Autoimmune encephalitis(AE)is a type of encephalitis caused by autoimmune disease.AE was included on a list of the first batch of 121 rare diseases published by the Chinese National Health Commission on 11^(th)May 201...Autoimmune encephalitis(AE)is a type of encephalitis caused by autoimmune disease.AE was included on a list of the first batch of 121 rare diseases published by the Chinese National Health Commission on 11^(th)May 2018.Currently,patients with AE account for 10%-20% of encephalitis cases,with 54%-80% of those cases classified as the anti-N-methyl-D-aspartate receptor(NMDAR)type,which is the most common type.[1]In 2010,China reported the first case of a patient withanti-NMDARtype AE.展开更多
This study established a simple,rapid,and accurate nuclear magnetic resonance(NMR)quantitative method to determine the cefpodoxime proxetil content in raw materials and dry suspensions,and evaluated the uncertainty.Th...This study established a simple,rapid,and accurate nuclear magnetic resonance(NMR)quantitative method to determine the cefpodoxime proxetil content in raw materials and dry suspensions,and evaluated the uncertainty.The relative content of cefpodoxime proxetil iso-A and iso-B was also analyzed based on 1H NMR.In this study,an internal standard method was used,with DMSO-d6 as the solvent and maleic acid and 1,3,5-trimethylbenzene as internal standards,to calculate the concentration of the samples.Quantitative analysis was performed using both the traditional quantitative NMR(traditional qNMR)and the quantitative Global Spectral Deconvolution(qGSD)method.The linearity range,quantitation limit,precision,robustness,and accuracy of these quantitative analysis methods were validated.The results indicated that both internal standards and integration methods met the requirements of the“9101 Guidelines for Analytical Method Validation”in the 2020 edition of the Chinese Pharmacopoeia.Compared to the traditional qNMR,qGSD has unique advantages in accurate quantitative analysis in complex systems.By using the combined HPLC-SPE-NMR technique,cefpodoxime proxetil iso-A and iso-B were enriched and analyzed,and their NMR data were accurately assigned.The quantitative analysis results were in line with the requirements of the Chinese Pharmacopoeia.展开更多
Various drug transporters are widely expressed throughout the intestine and play important roles in absorbing nutrients and drugs,thus providing high quality targets for the design of prodrugs or nanoparticles to faci...Various drug transporters are widely expressed throughout the intestine and play important roles in absorbing nutrients and drugs,thus providing high quality targets for the design of prodrugs or nanoparticles to facilitate oral drug delivery.In particular,intestinal carnitine/organic cation transporter 2(OCTN2)and mono-carboxylate transporter protein 1(MCT1)possess high transport capacities and complementary distributions.Therefore,we outline recent developments in transporter-targeted oral drug delivery with regard to the OCTN2 and MCT1 proteins in this review.First,basic information of the two transporters is reviewed,including their topological structures,characteristics and functions,expression and key features of their substrates.Furthermore,progress in transporter-targeting prodrugs and nanoparticles to increase oral drug delivery is discussed,including improvements in the oral absorption of anti-inflammatory drugs,antiepileptic drugs and anticancer drugs.Finally,the potential of a dual transporter-targeting strategy is discussed.展开更多
Although it is reported that the targeting ability of hyaluronic acid(HA)-based nanoparticles(NPs) is molecular weight(MW) dependent,the influence of HA MW on targeting efficiency of HA-functionalized NPs and the unde...Although it is reported that the targeting ability of hyaluronic acid(HA)-based nanoparticles(NPs) is molecular weight(MW) dependent,the influence of HA MW on targeting efficiency of HA-functionalized NPs and the underlying mechanism remain elusive. In this study,we constituted three HA-functionalized Dox-loaded NPs(Dox/HCVs) different HA MWs(7,63,and 102 k Da) and attempted to illustrate the effects of HA MW on the targeting efficiency.The three Dox/HCVs had similar physiochemical and pharmaceutical characteristics,but showed different affinity to CD44 receptor. Furthermore,Dox/HCV-63 exerted the best targeting effect and the highest cytotoxicity compared with Dox/HCV-7 and Dox/HCV-102. It was interesting to found that both the HA-CD44 binding affinity and induced CD44 clustering by HA-based NPs were HA MW-dependent,the two of which determine the apparent targeting efficacy of Dox/HCV NPs in the conflicting directions. Those results laid a good foundation for rationally designing HA-based NPs in cancer therapy.展开更多
