Until now, there are no publications about the preformulation studies on(S)-zaltoprofen((S)-ZPF). Hence, we first investigated the solubility of(S)-ZPF, screened solubilizers and performed the pharmacokinetic study of...Until now, there are no publications about the preformulation studies on(S)-zaltoprofen((S)-ZPF). Hence, we first investigated the solubility of(S)-ZPF, screened solubilizers and performed the pharmacokinetic study of(S)-ZPF in the presence of the solubilizers. The measurement of the solubility of(S)-ZPF in 26 different solvents was carried out, including d-alpha tocopheryl polyethylene glycol 1000 succinate(TPGS), 2-hydroxypropyl-β-cyclodextrin(HPCD), and mixtures of individual solvent. The plasma concentration of(S)-ZPF and the amount of(S)-ZPF retained in stomach were determined after oral(35.0 mg/kg) and intravenous(5.0 mg/kg) administration. The solubility of(S)-ZPF showed an increase of 484-fold in TPGS compared to its aqueous solubility. There was a significant increase of AUC 0-24 h for pure(S)-ZPF in the TPGS group(813.59 ± 64.17 μg h/ml) in comparison with AUC 0-24 h in the HPCD group(595.57 ± 71.76 μg h/ml) and water group(465.57 ± 90.89 μg h/ml). In addition, the T max of(S)-ZPF in the TPGS group was 2 h, much faster than that in the HPCD or water groups(5.50 or 5.67 h, respectively). This suggested that TPGS played a significant role in the increase of solubility and bioavailability of(S)-ZPF.展开更多
Comprehensive Summary An asymmetric synthesis of dihydrospirotryprostatin B was achieved in 15 steps(8 purifications)from L-tryptophan.The main feature of our synthetic strategy is the efficient construction of spiroc...Comprehensive Summary An asymmetric synthesis of dihydrospirotryprostatin B was achieved in 15 steps(8 purifications)from L-tryptophan.The main feature of our synthetic strategy is the efficient construction of spirocyclic oxindole intermediate containing a chiral quaternary carbon center,involving the silica gel-mediated cyclization of tryptamine-ynamide and oxidation under neat conditions.展开更多
The study aimed to achieve enhanced targeted cytotoxicity and cell-internalization of cisplatin-loaded deoxyribonucleic acid-nanothread(CPT-DNA-NT),mediated by scavenger receptors into HeLa cells.DNA-NT was developed ...The study aimed to achieve enhanced targeted cytotoxicity and cell-internalization of cisplatin-loaded deoxyribonucleic acid-nanothread(CPT-DNA-NT),mediated by scavenger receptors into HeLa cells.DNA-NT was developed with stiff-topology utilizing circular-scaffold to encapsulate CPT.Atomic force microscopy(AFM)characterization of the DNA-NT showed uniformity in the structure with a diameter of 50-150 nm and length of 300-600 nm.The successful fabrication of the DNA-NT was confirmed through native-polyacrylamide gel electrophoresis analysis,as large the molecular-weight(polymeric)DNA-NT did not split into constituting strands under applied current and voltage.The results of cell viability confirmed that blank DNA-NT had the least cytotoxicity at the highest concentration(512 nM)with a viability of 92%as evidence of its biocompatibility for drug delivery.MTT assay showed superior cytotoxicity of CPT-DNA-NT than that of the free CPT due to the depot release of CPT after DNA-NT internalization.The DNA-NT exhibited targeted cell internalizations with the controlled intracellular release of CPT(from DNA-NT),as illustrated in confocal images.Therefore,in vitro cytotoxicity assessment through flow cytometry showed enhanced apoptosis(72.7%)with CPT-DNA-NT(compared to free CPT;64.4%).CPT-DNA-NT,being poly-anionic,showed enhanced endocytosis via scavenger receptors.展开更多
