OBJECTIVE To explore the efficacy of Jiaotai pill(JTW)and JTW modified prescriptions(JTW^(+))plus benzodiazepines(BDZ)for insomnia in China by systematic review and network meta-analysis,especially optimization ratio(...OBJECTIVE To explore the efficacy of Jiaotai pill(JTW)and JTW modified prescriptions(JTW^(+))plus benzodiazepines(BDZ)for insomnia in China by systematic review and network meta-analysis,especially optimization ratio(_(m:n))between Coptis chinensis and Cinnamo.METHODS Randomized controlled trials(RCTs)regarding JTW and JTW^(+)+BDZ for insomina were comprehensively searched in CNKI,VIP,Wanfang,and PubMed,Cochrane Library,OVID,Embase databases from their inception to December 2017.The risk of bias was assessed by the Cochrane collaboration′s tool and Jadad scale.Systematic review and network meta-analysis were performed to evaluate the relative risk(RR)plus 95%confidence interval(95%CI)or prediction interval(95%PrI),and draw surface under the cumulative ranking curves(SUCRA)by Stata 14.0 and RevMan 5.0 software.RESULTS A total of 13 RCTs(1 RCT was omitted by sensitivity analysis)with 1040 patients were included.Overall heterogeneity was acceptable,except publication bias.Based on classical meta-analysis,JTW and JTW_(m:n)^(+)+BDZ,such as JTW_(2:1)^(+)+BDZ,JTW_(5:1)^(+)+BDZ,JTW_(6:1)^(+)+BDZ,JTW_(10:1)^(+)+BDZ,had more efficacy than BDZ.Based on network meta-analysis,JTW and JTW_(m:n)^(+)+BDZ,such as JTW_(2:1)^(+)+BDZ,JTW_(6:1)^(+)+BDZ,JTW_(10:1)^(+)+BDZ,had more efficacy than BDZ;meanwhile,SUCRA showed the best rank of JTW/JTW+(BDZ<JTW_(m:n)^(+)+BDZ<JTW)for insomina,as same as that of JTW_(m:n)+(BDZ<JTW_(5:1)^(+)+BDZ<JTW_(10:1)^(+)+BDZ<JTW_(2:1)^(+)+BDZ<JTW_(6:1)^(+)+BDZ).CONCLUSION Based on the existing clinical evidence,JTW has efficacy for insomnia,but the optimization ratio between Coptis chinensis and cinnamo of JTW_(m:n)^(+)+BDZ for insomnia needs more supports.展开更多
Objective:The pharmacokinetics and relative bioavailability of Jiaotai pill self-microemulsion were evaluated by investigating the blood concentration of Berberine,Coptisine,Palmatine and Jatrorrhizine in insomnia rat...Objective:The pharmacokinetics and relative bioavailability of Jiaotai pill self-microemulsion were evaluated by investigating the blood concentration of Berberine,Coptisine,Palmatine and Jatrorrhizine in insomnia rats.Methods:Insomnia rat model was established by intraperitoneal injection of p-chlorophenylalanine(PCPA).The model rats were given Jiaotai pill self-microemulsion and Jiaotai pill suspension.The contents of Berberine,Coptisine,Palmatine and Jatrorrhizine in plasma at different times after administration were determined by UPLC-MS/MS,and calculate pharmacokinetic parameters.Results:Under the set chromatographic conditions,the linear relationship of the four components was good,and the precision,accuracy and stability meet the requirements of biological samples.After intragastric administration of Jiaotai pill self-microemulsion,The C_(max) of Berberine,Coptisine,Palmatine and Jatrorrhizine were(412.68±28.45),(68.65±3.92),(34.06±3.13),(40.60±1.22)ng/mL,and AUC_(0-∞)were(672.70±72.55),(146.04±25.01),(71.49±18.67),(72.25±9.54)ng·mL^(-1)·h^(-1),respectively.Compared with Jiaotai pill suspension,the Cmax,AUC_(0-t) and AUC_(0-∞)of the four components in insomnia rats were significantly increased(P<0.01).Conclusion:Jiaotai pill self-microemulsionl can promote the absorption of effective components in insomnia rats and improve its bioavailability.展开更多