A simple and rapid UPLC–MS/MS method to simultaneously determine gemcitabine and its L-carnitine ester derivative(2’-deoxy-2’, 2’-difluoro-N-((4-amino-4-oxobutanoyl) oxy)-4-(trimethyl amm-onio) butanoate-cytidine,...A simple and rapid UPLC–MS/MS method to simultaneously determine gemcitabine and its L-carnitine ester derivative(2’-deoxy-2’, 2’-difluoro-N-((4-amino-4-oxobutanoyl) oxy)-4-(trimethyl amm-onio) butanoate-cytidine, JDR) in rat plasma was developed and validated.The conventional plasma sample preparation method of nucleoside analogues is solidphase extraction(SPE) which is time-consuming and cost-expensive. In this study, gradient elution with small particles size solid phase was applied to effectively separate gemcitabine and JDR, and protein precipitation pretreatment was adopted to remove plasma protein and extract the analytes with high recovery(>81%). Method validation was performed as per the FDA guidelines, and the standard curves were found to be linear in the range of 5–4000 ng/ml for JDR and 4–4000 ng/ml for gemcitabine, respectively. The lower limit of quantitation(LLOQ)of gemcitabine and JDR was 4 and 5 ng/ml, respectively. The intra-day and inter-day precision and accuracy results were within the acceptable limits. Finally, the developed method was successfully applied to investigate the pharmacokinetic studies of JDR and gemcitabine after oral administration to rats.展开更多
Monocarboxylate transporter 1(MCT1)is responsible for oral absorption of short-chain monocarboxylic acids from small intestine,hence,it’s likely to serve as an ideal design target for the development of oral prodrugs...Monocarboxylate transporter 1(MCT1)is responsible for oral absorption of short-chain monocarboxylic acids from small intestine,hence,it’s likely to serve as an ideal design target for the development of oral prodrugs.However,potential application of MCT1 to facilitate the oral delivery is still unclear.Irregular oral absorption,poor permeability and bioavailability greatly limit the oral delivery efficiency of 5-fluorouracil(5-FU).Herein,we design three 5-FU-fatty acid conjugates targeting intestinal MCT1 with different lipophilic linkages.Interestingly,due to high MCT1 affinity and good gastrointestinal stability,5-FUoctanedioic acid monoester prodrug exhibited significant improvement in membrane permeability(13.1-fold)and oral bioavailability(4.1-fold)compared to 5-FU.More surprisingly,stability experiment in intestinal homogenates showed that 5-FU prodrugs could be properly activated to release 5-FU within intestinal cells,which provides an ideal foundation for the improvement of oral bioavailability.In summary,good gastrointestinal stability,high membrane permeability and appropriate intestinal cell bioactivation are the important factors for high-efficiency 5-FU oral prodrugs,and such work provides a good platform for the development of novel oral prodrugs targeting intestinal transporters.展开更多
The preparation of medium-sized benzo[b]azocines has always been challenging because of inherently unfavorable enthalpy and entropy factors.This report presents a novel approach for accessing 8-membered seleno-benzo[b...The preparation of medium-sized benzo[b]azocines has always been challenging because of inherently unfavorable enthalpy and entropy factors.This report presents a novel approach for accessing 8-membered seleno-benzo[b]azocines via electrochemically-driven seleno-cyclization.This method enables room-temperature preparation of various structurally diverse medium-sized seleno-benzo[b]azocines.The facile deselenation of the seleno-cyclization products to generate functionalized dienes is an additional benefit of this indispensable reaction.Mechanistic insights are presented based on radical inhibition experiments and cyclic voltammetry measurements,which elucidate the radical pathway.Finally,density functional theory calculations further rationalize the rate-determining step and the unique chemoselectivity observed in this transformation.展开更多
BACKGROUND:Circulating biomarkers for sepsis are lacking,and research on circular RNAs(circR NAs)as potential biomarkers of pneumonia-induced sepsis is limited.This study aims to investigate the diagnostic and prognos...BACKGROUND:Circulating biomarkers for sepsis are lacking,and research on circular RNAs(circR NAs)as potential biomarkers of pneumonia-induced sepsis is limited.This study aims to investigate the diagnostic and prognostic potential of circRNAs in patients with pneumonia-induced sepsis.METHODS:This prospective cohort study included 40 healthy individuals,60 patients with pneumonia,and 80 patients with pneumonia-induced sepsis.CircRNAs identified through RNA-sequencing were validated using quantitative real-time polymerase chain reaction(qRT-PCR).Spearman correlation analysis was used to evaluate the associations between circRNAs,inflammatory markers,Sequential Organ Failure Assessment(SOFA)scores,and Acute Physiology and Chronic Health EvaluationⅡ(APACHEⅡ)scores.Receiver operating characteristic(ROC)curves analysis were used to assess the diagnostic performance of circRNAs,while ROC curves and Kaplan-Meier survival analysis were used to evaluate their prognostic value of 28-day mortality.RESULTS:qRT-PCR confirmed the significant upregulation of Circ-CTD-2281E23.2 and downregulation of Circ-0075723 and Circ-0008679 in sepsis patients.Spearman correlation analysis showed that Circ-CTD-2281E23.2 was positively correlated with inflammatory markers and severity scores,whereas Circ-0075723 and Circ-0008679 were negatively correlated with these parameters.The area under the curve(AUC)values for Circ-CTD-2281E23.2,Circ-0075723,and Circ-0008679 in diagnosing pneumonia-induced sepsis were 0.728,0.706,and 0.793,respectively.The combination of these circRNAs(AUC=0.846)and the combination with other clinical indicators(AUC=0.990)demostrated enhanced AUC values.The AUC values for Circ-CTD-2281E23.2 and Circ-0075723 in predicting 28-day mortality were 0.664 and 0.765,respectively.CONCLUSION:This study suggest the additional diagnostic and prognostic value of circRNAs in pneumonia-induced sepsis.Circ-CTD-2281E23.2,Circ-0075723,and Circ-0008679 exhibit diagnostic potential,with Circ-CTD-2281E23.2 and Circ-0075723 showing positive prognostic value for 28-day mortality in sepsis patients.展开更多
