Salvianolic acid A(SalA) is an effective compound extracted from traditional Chinese medicine Salvia miltiorrhiza Bunge. The Forkhead box O3a(FOXO3a) signaling pathway plays crucial roles in the modulation of ischemia...Salvianolic acid A(SalA) is an effective compound extracted from traditional Chinese medicine Salvia miltiorrhiza Bunge. The Forkhead box O3a(FOXO3a) signaling pathway plays crucial roles in the modulation of ischemia-induced cell apoptosis. However, no information about the regulatory effect of SalA on FoxO3a is available. To explore the anti-cerebral ischemia effect and clarify the therapeutic mechanism of SalA, SH-SY5Y cells and Sprague–Dawley rats were applied, which were exposed to oxygen glucose deprivation/reoxygenation(OGD/R) and middle cerebral artery occlusion/reperfusion(MCAO/R) injuries, respectively. The involved pathway was identified using the specific inhibitor LY294002. Results showed that SalA concentration-dependently inhibited OGD/R injury triggered cell viability loss. SalA reduced cerebral infarction, lowered brain edema, improved neurological function, and inhibited neuron apoptosis in MCAO/R rats, which were attenuated by the treatment of phosphatidylinositol-4,5-bisphosphate 3-kinase(PI3K) specific inhibitor LY294002. SalA time-and concentration-dependently upregulated the phosphorylation levels of protein kinase B(AKT) and its downstream protein FOXO3a. Moreover, the nuclear translocation of FOXO3a was inhibited by SalA both in vivo and in vitro, which was also reversed by LY294002. The above results indicated that SalA fought against ischemia/reperfusion damage at least partially via the AKT/FOXO3a/BIM pathway.展开更多
A mangiferin aglycon derivative J99745 has been identified as a potent xanthine oxidase(XOD) inhibitor by previous in vitro study. This study aimed to evaluate the hypouricemic effects of J99745 in experimental hyperu...A mangiferin aglycon derivative J99745 has been identified as a potent xanthine oxidase(XOD) inhibitor by previous in vitro study. This study aimed to evaluate the hypouricemic effects of J99745 in experimental hyperuricemia mice, and explore the underlying mechanisms. Mice were orally administered 600 mg/kg xanthine once daily for 7 days and intraperitoneally injected 250 mg/kg oxonic acid on the 7 th day to induce hyperuricemia. Meanwhile, J99745(3, 10, and 30 mg/kg), allopurinol(20 mg/kg) or benzbromarone(20 mg/kg) were orally administered to mice for 7 days. On the 7 th day,uric acid and creatinine in serum and urine, blood urea nitrogen(BUN), malondialdehyde(MDA) content and XOD activities in serum and liver were determined. Morphological changes in kidney were observed using hematoxylin and eosin(H&E) staining. Hepatic XOD, renal urate transporter 1(URAT1), glucose transporter type 9(GLUT9), organic anion transporter 1(OAT1) and ATP-binding cassette transporter G2(ABCG2) were detected by Western blot and real time polymerase chain reaction(PCR). The results showed that J99745 at doses of 10 and 30 mg/kg significantly reduced serum urate, and enhanced fractional excretion of uric acid(FEUA). H&E staining confirmed that J99745 provided greater nephroprotective effects than allopurinol and benzbromarone. Moreover, serum and hepatic XOD activities and renal URAT1 expression declined in J99745-treated hyperuricemia mice. In consistence with the ability to inhibit XOD, J99745 lowered serum MDA content in hyperuricemia mice. Our resultssuggest that J99745 exerts urate-lowering effect by inhibiting XOD activity and URAT1 expression, thus representing a promising candidate as an anti-hyperuricemia agent.展开更多
