003)the Shanghai Rising-Star Program,China(Grant No.:22QA1411100)the Youth Innovation Promotion Association of the Chinese Academy of Sciences(Grant No.:2021276)the Young Elite Scientists Sponsorship Program by China Association for Science and Technology,China(Grant No.:2022QNRC001)the open fund of State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University,China(Grant No.:KF-202201)We also thank the support of the Innovative Research Team of High-Level Local Universities in Shanghai,China(Grant No.:SHSMU-ZDCX20212700)Sanofi scholarship program.
文摘Pharmacological perturbation studies based on protein-level signatures are fundamental for drug discovery. In the present study, we used a mass spectrometry (MS)-based proteomic platform to profile the whole proteome of the breast cancer MCF7 cell line under stress induced by 78 bioactive compounds. The integrated analysis of perturbed signal abundance revealed the connectivity between phenotypic behaviors and molecular features in cancer cells. Our data showed functional relevance in exploring the novel pharmacological activity of phenolic xanthohumol, as well as the noncanonical targets of clinically approved tamoxifen, lovastatin, and their derivatives. Furthermore, the rational design of synergistic inhibition using a combination of histone methyltransferase and topoisomerase was identified based on their complementary drug fingerprints. This study provides rich resources for the proteomic landscape of drug responses for precision therapeutic medicine.
基金supported by the National Natural Science Foundation of China(Grant No.81521005)the National Key Research Project of the Chinese Academy of Sciences(Grant No.XDA12050306)。
文摘Liquid chromatography tandem mass spectrometry(LC-MS/MS)has gradually become a promising alternative to ligand binding assay for the bioanalysis of biotherapeutic molecules,due to its rapid method development and high accuracy.In this study,we established a new LC-MS/MS method for the determination of the anti-sclerostin monoclonal antibody(SHR-1222)in cynomolgus monkey serum,and compared it to a previous electrochemiluminescence method.The antibody was quantified by detecting the surrogate peptide obtained by trypsin digestion.The surrogate peptide was carefully selected by investigating its uniqueness,stability and MS response.The quantitative range of the proposed method was 2.00-500μg/mL,and this verified method was successfully applied to the toxicokinetic assessment of SHR-1222 in cynomolgus monkey serum.It was found that the concentrations of SHR-1222 in cynomolgus monkeys displayed an excellent agreement between the LC-MS/MS and electrochemiluminescence methods(ratios of drug exposure,0.8-1.0).Notably,two monkeys in the60 mg/kg dose group had abnormal profiles with a low detection value of SHR-1222 in their individual sample.Combining the high-level anti-drug antibodies(ADAs)in these samples and the consistent quantitative results of the two methods,we found that the decreased concentration of SHR-1222 was due to the accelerated clearance mediated by ADAs rather than the interference of ADAs to the detection platform.Taken together,we successfully developed an accurate,efficient and cost-effective LC-MS/MS method for the quantification of SHR-1222 in serum samples,which could serve as a powerful tool to improve the preclinical development of antibody drugs.
文摘A series of novel L-amino acid esters prodrugs of acyclic nucleoside phosphonates was synthesized and their anti-HBV activity was evaluated in HepG2 2.2.15 cells. Compound 1d exhibited more potent anti-HBV activity and lower cytotoxicity than those of adefovir dipivoxil with EC50 and CC50 values of 0.207 μmol/L and 2530 μmol/L, respectively.
基金supported by the National Natural Science Foundation of China(Grant No.:81673388)the Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases(Grant No.:BM2013003)the Priority Academic Program Development of Jiangsu Higher Education Institutes(PAPD)
文摘The National Medical Products Administration has authorized sodium oligomannate for treating mild-to-moderate Alzheimer’s disease.In this study,an LC-MS/MS method was developed and validated to quantitate sodium oligomannate in different biomatrices.The plasma pharmacokinetics,tissue distribution,and excretion of sodium oligomannate in Sprague-Dawley rats and beagle dogs were systematically investigated.Despite its complicated structural composition,the absorption,distribution,metabolism,and excretion profiles of the oligosaccharides in sodium oligomannate of different sizes and terminal derivatives were indiscriminate.Sodium oligomannate mainly crossed the gastrointestinal epithelium through paracellular transport following oral administration,with very low oral bioavailability in rats(0.6%-1.6%)and dogs(4.5%-9.3%).Absorbed sodium oligomannate mainly resided in circulating body fluids in free form with minimal distribution into erythrocytes and major tissues.Sodium oligomannate could penetrate the blood-cerebrospinal fluid(CSF)barrier of rats,showing a constant area under the concentration-time curve ratio(CSF/plasma)of approximately 5%.The cumulative urinary excretion of sodium oligomannate was commensurate with its oral bioavailability,supporting that excretion was predominantly renal,whereas no obvious biliary secretion was observed following a single oral dose to bile duct-cannulated rats.Moreover,only 33.7%(male)and 26.3%(female)of the oral dose were recovered in the rat excreta within 96 h following a single oral administration,suggesting that the intestinal flora may have ingested a portion of unabsorbed sodium oligomannate as a nutrient.
