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
Prescriptions are the main clinical application of traditional Chinese medicines(TCMs).Common forms include Chinese patent medicines,Kampo formulas,and hospital decoctions.A new pre-scription called“famous classical ...Prescriptions are the main clinical application of traditional Chinese medicines(TCMs).Common forms include Chinese patent medicines,Kampo formulas,and hospital decoctions.A new pre-scription called“famous classical formulas”is recently developed and expected to boom in the market.Identifying constituent me-dicinal plants in prescriptions is critical for new drug development and quality control[1],which could avoid safety issues from adulteration or substandard ingredients,as seen in the notorious Longdan Xiegan Pill event.展开更多
Pheretima,also called“earthworms”,is a well-known animal-derived traditional Chinese medicine that is extensively used in over 50 Chinese patent medicines(CPMs)in Chinese Pharmacopoeia(2020 edition).However,its zool...Pheretima,also called“earthworms”,is a well-known animal-derived traditional Chinese medicine that is extensively used in over 50 Chinese patent medicines(CPMs)in Chinese Pharmacopoeia(2020 edition).However,its zoological origin is unclear,both in the herbal market and CPMs.In this study,a strategy for integrating in-house annotated protein databases constructed from close evolutionary relationship-sourced RNA sequencing data from public archival resources and various sequencing algorithms(restricted search,open search,and de novo)was developed to characterize the phenotype of natural peptides of three major commercial species of Pheretima,including Pheretima aspergillum(PA),Pheretima vulgaris(PV),and Metaphire magna(MM).We identified 10,477 natural peptides in the PA,7,451 in PV,and 5,896 in MM samples.Five specific signature peptides were screened and then validated using synthetic peptides;these demonstrated robust specificity for the authentication of PA,PV,and MM.Finally,all marker peptides were successfully applied to identify the zoological origins of Brain Heart capsules and Xiaohuoluo pills,revealing the inconsistent Pheretima species used in these CPMs.In conclusion,our integrated strategy could be used for the in-depth characterization of natural peptides of other animal-derived traditional Chinese medicines,especially non-model species with poorly annotated protein databases.展开更多
Clinically,arsenic trioxide(ATO)was applied to the treatment of acute promyelocytic leukemia(APL)as a reliable and effective frontline drug.However,the administration regimen of AsⅢwas limited due to its fast clearan...Clinically,arsenic trioxide(ATO)was applied to the treatment of acute promyelocytic leukemia(APL)as a reliable and effective frontline drug.However,the administration regimen of AsⅢwas limited due to its fast clearance,short therapeutic window and toxicity as well.Based on CD71 overexpressed on APL cells,in present study,a transferrin(Tf)-modified liposome(LP)was established firstly to encapsulate AsⅢin arsenic-nickel complex by nickel acetate gradient method.The AsⅢ-loaded liposomes(AsLP)exhibited the feature of acid-sensitive release in vitro.Tf-modified AsLP(Tf-AsLP)were specifically taken up by APL cells and the acidic intracellular environment triggered liposome to release AsⅢwhich stimulated reactive oxygen species level and caspase-3 activity.Tf-AsLP prolonged half-life of AsⅢin blood circulation,lowered systemic toxicity,and promoted apoptosis and induced cell differentiation at lesion site in vivo.Considering that ATO combined with RA is usually applied as the first choice in clinic for APL treatment to improve the therapeutic effect,accordingly,a Tf-modified RA liposome(Tf-RALP)was designed to reduce the severe side effects of free RA and assist Tf-AsLP for better efficacy.As expected,the tumor inhibition rate of Tf-AsLP was improved significantly with the combination of Tf-RALP on subcutaneous tumor model.Furthermore,APL orthotopic NOD/SCID mice model was established by 60CO irradiation and HL-60 cells intravenously injection.The effect of co-administration(Tf-AsLP+Tf-RALP)was also confirmed to conspicuous decrease the number of leukemia cells in the circulatory system and prolong the survival time of APL mice by promoting the APL cells’apoptosis and differentiation in peripheral blood and bone marrow.Collectively,Tf-modified acid-sensitive AsLP could greatly reduce the systemic toxicity of free drug.Moreover,Tf-AsLP combined with Tf-RALP could achieve better efficacy.Thus,transferrinmodified AsⅢliposome would be a novel clinical strategy to improve patient compliance,with promising translation prospects.展开更多
Four new norditerpenoid heterodimers with different dimerization patterns-namely,trigofragiloids A-C(denoted as compounds 1-3)and(+)-and(-)-trigofragiloid D(compound 4)-and three new phenanthrenone norditerpenoids-nam...Four new norditerpenoid heterodimers with different dimerization patterns-namely,trigofragiloids A-C(denoted as compounds 1-3)and(+)-and(-)-trigofragiloid D(compound 4)-and three new phenanthrenone norditerpenoids-namely,trigofragiloids E-G(compounds 5-7)-were isolated from Trigonostemon fragilis.Compounds 1 and 2 feature a novel heterodimeric carbon skeleton formed by the conjugation of a tetra-norditerpenoid and an ennea-norditerpenoid;they have been identified as class 2 atropisomers by means of quantum chemical calculations.Compound 3 is an unprecedented phenylpropanoid-norditerpenoid adduct with a new dimerization pattern.Compounds(+)-and(-)-4 are the first example of S-shaped 1,4-dioxane-fused norditerpenoid dimers.Inspired by the structure elucidation of compound 4,two co-occurring analogues,actephilol A and epiactephilol A,were structurally revised as a pair of geometrical isomers and were identified as two pairs of enantiomers,(+)-and(-)-8 and(+)-and(-)-9,respectively.Their structures were characterized using a combined method.Notably,compound 7 exhibits remarkable adenosine triphosphate-citrate lyase(ACLY)inhibition with a halfmaximal inhibition concentration(IC50)value of(0.46±0.11)lmol·L^(-1),as active as the positive control BMS-303141,and a molecular docking study offers deep insight into the interaction between compound 7 and ACLY.展开更多