Flavonoids are now considered as an indispensable component in a variety of nutraceutical and pharmaceutical applications.Most recent researches have focused on the health aspects of flavonoids for humans.Especially,d...Flavonoids are now considered as an indispensable component in a variety of nutraceutical and pharmaceutical applications.Most recent researches have focused on the health aspects of flavonoids for humans.Especially,different flavonoids have been investigated for their potential antiviral activities,and several natural flavonoids exhibited significant antiviral properties both in vitro and in vivo.This review provides a survey of the literature regarding the evidence for antiviral bioactivities of natural flavonoids,highlights the cellular and molecular mechanisms of natural flavonoids on viruses,and presents the details of most reported flavonoids.Meanwhile,future perspectives on therapeutic applications of flavonoids against viral infections were discussed.展开更多
The pharmacokinetic profile of gallocatechin-7-gallate (J10688) was studied in rats after intravenous administration. Male and female Sprague-Dawley (SD) rats received 1, 3, and 10 mg/kg (i.v.) of J10688 and plasma dr...The pharmacokinetic profile of gallocatechin-7-gallate (J10688) was studied in rats after intravenous administration. Male and female Sprague-Dawley (SD) rats received 1, 3, and 10 mg/kg (i.v.) of J10688 and plasma drug concentrations were determined by a high performance liquid chromatography-mass spectrometry (LC-MS) method. The pharmacokinetic software Data Analysis System (Version 3.0) was used to calculate the pharmacokinetic parameters. For different i.v. doses of J10688, the mean peak plasma concentration (C-0) values ranged from 11.26 to 50.82 mg/L, and mean area under the concentration -time curve (ALC(0-i)) values ranged from 1.75 to 11.80 (mg ' h/L). J10688 lacked dose dependent pharmacokinetic properties within doses between 1 and 10 mg/kg, based on the power model. The method developed in this study was sensitive, precise, and stable. The pharmacokinetic properties of J10688 in SD rats were shown to have rapid distribution and clearance values. These pharmacokinetic results may contribute to an improved understanding of the pharmacological actions of J10688. (C) 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.展开更多
Rhein(Rhe), an anthraquinone derivative, exhibits excellent anti-inflammatory effects and other pharmacological activities, but its clinical application remains limited due to poor solubility. The present work aims at...Rhein(Rhe), an anthraquinone derivative, exhibits excellent anti-inflammatory effects and other pharmacological activities, but its clinical application remains limited due to poor solubility. The present work aims at the improvement of solubility and oral bioavailability of Rhe through cocrystal formation. For this purpose, Rhe and matrine(Mat) were selected as pharmaceutical ingredient(API) and cocrystal former(CCF), respectively, and the Rhe-Mat cocrystal was synthesized and characterized by single crystal X-ray diffraction(SXRD), powder X-ray diffraction(PXRD), thermogravimetric analysis(TGA), differential scanning calorimetry(DSC). The formation mechanism of Rhe-Mat cocrystal was elucidated by molecular surface electrostatic potential(MSEP). It is worth mentioning that the 50-fold increment of dissolution in vitro was observed in pure water in the form of Rhe-Mat cocrystal. Furthermore, the in vivo studies revealed that Rhe-Mat cocrystal indicated the faster absorption rate and the higher peak blood concentration than the pure Rhe. Hence, it can be concluded that current study successfully improved the solubility and oral bioavailability of Rhe.展开更多