基金This study was supported by the National Science Fund of Distinguished Young Scholars(No.82025032,China)the National Natural Science Foundation of China(No.82073773,China)+1 种基金the Key Research Program of Chinese Academy of Sciences(ZDBS-ZRKJZ-TLC005,China)Young Elite Scientists Sponsorship Program by CAST(No.2022QNRC001,China).
文摘Diabetes,characterized by hyperglycemia,is a major cause of death and disability worldwide.Peptides,such as insulin and glucagon-like peptide-1(GLP-1)analogs,have shown promise as treatments for diabetes due to their ability to mimic or enhance insulin's actions in the body.Compared to subcutaneous injection,oral administration of anti-diabetic peptides is a preferred approach.However,biological barriers significantly reduce the efficacy of oral peptide therapeutics.Recent advancements in drug delivery systems and formulation techniques have greatly improved the oral delivery of peptide therapeutics and their efficacy in treating diabetes.This review will highlight(1)the benefits of oral anti-diabetic peptide therapeutics;(2)the biological barriers for oral peptide delivery,including pH and enzyme degradation,intestinal mucosa barrier,and biodistribution barrier;(3)the delivery platforms to overcome these biological barriers.Additionally,the review will discuss the prospects in this field.The information provided in this review will serve as a valuable guide for future developments in oral anti-diabetic peptide therapeutics.
基金supported by National Natural Science Foundation of China(22137002[Y.D.],32071432[M.T.],81872102[H.J.])University Innovation Research Group Project of Chongqing(CXQT21016[Y.D.])+3 种基金High-Level Innovation Platform Project of Chongqing[Y.D.]Talent Program of Chongqing(CQYC202003053[Y.D.])The collaborative project of Chinese Academy of Sciences institutions and universities in Chongqing(HZ2021006[Y.D.])Innovative Research Team of High-Level Local Universities in Shanghai(SSMU-ZDCX20181202[M.T.]).
文摘Prostate cancer(PCa)is the second most prevalent malignancy in males across the world.A greater knowledge of the relationship between protein abundance and drug responses would benefit precision treatment for PCa.Herein,we establish 35 Chinese PCa primary cell models to capture specific characteristics among PCa patients,including gene mutations,mRNA/protein/surface protein distributions,and pharmaceutical responses.The multi-omics analyses identify Anterior Gradient 2(AGR2)as a pre-operative prognostic biomarker in PCa.Through the drug library screening,we describe crizotinib as a selective compound for malignant PCa primary cells.We further perform the pharmacoproteome analysis and identify 14,372 significant protein-drug correlations.Surprisingly,the diminished AGR2 enhances the inhibition activity of crizotinib via ALK/c-MET-AKT axis activation which is validated by PC3 and xenograft model.Our integrated multi-omics approach yields a comprehensive understanding of PCa biomarkers and pharmacological responses,allowing for more precise diagnosis and therapies.
基金Acknowledgments We thank Dr Boja Emily S (NHLBI, NIH, USA) for expert technical assistance in mass spectrometry analyses, and our colleagues Drs Bin Lu, Zhao-Qiu Wu for helpful comments. This work was supported by a National Basic Research Program grant from the Ministry of Science and Technology of China (G2003CB515401), National Science Fund for Distinguished Young Scholar from the National Natural Science Foundation of China (30425002) and a fund supported by the "100 Talents Project" of Chinese Academy of Sciences (J-G Liu).