Chemotherapy-induced cachexia(CIC)is a debilitating condition characterized by weight loss,muscle atrophy,and anorexia[1].While peripheral mechanisms of cachexia have been extensively studied,the involvement of the ce...Chemotherapy-induced cachexia(CIC)is a debilitating condition characterized by weight loss,muscle atrophy,and anorexia[1].While peripheral mechanisms of cachexia have been extensively studied,the involvement of the central nervous system(CNS)in CIC is often overlooked.Chemotherapeutic drugs cause stress responses and inflammation,which may impact the hypothalamus and disrupt systemic energy and neuroendocrine functions.Understanding hypothalamic roles in regulating these processes can provide insights into CIC's mechanisms and aid in developing novel therapies.展开更多
Non-alcoholic fatty liver disease(NAFLD)is the main cause of chronic liver disease worldwide.Bupleurum is widely used in the treatment of non-alcoholic fatty liver,and saikosaponin D(SSD)is one of the main active comp...Non-alcoholic fatty liver disease(NAFLD)is the main cause of chronic liver disease worldwide.Bupleurum is widely used in the treatment of non-alcoholic fatty liver,and saikosaponin D(SSD)is one of the main active components of Bupleurum.The purpose of this study was to investigate the efficacy of SSD in the treatment of NAFLD and to explore the mechanism of SSD in the improvement of NAFLD based on“gut-liver axis”.Our results showed that SSD dose-dependently alleviated high fat diet-induced weight gain in mice,improved insulin sensitivity,and also reduced liver lipid accumulation and injury-related biomarkers aspartate aminotransferase(AST)and alanine aminotransferase(ALT).Further exploration found that SSD inhibited the mRNA expression levels of farnesoid X receptor(Fxr),small heterodimer partner(Shp),recombinant fibroblast growth factor 15(Fgf15)and apical sodium dependent bile acid transporter(Asbt)in the intestine,suggesting that SSD improved liver lipid metabolism by inhibiting intestinal FXR signaling.SSD can significantly reduce the gut microbiota associated with bile salt hydrolase(BSH)expression,such as Clostridium.Decreased BSH expression reduced the ratio of unconjugated to conjugated bile acids,thereby inhibiting the intestinal FXR.These data demonstrated that SSD ameliorated NAFLD potentially through the gut microbiota-bile acidintestinal FXR pathway and suggested that SSD is a promising therapeutic agent for the treatment of NAFLD.展开更多
Dear Editor,Great progress has been made using artificial intelligence(AI) techniques in learning knowledge from biomedical databases in recent years, revolutionizing the study of many fields, such as protein structur...Dear Editor,Great progress has been made using artificial intelligence(AI) techniques in learning knowledge from biomedical databases in recent years, revolutionizing the study of many fields, such as protein structure prediction and protein design(Madani et al., 2023). However, there is massive biomedical knowledge not curated in the form of structured data but hidden in primary scientific literature.展开更多
Noradrenaline transporter,also known as the norepinephrine transporter(NET),is a member of the monoamine transporters(MATs)family,which also includes serotonin transporter(SERT)and dopamine transporter(DAT).These tran...Noradrenaline transporter,also known as the norepinephrine transporter(NET),is a member of the monoamine transporters(MATs)family,which also includes serotonin transporter(SERT)and dopamine transporter(DAT).These transporters collectively regulate neurotransmitter concentrations at synapses and maintain neurotransmitter balance in the body.展开更多
AIM To investigate the effects of Xiangbin prescription(XBP), a Chinese herbal concoction, on gastrointestinal motility.METHODS Forty healthy volunteers were recruited for this randomized controlled trial of XBP. Antr...AIM To investigate the effects of Xiangbin prescription(XBP), a Chinese herbal concoction, on gastrointestinal motility.METHODS Forty healthy volunteers were recruited for this randomized controlled trial of XBP. Antroduodenojejunal manometry was used to monitor gastrointestinal motility in these subjects. After the subjects had fasted for at least 12 h, XBP(n = 30) or placebo(n = 10) was orally administrated and gastrointestinal motility was recorded for 4 h. Plasma motilin and ghrelin were measured by enzyme-linked immunosorbent assay.RESULTS Oral administration of XBP significantly increased the amplitude of duodenal contractions [19.5(13.0-26.7) vs 16.9(12.3-23.9), P < 0.05], jejunal contractions [18.3(15.3-25.0) vs 15.4(11.7-23.9), P < 0.01], and the motility index of duodenal contractions [522.0(146.0-139.0) vs 281.0(76.5-1006.0), P < 0.01] in phase Ⅱ of the migratory motor complex(MMC), which subsequently initiated the MMC cycle [74.0(30.0-118.0) vs 116.5(24.0-219.0), P < 0.05], shortened the duration of phase I of the MMC [42.0(0.0-90.0) vs 111.5(42.0-171.0), P < 0.01], and lengthened the duration of phase Ⅱ of the MMC [120(21-240) vs 58(16-170), P < 0.01] compared to the duration before XBP administration. There were significant differences in the amplitude of jejunal contractions [19.8(14.0-30.0) vs 18.0(13.0-28.5), P < 0.05], the motility index of duodenal contractions [236.0(115.0-306.0) vs 195.0(109.0-310.0), P < 0.05], and jejunal contractions [214.0(95.0-403.0) vs 178.0(55.0-304.0), P < 0.01] in phase Ⅲ of the MMC. Oral administration of XBP greatly increased plasma motilin(57.69 ± 9.03 vs 49.38 ± 8.63, P < 0.01) and ghrelin(279.20 ± 104.31 vs 238.73 ± 115.59, P < 0.01) concentrations compared to concentrations after oral administration of the placebo.CONCLUSION XBP can stimulate duodenal and jejunal motility and increase the concentrations of plasma motilin and ghrelin. The clinical applicability of XBP in treating GDIM deserves investigation.展开更多