Hypoxia, a salient feature of most solid tumors, confers invasiveness and resistance to the tumor cells. Oxygen-consumption photodynamic therapy(PDT) suffers from the undesirable impediment of local hypoxia in tumors....Hypoxia, a salient feature of most solid tumors, confers invasiveness and resistance to the tumor cells. Oxygen-consumption photodynamic therapy(PDT) suffers from the undesirable impediment of local hypoxia in tumors. Moreover, PDT could further worsen hypoxia. Therefore, developing effective strategies for manipulating hypoxia and improving the effectiveness of PDT has been a focus on antitumor treatment. In this review, the mechanism and relationship of tumor hypoxia and PDT are discussed.Moreover, we highlight recent trends in the field of nanomedicines to modulate hypoxia for enhancing PDT, such as oxygen supply systems, down-regulation of oxygen consumption and hypoxia utilization.Finally, the opportunities and challenges are put forward to facilitate the development and clinical transformation of PDT.展开更多
Hyaluronic acid(HA) is a natural ligand of tumor-targeted drug delivery systems(DDS) due to the relevant CD44 receptor overexpressed on tumor cell membranes. However, other HA receptors(HARE and LYVE-1) are also overe...Hyaluronic acid(HA) is a natural ligand of tumor-targeted drug delivery systems(DDS) due to the relevant CD44 receptor overexpressed on tumor cell membranes. However, other HA receptors(HARE and LYVE-1) are also overexpressing in the reticuloendothelial system(RES). Therefore,polyethylene glycol(PEG) modification of HA-based DDS is necessary to reduce RES capture.Unfortunately, pegylation remarkably inhibits tumor cellular uptake and endosomal escapement,significantly compromising the in vivo antitumor efficacy. Herein, we developed a Dox-loaded HA-based transformable supramolecular nanoplatform(Dox/HCVBP) to overcome this dilemma. Dox/HCVBP contains a tumor extracellular acidity-sensitive detachable PEG shell achieved by a benzoic imine linkage.The in vitro and in vivo investigations further demonstrated that Dox/HCVBP could be in a "stealth" state at blood stream for a long circulation time due to the buried HA ligands and the minimized nonspecific interaction by PEG shell. However, it could transform into a "recognition" state under the tumor acidic microenvironment for efficient tumor cellular uptake due to the direct exposure of active targeting ligand HA following PEG shell detachment. Such a transformative concept provides a promising strategy to resolve the dilemma of natural ligand-based DDS with conflicting two processes of tumor cellular uptake and in vivo nonspecific biodistribution.展开更多
The unique characteristics of the tumor microenvironment(TME)could be exploited to develop antitumor nanomedicine strategies.However,in many cases,the actual therapeutic effect is far from reaching our expectations du...The unique characteristics of the tumor microenvironment(TME)could be exploited to develop antitumor nanomedicine strategies.However,in many cases,the actual therapeutic effect is far from reaching our expectations due to the notable tumor heterogeneity.Given the amplified characteristics of TME regulated by vascular disrupting agents(VDAs),nanomedicines may achieve unexpected improved efficacy.Herein,we fabricate platelet membrane-fusogenic liposomes(PML/DP&PPa),namely“platesomes”,which actively load the hypoxia-activated pro-prodrug DMG-PR104A(DP)and physically encapsulate the photosensitizer pyropheophorbide a(PPa).Considering the different stages of tumor vascular collapse and shutdown induced by a VDA combretastatin-A4 phosphate(CA4P),PML/DP&PPa is injected 3 h after intraperitoneal administration of CA4P.First,CA4P-mediated tumor hemorrhage amplifies the enhanced permeation and retention(EPR)effect,and the platesome-biological targeting further promotes the tumor accumulation of PML/DP&PPa.Besides,CA4P-induced vascular occlusion inhibits oxygen supply,followed by photodynamic therapy-caused acute tumor hypoxia.This prolonged extreme hypoxia contributes to the complete activation of DP and then high inhibitory effect on tumor growth and metastasis.Thus,such a combining strategy of artificially-regulated TME and bio-inspired platesomes pronouncedly improves tumor drug delivery and boosts tumor hypoxia-selective activation,and provides a preferable solution to high-efficiency cancer therapy.展开更多