A sensitive, specific and rapid LC-MS method was developed and validated for the determination of salvianolic acid D (SAlD) in rat plasma. This method used a single quadrupole mass spectrometer with an electrospray io...A sensitive, specific and rapid LC-MS method was developed and validated for the determination of salvianolic acid D (SAlD) in rat plasma. This method used a single quadrupole mass spectrometer with an electrospray ionization (ESI) source. A single ion monitoring scanning (SIM) mode was employed. it showed good linearity over the concentration range from 3.3 to 666.7 ngfint. for the determination of Sala The R.S.D.% of intra-day and inter-day precision values were no more than 7.69%, and the accuracy was within 91%-104% at all quality control Levels. This LC MS method was applied to the pharmacokinetic study of SaID in rats. A two-compartmental model analysis was employed. The plasma concentrations at 2 mm (C-2min) were 5756.06 +/- 719.61, 11,073.01 +/- 1783.46 and 21,077.58 +/- 5581.97 nit, for 0.25, 0.5 and I mg/kg intravenous injection, respectively. The peak plastna concentration (C-max) was 333.08 +/- 61.21 pg/L for 4 mg/kg oral administration. The area under curve (AUC(0-t)) was 14,384.379 +/- 8443.t84. 22,813.369 +/- 11,860.823, 46,406.122 +/- 27,592.645 and 8201.740+4711.961 mu g/L.h for intravenous injection (0.25, 0.5 and 1 mg/kg) and oral administration (4 mg/kg), respectively. The bioavailability of SalD) was calculated to be 4.159% +/- 0.517%. (C) 2015 Chinese Pharmaceutical Association and Institute of Materia IMedica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.展开更多
Salvianolic acid A(Sal A),a water-soluble ingredient in Danshen,has various biological activities.Sal A and its impurities have similar physical and chemical properties,as well as strong reducibility;therefore,they ar...Salvianolic acid A(Sal A),a water-soluble ingredient in Danshen,has various biological activities.Sal A and its impurities have similar physical and chemical properties,as well as strong reducibility;therefore,they are difficult to prepare and purify.In this study,high-purity Sal A was obtained by purification of sephadex chromatography and preparative chromatography.Furthermore,HPLC-DAD tandem ECD and HPLC-DAD tandem MS methods were used for non-volatile organic impurity analysis,ICP-MS method was used for non-volatile inorganic impurities and mass balance method and quantitative nuclear magnetic resonance were employed to certify the product.The structures of Sal A and its relative impurities were validated by nuclear magnetic resonance spectroscopy and mass spectrometry,and their contents were quantified as well.Following the principles of ISO Guides 34:2009 and 35:2005,a Sal A reference material was certified,covering homogeneity studies,stability studies,characterization,and uncertainty estimations.展开更多
基金supported by grants from National Natural Science Foundation of China (No. 81603100)the CAMS Innovation Fund for Medical Sciences (2017-I2M-1-010, China)
文摘Salvianolic acid A(SalA) is an effective compound extracted from traditional Chinese medicine Salvia miltiorrhiza Bunge. The Forkhead box O3a(FOXO3a) signaling pathway plays crucial roles in the modulation of ischemia-induced cell apoptosis. However, no information about the regulatory effect of SalA on FoxO3a is available. To explore the anti-cerebral ischemia effect and clarify the therapeutic mechanism of SalA, SH-SY5Y cells and Sprague–Dawley rats were applied, which were exposed to oxygen glucose deprivation/reoxygenation(OGD/R) and middle cerebral artery occlusion/reperfusion(MCAO/R) injuries, respectively. The involved pathway was identified using the specific inhibitor LY294002. Results showed that SalA concentration-dependently inhibited OGD/R injury triggered cell viability loss. SalA reduced cerebral infarction, lowered brain edema, improved neurological function, and inhibited neuron apoptosis in MCAO/R rats, which were attenuated by the treatment of phosphatidylinositol-4,5-bisphosphate 3-kinase(PI3K) specific inhibitor LY294002. SalA time-and concentration-dependently upregulated the phosphorylation levels of protein kinase B(AKT) and its downstream protein FOXO3a. Moreover, the nuclear translocation of FOXO3a was inhibited by SalA both in vivo and in vitro, which was also reversed by LY294002. The above results indicated that SalA fought against ischemia/reperfusion damage at least partially via the AKT/FOXO3a/BIM pathway.