Inflammatory bowel diseases(IBD)are the incurable chronic recurrent gastrointestinal disorders and currently lack in safe and effective drugs.In this study,patchouli alcohol,a main active compound of traditional Chine...Inflammatory bowel diseases(IBD)are the incurable chronic recurrent gastrointestinal disorders and currently lack in safe and effective drugs.In this study,patchouli alcohol,a main active compound of traditional Chinese herb patchouli,was developed into biomimetic liposomes for macrophagetargeting delivery for IBD treatment.The developed lactoferrin-modified liposomes(LF-lipo)can specifically bind to LRP-1 expressed on the activated colonic macrophages and achieve cell-targeting anti-inflammatory therapy.LF-lipo reduced the levels of inflammatory cytokines and ROS and suppressed the MAPK/NF-κB pathway.LF-lipo also suppressed the formation of NLRP3 inflammasome and the consequent IL-1βactivation.LF-lipo showed improved therapeutic efficacy in a DSS-induced colitis murine model,evidenced by the reduced disease activity index,the improved colon functions,and the downregulated inflammatory cytokines in the colon.LF-lipo provided an effective and safe macrophagetargeting delivery and therapeutic strategy for addressing the unmet medical need in IBD management.展开更多
OBJECTIVE: To systematically investigate the safety of Xingxue~ Shuxuening injection(SXN) in preand post-marketing, and to ensure clinical drug safety.METHODS: Strict quality control in raw herb selection and producti...OBJECTIVE: To systematically investigate the safety of Xingxue~ Shuxuening injection(SXN) in preand post-marketing, and to ensure clinical drug safety.METHODS: Strict quality control in raw herb selection and production processes was adopted and pharmacology research on SXN was performed by the drug manufacturing company, Heilongjiang ZBD Pharmaceutical Co., Ltd. We systematically reviewed the safety literature of Xingxue~ SXN. Adverse drug reaction(ADR) data of the drug, extracted from Spontaneous Reporting System(SRS), and clinical characters based on 20 hospital information systems(HIS) in China, were analyzed. Large-scale prospective safety monitoring and Risk Minimization Action Plans(Risk MAPs) of Xingxue~SXN were carried out.RESULTS: The quality of SXN was stable and controllable when it was produced. Drug toxicology studies found no effect on rabbits with hemolytic or condensed, local stimulation and muscle stimulation, and no allergic reactions in guinea pigs. The ADRs of Xingxue~ SXN were dizziness, phlebitis,and vomiting based on SRS data. The injection did not conform to instructions in clinical practice when we analyzed HIS database, and patient’s abnormal blood urea nitrogen levels may be related to the drug, when analyzed using the propensity score method. A nested case-control study was designed and performed to analyze the influencing factors of suspected allergic reactions to SXN. The study showed that patients with an allergy history were more prone to allergic reactions(P<0.001),and some medicine combinations could cause allergic reactions.CONCLUSION: These studies have established a body of evidence on Xingxue~ SXN safety, and provide a good model for Chinese medicine injection for clinical safety. The Xingxue~ SXN production process and toxicology research indicate the safety of the injection. However, the use of the injection is not consistent with instructed clinical practice.Xingxue~ SXN causes ADRs perhaps from inappropriate usage or its pharmacological action. This injection needs better Risk MAPs to ensure its clinical safety.展开更多
Objective To investigate the effects of total flavonoid fraction(TFF) from Nervilia fordii on lipopolysaccharide(LPS)-induced acute lung injury(ALI) in rats,and to explore their protective mechanism.Methods LPS-induce...Objective To investigate the effects of total flavonoid fraction(TFF) from Nervilia fordii on lipopolysaccharide(LPS)-induced acute lung injury(ALI) in rats,and to explore their protective mechanism.Methods LPS-induced ALI model was established by LPS(5 mg/kg) injection via left cervical vein.Blood samples were collected from the cervical artery of all rats at 5 and 6 h