基金financial support received from the National Natural Science Foundation of China(81373356,81573378 and 81703436)the Science and Technology Innovation Action Plan for Basic Research of Shanghai 2014 (14JC1493200)CASIMM0120153020,Shanghai Sailing Program 2017(17YF1423500)
文摘Self-nanoemulsifying systems(SNEs) have excellent ability to improve the solubility ofpoorly water-soluble drugs(PWSD). However, SNEs are likely to be degraded in gastroin-testinal(GIT) when their surface is recognized by lipase/co-lipase enzyme complex, result-ing in rapid release and precipitation of encapsulated drugs. The precipitates are then cap-tured and removed by intestinal mucus, reducing the delivery efficacy of SNEs. Herein, theamphiphilic polymer Pluronic? F127 was incorporated into long and short-chain triglyc-erides(LCT, SCT) based SNEs to diminish the recognition and therefore minimized theirdegradation by enzymes and clearance by mucus. The SNEs were characterized in termsof particle size, zeta potential and stability. Ex vivo multiple particles tracking studies wereperformed by adding particle solution into fresh rat mucus. Cellular uptake of SNEs wereconducted by using E12 cells, the absorption and distribution in small intestine were alsostudied after oral administration in male Sprague-Dawley(SD) rats. The in vitro digestionrate of SNEs were found to be in following order SCT-SNE > SCT-F127-SNE > LCT-SNE > LCT-F127-SNE. Moreover, the LCT-F127-SNE was found to be most effective in enhancing cellularuptake, resulting in 3.5-fold, 2.1-fold and 1.7-fold higher than that of SCT-SNE, LCT-SNE andSCT-F127-SNE, respectively. After incubating the SNE with E12 cells, the LCT-F127-SNE ex-hibited the highest amount regarding both mucus penetration and cellular uptake, with anuptake amount number(via bicinchoninic acid(BCA) analysis) of 3.5-fold, 2.1-fold and 1.7-fold higher than that of SCT-SNE, LCT-SNE and SCT-F127-SNE, respectively. The in vivo results revealed that orally administered LCT-F127-SNE could significantly increase the bioavailability of Cyclosporine A(CsA), which was approximately 2.43-fold, 1.33-fold and 1.80-fold higher than that of SCT-SNE, SCT-F127-SNE and LCT-SNE, respectively. We address in this work that F127-modified SNEs have potentials to improve oral drug absorption by significantly reducing gastrointestinal enzymatic degradation and simultaneously enhancing mucus penetration.
文摘Objective:Fluzoparib(SHR3162)is a novel,potent poly(ADP-ribose)polymerases(PARP)1,2 inhibitor that showed anti-tumor activity in xenograft models.We conducted a phaseⅠ,first-in-human,dose-escalation and expansion(D-Esc and D-Ex)trial in patients with advanced solid cancer.Methods:This was a 3+3 phaseⅠD-Esc trial with a 3-level D-Ex at 5 hospitals in China.Eligible patients for DEsc had advanced solid tumors refractory to standard therapies,and D-Ex enrolled patients with ovarian cancer(OC).Fluzoparib was administered orally once or twice daily(bid)at 11 dose levels from 10 to 400 mg/d.Endpoints included dose-finding,safety,pharmacokinetics,and antitumor activity.Results:Seventy-nine patients were enrolled from March,2015 to January,2018[OC(47,59.5%);breast cancer(BC)(16,20.3%);colorectal cancer(8,10.1%),other tumors(8,10.1%)];48 patients were treated in the D-Esc arm and 31 in the D-Ex arm.The maximum tolerated dose(MTD)was 150 mg bid,with a half-life of 9.14 h.Grade 3/4 adverse events included anemia(7.6%)and neutropenia(5.1%).The objective response rate(ORR)was 30%(3/10)in patients with platinum-sensitive OC and 7.7%(1/13)in patients with BC.Among patients treated with fluzoparib≥120 mg/d,median progression-free survival(m PFS)was 7.2[95%confidence interval(95%CI),1.8-9.3]months in OC,9.3(95%CI,7.2-9.3)months in platinum-sensitive OC,and 3.5(range,2.0-28.0)months in BC.In patients with germline BC susceptibility gene mutation(g BRCAMut)(11/43 OC;2/16 BC),m PFS was 8.9 months for OC(range,1.0-23.2;95%CI,1.0-16.8)and 14 and 28 months for BC(those two patients both also had somatic BRCAMut).Conclusions:The MTD of fluzoparib was 150 mg bid in advanced solid malignancies.Fluzoparib demonstrated single-agent antitumor activity in BC and OC,particularly in BRCAMut and platinum-sensitive OC.
基金funded by grants from the National Natural Science Foundation of China(Grant Nos.:82074176 and 81503345)Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(Grant No.:ZYYCXTD-C-202009)the National Key R&D Program of China(Grant No.:2018YFC1704500).