基金supported by National Natural Science Foundation of China(81573645,81202538 and 81673422)CAMS Innovation Fund for Medical Sciences(CIFMS,2016-I2M-3-007)National Science and Technology Major Projects for "Major New Drugs Innovation and Development"(2013ZX09508104and 2013ZX09402203)
文摘A mangiferin aglycon derivative J99745 has been identified as a potent xanthine oxidase(XOD) inhibitor by previous in vitro study. This study aimed to evaluate the hypouricemic effects of J99745 in experimental hyperuricemia mice, and explore the underlying mechanisms. Mice were orally administered 600 mg/kg xanthine once daily for 7 days and intraperitoneally injected 250 mg/kg oxonic acid on the 7 th day to induce hyperuricemia. Meanwhile, J99745(3, 10, and 30 mg/kg), allopurinol(20 mg/kg) or benzbromarone(20 mg/kg) were orally administered to mice for 7 days. On the 7 th day,uric acid and creatinine in serum and urine, blood urea nitrogen(BUN), malondialdehyde(MDA) content and XOD activities in serum and liver were determined. Morphological changes in kidney were observed using hematoxylin and eosin(H&E) staining. Hepatic XOD, renal urate transporter 1(URAT1), glucose transporter type 9(GLUT9), organic anion transporter 1(OAT1) and ATP-binding cassette transporter G2(ABCG2) were detected by Western blot and real time polymerase chain reaction(PCR). The results showed that J99745 at doses of 10 and 30 mg/kg significantly reduced serum urate, and enhanced fractional excretion of uric acid(FEUA). H&E staining confirmed that J99745 provided greater nephroprotective effects than allopurinol and benzbromarone. Moreover, serum and hepatic XOD activities and renal URAT1 expression declined in J99745-treated hyperuricemia mice. In consistence with the ability to inhibit XOD, J99745 lowered serum MDA content in hyperuricemia mice. Our resultssuggest that J99745 exerts urate-lowering effect by inhibiting XOD activity and URAT1 expression, thus representing a promising candidate as an anti-hyperuricemia agent.
基金supported by CAMS Innovation Fund for Medical Sciences(Grant No.2017-I2M-1-010)National Key Research and Development Program(Grant No.2018YFC0311005)National Science and Technology Major Projects(Grant No.2018ZX09711001-012).
文摘Flavonoids are now considered as an indispensable component in a variety of nutraceutical and pharmaceutical applications.Most recent researches have focused on the health aspects of flavonoids for humans.Especially,different flavonoids have been investigated for their potential antiviral activities,and several natural flavonoids exhibited significant antiviral properties both in vitro and in vivo.This review provides a survey of the literature regarding the evidence for antiviral bioactivities of natural flavonoids,highlights the cellular and molecular mechanisms of natural flavonoids on viruses,and presents the details of most reported flavonoids.Meanwhile,future perspectives on therapeutic applications of flavonoids against viral infections were discussed.
基金supported by Beijing Natural Science Foundation(7152103)the National Great Science and Technology Projects(2014ZX09507003-002 and 2012ZX09301002-2013HXW-11)the International Collaboration Project(2011DFR31240)
文摘The pharmacokinetic profile of gallocatechin-7-gallate (J10688) was studied in rats after intravenous administration. Male and female Sprague-Dawley (SD) rats received 1, 3, and 10 mg/kg (i.v.) of J10688 and plasma drug concentrations were determined by a high performance liquid chromatography-mass spectrometry (LC-MS) method. The pharmacokinetic software Data Analysis System (Version 3.0) was used to calculate the pharmacokinetic parameters. For different i.v. doses of J10688, the mean peak plasma concentration (C-0) values ranged from 11.26 to 50.82 mg/L, and mean area under the concentration -time curve (ALC(0-i)) values ranged from 1.75 to 11.80 (mg ' h/L). J10688 lacked dose dependent pharmacokinetic properties within doses between 1 and 10 mg/kg, based on the power model. The method developed in this study was sensitive, precise, and stable. The pharmacokinetic properties of J10688 in SD rats were shown to have rapid distribution and clearance values. These pharmacokinetic results may contribute to an improved understanding of the pharmacological actions of J10688. (C) 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
基金supported by Drug Innovation Major Project (Nos. 2018ZX09711001–001–015, 2018ZX09711001–003– 022)CAMS Innovation Fund for Medical Sciences (No. 2016I2M-3–007)。
文摘Rhein(Rhe), an anthraquinone derivative, exhibits excellent anti-inflammatory effects and other pharmacological activities, but its clinical application remains limited due to poor solubility. The present work aims at the improvement of solubility and oral bioavailability of Rhe through cocrystal formation. For this purpose, Rhe and matrine(Mat) were selected as pharmaceutical ingredient(API) and cocrystal former(CCF), respectively, and the Rhe-Mat cocrystal was synthesized and characterized by single crystal X-ray diffraction(SXRD), powder X-ray diffraction(PXRD), thermogravimetric analysis(TGA), differential scanning calorimetry(DSC). The formation mechanism of Rhe-Mat cocrystal was elucidated by molecular surface electrostatic potential(MSEP). It is worth mentioning that the 50-fold increment of dissolution in vitro was observed in pure water in the form of Rhe-Mat cocrystal. Furthermore, the in vivo studies revealed that Rhe-Mat cocrystal indicated the faster absorption rate and the higher peak blood concentration than the pure Rhe. Hence, it can be concluded that current study successfully improved the solubility and oral bioavailability of Rhe.
