The anterior cruciate ligament(ACL)mainly plays a role in stabilizing the knee joint by limiting the forward translation of tibial force and rotational force at the tibial joint,and if this ligament is damaged,it will...The anterior cruciate ligament(ACL)mainly plays a role in stabilizing the knee joint by limiting the forward translation of tibial force and rotational force at the tibial joint,and if this ligament is damaged,it will cause joint pain,limited mobility,knee instability,etc.According to related studies,the incidence of traumatic osteoarthritis(PTOA)after ACL injury is as high as 87%,although many studies have shown that patients with ACL injury are susceptible to PTOA,but the exact mechanism is currently unknown.This may be related to biological,structural,and mechanical factors caused by the ligament injury.Previous studies have shown that elevated inflammatory mediators in the joint cavity following ACL injury can lead to chondrocytes necrosis and degradation of the cartilage matrix.These potential biochemical mediators contribute to PTOA formation,and early intervention can reduce future episodes of PTOA.In recent years,many scholars have devoted themselves to studying the potential important factors and signaling pathways involved in the formation of osteoarthritis after ACL injury,and exploring its molecular mechanism,which has led to great progress in this field.This paper mainly studies and discusses the mechanism of osteoarthritis formation after ACL injury from the biological perspective.展开更多
OBJECTIVE To identify the bioactive anti-angiogenic constitutes targeting tumor endothelial cells(TECs)in Shenmai Injection(SMI).METHEODS For pharmacokinetic(PK)studies,Balb/c mice harboring human colorectal cancer(Lo...OBJECTIVE To identify the bioactive anti-angiogenic constitutes targeting tumor endothelial cells(TECs)in Shenmai Injection(SMI).METHEODS For pharmacokinetic(PK)studies,Balb/c mice harboring human colorectal cancer(LoVo)xenografts were treated with SMI 10 mL·kg^-1 daily for 1 or 8 d.Multidimensional PK profiles of ginsenosides in plasma,subcutaneous tumors,and TECs were investigated.For PD studies,the tumor-bearing mice Intravital multi-photon imaging and CD31 immunofluorescence staining were used to evaluate the number of microves⁃sels and braches.Double staining of CD31 and α-SMA was performed to evaluate pericytes coverage ratios around vessels.ELISA was performed to determine the concentrations of VEGF and FGF in tumor tissues.For synergistic anti-tumor study,the tumor-bearing mice were treated with SMI 10 mL·kg^-1 daily,Rd 5 mg·kg^-1 daily with or without 5-FU 15 mg·kg^-1 every 3 d for 20 d.HPLC-MS/MS was used to determine the concentrations of 5-FU in plasma and tumor tissues.RESULTS SMI decreased the number of microvessels(P<0.05)and vessel branches(P<0.05)and improved vascular pericytes coverage(P<0.05).PK studies showed that the concentrations of protopanaxadiol-type(PPD)ginsenosides(Rb1,Rb2/Rb3,Rc,and Rd)in both,plasma and tumors,were higher than those of protopanaxatriol-type(Rg1 and Re)and oleanane-type(Ro)ginsenosides.Among PPD ginsenosides,Rd exhibited the greatest concentrations in tumors and TECs after repeated injection.In fact,the proportion of Rd in the detectable components of SMI gradually increased in the following order:SMI formula(2.8%),plasma(16.0%),tumor tissues(34.3%),and TECs(40.3%).In vivo bioactivity results showed that Rd 5 mg·kg^-1 daily significantly decreased the number of microvessels(P<0.05)and vessel branches(P<0.05)and increased pericytes coverage(P<0.05)while Rd 0.5 mg·kg^-1 daily,Rb1 and Rg1 had no significant effect on them.Rd 5 mg·kg^-1 suppressed the expression of VEGF and FGF simultaneously.Rd 5 mg·kg^-1 enhanced the antitumor effect of 5-FU via increasing the distribution of 5-FU in tumor tissues(P<0.05)in xenograft mice.CONCLUSION Ginsenoside Rd may be the major bioactive anti-angiogenic constituent targeting TECs after SMI treatment.展开更多