AIM:To assess the anti-cancer effect of lobaplatin on human gastric cancer cells,and to explore the underlying molecular mechanisms.METHODS:The human gastric cancer cell lines MKN-28,AGS and MKN-45 were used.The cytot...AIM:To assess the anti-cancer effect of lobaplatin on human gastric cancer cells,and to explore the underlying molecular mechanisms.METHODS:The human gastric cancer cell lines MKN-28,AGS and MKN-45 were used.The cytotoxicity of lobaplatin was detected using an MTS cell proliferation assay.Flow cytometry was used to detect cell apoptosis using Annexin V-FITC Apoptosis Detection Kit.The expression of apoptosis-regulated genes was examined at the protein level using Western blot.RESULTS:Lobaplatin inhibited the proliferation of human gastric cancer cells and induced apoptosis,which may be associated with the up-regulation of Bax expression,poly(ADP-ribose)polymerase(PARP)cleavage,p53 expression and the reduction of Bcl-2 expression.CONCLUSION:The cytotoxicity of lobaplatin may be due to its ability of inducing apoptosis of gastric cancer cells,which would support the potential use of lobaplatin for the therapy of gastric cancer.展开更多
Inherent complexity of plant metabolites necessitates the use of multi-dimensional information to accomplish comprehensive profiling and confirmative identification.A dimension-enhanced strategy,by offline two-dimensi...Inherent complexity of plant metabolites necessitates the use of multi-dimensional information to accomplish comprehensive profiling and confirmative identification.A dimension-enhanced strategy,by offline two-dimensional liquid chromatography/ion mobility-quadrupole time-of-flight mass spectrometry(2 D-LC/IM-QTOF-MS)enabling four-dimensional separations(2 D-LC,IM,and MS),is proposed.In combination with in-house database-driven automated peak annotation,this strategy was utilized to characterize ginsenosides simultaneously from white ginseng(WG)and red ginseng(RG).An offline 2 DLC system configuring an Xbridge Amide column and an HSS T3 column showed orthogonality 0.76 in the resolution of ginsenosides.Ginsenoside analysis was performed by data-independent high-definition MSE(HDMSE)in the negative ESI mode on a Vion?IMS-QTOF hybrid high-resolution mass spectrometer,which could better resolve ginsenosides than MSEand directly give the CCS information.An in-house ginsenoside database recording 504 known ginsenosides and 58 reference compounds,was established to assist the identification of ginsenosides.Streamlined workflows,by applying UNIFI?to automatedly annotate the HDMSEdata,were proposed.We could separate and characterize 323 ginsenosides(including 286 from WG and 306 from RG),and 125 thereof may have not been isolated from the Panax genus.The established 2 D-LC/IM-QTOF-HDMSEapproach could also act as a magnifier to probe differentiated components between WG and RG.Compared with conventional approaches,this dimensionenhanced strategy could better resolve coeluting herbal components and more efficiently,more reliably identify the multicomponents,which,we believe,offers more possibilities for the systematic exposure and confirmative identification of plant metabolites.展开更多
Traditional Chinese medicine (TCM) is deeply rooted in ancient Chinese culture and has been practiced by Chinese people for thousands of years in order to maintain their health and fight against disease. This ancient ...Traditional Chinese medicine (TCM) is deeply rooted in ancient Chinese culture and has been practiced by Chinese people for thousands of years in order to maintain their health and fight against disease. This ancient Chinese wisdom has accumulated from the long struggle to cope with various diseases through hundreds or even thousands of trial-and-error practices. However, due to its empirical character, TCM has long been criticized as being deficient in scientific evidence, and is still not widely accepted by the mainstream conventional medical system. The complexity of the chemical components of TCM and the clarification of its mechanisms remain an enormous challenge in the conversion of TCM into an evidence-based medicine. Thanks to incredible progress in biomedical research, TCM has evolved at an astonishing pace in various aspects, as indicated by the 2015 Nobel Prize awarded to Professor Youyou Tu for her discovery of artemisinin.展开更多
OBJECTIVE To explore the potential effect and mechanisms of protopanaxadiol deriva.tive 1-(3,4-dimethoxyphenethyl)-3-(3-dehydroxyl-20(s)-protopa-naxadiol-3 b-yl)-urea(DDPU) in the treatment of Alzheimer disease.METHOD...OBJECTIVE To explore the potential effect and mechanisms of protopanaxadiol deriva.tive 1-(3,4-dimethoxyphenethyl)-3-(3-dehydroxyl-20(s)-protopa-naxadiol-3 b-yl)-urea(DDPU) in the treatment of Alzheimer disease.METHODS ELISA assay was performed in both HEK293-APPswe and CHO-APP cells to demonstrate the efficacy of DDPU in reducing Ab level.SH-SY5 Y,primary neurons and astrocyte cellswereused to study the regulation of DDPU against the signaling pathways involved in Aβ/ER-stress pathology.APP/PS1 transgenic mice wereusedto study the regulation of DDPU against ADL and cognitive deficits.APP/PS1 transgenic mice were randomly placed into three groups(n=10):The two 6-month transgenic groups were administrated with 30 mg·kg^(-1) DDPU or vehicle and the 6-month non-transgenic group was administrated with vehicle for 100 days by intraperitonealinjec.tion.After 100-day administration,nest construction assay and Morris water maze(MWM) assay were applied to evaluate the daily living activities and cognitive abilities of the mice with continuous DDPU treatment.Upon completion of behavior assays,mice were euthanized,and the brains were removed and bisected in mid-sagittal plane.The right hemispheres were frozen and stored at-80°C,and the left hemispheres were fixed in 4% paraformaldehyde.RESULTS DDPU effectively improved learning and memory impairments in APP/PS1 transgenic mice,and the underlying mechanisms have been inten.sively investigated.DDPU reduced Ab production by inhibiting the PERK/eIF2 a signaling-mediated BACE1 translation,while promoted Ab clearance as a PI3K inhibitor thus negatively regulating PI3K/AKT/mTOR signaling in promotion of autophagy.Moreover,DDPU also exhibited neuroprotective effect by attenuating ER stress.Therefore,all findings have clearly demonstrated the crosstalk between Ab and ER stress,and confirmed that targeting ER stress should be a potential target for innovative anti-AD drug development,while highlighted the potential of DDPU in the treatment of AD.展开更多