Chalcogenative sulfones(thiosulfonates and selenosulfonates), as reactants for organic transformations,are widely used and interesting because of their potential to react with nucleophiles, electrophiles, and free rad...Chalcogenative sulfones(thiosulfonates and selenosulfonates), as reactants for organic transformations,are widely used and interesting because of their potential to react with nucleophiles, electrophiles, and free radicals. As stable radical reagents, the synthesis and applications of chalcogenative sulfones have opened up a novel pathway to synthesize many kinds of compounds containing sulfur or selenium motifs. However, despite the numerous recent works on the synthesis and applications of thiosulfonates and selenosulfonates as radical reagents, no review has yet provided a summary of the literature. In this paper, we aim to review the synthesis and applications strategies of chalcogenative sulfones as radical reagents reported over the past several decades. Different types of catalysis are discussed in this review:(i) metal catalysis;(ii) visible-light catalysis;(iii) synergistic catalysis;and(iiii) other types. Concurrently,in visible-light catalysis and metallaphotoredox catalysis sections, we highlight that developing relatively environmentally friendly synthetic methods in this area is always a great challenge, but also a persistent pursuit. Finally, the scopes, limitations, mechanisms, and existing problems of some reactions are described briefly.展开更多
An efficient photochemical radical sulfonyl cyclization of designed dienes to medium-sized benzo[b]azocines and benzo[b]azonines was developed.This chemoselective method provides new highly functionalized eight-and ni...An efficient photochemical radical sulfonyl cyclization of designed dienes to medium-sized benzo[b]azocines and benzo[b]azonines was developed.This chemoselective method provides new highly functionalized eight-and nine-membered N-heterocycles.Radical inhibition experiments,light on/off experiments,and apparent quantum efficiency calculations were used to clarify the radical mechanism.Density functional theory calculations enabled rationalization of the rate-determining step and observed chemoselectivity.Large-scale synthesis and derivatizations via epoxidation and convenient N-Ts deprotection showed the potential utility of this strategy.This photochemical method for synthesizing sulfonylbenzo[b]azocines and sulfonylbenzo[b]azonines with insertion of sulfur dioxide provides new sustainable routes for the synthesis of valuable medium-sized Nheterocycles.展开更多
The buried heterointerface of perovskite solar cells(PSCs)suffers from serious nonradiative recombination and ultraviolet(UV)light stress,relentlessly limiting further increase in their power conversion efficiency and...The buried heterointerface of perovskite solar cells(PSCs)suffers from serious nonradiative recombination and ultraviolet(UV)light stress,relentlessly limiting further increase in their power conversion efficiency and operational stability.Herein,we develop an emerging strategy of incorporating a thin UV-activated tautomeric transition layer onto underlying charge transport layer and then depositing perovskite layer to construct an efficient hole-selective buried heterojunction.It is revealed that the UV-activated tautomeric transition interlayer not only improves upper perovskite crystallinity,diminishes thermionic loss for collecting hole and passivates defect site at such buried contact that significantly promote charge transport and suppress nonradiative recombination,but also effectively protects adjacent perovskite from UV degradation through“UV sunscreen”effect.As a result,we report a remarkably enhanced efficiency of 24.76%compared to 22.02%of the control device.More importantly,the achieved high-efficiency PSC features excellent resistance against UV radiation at 365 nm of 100 and 850 mW cm^(−2),which are approximately 21 and 184 times of UV flux(4.6 mW cm^(−2))under AM 1.5G solar illumination.This work provides a promising approach of strengthening buried heterointerface for simultaneous realization of highly efficient and UV robust PSCs.展开更多
基金supported by grants from the National Natural Science Foundation of China(81970072 to LXT)the Leading Medical Talent Project of Shanghai Pudong Heath Bureau(PWRI2019-05 to LXT)+3 种基金the Action Plan for Scientific and Technological Innovation of Shanghai Scientific Committee of China(20Y11901200 to LXT)the Municipal Natural Science Foundation of Shanghai Scientific Committee of China(22ZR1451000 to LXT)the Key Clinical Discipline of Shanghai Pudong Heath Bureau(PWZxk2022-17 to LXT)the Clinical Peak Discipline of Shanghai Pudong Heath Bureau(PWYgf2021-03)。
文摘Autoimmune encephalitis(AE)is a type of encephalitis caused by autoimmune disease.AE was included on a list of the first batch of 121 rare diseases published by the Chinese National Health Commission on 11^(th)May 2018.Currently,patients with AE account for 10%-20% of encephalitis cases,with 54%-80% of those cases classified as the anti-N-methyl-D-aspartate receptor(NMDAR)type,which is the most common type.[1]In 2010,China reported the first case of a patient withanti-NMDARtype AE.