We investigated the potential hepatoprotective effect of Radix Bupleuri(RB) by inducing acute liver injury(ALI) in an animal model using acetaminophen(APAP) after pretreatment with RB aqueous extract for three consecu...We investigated the potential hepatoprotective effect of Radix Bupleuri(RB) by inducing acute liver injury(ALI) in an animal model using acetaminophen(APAP) after pretreatment with RB aqueous extract for three consecutive days. Compared to those of the APAP group, the biochemical and histological results of the RB pretreatment group showed lower serum aspartate transaminase(AST) and alanine transaminase(ALT) levels as well as less liver damage. Pharmacokinetic study of the toxicity related marker acetaminophen-cysteine(APC) revealed a lower exposure level in rats, suggesting that RB alleviated APAP-induced liver damage by preventing glutathione(GSH) depletion. The results of cocktail approach showed significant inhibition of CYP2 E1 and CYP3 A activity. Further investigation revealed the increasing of CYP2 E1 and CYP3 A protein was significantly inhibited in pretreatment group,while no obvious effect on gene expression was found. Therefore, this study clearly demonstrates that RB exhibited significant protective action against APAP-induced acute live injury via pretreatment, and which is partly through inhibiting the increase of activity and translation of cytochrome P450 enzymes, rather than gene transcription.展开更多
Ginkgo diterpene lactones meglumine injection(GDLI)is a commercially available product used for neuroprotection.However,the pharmacokinetic properties of the prototypes and hydrolyzed carboxylic forms of the primary c...Ginkgo diterpene lactones meglumine injection(GDLI)is a commercially available product used for neuroprotection.However,the pharmacokinetic properties of the prototypes and hydrolyzed carboxylic forms of the primary components in GDLI,i.e.,ginkgolide A(GA),ginkgolide B(GB),and ginkgolide K(GK),have never been fully evaluated in beagle dogs.In this work,a simple,sensitive,and reliable method based on ultra-fast liquid chromatography-tandem mass spectrometry(UFLC-MS/MS)was developed,and the prototypes and total amounts of GA,GB,and GK were determined in beagle dog plasma.The plasma concentrations of the hydrolyzed carboxylic forms were calculated by subtracting the prototype concentrations from the total lactone concentrations.For the first time,the pharmacokinetics of GA,GB,and GK were fully assessed in three forms,i.e.,the prototypes,the hydrolyzed carboxylic forms,and the total amounts,after intravenous administration of GDLI in beagle dogs.It was shown that ginkgolides primarily existed in the hydrolyzed form in plasma,and the ratio of hydrolysates to prototype forms of GA and GB decreased gradually to a homeostatic ratio.All of the three forms of the three ginkgolides showed linear exposure of AUC to the dosages.GA,GB,and GK showed a constant half-life approximately 2.7,3.4,and 1.2 h,respectively,which were consistent for the forms at three dose levels(0.3,1.0,and 3.0 mg·kg^(-1))and after a consecutive injection of GDLI for 7 days(1.0 mg·kg^(-1)).展开更多
Isochlorogenic acid A(ICQA), which has anti-inflammatory, hepatoprotective, and antiviral properties, is commonly presented in fruits, vegetables, coffee, plant-based food products, and herbal medicines. These herbal ...Isochlorogenic acid A(ICQA), which has anti-inflammatory, hepatoprotective, and antiviral properties, is commonly presented in fruits, vegetables, coffee, plant-based food products, and herbal medicines. These herbal medicines are usually used in combination with other medicines in the clinic. However, little is known about the regulatory effects of ICQA on drug-metabolizing enzymes and the herb-drug interactions. In the present study, we evaluated the inhibitory potentials of ICQA on CYP1A2, CYP2C9,CYP2C19, CYP3A4, CYP2D6, and CYP2E1 in vitro based on a cocktail approach. The P450 and UGT activities in mice treated with ICQA for a prolonged period were also determined. Our results demonstrated that ICQA exhibited a weak inhibitory effect on CYP2C9 in human liver microsomes with IC_(50) being 57.25 μmol·L^(-1) and Ki being 26.77 μmol·L^(-1). In addition, ICQA inhibited UGT1A6 activity by 25%, in the mice treated with ICQA(i.p.) at 30 mg·kg^(-1)for 14 d, compared with the control group. Moreover, ICQA showed no mechanism-based inhibition on CYP2C9 or UGT1A6. In conclusion, our results further confirm a safe use of ICQA in clinical practice.展开更多