after LPS challenge for arterial blood gas test and cytokines measurements,and pulmonary microvascular permeability(PMP),lung wet/dry weight ratio(W/D),and pathological features were observed.Results Phytochemical study showed that the TFF contained 67.3% of flavonoids expressed in rutin and three flavone glycosides.The TFF pretreatment(6.24 and 12.48 mg/kg) attenuated the partial arterial pressure of oxygen decline in blood significantly,and decreased the PMP and lung W/D in ALI rats.In addition,the TFF(6.24 and 12.48 mg/kg) also ameliorated the LPS-induced lung damages including alveolar edema,neutrophils infiltration,alveolar hemorrhage,and thickening of the alveolar wall.Furthermore,the treatment with the TFF(6.24 and 12.48 mg/kg) also down-regulated the levels of pro-inflammatory cytokines,such as tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),and intercellular adhesion molecule-1(ICAM-1),and up-regulated the level of anti-inflammatory cytokine IL-10 in serum of ALI rats simultaneously.Conclusion These results suggest that the TFF could protect LPS-induced ALI in rats,which may be mediated,at least in part,by adjusting the production of inflammatory cytokines including TNF-α,IL-6,ICAM-1,and IL-10.展开更多
A gold(Ⅰ)-catalyzed 6-endo-dig cyclization of aromatic 1,5-enynes was developed to synthesize 2-(naphthalen-2-yl)anilines.The functional group tolerance of this cyclization was examined systematically and a possible ...A gold(Ⅰ)-catalyzed 6-endo-dig cyclization of aromatic 1,5-enynes was developed to synthesize 2-(naphthalen-2-yl)anilines.The functional group tolerance of this cyclization was examined systematically and a possible mechanism was proposed.The derivatization of 2-(naphthalen-2-yl)aniline was carried out to facile access to benzo[α]carbazole,benzo[c,h]cinnoline and dibenzo[i]phenanthridine derivatives in a divergent way.展开更多
Gene therapy has drawn great attention in the treatments of many diseases,especially for cardiovascular diseases.However,the development of gene carriers with low cytotoxicity and multitargeting function is still a ch...Gene therapy has drawn great attention in the treatments of many diseases,especially for cardiovascular diseases.However,the development of gene carriers with low cytotoxicity and multitargeting function is still a challenge.Herein,the multitargeting REDV-G-TATG-NLS peptide was conjugated to amphiphilic cationic copolymer poly(e-caprolactone-co-3(S)-methyl-morpho-line-2,5-dione)-g-polyethyleneimine(PCLMD-g-PEI)via a heterobifunctional orthopyridyl disulfde-poly(ethylene glycol)-N-hydroxysuccinimide(OPSS-PEG-NHS)linker to prepare PCLMD-g-PEI-PEG-REDV-G-TAT-G-NLS copolymers with the aim to develop the gene carriers with low cytotoxicity and high transfection efficiency.The multitargeting micelles were prepared from PCLMD-g-PEI-PEG-REDV-G-TAT-G-NLS copolymers by self-assembly method and used to load pEGFP-ZNF580 plasmids(pDNA)to form gene complexes for enhancing the proliferation and migration of endothelial cells(ECs).The loading pDNA capacity was proved by agarose gel electrophoresis assay.These multitargeting gene com-plexes exhibited low cytotoxicity by 3-(4,-dimethylthia-zol-2-yl)-2,5-diphenyltetrazolium bromide assay.The high internalization efficiency of these gene complexes was confirmed by flow cytometry.The results of in vitro transfection demonstrated that these multitargeting gene complexes possessed relatively high transfection effi-ciency.The rapid migration of ECs transfected by these gene complexes was verified by wound healing assay.Owing to ECs-targeting ability,cell-penetrating ability and nuclear targeting capacity of REDV-G-TAT-G-NLS pep-tide,the multitargeting polycationic gene carrier with low cytotoxicity and high transfection efficiency has great potential in gene therapy.展开更多