基金supported by grants from The Key Project for Drug Innovation (No.2009ZX09102-123)National Natural Science Foundation of China (No.81102492)Major Scientific and Technological Special Project for "Significant New Drugs Creation" (Nos.2012ZX09301002001001 and 2013ZX09508104001002)
文摘A sensitive, specific and rapid LC-MS method was developed and validated for the determination of salvianolic acid D (SAlD) in rat plasma. This method used a single quadrupole mass spectrometer with an electrospray ionization (ESI) source. A single ion monitoring scanning (SIM) mode was employed. it showed good linearity over the concentration range from 3.3 to 666.7 ngfint. for the determination of Sala The R.S.D.% of intra-day and inter-day precision values were no more than 7.69%, and the accuracy was within 91%-104% at all quality control Levels. This LC MS method was applied to the pharmacokinetic study of SaID in rats. A two-compartmental model analysis was employed. The plasma concentrations at 2 mm (C-2min) were 5756.06 +/- 719.61, 11,073.01 +/- 1783.46 and 21,077.58 +/- 5581.97 nit, for 0.25, 0.5 and I mg/kg intravenous injection, respectively. The peak plastna concentration (C-max) was 333.08 +/- 61.21 pg/L for 4 mg/kg oral administration. The area under curve (AUC(0-t)) was 14,384.379 +/- 8443.t84. 22,813.369 +/- 11,860.823, 46,406.122 +/- 27,592.645 and 8201.740+4711.961 mu g/L.h for intravenous injection (0.25, 0.5 and 1 mg/kg) and oral administration (4 mg/kg), respectively. The bioavailability of SalD) was calculated to be 4.159% +/- 0.517%. (C) 2015 Chinese Pharmaceutical Association and Institute of Materia IMedica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
基金The authors acknowledge National Key R&D Program of China(Grant No.2016YFC1000900)The Drug Innovation Major Project(Grant No.2018ZX09711001-001-015)should be substituted by Drug Innovation Major Project(Grant No.2018ZX09711001-003-022)CAMS Innovation Fund for Medical Sciences(Grant No.2016-I2M-3-007)for financing this work.
文摘Salvianolic acid A(Sal A),a water-soluble ingredient in Danshen,has various biological activities.Sal A and its impurities have similar physical and chemical properties,as well as strong reducibility;therefore,they are difficult to prepare and purify.In this study,high-purity Sal A was obtained by purification of sephadex chromatography and preparative chromatography.Furthermore,HPLC-DAD tandem ECD and HPLC-DAD tandem MS methods were used for non-volatile organic impurity analysis,ICP-MS method was used for non-volatile inorganic impurities and mass balance method and quantitative nuclear magnetic resonance were employed to certify the product.The structures of Sal A and its relative impurities were validated by nuclear magnetic resonance spectroscopy and mass spectrometry,and their contents were quantified as well.Following the principles of ISO Guides 34:2009 and 35:2005,a Sal A reference material was certified,covering homogeneity studies,stability studies,characterization,and uncertainty estimations.