Nicotinamide phosphoribosyltransferase(NAMPT) catalyzes the first rate-limiting step in converting nicotinamide to NAD^+, essential for a number of enzymes and regulatory proteins involved in a variety of cellular pro...Nicotinamide phosphoribosyltransferase(NAMPT) catalyzes the first rate-limiting step in converting nicotinamide to NAD^+, essential for a number of enzymes and regulatory proteins involved in a variety of cellular processes, including deacetylation enzyme SIRT1 which modulates several tumor suppressors such as p53 and FOXO. Herein we report that NQO1 substrates Tanshione IIA(TSA) and β-lapachone(β-lap) induced a rapid depletion of NAD^+ pool but adaptively a significant upregulation of NAMPT. NAMPT inhibition by FK866 at a nontoxic dose significantly enhanced NQO1-targeting agent-induced apoptotic cell death. Compared with TSA or β-lap treatment alone, co-treatment with FK866 induced a more dramatic depletion of NAD^+, repression of SIRT1 activity, and thereby the increased accumulation of acetylated FOXO1 and the activation of apoptotic pathway. In conclusion, the results from the present study support that NAMPT inhibition can synergize with NQO1 activation to induce apoptotic cell death, thereby providing a new rationale for the development of combinative therapeutic drugs in combating non-small lung cancer.展开更多
Nonalcoholic fatty liver disease(NAFLD)is regarded as the most common liver disease with no approved therapeutic drug currently.Silymarin,an extract from the seeds of Silybum marianum,has been used for centuries for t...Nonalcoholic fatty liver disease(NAFLD)is regarded as the most common liver disease with no approved therapeutic drug currently.Silymarin,an extract from the seeds of Silybum marianum,has been used for centuries for the treatment of various liver diseases.Although the hepatoprotective effect of silybin against NAFLD is widely accepted,the underlying mechanism and therapeutic target remain unclear.In this study,NAFLD mice caused by methionine-choline deficient(MCD)diet were orally administrated with silybin to explore the possible mechanism and target.To clarify the contribution of peroxisome proliferator-activated receptorα(PPARα),PPARαantagonist GW6471 was co-administrated with silybin to NAFLD mice.Since silybin was proven as a PPARαpartial agonist,the combined effect of silybin with PPARαagonist,fenofibrate,was then evaluated in NAFLD mice.Serum and liver samples were collected to analyze the pharmacological efficacy and expression of PPARαand its targets.As expected,silybin significantly protected mice from MCD-induced NAFLD.Furthermore,silybin reduced lipid accumulation via activating PPARα,inducing the expression of liver cytosolic fatty acid-binding protein,carnitine palmitoyltransferase(Cpt)-1a,Cpt-2,medium chain acyl-CoA dehydrogenase and stearoyl-CoA desaturase-1,and suppressing fatty acid synthase and acetyl-CoA carboxylaseα.GW6471 abolished the effect of silybin on PPARαsignal and hepatoprotective effect against NAFLD.Moreover,as a partial agonist for PPARα,silybin impaired the powerful lipid-lowering effect of fenofibrate when used together.Taken together,silybin protected mice against NAFLD via activating PPARαto diminish lipid accumulation and it is not suggested to simultaneously take silybin and classical PPARαagonists for NAFLD therapy.展开更多
Liquid chromatography hybrid ion trap/time-of-flight mass spectrometry possesses both the MS^n ability of ion trap and the excellent resolution of a time-of-flight and has been widely used to identify drug metabolites...Liquid chromatography hybrid ion trap/time-of-flight mass spectrometry possesses both the MS^n ability of ion trap and the excellent resolution of a time-of-flight and has been widely used to identify drug metabolites and determine trace multi-components in natural products. Collision energy, one of the most important factors in acquiring MS^n information, could be set freely in the range of 10%–400%. Herein, notoginsenosides were chosen as model compounds to build a novel methodology for the collision energy optimization. Firstly, the fragmental patterns of the representatives for the authentic standards of protopanaxadiol-type and protopanaxatriol-type notoginsenosides were obtained based on accurate MS^2 and MS^3 measurements via liquid chromatography hybrid ion trap/time-of-flight mass spectrometry. The extracted ion chromatograms of characteristic product ions of notoginsenosides in Panax Notoginseng Extract were produced under a series of collision energies and compared to screen the optimum collision energies values for MS^2 and MS^3. The results demonstrated that the qualitative capability of liquid chromatography hybrid ion trap/time-of-flight mass spectrometry was greatly influenced by collision energies, and 50% of MS^2 collision energy was found to produce the highest collision-induced dissociation efficiency for notoginsenosides. Addtionally, the highest collision-induced dissociation efficiency appeared when the collision energy was set at 75% in the MS^3 stage.展开更多
