Acute kidney injury(AKI)is a common clinical serious illness.Esculin(ES)is a coumarin compound of traditional Chinese medicine Cortex Fraxini.Our previous study has found that ES protects against inflammation and rena...Acute kidney injury(AKI)is a common clinical serious illness.Esculin(ES)is a coumarin compound of traditional Chinese medicine Cortex Fraxini.Our previous study has found that ES protects against inflammation and renal damage in diabetic rats.In the present study,we aimed to investigate the effects and the possible mechanism of ES against lipopolysaccharides(LPS)-induced AKI in mice.Renal morphology was observed by H&E staining.Renal function was evaluated by blood urea nitrogen(BUN)level and creatinine content in serum.Inflammatory factor levels were measured by ELISA assay.The inflammatory proteins were analyzed by RT-PCR and Western blotting analysis.The results showed that ES alleviated LPS-induced pathological injury and renal dysfunction,and decreased BUN level and creatinine content in serum.In addition,ES significantly reduced the release of pro-inflammatory factors,including IL-1β,IL-6 and TNF-α,chemokine MCP-1 and cell adhesion molecule ICAM-1.Furthermore,the expressions of inflammatory pathway proteins P2 X7,HMGB1,TLR4 and MyD88 both at the mRNA and protein levels were all down-regulated by ES in the kidney tissue of LPS-challenged mice.These results suggested ES protected against LPS-induced AKI through inhibiting P2 X7 expression and HMGB1/TLR4 inflammatory pathway.展开更多
A sensitive LC-ESI-MS/MS method for determination of isochlorogenic acid B in rat plasma was developed and validated in the present study. Plasma samples were prepared by a simple protein precipitation with methanol c...A sensitive LC-ESI-MS/MS method for determination of isochlorogenic acid B in rat plasma was developed and validated in the present study. Plasma samples were prepared by a simple protein precipitation with methanol containing resveratrol as internal standard (IS). The chromatographic separation was performed on a Zorbax SB-Cjg column (3.5 pm, 2.1 mmx 100 mm, Agilent, USA) at a flow rate of 0.2 mL/min using methanol/water containing 0.1% formic acid (v/v) as mobile phase. The detection was performed on a triple quadrupole tandem mass spectrometer equipped with Electronic Spray Ion by selected reaction monitoring (SRM) of the transitions at m/z 515.3->352.9 for isochlorogenic acid B and m/z 227.1-143.1 for IS, respectively. The calibration curve of the method was linear over the range of 5-2500 ng/mL (r^2= 0.9982). The intra- and inter-day precisions (R.S.D.%) were less than 12.46%, and the accuracy (R.E.%) was within ±5.80%. Isochlorogenic acid B was sufficiently stable under all relevant analytical conditions. The validated method was successfully applied to the plasma pharmacokinetic studies of isochlorogenic acid B in rats. It was found that isochlorogenic acid B had non-linear pharmacokinetic characteristics in rats within the dosage ranges from 5 to 20 mg/kg.展开更多
Deferasirox is the first-line drug for iron overload due to thalassemia in adults and pediatric patients. It is classified as a type II compound in the Biopharmaceutics Classification System, and thus the particle siz...Deferasirox is the first-line drug for iron overload due to thalassemia in adults and pediatric patients. It is classified as a type II compound in the Biopharmaceutics Classification System, and thus the particle size of its active pharmaceutical ingredient(API) should be strictly controlled during the manufacturing process. In the present study, laser diffraction was adopted to measure the particle size distribution of deferasirox API. We also developed and validated an accurate and convenient method by investigating important optical parameters and sample dispersing conditions. The relative standard deviation values, namely, d(0.1), d(0.5), d(0.9), and d(4,3), measured via methodology validation and actual sample measurement were < 3%. The dissolution curves of several batches of dispersible tablets prepared using deferasirox with different particle sizes were compared in the four dissolved media to investigate the influence of particle size on drug dissolution in vitro. Results indicated that the particle size distribution of deferasirox API significantly affected the release of its dispersible tablet.展开更多