文摘XueBiJing is an intravenous five-herb injection used to treat sepsis in China.The study aimed to develop a liquid chromatography-tandem mass spectrometry(LC-MS/MS)-or liquid chromatography-ultraviolet(LC-UV)-based assay for quality evaluation of XueBiJing.Assay development involved identifying marker constituents to make the assay therapeutically relevant and building a reliable one-point calibrator for monitoring the various analytes in parallel.Nine marker constituents from the five herbs were selected based on XueBiJing's chemical composition,pharmacokinetics,and pharmacodynamics.A selectivity test(for“similarity of response”)was developed to identify and minimize interference by nontarget constituents.Then,an intercept test was developed to fulfill“linearity through zero”for each analyte(absolute ratio of intercept to C response,<2%).Using the newly developed assays,we analyzed samples from 33 batches of XueBiJing,manufactured over three years,and found small batch-to-batch variability in contents of the marker constituents(4.1%-14.8%),except for senkyunolide I(26.5%).
基金Supported by Shanghai Leading Discipline Project(No. Y0301) and the Funds of Shanghai Scientific and Technology Develop-ment(No. 03DZ19546)
文摘Mevinolin is one of the earlier statin drugs which is effective for the treatment of hypercholesterolemia, as an inhibitor of the HMG-CoA reductase. The transformations of mevinolin in acidic alcohol( such as ethanol, methanol and isopropanol) solutions caused by solvent effects were revealed in the present article. The solvates, that is, mevinolinic methyl ester, mevinolinic ethyl ester and mevinolinic isopropyl ester, were identified by LC/PDA and LC/MS. The kinetics parameters of the transformations caused by solvent effects, such as the observed rate constant of mevinolin (kobs), the maximum concentration( Cmax ), and its corresponding maximum time( t time for the acid form to reach the maximum concentration) of mevinolinic acid, are discussed. The influencing factors, such as the kind of solvents, the acidic concentration, the initial mevinolin concentration, and the water content as well as temperature were investigated. Two kinds of comparative reactions, hydrolysis and alcoholysis, of mevinolin in solution were studied. This detailed study on the kinetics of mevinolin transformations is valuable and meaningful for the purification, preparation, injection manufacturing, extraction, storage, etc. , of mevinolin or other similar compounds. This work provides useful information for the quality control of mevinolin and mevinolin-like drugs as well.
基金supported by the National Natural Science Foundation of China(Grant Nos.31871329,1670066,81872888,and 81821005)Shanghai Municipal Science and Technology Major Project(Grant No.2017SHZDZX01)+2 种基金the Key New Drug Creation and Manufacturing Program of China(Grant No.2018ZX09711002-004)the Special Project on Precision Medicine under the National Key R&D Program(Grant No.SQ2017YFSF090210)the K.C.Wong Education Foundation。
文摘Objective:Drug repurposing,the application of existing therapeutics to new indications,holds promise in achieving rapid clinical effects at a much lower cost than that of de novo drug development.The aim of our study was to perform a more comprehensive drug repurposing prediction of diseases,particularly cancers.Methods:Here,by targeting 4,096 human diseases,including 384 cancers,we propose a greedy computational model based on a heterogeneous multilayer network for the repurposing of 1,419 existing drugs in Drug Bank.We performed additional experimental validation for the dominant repurposed drugs in cancer.Results:The overall performance of the model was well supported by cross-validation and literature mining.Focusing on the top-ranked repurposed drugs in cancers,we verified the anticancer effects of 5 repurposed drugs widely used clinically in drug sensitivity experiments.Because of the distinctive antitumor effects of nifedipine(an antihypertensive agent)and nortriptyline(an antidepressant drug)in prostate cancer,we further explored their underlying mechanisms by using quantitative proteomics.Our analysis revealed that both nifedipine and nortriptyline affected the cancer-related pathways of DNA replication,the cell cycle,and RNA transport.Moreover,in vivo experiments demonstrated that nifedipine and nortriptyline significantly inhibited the growth of prostate tumors in a xenograft model.Conclusions:Our predicted results,which have been released in a public database named The Predictive Database for Drug Repurposing(PAD),provide an informative resource for discovering and ranking drugs that may potentially be repurposed for cancer treatment and determining new therapeutic effects of existing drugs.
基金This research work was financially supported by the National Marine‘863’Projects(No.2013AA092902)the Natural Science Foundation of China(Nos.21021063,81273430,and 2107224)was partially funded by the EU 7th Framework Programme-IRSES Project(No.246987).