As a computer-assisted approach, molecular docking has been universally applied in drug research and development and plays an important role in the investigation and evaluation of herbal medicines. Herein, the method ...As a computer-assisted approach, molecular docking has been universally applied in drug research and development and plays an important role in the investigation and evaluation of herbal medicines. Herein, the method was used to estimate the pharmacodynamics of Mai-Luo-Ning injection, a traditional Chinese compound herbal prescription. Through investigating the interactions between several important proteins in cardiovascular system and characteristic components of the formula, its effect on cardiovascular protection was evaluated. Results showed the differences in the interactions between each component and the selected target proteins and revealed the possible mechanisms for synergistic effects of various characteristic components on cardiovascular protection. The study provided scientific evidence supporting the mechanistic study of the interactions among multi-components and targets, offering a general approach to investigating the pharmacodynamics of complicated materials in compound herbal prescriptions.展开更多
Glycyrrhizin is a major bioactive component of liquorice, which exerts multiple biochemical and pharmacological activities and is frequently used in combination with other drugs in the clinic. Mycophenolate mofetil(MM...Glycyrrhizin is a major bioactive component of liquorice, which exerts multiple biochemical and pharmacological activities and is frequently used in combination with other drugs in the clinic. Mycophenolate mofetil(MMF), an immunosuppressant widely used in transplant patients, is metabolized by UDP-glucuronyltransferases(UGTs). Although significant evidence supports that glycyrrhizin could interact with the cytochrome P450s(CYPs), few studies have addressed its effects on UGTs. The present study aimed at investigating the regulatory effects of diammonium glycyrrhizinate(GLN) on UGTs in vitro and in vivo. We found that long-term administration of GLN in rats induced overall metabolism of MMF, which might be due to the induction of UGT1A protein expression. Hepatic UGT1A activity and UGT1A mRNA and protein expression were significantly increased in GLN-treated rats. UGT1A expression levels were also increased in the intestine, contradicting with the observed decrease in intestinal UGT1A activities. This phenomenon may be attributed to different concentrations of glycyrrhetinic acid(GA) in liver and intestine and the inhibitory effects of GA on UGT1A activity. In conclusion, our study revealed that GLN had multiple effects on the expression and activities of UGT1A isoforms, providing a basis for a better understanding of interactions between GLN and other drugs.展开更多
基金Research Foundation of Hainan Medical University(No.HYPY2020014)National Natural Science Foundation of China(No.2021MSXM10)。
文摘The anterior cruciate ligament(ACL)mainly plays a role in stabilizing the knee joint by limiting the forward translation of tibial force and rotational force at the tibial joint,and if this ligament is damaged,it will cause joint pain,limited mobility,knee instability,etc.According to related studies,the incidence of traumatic osteoarthritis(PTOA)after ACL injury is as high as 87%,although many studies have shown that patients with ACL injury are susceptible to PTOA,but the exact mechanism is currently unknown.This may be related to biological,structural,and mechanical factors caused by the ligament injury.Previous studies have shown that elevated inflammatory mediators in the joint cavity following ACL injury can lead to chondrocytes necrosis and degradation of the cartilage matrix.These potential biochemical mediators contribute to PTOA formation,and early intervention can reduce future episodes of PTOA.In recent years,many scholars have devoted themselves to studying the potential important factors and signaling pathways involved in the formation of osteoarthritis after ACL injury,and exploring its molecular mechanism,which has led to great progress in this field.This paper mainly studies and discusses the mechanism of osteoarthritis formation after ACL injury from the biological perspective.