基金funded by the National Key R&D Program of China(2022YFE0199700).
文摘This study established a simple,rapid,and accurate nuclear magnetic resonance(NMR)quantitative method to determine the cefpodoxime proxetil content in raw materials and dry suspensions,and evaluated the uncertainty.The relative content of cefpodoxime proxetil iso-A and iso-B was also analyzed based on 1H NMR.In this study,an internal standard method was used,with DMSO-d6 as the solvent and maleic acid and 1,3,5-trimethylbenzene as internal standards,to calculate the concentration of the samples.Quantitative analysis was performed using both the traditional quantitative NMR(traditional qNMR)and the quantitative Global Spectral Deconvolution(qGSD)method.The linearity range,quantitation limit,precision,robustness,and accuracy of these quantitative analysis methods were validated.The results indicated that both internal standards and integration methods met the requirements of the“9101 Guidelines for Analytical Method Validation”in the 2020 edition of the Chinese Pharmacopoeia.Compared to the traditional qNMR,qGSD has unique advantages in accurate quantitative analysis in complex systems.By using the combined HPLC-SPE-NMR technique,cefpodoxime proxetil iso-A and iso-B were enriched and analyzed,and their NMR data were accurately assigned.The quantitative analysis results were in line with the requirements of the Chinese Pharmacopoeia.
基金This work was financially supported by the Natural Science Foundation of Guangxi Province(Nos.2018JJB140325,2018JJB140377)Guangxi Scientific and Technology Base and Talents of Project(Nos.2018AD19035)+2 种基金Talents Project for Cultivating High-level Talent Teams in the Qi Huang Project of Guangxi University of Chinese Medicine(2018002)the specific subject of the dominant discipline construction of Chinese Pharmacy of Guangxi University of Chinese Medicine,Guang Xi Key Laboratory of Translational Medicine for Treating High-incidence Infectious Diseases with Integrative Medicine and School research projects(no.B170021,2018MS003)Scientific Research Projects of Guangxi University of Chinese Medicine(B170021,2018MS003).
文摘Various drug transporters are widely expressed throughout the intestine and play important roles in absorbing nutrients and drugs,thus providing high quality targets for the design of prodrugs or nanoparticles to facilitate oral drug delivery.In particular,intestinal carnitine/organic cation transporter 2(OCTN2)and mono-carboxylate transporter protein 1(MCT1)possess high transport capacities and complementary distributions.Therefore,we outline recent developments in transporter-targeted oral drug delivery with regard to the OCTN2 and MCT1 proteins in this review.First,basic information of the two transporters is reviewed,including their topological structures,characteristics and functions,expression and key features of their substrates.Furthermore,progress in transporter-targeting prodrugs and nanoparticles to increase oral drug delivery is discussed,including improvements in the oral absorption of anti-inflammatory drugs,antiepileptic drugs and anticancer drugs.Finally,the potential of a dual transporter-targeting strategy is discussed.
基金supported by the National Basic Research Program of China (No. 81573371)the key projects of Liaoning Province Department of Education (No. 2017LZD03)
文摘Although it is reported that the targeting ability of hyaluronic acid(HA)-based nanoparticles(NPs) is molecular weight(MW) dependent,the influence of HA MW on targeting efficiency of HA-functionalized NPs and the underlying mechanism remain elusive. In this study,we constituted three HA-functionalized Dox-loaded NPs(Dox/HCVs) different HA MWs(7,63,and 102 k Da) and attempted to illustrate the effects of HA MW on the targeting efficiency.The three Dox/HCVs had similar physiochemical and pharmaceutical characteristics,but showed different affinity to CD44 receptor. Furthermore,Dox/HCV-63 exerted the best targeting effect and the highest cytotoxicity compared with Dox/HCV-7 and Dox/HCV-102. It was interesting to found that both the HA-CD44 binding affinity and induced CD44 clustering by HA-based NPs were HA MW-dependent,the two of which determine the apparent targeting efficacy of Dox/HCV NPs in the conflicting directions. Those results laid a good foundation for rationally designing HA-based NPs in cancer therapy.