The authors regret that there was an error in our publication.Considering Lingchuang Bai made great contributions to this work,Xinghong Duo and Lingchuang Bai should be co-first authors,but there was no statement that...The authors regret that there was an error in our publication.Considering Lingchuang Bai made great contributions to this work,Xinghong Duo and Lingchuang Bai should be co-first authors,but there was no statement that“Xinghong Duo and Lingchuang Bai contributed equally to this work”.The authors would like to apologize for any inconvenience caused.展开更多
基金supported by the Basic Science Research Program (2016R1A2B4011294) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology
文摘Until now, there are no publications about the preformulation studies on(S)-zaltoprofen((S)-ZPF). Hence, we first investigated the solubility of(S)-ZPF, screened solubilizers and performed the pharmacokinetic study of(S)-ZPF in the presence of the solubilizers. The measurement of the solubility of(S)-ZPF in 26 different solvents was carried out, including d-alpha tocopheryl polyethylene glycol 1000 succinate(TPGS), 2-hydroxypropyl-β-cyclodextrin(HPCD), and mixtures of individual solvent. The plasma concentration of(S)-ZPF and the amount of(S)-ZPF retained in stomach were determined after oral(35.0 mg/kg) and intravenous(5.0 mg/kg) administration. The solubility of(S)-ZPF showed an increase of 484-fold in TPGS compared to its aqueous solubility. There was a significant increase of AUC 0-24 h for pure(S)-ZPF in the TPGS group(813.59 ± 64.17 μg h/ml) in comparison with AUC 0-24 h in the HPCD group(595.57 ± 71.76 μg h/ml) and water group(465.57 ± 90.89 μg h/ml). In addition, the T max of(S)-ZPF in the TPGS group was 2 h, much faster than that in the HPCD or water groups(5.50 or 5.67 h, respectively). This suggested that TPGS played a significant role in the increase of solubility and bioavailability of(S)-ZPF.
基金the National Natural Science Foundation of China(22277082)Liaoning Province Education Administration of China(LJKQz2022236)+1 种基金Liaoning Provincial Foundation of Natural Science(2022-MS-245)China Postdoctoral Science Foundation(2022MD723807)for financial support.
文摘Comprehensive Summary An asymmetric synthesis of dihydrospirotryprostatin B was achieved in 15 steps(8 purifications)from L-tryptophan.The main feature of our synthetic strategy is the efficient construction of spirocyclic oxindole intermediate containing a chiral quaternary carbon center,involving the silica gel-mediated cyclization of tryptamine-ynamide and oxidation under neat conditions.
基金supported by the China Scholarship Council(CSC)grant(Grant No.20180500458)。
文摘The study aimed to achieve enhanced targeted cytotoxicity and cell-internalization of cisplatin-loaded deoxyribonucleic acid-nanothread(CPT-DNA-NT),mediated by scavenger receptors into HeLa cells.DNA-NT was developed with stiff-topology utilizing circular-scaffold to encapsulate CPT.Atomic force microscopy(AFM)characterization of the DNA-NT showed uniformity in the structure with a diameter of 50-150 nm and length of 300-600 nm.The successful fabrication of the DNA-NT was confirmed through native-polyacrylamide gel electrophoresis analysis,as large the molecular-weight(polymeric)DNA-NT did not split into constituting strands under applied current and voltage.The results of cell viability confirmed that blank DNA-NT had the least cytotoxicity at the highest concentration(512 nM)with a viability of 92%as evidence of its biocompatibility for drug delivery.MTT assay showed superior cytotoxicity of CPT-DNA-NT than that of the free CPT due to the depot release of CPT after DNA-NT internalization.The DNA-NT exhibited targeted cell internalizations with the controlled intracellular release of CPT(from DNA-NT),as illustrated in confocal images.Therefore,in vitro cytotoxicity assessment through flow cytometry showed enhanced apoptosis(72.7%)with CPT-DNA-NT(compared to free CPT;64.4%).CPT-DNA-NT,being poly-anionic,showed enhanced endocytosis via scavenger receptors.