基金This work was financially supported by National natural science foundation of P.R.China (No.30572228 ,30630076)the National Eleventh Five Years Supporting Project (2006BAI08B04-05) .
基金National Nature Science Foundation of China(81773989and 81530098)
文摘OBJECTIVE To identify the bioactive anti-angiogenic constitutes targeting tumor endothelial cells(TECs)in Shenmai Injection(SMI).METHEODS For pharmacokinetic(PK)studies,Balb/c mice harboring human colorectal cancer(LoVo)xenografts were treated with SMI 10 mL·kg^-1 daily for 1 or 8 d.Multidimensional PK profiles of ginsenosides in plasma,subcutaneous tumors,and TECs were investigated.For PD studies,the tumor-bearing mice Intravital multi-photon imaging and CD31 immunofluorescence staining were used to evaluate the number of microves⁃sels and braches.Double staining of CD31 and α-SMA was performed to evaluate pericytes coverage ratios around vessels.ELISA was performed to determine the concentrations of VEGF and FGF in tumor tissues.For synergistic anti-tumor study,the tumor-bearing mice were treated with SMI 10 mL·kg^-1 daily,Rd 5 mg·kg^-1 daily with or without 5-FU 15 mg·kg^-1 every 3 d for 20 d.HPLC-MS/MS was used to determine the concentrations of 5-FU in plasma and tumor tissues.RESULTS SMI decreased the number of microvessels(P<0.05)and vessel branches(P<0.05)and improved vascular pericytes coverage(P<0.05).PK studies showed that the concentrations of protopanaxadiol-type(PPD)ginsenosides(Rb1,Rb2/Rb3,Rc,and Rd)in both,plasma and tumors,were higher than those of protopanaxatriol-type(Rg1 and Re)and oleanane-type(Ro)ginsenosides.Among PPD ginsenosides,Rd exhibited the greatest concentrations in tumors and TECs after repeated injection.In fact,the proportion of Rd in the detectable components of SMI gradually increased in the following order:SMI formula(2.8%),plasma(16.0%),tumor tissues(34.3%),and TECs(40.3%).In vivo bioactivity results showed that Rd 5 mg·kg^-1 daily significantly decreased the number of microvessels(P<0.05)and vessel branches(P<0.05)and increased pericytes coverage(P<0.05)while Rd 0.5 mg·kg^-1 daily,Rb1 and Rg1 had no significant effect on them.Rd 5 mg·kg^-1 suppressed the expression of VEGF and FGF simultaneously.Rd 5 mg·kg^-1 enhanced the antitumor effect of 5-FU via increasing the distribution of 5-FU in tumor tissues(P<0.05)in xenograft mice.CONCLUSION Ginsenoside Rd may be the major bioactive anti-angiogenic constituent targeting TECs after SMI treatment.