基金the financial support from the National Natural Science Foundation of China (No. 81173009)Technology Bureau in Shenyang (No. ZCJJ2013402)+2 种基金the financial support from Project for New Century Excellent Talents of Ministry of Education (No.NCET-12-1015)Specific Science Foundation of Shenyang Pharmaceutical University (No. ZCJJ2014409)National Undergraduate Training Program for Innovation and Entrepreneurship (2016)
文摘A simple and rapid UPLC–MS/MS method to simultaneously determine gemcitabine and its L-carnitine ester derivative(2’-deoxy-2’, 2’-difluoro-N-((4-amino-4-oxobutanoyl) oxy)-4-(trimethyl amm-onio) butanoate-cytidine, JDR) in rat plasma was developed and validated.The conventional plasma sample preparation method of nucleoside analogues is solidphase extraction(SPE) which is time-consuming and cost-expensive. In this study, gradient elution with small particles size solid phase was applied to effectively separate gemcitabine and JDR, and protein precipitation pretreatment was adopted to remove plasma protein and extract the analytes with high recovery(>81%). Method validation was performed as per the FDA guidelines, and the standard curves were found to be linear in the range of 5–4000 ng/ml for JDR and 4–4000 ng/ml for gemcitabine, respectively. The lower limit of quantitation(LLOQ)of gemcitabine and JDR was 4 and 5 ng/ml, respectively. The intra-day and inter-day precision and accuracy results were within the acceptable limits. Finally, the developed method was successfully applied to investigate the pharmacokinetic studies of JDR and gemcitabine after oral administration to rats.
基金financially Supported by National Nature Sci-ence Foundation of China(No.81773656,U1608283,81573497)Liaoning Revitalization Talents Program,No XLYC1808017,Key projects of Technology bureau in Shenyang,No18400408Key projects of Liaoning Province Department of Education,No.2017LZD03
文摘Monocarboxylate transporter 1(MCT1)is responsible for oral absorption of short-chain monocarboxylic acids from small intestine,hence,it’s likely to serve as an ideal design target for the development of oral prodrugs.However,potential application of MCT1 to facilitate the oral delivery is still unclear.Irregular oral absorption,poor permeability and bioavailability greatly limit the oral delivery efficiency of 5-fluorouracil(5-FU).Herein,we design three 5-FU-fatty acid conjugates targeting intestinal MCT1 with different lipophilic linkages.Interestingly,due to high MCT1 affinity and good gastrointestinal stability,5-FUoctanedioic acid monoester prodrug exhibited significant improvement in membrane permeability(13.1-fold)and oral bioavailability(4.1-fold)compared to 5-FU.More surprisingly,stability experiment in intestinal homogenates showed that 5-FU prodrugs could be properly activated to release 5-FU within intestinal cells,which provides an ideal foundation for the improvement of oral bioavailability.In summary,good gastrointestinal stability,high membrane permeability and appropriate intestinal cell bioactivation are the important factors for high-efficiency 5-FU oral prodrugs,and such work provides a good platform for the development of novel oral prodrugs targeting intestinal transporters.
基金supported by the National Natural Science Foundation of China(No.21801007)Qingchuang Technology Support Program of University in Shandong Province(No.2021KJ066)S.-F.Ni acknowledges funding from the STU Scientific Research Foundation for Talents(No.NTF20022).
文摘The preparation of medium-sized benzo[b]azocines has always been challenging because of inherently unfavorable enthalpy and entropy factors.This report presents a novel approach for accessing 8-membered seleno-benzo[b]azocines via electrochemically-driven seleno-cyclization.This method enables room-temperature preparation of various structurally diverse medium-sized seleno-benzo[b]azocines.The facile deselenation of the seleno-cyclization products to generate functionalized dienes is an additional benefit of this indispensable reaction.Mechanistic insights are presented based on radical inhibition experiments and cyclic voltammetry measurements,which elucidate the radical pathway.Finally,density functional theory calculations further rationalize the rate-determining step and the unique chemoselectivity observed in this transformation.