Microemulsion systems, composed of water, isopropyl myristate （IPM）, polyoxyethylene sorbitan trioleate （Tween 85 ）, and ethanol, were investigated as transdermal drug delivery vehicles for a lipophilic model drug...Microemulsion systems, composed of water, isopropyl myristate （IPM）, polyoxyethylene sorbitan trioleate （Tween 85 ）, and ethanol, were investigated as transdermal drug delivery vehicles for a lipophilic model drug（ meloxicam）. The purpose of this study was to investigate the physicochemieal properties of the tested microemulsion and to find the correlation between the physicoehemical properties and the skin permeation rate of the microemulsion. Pseudo-ternary phase diagram of the investigated system at a constant surfactant/cosurfactant mass ratio （ Km = 1 ： 1 ） was constructed by titration at 20℃, and the five fommlations were selected for further research in the o/w microemulsion domains. The values of electrical conductivity and viscosity showed that the selected systems were bicontinuous or non-spherical o/w microemulsion, and the electrical conductivity and viscosity were increased with increasing the content of water. These results suggest that the optimum formulation of microemulsion, containing 0. 375 meloxicam, 5% isopropyl myristate, 25% Tween 85. 25% ethanol, and water, showed the maximum permeation rate. It had a high electrical conductivity, small droplet size, and proper viscocity.展开更多
In order to probe the effect of C-2(S)-substituted groups in the antibacterial activity,a series of novel C-2(S)-substituted pleuromutilin analogues of SB-225586 were synthesized and evaluated for their in vitro antib...In order to probe the effect of C-2(S)-substituted groups in the antibacterial activity,a series of novel C-2(S)-substituted pleuromutilin analogues of SB-225586 were synthesized and evaluated for their in vitro antibacterial activity.The results of antibacterial activities indicated that C-2(S)-substituted pleuromutilin derivatives retained appreciable antibacterial activity,and the 2-fluorination compounds 6a and 6b are more potent than the corresponding 2-hydroxylation analogues 7a and 7b.展开更多
The microsphere was a primary particulate system for taste-masking with unique structural features defined by production process. In this article, ibuprofen lipid microspheres of octadecanol and glycerin monostearate ...The microsphere was a primary particulate system for taste-masking with unique structural features defined by production process. In this article, ibuprofen lipid microspheres of octadecanol and glycerin monostearate were prepared to mask the undesirable taste of ibuprofen via three kinds of spray congealing processes, namely, air-cooling, water-cooling and citric acid solution-cooling. The stereoscopic and internal structures of ibuprofen microspheres were quantitatively analyzed by synchrotron radiation X-ray micro-computed tomography(SR-μCT) to establish the relationship between the preparation process and microsphere architectures. It was found that the microstructure and morphology of the microspheres were significantly influenced by preparation processes as the primary factors to determine the release profiles and taste-masking effects. The sphericity of ibuprofen microspheres congealed in citric acid solution was higher than that of other two and its morphology was more regular than that being congealed in air or distilled water, and the contact angles between congealing media and melted ibuprofen in octadecanol and glycerin monostearate well demonstrated the structure differences among microspheres of three processes which controlled the release characteristics of the microspheres. The structure parameters like porosity, sphericity, and radius ratio from quantitative analysis were correlated well with drug release behaviors. The results demonstrated that the exterior morphology and internal structure of microspheres had considerable influences on the drug release behaviors as well as taste-masking effects.展开更多
The protein binding of non-steroidal anti-inflammatory drugs flurbiprofen, ketoprofen and etodolac with human serum albumin （HSA） was investigated using indirect chiral high performance liquid chromatography （HPLC...The protein binding of non-steroidal anti-inflammatory drugs flurbiprofen, ketoprofen and etodolac with human serum albumin （HSA） was investigated using indirect chiral high performance liquid chromatography （HPLC） and ultrafiltration techniques. S-（-）-1-（1-naphthyl）- ethylamine （S-NEA） was utilized as chiral derivatization reagent and pre-column derivatization RP-HPLC method was established for the separation and assay of the three pairs of enantiomer. The method had good linear relationship over the investigated concentration range without interference. The average extraction efficiency was higher than 85% in different systems, and the intra-day and inter-day precisions were less than 15%. In serum albumin, the protein binding of etodolac enantiomers showed significant stereoselectivity that the affinity of S-enantiomer was stronger than R-enantiomer, and the stereoselectivity ratio reached 6.06; Flurbiprofen had only weak stereoselectivity in HSA, and ketoprofen had no stereoselectivity at all. Scatchard curves showed that all the three chiral drugs had two types of binding sites in HSA.展开更多
Objective To screen the antimalarial compounds of daphnetin derivatives against Plasmodium falciparum in vitro. Method Plasmodium faciparum （FCC1） was cultured in vitro by a modified method of Trager and Jensen. Ant...Objective To screen the antimalarial compounds of daphnetin derivatives against Plasmodium falciparum in vitro. Method Plasmodium faciparum （FCC1） was cultured in vitro by a modified method of Trager and Jensen. Antimalarial compounds were screened by microscopy-based assay and microfluorimetric method. Results DA79 and DA78 showed potent antimalarial activity against Plasmodiumfalciparum cultured in vitro. Conclusion Though the relationship between the structures of daphnetin derivatives and their antimalarial activities has not been clarified yet, this study may provide a new direction for discovery of more potential antimalarial compounds.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
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the Guangxi Science and Technology Major Program(Grant No.:GUIKEAA23023035)Key Program of National Natural Science Foundation of China(Grant No.:82130111)+1 种基金Guangxi Science and Technology Major Project(Grant No.:GUIKEAA22096029)Science and Technology Major Project of Inner Mongolia(Grant No.:2021ZD0017).