We reported herein the synthesis and antibacterial activity evaluation of two oxazolidinone-deferasirox conjugates with different linkers that were designed based on the“Trojan horse”strategy.The conjugates could co...We reported herein the synthesis and antibacterial activity evaluation of two oxazolidinone-deferasirox conjugates with different linkers that were designed based on the“Trojan horse”strategy.The conjugates could combine with Fe^(3+)ions as the deferasirox.However,both conjugates were inactive against tested bacteria,including S.aureus,E.coli,A.baumannii,and P.aeruginosa.The results suggested that the synthesized iron chelator deferasirox was not suitable as a siderophore of the bacteria to transport the antibiotic,or the coupling linker of the synthesized conjugates could not be hydrolyzed to release the oxazolidinone in the cytoplasm.Therefore,the design and synthesis of oxazolidinone-deferasirox conjugates need further exploration.展开更多
C-glycosylation and C-prenylation are two important C-C-bond forming reactions for preparation,diversification and structural modification of natural/unnatural products with pharmacological activities.Here,we describe...C-glycosylation and C-prenylation are two important C-C-bond forming reactions for preparation,diversification and structural modification of natural/unnatural products with pharmacological activities.Here,we described unprecedented enzymatic cascades to C-glycosylate/prenylate different acyl resorcinol derivatives in stepwise,one-pot reactions by combining two promiscuous enzymes,MiCGT,a C-glycosyltransferase,and AtaPT,a prenyltransferase.Five novel bis-C-alkylated products were obtained and structurally identified by MS and NMR spectroscopic data as well as comparison with the literature.This study provided a potential synthetic strategy for synthesizing structurally novel and diverse compounds bearing both C-glycosyl and C-prenyl moieties by a two-step,enzymatic bis-C-alkylation.展开更多
Three new compounds(1–3), including a chlorine-containing dihydroisocoumarin pericochlorosin A(1), a chlorinated phenol pericochlorosin B(2) and a decalin derivative pericoannosin G(3), were isolated from endophytic ...Three new compounds(1–3), including a chlorine-containing dihydroisocoumarin pericochlorosin A(1), a chlorinated phenol pericochlorosin B(2) and a decalin derivative pericoannosin G(3), were isolated from endophytic fungus Periconia sp. F-31 of the medicinal plant Annona muricata. The structures and absolute configurations were elucidated by extensive spectroscopic methods and calculated electronic circular dichroism analysis. Compound 2 displayed potent anti-HIV activity with IC50 value of 2.2 μM.展开更多
基金The National Key Research&Development Plan(Grant No.2018YFC0311005)the National Natural Science Foundation of China(Grant No.81473383)+2 种基金the Significant New-Drugs Creation of Science and Technology Major Projects(Grant No.2012ZX09103101-078)the Medical and Health Innovation Project of Chinese Academy of Medical Sciences(Grant No.2016-I2M-3-007)Innovation Fund for Doctoral Students of Beijing Union Medical College(Grant No.2018-1007-04).
文摘Acute kidney injury(AKI)is a common clinical serious illness.Esculin(ES)is a coumarin compound of traditional Chinese medicine Cortex Fraxini.Our previous study has found that ES protects against inflammation and renal damage in diabetic rats.In the present study,we aimed to investigate the effects and the possible mechanism of ES against lipopolysaccharides(LPS)-induced AKI in mice.Renal morphology was observed by H&E staining.Renal function was evaluated by blood urea nitrogen(BUN)level and creatinine content in serum.Inflammatory factor levels were measured by ELISA assay.The inflammatory proteins were analyzed by RT-PCR and Western blotting analysis.The results showed that ES alleviated LPS-induced pathological injury and renal dysfunction,and decreased BUN level and creatinine content in serum.In addition,ES significantly reduced the release of pro-inflammatory factors,including IL-1β,IL-6 and TNF-α,chemokine MCP-1 and cell adhesion molecule ICAM-1.Furthermore,the expressions of inflammatory pathway proteins P2 X7,HMGB1,TLR4 and MyD88 both at the mRNA and protein levels were all down-regulated by ES in the kidney tissue of LPS-challenged mice.These results suggested ES protected against LPS-induced AKI through inhibiting P2 X7 expression and HMGB1/TLR4 inflammatory pathway.