基金supported by grants from the municipal Natural Science Foundation of Shanghai Scientific Committee of China(22ZR1451000 to TL)the peak supporting clinical discipline of Shanghai Health Bureau(2023ZDFC0104 to TL)+3 种基金the key clinical discipline of Shanghai Pudong Health Bureau(PWZxk2022-17 to TL)the clinical peak discipline of Shanghai Pudong Heath Bureau(PWYgf2021-03)the top-notch innovative medical talents of Shanghai Pudong Health Bureau(2025PDWSYCBJ-03 to TL)the leading medical talent project of Shanghai Pudong Heath Bureau(PWR12020-07 to LS)。
文摘BACKGROUND:Circulating biomarkers for sepsis are lacking,and research on circular RNAs(circR NAs)as potential biomarkers of pneumonia-induced sepsis is limited.This study aims to investigate the diagnostic and prognostic potential of circRNAs in patients with pneumonia-induced sepsis.METHODS:This prospective cohort study included 40 healthy individuals,60 patients with pneumonia,and 80 patients with pneumonia-induced sepsis.CircRNAs identified through RNA-sequencing were validated using quantitative real-time polymerase chain reaction(qRT-PCR).Spearman correlation analysis was used to evaluate the associations between circRNAs,inflammatory markers,Sequential Organ Failure Assessment(SOFA)scores,and Acute Physiology and Chronic Health EvaluationⅡ(APACHEⅡ)scores.Receiver operating characteristic(ROC)curves analysis were used to assess the diagnostic performance of circRNAs,while ROC curves and Kaplan-Meier survival analysis were used to evaluate their prognostic value of 28-day mortality.RESULTS:qRT-PCR confirmed the significant upregulation of Circ-CTD-2281E23.2 and downregulation of Circ-0075723 and Circ-0008679 in sepsis patients.Spearman correlation analysis showed that Circ-CTD-2281E23.2 was positively correlated with inflammatory markers and severity scores,whereas Circ-0075723 and Circ-0008679 were negatively correlated with these parameters.The area under the curve(AUC)values for Circ-CTD-2281E23.2,Circ-0075723,and Circ-0008679 in diagnosing pneumonia-induced sepsis were 0.728,0.706,and 0.793,respectively.The combination of these circRNAs(AUC=0.846)and the combination with other clinical indicators(AUC=0.990)demostrated enhanced AUC values.The AUC values for Circ-CTD-2281E23.2 and Circ-0075723 in predicting 28-day mortality were 0.664 and 0.765,respectively.CONCLUSION:This study suggest the additional diagnostic and prognostic value of circRNAs in pneumonia-induced sepsis.Circ-CTD-2281E23.2,Circ-0075723,and Circ-0008679 exhibit diagnostic potential,with Circ-CTD-2281E23.2 and Circ-0075723 showing positive prognostic value for 28-day mortality in sepsis patients.
基金financially supported by National Natural Science Foundation of China(Nos.81573371 and U1608283)Liaoning Revitalization Talents Program(No.XLYC1808017,China)+1 种基金Key projects of Technology Bureau in Shenyang(No.18400408,China)Key Projects of Liaoning Province Department of Education(No.2017LZD03,China)
文摘Hypoxia, a salient feature of most solid tumors, confers invasiveness and resistance to the tumor cells. Oxygen-consumption photodynamic therapy(PDT) suffers from the undesirable impediment of local hypoxia in tumors. Moreover, PDT could further worsen hypoxia. Therefore, developing effective strategies for manipulating hypoxia and improving the effectiveness of PDT has been a focus on antitumor treatment. In this review, the mechanism and relationship of tumor hypoxia and PDT are discussed.Moreover, we highlight recent trends in the field of nanomedicines to modulate hypoxia for enhancing PDT, such as oxygen supply systems, down-regulation of oxygen consumption and hypoxia utilization.Finally, the opportunities and challenges are put forward to facilitate the development and clinical transformation of PDT.
基金supported by the National Basic Research Program of China(No.81573371)the Key Projects of Liaoning Province Department of Education(No.2017LZD03,China)
文摘Hyaluronic acid(HA) is a natural ligand of tumor-targeted drug delivery systems(DDS) due to the relevant CD44 receptor overexpressed on tumor cell membranes. However, other HA receptors(HARE and LYVE-1) are also overexpressing in the reticuloendothelial system(RES). Therefore,polyethylene glycol(PEG) modification of HA-based DDS is necessary to reduce RES capture.Unfortunately, pegylation remarkably inhibits tumor cellular uptake and endosomal escapement,significantly compromising the in vivo antitumor efficacy. Herein, we developed a Dox-loaded HA-based transformable supramolecular nanoplatform(Dox/HCVBP) to overcome this dilemma. Dox/HCVBP contains a tumor extracellular acidity-sensitive detachable PEG shell achieved by a benzoic imine linkage.The in vitro and in vivo investigations further demonstrated that Dox/HCVBP could be in a "stealth" state at blood stream for a long circulation time due to the buried HA ligands and the minimized nonspecific interaction by PEG shell. However, it could transform into a "recognition" state under the tumor acidic microenvironment for efficient tumor cellular uptake due to the direct exposure of active targeting ligand HA following PEG shell detachment. Such a transformative concept provides a promising strategy to resolve the dilemma of natural ligand-based DDS with conflicting two processes of tumor cellular uptake and in vivo nonspecific biodistribution.