文摘A new trijugin-type limonoid,cipatrijugin G(1),together with the related known cipatrijugin A(2),were isolated from the aerial parts of Cipadessa cinerascens.The structure of the new compound was determined by extensive analysis of its spectroscopic data and by comparison of its NMR data with those reported in the literature.Compound 1 showed cytotoxicity against tumor cell line A549 with an IC_(50) value of 9.78μM.This is the first report of a trijugin-type limonoid bearing aγ-hydroxybutenolide unit,in comparison to the common furan unit as ring E.
基金supported by the National Natural Science Foundation of China(NSFC)(Nos.81991521,41676073)the National Key Research and Development Program of China(No.2018YFC0310903)+2 种基金the Drug Innovation Major Project(No.2018ZX09711-001-001-009)the SKLDR/SIMM Project(No.SIMM1903ZZ-04)Changsha Engineering Technology Research Center of Woody flower(kq1907081).
文摘A phytochemical investigation of the EtOH extract of the flowers of Lagerstroemia indica L.led to the isolation and char-acterization of a new pyrrole alkaloid,named lagerindicine(1),along with four known compounds(2-5).Their structures were elucidated by the detailed spectroscopic analysis and comparison with literature data,whereas the structure,in par-ticularly,the absolute configuration(AC)of 1,was firmly determined by total synthesis.All the isolates were evaluated for their cytotoxic effects against human colon cancer cell(HCT-116),and compound 3 exhibited weak cytotoxicity with IC50 value of 28.4μM.
基金Supported by National Natural Science Foundation of China(No.81402850)the Natural Science Basic Research Plan in Shaanxi Province of China(No.2015JM3114)+1 种基金the Introduced talents Foundation of Xi’an Medical University(No.2015 RCYJ01)the Doctorate Foundation of Xi’an Medical University(No.2015 DOC23)
文摘The N-terminal domain of heat shock protein 90(Hsp90~N) is responsible for the catalytic activity of Hsp90.The reported inhibitors of Hsp90 bind to this domain and would inhibit tumor growth and progression. Here,we synthesized FS23, a small molecule inhibitor of hsp90 and collected X-ray diffraction data of the complex crystal of Hsp90-FS23. High resolution X-ray crystallography shows that FS23 interacted with Hsp90 Nat the nucleotide binding cleft, and this suggests that FS23 may complete with nucleotides to bind to Hsp90~N. The crystal structure and the interaction between Hsp90 Nand FS23 suggest a rational basis for the design of novel antitumor drugs.
文摘A mild and efficient procedure to build up various chromone-2-carboxylates was developed. Condensation of diverse 2-hydroxyacetophones with tetr-butyl oxalate in the presence of sodium ethoxide could be accomplished rapidly under mild condition. Cyclodehydration was carried out to achieve chromone-2-carboxylates in one-pot with impressive yield. Advantages over conventional methods with diethyl oxalate were observed in yield and reaction time.
基金Supported by Science and Technology Committee of Shanghai, P R China(No 036505003)
文摘As a part of the ongoing search for new constituents of Stemona species in China, chemical investigation of Stemona sessilifolia, a plant used in the traditional Chinese medicine to treat respiratory disorders, was carried out. To identify the chemical components rapidly, a selected sample of S. sessilifolia containing bibenzyls was tested using LC-ESIMS and analyzed further using stop-flow LC-UV-NMR, which was sensitive for the detection of the main constituents. LC microfractions were collected using the LC-UV-NMR technique and HR-EIMS off-line analysis was cartied out on the collected fractions. This chemical screening strategy allowed for the on-line identification of the main constituents of S. sessilifolia and provided information that was useful for a further peak-guided isolation procedure. Using these methods, four bibenzyls were isolated: two known compounds, 3,5-dihydroxy-4-methyl bibenzyl(1) and 3, 5-dihydroxy-2'-methoxy-4-methyl bibenzyl ( 2 ), and two novel compounds, 3,3'-dihydroxy-5, 6'-dimethoxy bibenzyl(3) and 3,5-dihydroxy-2', 5'-dimethoxy bibenzyl (4).
文摘A series of novel bis(trifluoroethyl)phosphonomethyl ether derivatives of acyclovir was synthesized and their in vitro anti-HBV activity was evaluated in HepG2 2.2.15 cells. In contrast to acyclovir, most of the described phosphonates emerged as potent inhibitors of HBV replication. Especially, the most active compound 11 with IC50 value of 2.92 μmol/L was 33 times more potent than acyclovir with ICso value of 100 μmol/L.