BACKGROUND Jiawei Jiaotai Pill is commonly used in clinical practice to reduce apoptosis,increase insulin secretion,and improve blood glucose tolerance.However,its mechanism of action in the treatment of diabetic card...BACKGROUND Jiawei Jiaotai Pill is commonly used in clinical practice to reduce apoptosis,increase insulin secretion,and improve blood glucose tolerance.However,its mechanism of action in the treatment of diabetic cardiomyopathy(DCM)remains unclear,hindering research efforts aimed at developing drugs specifically for the treatment of DCM.AIM To explore the pharmacodynamic basis and molecular mechanism of Jiawei Jiaotai Pill in DCM treatment.METHODS We explored various databases and software,including the Traditional Chinese Medicine Systems Pharmacology Database,Uniport,PubChem,GenCards,String,and Cytoscape,to identify the active components and targets of Jiawei Jiaotai Pill,and the disease targets in DCM.Protein-protein interaction network,gene ontology,and Kyoto Encyclopedia of Genes and Genomes analyses were used to determine the mechanism of action of Jiawei Jiaotai Pill in treating DCM.Molecular docking of key active components and core targets was verified using AutoDock software.RESULTS Total 42 active ingredients and 142 potential targets of Jiawei Jiaotai Pill were identified.There were 100 common targets between the DCM and Jiawei Jiaotai Pills.Through this screening process,TNF,IL6,TP53,EGFR,INS,and other important targets were identified.These targets are mainly involved in the positive regulation of the mitogen-activated protein kinase(MAPK)MAPK cascade,response to xenobiotic stimuli,response to hypoxia,positive regulation of gene expression,positive regulation of cell proliferation,negative regulation of the apoptotic process,and other biological processes.It was mainly enriched in the AGE-RAGE signaling pathway in diabetic complications,DCM,PI3K-Akt,interleukin-17,and MAPK signaling pathways.Molecular docking results showed that Jiawei Jiaotai Pill's active ingredients had good docking activity with DCM's core target.CONCLUSION The active components of Jiawei Jiaotai Pill may play a role in the treatment of DCM by reducing oxidative stress,cardiomyocyte apoptosis and fibrosis,and maintaining metabolic homeostasis.展开更多
[Objectives] To analyze the effect of Jiaotai acupuncture combined with Escitalopram on mild depression and its influence on inflammatory factors.[Methods] Eighty patients with mild depression admitted to Shenzhen Bao...[Objectives] To analyze the effect of Jiaotai acupuncture combined with Escitalopram on mild depression and its influence on inflammatory factors.[Methods] Eighty patients with mild depression admitted to Shenzhen Baoan District Central Hospital from March 2021 to March 2023 were randomly divided into observation group (40 cases) and control group (40 cases). The control group was treated with Escitalopram, and the observation group was treated with Jiaotai acupuncture on the basis of the control group. The overall efficacy, depression score before and after treatment, and the improvement of inflammation level were compared between the two groups.[Results] The total effective rate of the observation group was significantly higher than that of the control group ( P <0.05), and the improvement of depression score and inflammation level of the observation group was significantly better than that of the control group ( P <0.05).[Conclusions] Jiaotai acupuncture combined with Escitalopram can significantly reduce inflammation and improve symptoms in patients with mild depression.展开更多