基金financially supported by the National Natural Science Foundation of China(No.81773656)Liaoning Revitalization Talents Program(No.XLYC1808017,China)+1 种基金Shenyang Youth Science and Technology Innovation Talents Program(No.RC190454,China)College Student Innovation and Entrepreneurship Training Program of Shenyang Pharmaceutical University(No.X202010163141,China)。
文摘The unique characteristics of the tumor microenvironment(TME)could be exploited to develop antitumor nanomedicine strategies.However,in many cases,the actual therapeutic effect is far from reaching our expectations due to the notable tumor heterogeneity.Given the amplified characteristics of TME regulated by vascular disrupting agents(VDAs),nanomedicines may achieve unexpected improved efficacy.Herein,we fabricate platelet membrane-fusogenic liposomes(PML/DP&PPa),namely“platesomes”,which actively load the hypoxia-activated pro-prodrug DMG-PR104A(DP)and physically encapsulate the photosensitizer pyropheophorbide a(PPa).Considering the different stages of tumor vascular collapse and shutdown induced by a VDA combretastatin-A4 phosphate(CA4P),PML/DP&PPa is injected 3 h after intraperitoneal administration of CA4P.First,CA4P-mediated tumor hemorrhage amplifies the enhanced permeation and retention(EPR)effect,and the platesome-biological targeting further promotes the tumor accumulation of PML/DP&PPa.Besides,CA4P-induced vascular occlusion inhibits oxygen supply,followed by photodynamic therapy-caused acute tumor hypoxia.This prolonged extreme hypoxia contributes to the complete activation of DP and then high inhibitory effect on tumor growth and metastasis.Thus,such a combining strategy of artificially-regulated TME and bio-inspired platesomes pronouncedly improves tumor drug delivery and boosts tumor hypoxia-selective activation,and provides a preferable solution to high-efficiency cancer therapy.
基金supported by the National Natural Science Foundation of China (No. 21801007)Qingchuang Technology Support Program of University in Shandong Province (No. 2021KJ066)Hunan Engineering Laboratory for analyse and Drugs Development of Ethnomedicine in Wunlin Mountains (No. Hgxy2103)。
文摘Chalcogenative sulfones(thiosulfonates and selenosulfonates), as reactants for organic transformations,are widely used and interesting because of their potential to react with nucleophiles, electrophiles, and free radicals. As stable radical reagents, the synthesis and applications of chalcogenative sulfones have opened up a novel pathway to synthesize many kinds of compounds containing sulfur or selenium motifs. However, despite the numerous recent works on the synthesis and applications of thiosulfonates and selenosulfonates as radical reagents, no review has yet provided a summary of the literature. In this paper, we aim to review the synthesis and applications strategies of chalcogenative sulfones as radical reagents reported over the past several decades. Different types of catalysis are discussed in this review:(i) metal catalysis;(ii) visible-light catalysis;(iii) synergistic catalysis;and(iiii) other types. Concurrently,in visible-light catalysis and metallaphotoredox catalysis sections, we highlight that developing relatively environmentally friendly synthetic methods in this area is always a great challenge, but also a persistent pursuit. Finally, the scopes, limitations, mechanisms, and existing problems of some reactions are described briefly.
基金supported by the National Natural Science Foundation of China(21801007)Qingchuang Technology Support Program of University in Shandong Province(2021KJ066)funding from the STU Scientific Research Foundation for Talents(NTF20022)。
文摘An efficient photochemical radical sulfonyl cyclization of designed dienes to medium-sized benzo[b]azocines and benzo[b]azonines was developed.This chemoselective method provides new highly functionalized eight-and nine-membered N-heterocycles.Radical inhibition experiments,light on/off experiments,and apparent quantum efficiency calculations were used to clarify the radical mechanism.Density functional theory calculations enabled rationalization of the rate-determining step and observed chemoselectivity.Large-scale synthesis and derivatizations via epoxidation and convenient N-Ts deprotection showed the potential utility of this strategy.This photochemical method for synthesizing sulfonylbenzo[b]azocines and sulfonylbenzo[b]azonines with insertion of sulfur dioxide provides new sustainable routes for the synthesis of valuable medium-sized Nheterocycles.
基金supported by the National Natural Science Foundation of China(62322407,22279034,52261145698)the National Key Research and Development Program of China(2022YFB3803300)+1 种基金the Shanghai Science and Technology Innovation Action Plan(22ZR1418900)Xiong S thanks the project funded by China Postdoctoral Science Foundation(BX20220089,2022M720742).
文摘The buried heterointerface of perovskite solar cells(PSCs)suffers from serious nonradiative recombination and ultraviolet(UV)light stress,relentlessly limiting further increase in their power conversion efficiency and operational stability.Herein,we develop an emerging strategy of incorporating a thin UV-activated tautomeric transition layer onto underlying charge transport layer and then depositing perovskite layer to construct an efficient hole-selective buried heterojunction.It is revealed that the UV-activated tautomeric transition interlayer not only improves upper perovskite crystallinity,diminishes thermionic loss for collecting hole and passivates defect site at such buried contact that significantly promote charge transport and suppress nonradiative recombination,but also effectively protects adjacent perovskite from UV degradation through“UV sunscreen”effect.As a result,we report a remarkably enhanced efficiency of 24.76%compared to 22.02%of the control device.More importantly,the achieved high-efficiency PSC features excellent resistance against UV radiation at 365 nm of 100 and 850 mW cm^(−2),which are approximately 21 and 184 times of UV flux(4.6 mW cm^(−2))under AM 1.5G solar illumination.This work provides a promising approach of strengthening buried heterointerface for simultaneous realization of highly efficient and UV robust PSCs.