基金the financial support of National Natural Science Foundation of China(Nos.81925035,81673382 and 81521005)the Strategic Priority Research Program of Chinese Academy of Sciences(XDA12050307,China)+2 种基金National Special Project for Significant New Drugs Development(2018ZX09711002-010-002,China)Shanghai Sci Tech Innovation Initiative(19431903100 and 18430740800,China)the Fudan-SIMM Joint Research Fund(FU-SIMM20174009,China)for the support
文摘Inflammatory bowel diseases(IBD)are the incurable chronic recurrent gastrointestinal disorders and currently lack in safe and effective drugs.In this study,patchouli alcohol,a main active compound of traditional Chinese herb patchouli,was developed into biomimetic liposomes for macrophagetargeting delivery for IBD treatment.The developed lactoferrin-modified liposomes(LF-lipo)can specifically bind to LRP-1 expressed on the activated colonic macrophages and achieve cell-targeting anti-inflammatory therapy.LF-lipo reduced the levels of inflammatory cytokines and ROS and suppressed the MAPK/NF-κB pathway.LF-lipo also suppressed the formation of NLRP3 inflammasome and the consequent IL-1βactivation.LF-lipo showed improved therapeutic efficacy in a DSS-induced colitis murine model,evidenced by the reduced disease activity index,the improved colon functions,and the downregulated inflammatory cytokines in the colon.LF-lipo provided an effective and safe macrophagetargeting delivery and therapeutic strategy for addressing the unmet medical need in IBD management.
基金Supported by National Science and Technology Major Projects for "Major New Drugs Innovation and Development:Study on Key Technologies of Post-marketing Evaluation for Chinese Medicine(No.2009ZX09502-030)"Doctoral Candidate Innovation Personnel Training Funding in China Academy of Chinese Medical Sciences
文摘OBJECTIVE: To systematically investigate the safety of Xingxue~ Shuxuening injection(SXN) in preand post-marketing, and to ensure clinical drug safety.METHODS: Strict quality control in raw herb selection and production processes was adopted and pharmacology research on SXN was performed by the drug manufacturing company, Heilongjiang ZBD Pharmaceutical Co., Ltd. We systematically reviewed the safety literature of Xingxue~ SXN. Adverse drug reaction(ADR) data of the drug, extracted from Spontaneous Reporting System(SRS), and clinical characters based on 20 hospital information systems(HIS) in China, were analyzed. Large-scale prospective safety monitoring and Risk Minimization Action Plans(Risk MAPs) of Xingxue~SXN were carried out.RESULTS: The quality of SXN was stable and controllable when it was produced. Drug toxicology studies found no effect on rabbits with hemolytic or condensed, local stimulation and muscle stimulation, and no allergic reactions in guinea pigs. The ADRs of Xingxue~ SXN were dizziness, phlebitis,and vomiting based on SRS data. The injection did not conform to instructions in clinical practice when we analyzed HIS database, and patient’s abnormal blood urea nitrogen levels may be related to the drug, when analyzed using the propensity score method. A nested case-control study was designed and performed to analyze the influencing factors of suspected allergic reactions to SXN. The study showed that patients with an allergy history were more prone to allergic reactions(P<0.001),and some medicine combinations could cause allergic reactions.CONCLUSION: These studies have established a body of evidence on Xingxue~ SXN safety, and provide a good model for Chinese medicine injection for clinical safety. The Xingxue~ SXN production process and toxicology research indicate the safety of the injection. However, the use of the injection is not consistent with instructed clinical practice.Xingxue~ SXN causes ADRs perhaps from inappropriate usage or its pharmacological action. This injection needs better Risk MAPs to ensure its clinical safety.