Objective: To explore the effect and mechanism of Jiaotai Pill(交泰丸, JTW) on intestinal mucosal damage in rats with chronic partial sleep deprivation(PSD). Methods: Obesity resistant(OR) rats were selected, and unde...Objective: To explore the effect and mechanism of Jiaotai Pill(交泰丸, JTW) on intestinal mucosal damage in rats with chronic partial sleep deprivation(PSD). Methods: Obesity resistant(OR) rats were selected, and underwent 4 h PSD by being exposed to environmental noise for 4 weeks. During the whole PSD period, JTW and estazolam were orally given to the rats respectively in the treating groups. Plasma concentration of lipopolysaccharide(LPS) which is the marker of gut-origin endotoxemia was examined. Intestinal morphology changes were observed by optical microscopy. The protein expression of occludin(Ocln) in the intestine was measured by immunofluorescence technique and Western blot. The expressions of circadian proteins cryptochromes(Cry1 and Cry2) in the intestine were also determined. Results: The treatment of JTW significantly decreased LPS level in OR rats with PSD(P<0.05). JTW also attenuated insomnia-induced intestinal injury like shorter, sparse and incomplete villus, wide gap between the villus, mucosal swelling and congesting(P<0.05). These changes were associated with the effect of JTW on up-regulating the expressions of Cry1 protein, Cry2 protein and Ocln protein in the intestine. Conclusions: JTW has the beneficial effect on improving intestinal mucosal damage caused by PSD. The mechanism appears to be related to the modulation of the expressions of circadian proteins and Ocln protein in the intestine, thereby attenuating inflammation and improving insulin resistance in insomnia rats.展开更多
Objective To reveal the effect and mechanism of Jiaotai Pill(交泰丸,JTP)on insomniac rats.Methods The insomniac model was established by intraperitoneal injection of p-chlorophenylalanine(PCPA).In behavioral experimen...Objective To reveal the effect and mechanism of Jiaotai Pill(交泰丸,JTP)on insomniac rats.Methods The insomniac model was established by intraperitoneal injection of p-chlorophenylalanine(PCPA).In behavioral experiments,rats were divided into control,insomniac model,JTP[3.3 g/(kg•d)],and diazepam[4 mg/(kg•d)]groups.The treatment effect of JTP was evaluated by weight measurement(increasement of body weight),open field test(number of crossings)and forced swimming test(immobility time).A high performance liquid chromatography-electrochemical detection(HPLC-ECD)method was built to determine the concentration of monoamine transmitters in hypothalamus and peripheral organs from normal,model,JTP,citalopram[30 mg/(kg•d)],maprotiline[40 mg/(kg•d)]and bupropion[40 mg/(kg•d)]groups.Expressions of serotonin transporter(SERT),dopamine transporter(DAT),and norepinephrine transporter(NET)were analyzed by quantitative polymerase chain reaction(qPCR)and Western blot in normal,model and JTP groups.A high performance liquid chromatography-electrospray ionization mass spectrometry(HPLC-ESI-MS/MS)method was established to determine the pharmacokinetics,urine cumulative excretion of metformin in vivo,and tissue slice uptake in vitro,which were applied to assess the activity of organic cation transporters(OCTs)in hypothalamus and peripheral organs.Results Compared with the insomniac model group,the body weight and spontaneous locomotor were increased,and the immobility time was decreased after treatment with JTP(P<0.01).Both serotonin and dopamine contents in hypothalamus and peripheral organs were increased(P<0.01).The norepinephrine content was increased in peripheral organs and decreased in hypothalamus(P<0.05 or P<0.01).At the same time,SERT,DAT,OCT1,OCT2,and OCT3 were down-regulated in hypothalamus and peripheral organs(P<0.05).NET was down-regulated in peripheral organs and up-regulated in hypothalamus(P<0.05 or P<0.01).Moreover,the activity of OCTs in hypothalamus and peripheral organs was inhibited(P<0.05).Conclusion JTP alleviates insomnia through regulation of monoaminergic system and OCTs in hypothalamus and peripheral organs.展开更多