文摘Prescriptions are the main clinical application of traditional Chinese medicines(TCMs).Common forms include Chinese patent medicines,Kampo formulas,and hospital decoctions.A new pre-scription called“famous classical formulas”is recently developed and expected to boom in the market.Identifying constituent me-dicinal plants in prescriptions is critical for new drug development and quality control[1],which could avoid safety issues from adulteration or substandard ingredients,as seen in the notorious Longdan Xiegan Pill event.
基金supported by the Key Program of the National Natural Science Foundation of China(Grant No.:82130111)the National Natural Science Foundation of China(Grant No.:81803716)+1 种基金the Qi-Huang Chief Scientist Project of the National Administration of Traditional Chinese Medicine,China(2020)the SIMM-SHUTCM Traditional Chinese Medicine Innovation Joint Research Program,China(Grant No.:E2G809H).
文摘Pheretima,also called“earthworms”,is a well-known animal-derived traditional Chinese medicine that is extensively used in over 50 Chinese patent medicines(CPMs)in Chinese Pharmacopoeia(2020 edition).However,its zoological origin is unclear,both in the herbal market and CPMs.In this study,a strategy for integrating in-house annotated protein databases constructed from close evolutionary relationship-sourced RNA sequencing data from public archival resources and various sequencing algorithms(restricted search,open search,and de novo)was developed to characterize the phenotype of natural peptides of three major commercial species of Pheretima,including Pheretima aspergillum(PA),Pheretima vulgaris(PV),and Metaphire magna(MM).We identified 10,477 natural peptides in the PA,7,451 in PV,and 5,896 in MM samples.Five specific signature peptides were screened and then validated using synthetic peptides;these demonstrated robust specificity for the authentication of PA,PV,and MM.Finally,all marker peptides were successfully applied to identify the zoological origins of Brain Heart capsules and Xiaohuoluo pills,revealing the inconsistent Pheretima species used in these CPMs.In conclusion,our integrated strategy could be used for the in-depth characterization of natural peptides of other animal-derived traditional Chinese medicines,especially non-model species with poorly annotated protein databases.
基金supported by the Science and Technology Commission of Shanghai Municipality (20S11902600)the National Natural Science Foundation of China (82172615)the PDH-SPFDU Joint Research Fund (RHJJ2018-05)
文摘Clinically,arsenic trioxide(ATO)was applied to the treatment of acute promyelocytic leukemia(APL)as a reliable and effective frontline drug.However,the administration regimen of AsⅢwas limited due to its fast clearance,short therapeutic window and toxicity as well.Based on CD71 overexpressed on APL cells,in present study,a transferrin(Tf)-modified liposome(LP)was established firstly to encapsulate AsⅢin arsenic-nickel complex by nickel acetate gradient method.The AsⅢ-loaded liposomes(AsLP)exhibited the feature of acid-sensitive release in vitro.Tf-modified AsLP(Tf-AsLP)were specifically taken up by APL cells and the acidic intracellular environment triggered liposome to release AsⅢwhich stimulated reactive oxygen species level and caspase-3 activity.Tf-AsLP prolonged half-life of AsⅢin blood circulation,lowered systemic toxicity,and promoted apoptosis and induced cell differentiation at lesion site in vivo.Considering that ATO combined with RA is usually applied as the first choice in clinic for APL treatment to improve the therapeutic effect,accordingly,a Tf-modified RA liposome(Tf-RALP)was designed to reduce the severe side effects of free RA and assist Tf-AsLP for better efficacy.As expected,the tumor inhibition rate of Tf-AsLP was improved significantly with the combination of Tf-RALP on subcutaneous tumor model.Furthermore,APL orthotopic NOD/SCID mice model was established by 60CO irradiation and HL-60 cells intravenously injection.The effect of co-administration(Tf-AsLP+Tf-RALP)was also confirmed to conspicuous decrease the number of leukemia cells in the circulatory system and prolong the survival time of APL mice by promoting the APL cells’apoptosis and differentiation in peripheral blood and bone marrow.Collectively,Tf-modified acid-sensitive AsLP could greatly reduce the systemic toxicity of free drug.Moreover,Tf-AsLP combined with Tf-RALP could achieve better efficacy.Thus,transferrinmodified AsⅢliposome would be a novel clinical strategy to improve patient compliance,with promising translation prospects.
基金support from the National Natural Science Foundation of China(22237007 and 22177122)the Biological Resources Program of Chinese Academy of Sciences(CAS)(KFJ-BRP-008-001)the Youth Innovation Promotion Association of Chinese Academy of Sciences(2022282)is gratefully acknowledged.We thank Prof.Shi-Man Huang,Department of Biology,Hainan University,China,for the identification of the plant material.