基金supported by State Project for Essential Drug Research and Development of China(No.20152X09303001)
文摘We investigated the potential hepatoprotective effect of Radix Bupleuri(RB) by inducing acute liver injury(ALI) in an animal model using acetaminophen(APAP) after pretreatment with RB aqueous extract for three consecutive days. Compared to those of the APAP group, the biochemical and histological results of the RB pretreatment group showed lower serum aspartate transaminase(AST) and alanine transaminase(ALT) levels as well as less liver damage. Pharmacokinetic study of the toxicity related marker acetaminophen-cysteine(APC) revealed a lower exposure level in rats, suggesting that RB alleviated APAP-induced liver damage by preventing glutathione(GSH) depletion. The results of cocktail approach showed significant inhibition of CYP2 E1 and CYP3 A activity. Further investigation revealed the increasing of CYP2 E1 and CYP3 A protein was significantly inhibited in pretreatment group,while no obvious effect on gene expression was found. Therefore, this study clearly demonstrates that RB exhibited significant protective action against APAP-induced acute live injury via pretreatment, and which is partly through inhibiting the increase of activity and translation of cytochrome P450 enzymes, rather than gene transcription.
基金financially supported by the National Key Special Project of Science and Technology for Innovation Drugs of China(Nos.2013zx09402203 and 2013zx09402202)the Natural Science Foundation of Jiangsu Province,China(No.BK20130403)+1 种基金the National Natural Science Foundation of China(No.81503342)the Project for Jiangsu Province Key Lab of Drug Metabolism and Pharmacokinetics(No.BM2012012)
文摘Ginkgo diterpene lactones meglumine injection(GDLI)is a commercially available product used for neuroprotection.However,the pharmacokinetic properties of the prototypes and hydrolyzed carboxylic forms of the primary components in GDLI,i.e.,ginkgolide A(GA),ginkgolide B(GB),and ginkgolide K(GK),have never been fully evaluated in beagle dogs.In this work,a simple,sensitive,and reliable method based on ultra-fast liquid chromatography-tandem mass spectrometry(UFLC-MS/MS)was developed,and the prototypes and total amounts of GA,GB,and GK were determined in beagle dog plasma.The plasma concentrations of the hydrolyzed carboxylic forms were calculated by subtracting the prototype concentrations from the total lactone concentrations.For the first time,the pharmacokinetics of GA,GB,and GK were fully assessed in three forms,i.e.,the prototypes,the hydrolyzed carboxylic forms,and the total amounts,after intravenous administration of GDLI in beagle dogs.It was shown that ginkgolides primarily existed in the hydrolyzed form in plasma,and the ratio of hydrolysates to prototype forms of GA and GB decreased gradually to a homeostatic ratio.All of the three forms of the three ginkgolides showed linear exposure of AUC to the dosages.GA,GB,and GK showed a constant half-life approximately 2.7,3.4,and 1.2 h,respectively,which were consistent for the forms at three dose levels(0.3,1.0,and 3.0 mg·kg^(-1))and after a consecutive injection of GDLI for 7 days(1.0 mg·kg^(-1)).
基金supported by Natural Science Foundation of Jiangsu province for outstanding youth scholar(No.BK2012026)National Natural Science Foundation of China(Nos.81430091,81325025,and 81273586)
文摘Isochlorogenic acid A(ICQA), which has anti-inflammatory, hepatoprotective, and antiviral properties, is commonly presented in fruits, vegetables, coffee, plant-based food products, and herbal medicines. These herbal medicines are usually used in combination with other medicines in the clinic. However, little is known about the regulatory effects of ICQA on drug-metabolizing enzymes and the herb-drug interactions. In the present study, we evaluated the inhibitory potentials of ICQA on CYP1A2, CYP2C9,CYP2C19, CYP3A4, CYP2D6, and CYP2E1 in vitro based on a cocktail approach. The P450 and UGT activities in mice treated with ICQA for a prolonged period were also determined. Our results demonstrated that ICQA exhibited a weak inhibitory effect on CYP2C9 in human liver microsomes with IC_(50) being 57.25 μmol·L^(-1) and Ki being 26.77 μmol·L^(-1). In addition, ICQA inhibited UGT1A6 activity by 25%, in the mice treated with ICQA(i.p.) at 30 mg·kg^(-1)for 14 d, compared with the control group. Moreover, ICQA showed no mechanism-based inhibition on CYP2C9 or UGT1A6. In conclusion, our results further confirm a safe use of ICQA in clinical practice.