Objective:To compare the brain pharmacokinetics of five protoberberine-type alkaloids(i.e.berberine,palmatine,coptisine,epiberberine,and jatrorrhizine),which were the main bioactive constituents of Jiaotai Pills(...Objective:To compare the brain pharmacokinetics of five protoberberine-type alkaloids(i.e.berberine,palmatine,coptisine,epiberberine,and jatrorrhizine),which were the main bioactive constituents of Jiaotai Pills(JTP),in normal and insomnic rats orally administrated with JTP.Methods:The detection was conducted by a fully validated liquid chromatography-tandem mass spectrometry combinated with brain microdialysis method.Brain microdialysis probes were inserted into the hippocampus of rats.JTP extracts were administrated intragastrically and then brain microdialysates were collected at 30 min time intervals for 10 h.The separation of the five protoberberine-type alkaloids was carried out on a BDS Hypersilusing a mobile phase consisting of acetonitrile and water(containing 5 mmol ammonium acetate adjusted to p H 5.0)within 4 min.The quantification was performed by multiple reaction monitoring with the transitions of m/z 336.0-320.1 for berberine,m/z 352.0-336.1for palmatine,m/z 338.0-322.1 for jatrorrhizine,m/z 336.0-320.1 for epiberberine,m/z 320.0-292.1 for coptisine and m/z 356.4-192.1 for IS.Results:The lower limit of quantification for five protoberberine-type alkaloids was 0.05 ng/m L.Linearity,accuracy,precision,stability and matrix effect of five analytes were all satisfactory.Five protoberberinetype alkaloids were quickly distributed in the brain.Moreover,significant differences in the principal pharmacokinetic parameters such as AUC andthe analytes were observed between two groups.Conclusion:The LC-MS/MS method combinated with microdialysis is useful in the brain pharmacokinetic study of five protoberberine-type alkaloids.The results indicated that the rates of analytes absorption in insomnic rats were significantly higher than those in normal rats.Besides,the protoberberine-type alkaloids could bring a direct effect on the neuron in the hippocampus.展开更多
目的通过网络药理学和分子对接技术对交泰丸治疗失眠的作用机制进行研究。方法交泰丸活性成分由中药系统药理学数据库与分析平台(Traditional Chinese Medicine Systems Pharmacology Database andAnalysis Platform,TCMSP)、中医药整...目的通过网络药理学和分子对接技术对交泰丸治疗失眠的作用机制进行研究。方法交泰丸活性成分由中药系统药理学数据库与分析平台(Traditional Chinese Medicine Systems Pharmacology Database andAnalysis Platform,TCMSP)、中医药整合药理学研究平台(Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine,TCMIP)整合获得,SwissTargetPrediction数据库预测作用靶点,整合DisGeNET、DrugBank疾病基因数据库中失眠的靶点基因。采用Venny 2.1在线软件作图工具平台,获取活性成分与失眠靶点的交集靶,Cytoscape 3.9.1作图软件构建交泰丸活性成分的交集靶点网络,分析得到交泰丸核心成分。蛋白互作网络、核心靶点由STRING12.0数据库获得,DAVID数据进行基因本体(gene ontology,GO)功能注释和京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)通路富集分析,采用AutoDockTools1.5.7 Pymol软件对关键靶点与成分进行分子对接、可视化处理。结果筛选得到交泰丸中治疗失眠的5个核心成分依次为小檗碱、柠檬苦素、黄柏酮、N-反式阿魏酰酪胺、黄藤素,筛选出5-羟色胺(5-hydroxy tryptamine,5-HT)转运体(solute carrier family 6 member,SLC6A4)、多巴胺受体(dopamine receptor D2,DRD2)、烟碱乙酰胆碱受体(cholinergic receptor nicotinic alpha 4 subunit,CHRNA4)、肿瘤坏死因子(tumor necrosis factor,TNF)、前列腺素内过氧化物合酶(prostaglandin-endoperoxide synthase 2,PTGS2)等核心靶点。交泰丸治疗失眠的信号通路主要富集于调节5-HT能突触、多巴胺能突触等。分子对接显示核心成分小檗碱、柠檬苦素、黄柏酮等与核心靶点SLC6A4、DRD2、CHRNA4、TNF、PTGS2等对接程度良好。结论交泰丸中小檗碱、柠檬苦酸、黄柏酮等成分通过影响SLC6A4、DRD2、TNF、CHRNA4、PTGS2等蛋白的表达,多作用机制治疗失眠。展开更多
基金National Science and Technology Major Project of China(SQ2017ZX090301064)National Natural Science Foundation of China(81302887)+1 种基金Shandong Science and Technology Development Program(2014GSF119034)and Shandong Science and Technology Development Program of Traditional Chinese Medicine(2017-115,2019-0222)。