文摘Four new norditerpenoid heterodimers with different dimerization patterns-namely,trigofragiloids A-C(denoted as compounds 1-3)and(+)-and(-)-trigofragiloid D(compound 4)-and three new phenanthrenone norditerpenoids-namely,trigofragiloids E-G(compounds 5-7)-were isolated from Trigonostemon fragilis.Compounds 1 and 2 feature a novel heterodimeric carbon skeleton formed by the conjugation of a tetra-norditerpenoid and an ennea-norditerpenoid;they have been identified as class 2 atropisomers by means of quantum chemical calculations.Compound 3 is an unprecedented phenylpropanoid-norditerpenoid adduct with a new dimerization pattern.Compounds(+)-and(-)-4 are the first example of S-shaped 1,4-dioxane-fused norditerpenoid dimers.Inspired by the structure elucidation of compound 4,two co-occurring analogues,actephilol A and epiactephilol A,were structurally revised as a pair of geometrical isomers and were identified as two pairs of enantiomers,(+)-and(-)-8 and(+)-and(-)-9,respectively.Their structures were characterized using a combined method.Notably,compound 7 exhibits remarkable adenosine triphosphate-citrate lyase(ACLY)inhibition with a halfmaximal inhibition concentration(IC50)value of(0.46±0.11)lmol·L^(-1),as active as the positive control BMS-303141,and a molecular docking study offers deep insight into the interaction between compound 7 and ACLY.
基金the National Key Research and Development Program of China(Grant No.:2022YFC3501700)the Key-Area Research and Development Program of Guangdong Province,China(Grant No.:2020B1111110001)the Youth Program of the National Natural Science Foundation of China(Grant No.:82003939).
文摘Chemotherapy-induced cachexia(CIC)is a debilitating condition characterized by weight loss,muscle atrophy,and anorexia[1].While peripheral mechanisms of cachexia have been extensively studied,the involvement of the central nervous system(CNS)in CIC is often overlooked.Chemotherapeutic drugs cause stress responses and inflammation,which may impact the hypothalamus and disrupt systemic energy and neuroendocrine functions.Understanding hypothalamic roles in regulating these processes can provide insights into CIC's mechanisms and aid in developing novel therapies.
基金supported by National Natural Science Foundation of China (82222071, 82273990, 82104253)the opening project of State Key Laboratory of Natural Medicines (SKLNMKF202208)
文摘Non-alcoholic fatty liver disease(NAFLD)is the main cause of chronic liver disease worldwide.Bupleurum is widely used in the treatment of non-alcoholic fatty liver,and saikosaponin D(SSD)is one of the main active components of Bupleurum.The purpose of this study was to investigate the efficacy of SSD in the treatment of NAFLD and to explore the mechanism of SSD in the improvement of NAFLD based on“gut-liver axis”.Our results showed that SSD dose-dependently alleviated high fat diet-induced weight gain in mice,improved insulin sensitivity,and also reduced liver lipid accumulation and injury-related biomarkers aspartate aminotransferase(AST)and alanine aminotransferase(ALT).Further exploration found that SSD inhibited the mRNA expression levels of farnesoid X receptor(Fxr),small heterodimer partner(Shp),recombinant fibroblast growth factor 15(Fgf15)and apical sodium dependent bile acid transporter(Asbt)in the intestine,suggesting that SSD improved liver lipid metabolism by inhibiting intestinal FXR signaling.SSD can significantly reduce the gut microbiota associated with bile salt hydrolase(BSH)expression,such as Clostridium.Decreased BSH expression reduced the ratio of unconjugated to conjugated bile acids,thereby inhibiting the intestinal FXR.These data demonstrated that SSD ameliorated NAFLD potentially through the gut microbiota-bile acidintestinal FXR pathway and suggested that SSD is a promising therapeutic agent for the treatment of NAFLD.
基金supported by the National Natural Science Foundation of China(T2225002,82273855)Lingang Laboratory(LG202102-01-02)the National Key Research and Development Program of China(2022YFC3400504)。
文摘Dear Editor,Great progress has been made using artificial intelligence(AI) techniques in learning knowledge from biomedical databases in recent years, revolutionizing the study of many fields, such as protein structure prediction and protein design(Madani et al., 2023). However, there is massive biomedical knowledge not curated in the form of structured data but hidden in primary scientific literature.
文摘Noradrenaline transporter,also known as the norepinephrine transporter(NET),is a member of the monoamine transporters(MATs)family,which also includes serotonin transporter(SERT)and dopamine transporter(DAT).These transporters collectively regulate neurotransmitter concentrations at synapses and maintain neurotransmitter balance in the body.
基金Supported by Guangdong Provincial Department of Science and Technology,No.[2013]173
文摘AIM To investigate the effects of Xiangbin prescription(XBP), a Chinese herbal concoction, on gastrointestinal motility.METHODS Forty healthy volunteers were recruited for this randomized controlled trial of XBP. Antroduodenojejunal manometry was used to monitor gastrointestinal motility in these subjects. After the subjects had fasted for at least 12 h, XBP(n = 30) or placebo(n = 10) was orally administrated and gastrointestinal motility was recorded for 4 h. Plasma motilin and ghrelin were measured by enzyme-linked immunosorbent assay.RESULTS Oral administration of XBP significantly increased the amplitude of duodenal contractions [19.5(13.0-26.7) vs 16.9(12.3-23.9), P < 0.05], jejunal contractions [18.3(15.3-25.0) vs 15.4(11.7-23.9), P < 0.01], and the motility index of duodenal contractions [522.0(146.0-139.0) vs 281.0(76.5-1006.0), P < 0.01] in phase Ⅱ of the migratory motor complex(MMC), which subsequently initiated the MMC cycle [74.0(30.0-118.0) vs 116.5(24.0-219.0), P < 0.05], shortened the duration of phase I of the MMC [42.0(0.0-90.0) vs 111.5(42.0-171.0), P < 0.01], and lengthened the duration of phase Ⅱ of the MMC [120(21-240) vs 58(16-170), P < 0.01] compared to the duration before XBP administration. There were significant differences in the amplitude of jejunal contractions [19.8(14.0-30.0) vs 18.0(13.0-28.5), P < 0.05], the motility index of duodenal contractions [236.0(115.0-306.0) vs 195.0(109.0-310.0), P < 0.05], and jejunal contractions [214.0(95.0-403.0) vs 178.0(55.0-304.0), P < 0.01] in phase Ⅲ of the MMC. Oral administration of XBP greatly increased plasma motilin(57.69 ± 9.03 vs 49.38 ± 8.63, P < 0.01) and ghrelin(279.20 ± 104.31 vs 238.73 ± 115.59, P < 0.01) concentrations compared to concentrations after oral administration of the placebo.CONCLUSION XBP can stimulate duodenal and jejunal motility and increase the concentrations of plasma motilin and ghrelin. The clinical applicability of XBP in treating GDIM deserves investigation.