基金supported by the National Natural Science Foundation of China(Nos.81430091,81325025,and 81273586)Jiangsu Provincial Promotion Foundation for the Key Lab of Drug Metabolism and Pharmacokinetics(No.BM2012012)the Natural Science Foundation of Jiangsu Province for Outstanding Youth Scholar(No.BK2012026)
文摘Nicotinamide phosphoribosyltransferase(NAMPT) catalyzes the first rate-limiting step in converting nicotinamide to NAD^+, essential for a number of enzymes and regulatory proteins involved in a variety of cellular processes, including deacetylation enzyme SIRT1 which modulates several tumor suppressors such as p53 and FOXO. Herein we report that NQO1 substrates Tanshione IIA(TSA) and β-lapachone(β-lap) induced a rapid depletion of NAD^+ pool but adaptively a significant upregulation of NAMPT. NAMPT inhibition by FK866 at a nontoxic dose significantly enhanced NQO1-targeting agent-induced apoptotic cell death. Compared with TSA or β-lap treatment alone, co-treatment with FK866 induced a more dramatic depletion of NAD^+, repression of SIRT1 activity, and thereby the increased accumulation of acetylated FOXO1 and the activation of apoptotic pathway. In conclusion, the results from the present study support that NAMPT inhibition can synergize with NQO1 activation to induce apoptotic cell death, thereby providing a new rationale for the development of combinative therapeutic drugs in combating non-small lung cancer.
基金supported by the National Natural Science Foundation of China(Nos.81720108032,81930109,82073926,82073928)the Project for Major New Drug Innovation and Development(Nos.2018ZX09711001-002-003,2018ZX09711002-001-004)Overseas Expertise Introduction Project for Discipline Innovation(No.G20582017001).
文摘Nonalcoholic fatty liver disease(NAFLD)is regarded as the most common liver disease with no approved therapeutic drug currently.Silymarin,an extract from the seeds of Silybum marianum,has been used for centuries for the treatment of various liver diseases.Although the hepatoprotective effect of silybin against NAFLD is widely accepted,the underlying mechanism and therapeutic target remain unclear.In this study,NAFLD mice caused by methionine-choline deficient(MCD)diet were orally administrated with silybin to explore the possible mechanism and target.To clarify the contribution of peroxisome proliferator-activated receptorα(PPARα),PPARαantagonist GW6471 was co-administrated with silybin to NAFLD mice.Since silybin was proven as a PPARαpartial agonist,the combined effect of silybin with PPARαagonist,fenofibrate,was then evaluated in NAFLD mice.Serum and liver samples were collected to analyze the pharmacological efficacy and expression of PPARαand its targets.As expected,silybin significantly protected mice from MCD-induced NAFLD.Furthermore,silybin reduced lipid accumulation via activating PPARα,inducing the expression of liver cytosolic fatty acid-binding protein,carnitine palmitoyltransferase(Cpt)-1a,Cpt-2,medium chain acyl-CoA dehydrogenase and stearoyl-CoA desaturase-1,and suppressing fatty acid synthase and acetyl-CoA carboxylaseα.GW6471 abolished the effect of silybin on PPARαsignal and hepatoprotective effect against NAFLD.Moreover,as a partial agonist for PPARα,silybin impaired the powerful lipid-lowering effect of fenofibrate when used together.Taken together,silybin protected mice against NAFLD via activating PPARαto diminish lipid accumulation and it is not suggested to simultaneously take silybin and classical PPARαagonists for NAFLD therapy.