基金Chinese Academy of Medical Sciences(Grant No.CAMS-2017-I2M-1-011)
文摘A sensitive LC-ESI-MS/MS method for determination of isochlorogenic acid B in rat plasma was developed and validated in the present study. Plasma samples were prepared by a simple protein precipitation with methanol containing resveratrol as internal standard (IS). The chromatographic separation was performed on a Zorbax SB-Cjg column (3.5 pm, 2.1 mmx 100 mm, Agilent, USA) at a flow rate of 0.2 mL/min using methanol/water containing 0.1% formic acid (v/v) as mobile phase. The detection was performed on a triple quadrupole tandem mass spectrometer equipped with Electronic Spray Ion by selected reaction monitoring (SRM) of the transitions at m/z 515.3->352.9 for isochlorogenic acid B and m/z 227.1-143.1 for IS, respectively. The calibration curve of the method was linear over the range of 5-2500 ng/mL (r^2= 0.9982). The intra- and inter-day precisions (R.S.D.%) were less than 12.46%, and the accuracy (R.E.%) was within ±5.80%. Isochlorogenic acid B was sufficiently stable under all relevant analytical conditions. The validated method was successfully applied to the plasma pharmacokinetic studies of isochlorogenic acid B in rats. It was found that isochlorogenic acid B had non-linear pharmacokinetic characteristics in rats within the dosage ranges from 5 to 20 mg/kg.
基金CAMS Innovation Fund for Medical Sciences(CIFMS No.2016-I2M-3-010 and CIFMS No.2017-I2M-1-011)。
文摘Deferasirox is the first-line drug for iron overload due to thalassemia in adults and pediatric patients. It is classified as a type II compound in the Biopharmaceutics Classification System, and thus the particle size of its active pharmaceutical ingredient(API) should be strictly controlled during the manufacturing process. In the present study, laser diffraction was adopted to measure the particle size distribution of deferasirox API. We also developed and validated an accurate and convenient method by investigating important optical parameters and sample dispersing conditions. The relative standard deviation values, namely, d(0.1), d(0.5), d(0.9), and d(4,3), measured via methodology validation and actual sample measurement were < 3%. The dissolution curves of several batches of dispersible tablets prepared using deferasirox with different particle sizes were compared in the four dissolved media to investigate the influence of particle size on drug dissolution in vitro. Results indicated that the particle size distribution of deferasirox API significantly affected the release of its dispersible tablet.
基金The CAMS Innovation Fund for Medical Sciences(CIFMS 2021-I2M-1-028).
文摘We reported herein the synthesis and antibacterial activity evaluation of two oxazolidinone-deferasirox conjugates with different linkers that were designed based on the“Trojan horse”strategy.The conjugates could combine with Fe^(3+)ions as the deferasirox.However,both conjugates were inactive against tested bacteria,including S.aureus,E.coli,A.baumannii,and P.aeruginosa.The results suggested that the synthesized iron chelator deferasirox was not suitable as a siderophore of the bacteria to transport the antibiotic,or the coupling linker of the synthesized conjugates could not be hydrolyzed to release the oxazolidinone in the cytoplasm.Therefore,the design and synthesis of oxazolidinone-deferasirox conjugates need further exploration.
基金National Natural Science Foundation of China(Grant Nos.21572277,81573317 and 81703369)CAMS Innovation Fund for Medical Sciences(CIFMS-2016-I2M-3-012)
文摘C-glycosylation and C-prenylation are two important C-C-bond forming reactions for preparation,diversification and structural modification of natural/unnatural products with pharmacological activities.Here,we described unprecedented enzymatic cascades to C-glycosylate/prenylate different acyl resorcinol derivatives in stepwise,one-pot reactions by combining two promiscuous enzymes,MiCGT,a C-glycosyltransferase,and AtaPT,a prenyltransferase.Five novel bis-C-alkylated products were obtained and structurally identified by MS and NMR spectroscopic data as well as comparison with the literature.This study provided a potential synthetic strategy for synthesizing structurally novel and diverse compounds bearing both C-glycosyl and C-prenyl moieties by a two-step,enzymatic bis-C-alkylation.
基金National Natural Science Foundation of China(Grant No.81773607)CAMS Innovation Fund for Medical Sciences(Grant Nos.CIFMS-2018-I2M-3-005 and CIFMS-2016-I2M-2-002)the Drug Inn ovation Major Project(Grant No.2018ZX09711001-001-001)
文摘Three new compounds(1–3), including a chlorine-containing dihydroisocoumarin pericochlorosin A(1), a chlorinated phenol pericochlorosin B(2) and a decalin derivative pericoannosin G(3), were isolated from endophytic fungus Periconia sp. F-31 of the medicinal plant Annona muricata. The structures and absolute configurations were elucidated by extensive spectroscopic methods and calculated electronic circular dichroism analysis. Compound 2 displayed potent anti-HIV activity with IC50 value of 2.2 μM.