基金Supported by National Natural Science Foundation of China,No.81101648
文摘AIM:To assess the anti-cancer effect of lobaplatin on human gastric cancer cells,and to explore the underlying molecular mechanisms.METHODS:The human gastric cancer cell lines MKN-28,AGS and MKN-45 were used.The cytotoxicity of lobaplatin was detected using an MTS cell proliferation assay.Flow cytometry was used to detect cell apoptosis using Annexin V-FITC Apoptosis Detection Kit.The expression of apoptosis-regulated genes was examined at the protein level using Western blot.RESULTS:Lobaplatin inhibited the proliferation of human gastric cancer cells and induced apoptosis,which may be associated with the up-regulation of Bax expression,poly(ADP-ribose)polymerase(PARP)cleavage,p53 expression and the reduction of Bcl-2 expression.CONCLUSION:The cytotoxicity of lobaplatin may be due to its ability of inducing apoptosis of gastric cancer cells,which would support the potential use of lobaplatin for the therapy of gastric cancer.
基金the National Natural Science Foundation of China(Grant No.81872996)the State Key Research and Development Project(Grant No.2017YFC1702104)+1 种基金the State Key Project for the Creation of Major New Drugs(2018ZX09711001-009-010)the Tianjin Municipal Education Commission Research Project(Grant No.2017ZD07)。
文摘Inherent complexity of plant metabolites necessitates the use of multi-dimensional information to accomplish comprehensive profiling and confirmative identification.A dimension-enhanced strategy,by offline two-dimensional liquid chromatography/ion mobility-quadrupole time-of-flight mass spectrometry(2 D-LC/IM-QTOF-MS)enabling four-dimensional separations(2 D-LC,IM,and MS),is proposed.In combination with in-house database-driven automated peak annotation,this strategy was utilized to characterize ginsenosides simultaneously from white ginseng(WG)and red ginseng(RG).An offline 2 DLC system configuring an Xbridge Amide column and an HSS T3 column showed orthogonality 0.76 in the resolution of ginsenosides.Ginsenoside analysis was performed by data-independent high-definition MSE(HDMSE)in the negative ESI mode on a Vion?IMS-QTOF hybrid high-resolution mass spectrometer,which could better resolve ginsenosides than MSEand directly give the CCS information.An in-house ginsenoside database recording 504 known ginsenosides and 58 reference compounds,was established to assist the identification of ginsenosides.Streamlined workflows,by applying UNIFI?to automatedly annotate the HDMSEdata,were proposed.We could separate and characterize 323 ginsenosides(including 286 from WG and 306 from RG),and 125 thereof may have not been isolated from the Panax genus.The established 2 D-LC/IM-QTOF-HDMSEapproach could also act as a magnifier to probe differentiated components between WG and RG.Compared with conventional approaches,this dimensionenhanced strategy could better resolve coeluting herbal components and more efficiently,more reliably identify the multicomponents,which,we believe,offers more possibilities for the systematic exposure and confirmative identification of plant metabolites.
文摘Traditional Chinese medicine (TCM) is deeply rooted in ancient Chinese culture and has been practiced by Chinese people for thousands of years in order to maintain their health and fight against disease. This ancient Chinese wisdom has accumulated from the long struggle to cope with various diseases through hundreds or even thousands of trial-and-error practices. However, due to its empirical character, TCM has long been criticized as being deficient in scientific evidence, and is still not widely accepted by the mainstream conventional medical system. The complexity of the chemical components of TCM and the clarification of its mechanisms remain an enormous challenge in the conversion of TCM into an evidence-based medicine. Thanks to incredible progress in biomedical research, TCM has evolved at an astonishing pace in various aspects, as indicated by the 2015 Nobel Prize awarded to Professor Youyou Tu for her discovery of artemisinin.
基金supported by National Natural Science Foundation of China(8122010802581473141)+3 种基金 NSFC-TRF collaboration projects(81561148011DBG5980001) Drug Innovation Project of SIMM(CASIMM0120154035) Personalized Medicine-Molecular Signature-based Drug Discovery and
文摘OBJECTIVE To explore the potential effect and mechanisms of protopanaxadiol deriva.tive 1-(3,4-dimethoxyphenethyl)-3-(3-dehydroxyl-20(s)-protopa-naxadiol-3 b-yl)-urea(DDPU) in the treatment of Alzheimer disease.METHODS ELISA assay was performed in both HEK293-APPswe and CHO-APP cells to demonstrate the efficacy of DDPU in reducing Ab level.SH-SY5 Y,primary neurons and astrocyte cellswereused to study the regulation of DDPU against the signaling pathways involved in Aβ/ER-stress pathology.APP/PS1 transgenic mice wereusedto study the regulation of DDPU against ADL and cognitive deficits.APP/PS1 transgenic mice were randomly placed into three groups(n=10):The two 6-month transgenic groups were administrated with 30 mg·kg^(-1) DDPU or vehicle and the 6-month non-transgenic group was administrated with vehicle for 100 days by intraperitonealinjec.tion.After 100-day administration,nest construction assay and Morris water maze(MWM) assay were applied to evaluate the daily living activities and cognitive abilities of the mice with continuous DDPU treatment.Upon completion of behavior assays,mice were euthanized,and the brains were removed and bisected in mid-sagittal plane.The right hemispheres were frozen and stored at-80°C,and the left hemispheres were fixed in 4% paraformaldehyde.RESULTS DDPU effectively improved learning and memory impairments in APP/PS1 transgenic mice,and the underlying mechanisms have been inten.sively investigated.DDPU reduced Ab production by inhibiting the PERK/eIF2 a signaling-mediated BACE1 translation,while promoted Ab clearance as a PI3K inhibitor thus negatively regulating PI3K/AKT/mTOR signaling in promotion of autophagy.Moreover,DDPU also exhibited neuroprotective effect by attenuating ER stress.Therefore,all findings have clearly demonstrated the crosstalk between Ab and ER stress,and confirmed that targeting ER stress should be a potential target for innovative anti-AD drug development,while highlighted the potential of DDPU in the treatment of AD.