基金supported by the National Nature Science Foundation of China(Nos.81273589,81374054)the Nature Science Foundation of Jiangsu Province(BK20131311)+2 种基金the fundamental research special fund of China Pharmaceutical University(PT2014 YK0081)Jiangsu Provincial Promotion Foundation for the Key Laboratory of Drug Metabolism and Pharmacokinetics(BM2012012)Jiangsu Key Laboratory of Drug Design and Optimization
文摘Liquid chromatography hybrid ion trap/time-of-flight mass spectrometry possesses both the MS^n ability of ion trap and the excellent resolution of a time-of-flight and has been widely used to identify drug metabolites and determine trace multi-components in natural products. Collision energy, one of the most important factors in acquiring MS^n information, could be set freely in the range of 10%–400%. Herein, notoginsenosides were chosen as model compounds to build a novel methodology for the collision energy optimization. Firstly, the fragmental patterns of the representatives for the authentic standards of protopanaxadiol-type and protopanaxatriol-type notoginsenosides were obtained based on accurate MS^2 and MS^3 measurements via liquid chromatography hybrid ion trap/time-of-flight mass spectrometry. The extracted ion chromatograms of characteristic product ions of notoginsenosides in Panax Notoginseng Extract were produced under a series of collision energies and compared to screen the optimum collision energies values for MS^2 and MS^3. The results demonstrated that the qualitative capability of liquid chromatography hybrid ion trap/time-of-flight mass spectrometry was greatly influenced by collision energies, and 50% of MS^2 collision energy was found to produce the highest collision-induced dissociation efficiency for notoginsenosides. Addtionally, the highest collision-induced dissociation efficiency appeared when the collision energy was set at 75% in the MS^3 stage.
基金financially supported by Natural Science Foundation of Jiangsu province(Nos.BK2011065 and BK2012026)Jiangsu Province Key Lab of Drug Metabolism and Pharmacokinetics(No.BM2012012)+3 种基金National Basic Research Program of China("973 Program"No.2011 CB505300-03)Foundation for the Author of National Excellent Doctoral Dissertation of China(No.200979)the Program for New Century Excellent Talents in University(No.NCET-09-0770)
文摘As a computer-assisted approach, molecular docking has been universally applied in drug research and development and plays an important role in the investigation and evaluation of herbal medicines. Herein, the method was used to estimate the pharmacodynamics of Mai-Luo-Ning injection, a traditional Chinese compound herbal prescription. Through investigating the interactions between several important proteins in cardiovascular system and characteristic components of the formula, its effect on cardiovascular protection was evaluated. Results showed the differences in the interactions between each component and the selected target proteins and revealed the possible mechanisms for synergistic effects of various characteristic components on cardiovascular protection. The study provided scientific evidence supporting the mechanistic study of the interactions among multi-components and targets, offering a general approach to investigating the pharmacodynamics of complicated materials in compound herbal prescriptions.
基金supported by the Key Lab of Drug Metabolism and Pharmacokinetics of Jiangsu Province(No.BM2012012)
文摘Glycyrrhizin is a major bioactive component of liquorice, which exerts multiple biochemical and pharmacological activities and is frequently used in combination with other drugs in the clinic. Mycophenolate mofetil(MMF), an immunosuppressant widely used in transplant patients, is metabolized by UDP-glucuronyltransferases(UGTs). Although significant evidence supports that glycyrrhizin could interact with the cytochrome P450s(CYPs), few studies have addressed its effects on UGTs. The present study aimed at investigating the regulatory effects of diammonium glycyrrhizinate(GLN) on UGTs in vitro and in vivo. We found that long-term administration of GLN in rats induced overall metabolism of MMF, which might be due to the induction of UGT1A protein expression. Hepatic UGT1A activity and UGT1A mRNA and protein expression were significantly increased in GLN-treated rats. UGT1A expression levels were also increased in the intestine, contradicting with the observed decrease in intestinal UGT1A activities. This phenomenon may be attributed to different concentrations of glycyrrhetinic acid(GA) in liver and intestine and the inhibitory effects of GA on UGT1A activity. In conclusion, our study revealed that GLN had multiple effects on the expression and activities of UGT1A isoforms, providing a basis for a better understanding of interactions between GLN and other drugs.