基金Natural Science Foundation of China(30472209)Research Fund of the University of Macao(SRG013-ICMS11-CXP)
文摘Objective To investigate the effects of total flavonoid fraction(TFF) from Nervilia fordii on lipopolysaccharide(LPS)-induced acute lung injury(ALI) in rats,and to explore their protective mechanism.Methods LPS-induced ALI model was established by LPS(5 mg/kg) injection via left cervical vein.Blood samples were collected from the cervical artery of all rats at 5 and 6 h after LPS challenge for arterial blood gas test and cytokines measurements,and pulmonary microvascular permeability(PMP),lung wet/dry weight ratio(W/D),and pathological features were observed.Results Phytochemical study showed that the TFF contained 67.3% of flavonoids expressed in rutin and three flavone glycosides.The TFF pretreatment(6.24 and 12.48 mg/kg) attenuated the partial arterial pressure of oxygen decline in blood significantly,and decreased the PMP and lung W/D in ALI rats.In addition,the TFF(6.24 and 12.48 mg/kg) also ameliorated the LPS-induced lung damages including alveolar edema,neutrophils infiltration,alveolar hemorrhage,and thickening of the alveolar wall.Furthermore,the treatment with the TFF(6.24 and 12.48 mg/kg) also down-regulated the levels of pro-inflammatory cytokines,such as tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),and intercellular adhesion molecule-1(ICAM-1),and up-regulated the level of anti-inflammatory cytokine IL-10 in serum of ALI rats simultaneously.Conclusion These results suggest that the TFF could protect LPS-induced ALI in rats,which may be mediated,at least in part,by adjusting the production of inflammatory cytokines including TNF-α,IL-6,ICAM-1,and IL-10.
基金the financial support of the National Natural Science Foundation of China(Grants 21977073)the Liao-ning BaiQianWan Talents Program+2 种基金Liaoning Revitalization Tale nts Programthe program for the innoyative research team of the Ministry of Educationthe program for the Liaoning innovative research team in university.
文摘A gold(Ⅰ)-catalyzed 6-endo-dig cyclization of aromatic 1,5-enynes was developed to synthesize 2-(naphthalen-2-yl)anilines.The functional group tolerance of this cyclization was examined systematically and a possible mechanism was proposed.The derivatization of 2-(naphthalen-2-yl)aniline was carried out to facile access to benzo[α]carbazole,benzo[c,h]cinnoline and dibenzo[i]phenanthridine derivatives in a divergent way.
基金This project was supported by the National Natural Science Foundation of China(Grant Nos.51673145,51873149,21875157 and 51963018)the National Key Research and Development Program of China(Grant No.2016YFC1100300)the International Science and Technology Cooperation Program of China(Grant No.2013DFG52040).
文摘Gene therapy has drawn great attention in the treatments of many diseases,especially for cardiovascular diseases.However,the development of gene carriers with low cytotoxicity and multitargeting function is still a challenge.Herein,the multitargeting REDV-G-TATG-NLS peptide was conjugated to amphiphilic cationic copolymer poly(e-caprolactone-co-3(S)-methyl-morpho-line-2,5-dione)-g-polyethyleneimine(PCLMD-g-PEI)via a heterobifunctional orthopyridyl disulfde-poly(ethylene glycol)-N-hydroxysuccinimide(OPSS-PEG-NHS)linker to prepare PCLMD-g-PEI-PEG-REDV-G-TAT-G-NLS copolymers with the aim to develop the gene carriers with low cytotoxicity and high transfection efficiency.The multitargeting micelles were prepared from PCLMD-g-PEI-PEG-REDV-G-TAT-G-NLS copolymers by self-assembly method and used to load pEGFP-ZNF580 plasmids(pDNA)to form gene complexes for enhancing the proliferation and migration of endothelial cells(ECs).The loading pDNA capacity was proved by agarose gel electrophoresis assay.These multitargeting gene com-plexes exhibited low cytotoxicity by 3-(4,-dimethylthia-zol-2-yl)-2,5-diphenyltetrazolium bromide assay.The high internalization efficiency of these gene complexes was confirmed by flow cytometry.The results of in vitro transfection demonstrated that these multitargeting gene complexes possessed relatively high transfection effi-ciency.The rapid migration of ECs transfected by these gene complexes was verified by wound healing assay.Owing to ECs-targeting ability,cell-penetrating ability and nuclear targeting capacity of REDV-G-TAT-G-NLS pep-tide,the multitargeting polycationic gene carrier with low cytotoxicity and high transfection efficiency has great potential in gene therapy.
文摘The authors regret that there was an error in our publication.Considering Lingchuang Bai made great contributions to this work,Xinghong Duo and Lingchuang Bai should be co-first authors,but there was no statement that“Xinghong Duo and Lingchuang Bai contributed equally to this work”.The authors would like to apologize for any inconvenience caused.