基金Supported by of the "863" Program of China(No 2003AA2Z347C)
文摘Microemulsion systems, composed of water, isopropyl myristate （IPM）, polyoxyethylene sorbitan trioleate （Tween 85 ）, and ethanol, were investigated as transdermal drug delivery vehicles for a lipophilic model drug（ meloxicam）. The purpose of this study was to investigate the physicochemieal properties of the tested microemulsion and to find the correlation between the physicoehemical properties and the skin permeation rate of the microemulsion. Pseudo-ternary phase diagram of the investigated system at a constant surfactant/cosurfactant mass ratio （ Km = 1 ： 1 ） was constructed by titration at 20℃, and the five fommlations were selected for further research in the o/w microemulsion domains. The values of electrical conductivity and viscosity showed that the selected systems were bicontinuous or non-spherical o/w microemulsion, and the electrical conductivity and viscosity were increased with increasing the content of water. These results suggest that the optimum formulation of microemulsion, containing 0. 375 meloxicam, 5% isopropyl myristate, 25% Tween 85. 25% ethanol, and water, showed the maximum permeation rate. It had a high electrical conductivity, small droplet size, and proper viscocity.
文摘In order to probe the effect of C-2(S)-substituted groups in the antibacterial activity,a series of novel C-2(S)-substituted pleuromutilin analogues of SB-225586 were synthesized and evaluated for their in vitro antibacterial activity.The results of antibacterial activities indicated that C-2(S)-substituted pleuromutilin derivatives retained appreciable antibacterial activity,and the 2-fluorination compounds 6a and 6b are more potent than the corresponding 2-hydroxylation analogues 7a and 7b.
基金financial support from the National Natural Science Foundation of China(No.81773645)National Science and Technology Major Projects for the Major New Drugs Innovation and Development(2017ZX09101001-006)
文摘The microsphere was a primary particulate system for taste-masking with unique structural features defined by production process. In this article, ibuprofen lipid microspheres of octadecanol and glycerin monostearate were prepared to mask the undesirable taste of ibuprofen via three kinds of spray congealing processes, namely, air-cooling, water-cooling and citric acid solution-cooling. The stereoscopic and internal structures of ibuprofen microspheres were quantitatively analyzed by synchrotron radiation X-ray micro-computed tomography(SR-μCT) to establish the relationship between the preparation process and microsphere architectures. It was found that the microstructure and morphology of the microspheres were significantly influenced by preparation processes as the primary factors to determine the release profiles and taste-masking effects. The sphericity of ibuprofen microspheres congealed in citric acid solution was higher than that of other two and its morphology was more regular than that being congealed in air or distilled water, and the contact angles between congealing media and melted ibuprofen in octadecanol and glycerin monostearate well demonstrated the structure differences among microspheres of three processes which controlled the release characteristics of the microspheres. The structure parameters like porosity, sphericity, and radius ratio from quantitative analysis were correlated well with drug release behaviors. The results demonstrated that the exterior morphology and internal structure of microspheres had considerable influences on the drug release behaviors as well as taste-masking effects.
基金supported by National Major Projects for Science and Technology Development of Ministry Science and Technology of China (2009ZX09304-003)
文摘The protein binding of non-steroidal anti-inflammatory drugs flurbiprofen, ketoprofen and etodolac with human serum albumin （HSA） was investigated using indirect chiral high performance liquid chromatography （HPLC） and ultrafiltration techniques. S-（-）-1-（1-naphthyl）- ethylamine （S-NEA） was utilized as chiral derivatization reagent and pre-column derivatization RP-HPLC method was established for the separation and assay of the three pairs of enantiomer. The method had good linear relationship over the investigated concentration range without interference. The average extraction efficiency was higher than 85% in different systems, and the intra-day and inter-day precisions were less than 15%. In serum albumin, the protein binding of etodolac enantiomers showed significant stereoselectivity that the affinity of S-enantiomer was stronger than R-enantiomer, and the stereoselectivity ratio reached 6.06; Flurbiprofen had only weak stereoselectivity in HSA, and ketoprofen had no stereoselectivity at all. Scatchard curves showed that all the three chiral drugs had two types of binding sites in HSA.
文摘Objective To screen the antimalarial compounds of daphnetin derivatives against Plasmodium falciparum in vitro. Method Plasmodium faciparum （FCC1） was cultured in vitro by a modified method of Trager and Jensen. Antimalarial compounds were screened by microscopy-based assay and microfluorimetric method. Results DA79 and DA78 showed potent antimalarial activity against Plasmodiumfalciparum cultured in vitro. Conclusion Though the relationship between the structures of daphnetin derivatives and their antimalarial activities has not been clarified yet, this study may provide a new direction for discovery of more potential antimalarial compounds.
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.