文摘OBJECTIVE To explore the efficacy of Jiaotai pill(JTW)and JTW modified prescriptions(JTW^(+))plus benzodiazepines(BDZ)for insomnia in China by systematic review and network meta-analysis,especially optimization ratio(_(m:n))between Coptis chinensis and Cinnamo.METHODS Randomized controlled trials(RCTs)regarding JTW and JTW^(+)+BDZ for insomina were comprehensively searched in CNKI,VIP,Wanfang,and PubMed,Cochrane Library,OVID,Embase databases from their inception to December 2017.The risk of bias was assessed by the Cochrane collaboration′s tool and Jadad scale.Systematic review and network meta-analysis were performed to evaluate the relative risk(RR)plus 95%confidence interval(95%CI)or prediction interval(95%PrI),and draw surface under the cumulative ranking curves(SUCRA)by Stata 14.0 and RevMan 5.0 software.RESULTS A total of 13 RCTs(1 RCT was omitted by sensitivity analysis)with 1040 patients were included.Overall heterogeneity was acceptable,except publication bias.Based on classical meta-analysis,JTW and JTW_(m:n)^(+)+BDZ,such as JTW_(2:1)^(+)+BDZ,JTW_(5:1)^(+)+BDZ,JTW_(6:1)^(+)+BDZ,JTW_(10:1)^(+)+BDZ,had more efficacy than BDZ.Based on network meta-analysis,JTW and JTW_(m:n)^(+)+BDZ,such as JTW_(2:1)^(+)+BDZ,JTW_(6:1)^(+)+BDZ,JTW_(10:1)^(+)+BDZ,had more efficacy than BDZ;meanwhile,SUCRA showed the best rank of JTW/JTW+(BDZ<JTW_(m:n)^(+)+BDZ<JTW)for insomina,as same as that of JTW_(m:n)+(BDZ<JTW_(5:1)^(+)+BDZ<JTW_(10:1)^(+)+BDZ<JTW_(2:1)^(+)+BDZ<JTW_(6:1)^(+)+BDZ).CONCLUSION Based on the existing clinical evidence,JTW has efficacy for insomnia,but the optimization ratio between Coptis chinensis and cinnamo of JTW_(m:n)^(+)+BDZ for insomnia needs more supports.
基金Scientific Research Project of Heilongjiang Provincial Health Commission(No.2018-482)Excellent Discipline Team Project of Jiamusi University(No.JDXKTD-2019005)。
文摘Objective:The pharmacokinetics and relative bioavailability of Jiaotai pill self-microemulsion were evaluated by investigating the blood concentration of Berberine,Coptisine,Palmatine and Jatrorrhizine in insomnia rats.Methods:Insomnia rat model was established by intraperitoneal injection of p-chlorophenylalanine(PCPA).The model rats were given Jiaotai pill self-microemulsion and Jiaotai pill suspension.The contents of Berberine,Coptisine,Palmatine and Jatrorrhizine in plasma at different times after administration were determined by UPLC-MS/MS,and calculate pharmacokinetic parameters.Results:Under the set chromatographic conditions,the linear relationship of the four components was good,and the precision,accuracy and stability meet the requirements of biological samples.After intragastric administration of Jiaotai pill self-microemulsion,The C_(max) of Berberine,Coptisine,Palmatine and Jatrorrhizine were(412.68±28.45),(68.65±3.92),(34.06±3.13),(40.60±1.22)ng/mL,and AUC_(0-∞)were(672.70±72.55),(146.04±25.01),(71.49±18.67),(72.25±9.54)ng·mL^(-1)·h^(-1),respectively.Compared with Jiaotai pill suspension,the Cmax,AUC_(0-t) and AUC_(0-∞)of the four components in insomnia rats were significantly increased(P<0.01).Conclusion:Jiaotai pill self-microemulsionl can promote the absorption of effective components in insomnia rats and improve its bioavailability.
基金Supported by Natural Science Basic Research Plan in the Shaanxi Province of China,No.2021JM-549,The Plan Project of Shaanxi Provincial Administration of Traditional Chinese Medicine,No.2021-ZZ-JC011The Second Youth Science and Technology Talents Project of Shaanxi Provincial Administration of Traditional Chinese Medicine,No.2023-ZQNY-017.
文摘BACKGROUND Jiawei Jiaotai Pill is commonly used in clinical practice to reduce apoptosis,increase insulin secretion,and improve blood glucose tolerance.However,its mechanism of action in the treatment of diabetic cardiomyopathy(DCM)remains unclear,hindering research efforts aimed at developing drugs specifically for the treatment of DCM.AIM To explore the pharmacodynamic basis and molecular mechanism of Jiawei Jiaotai Pill in DCM treatment.METHODS We explored various databases and software,including the Traditional Chinese Medicine Systems Pharmacology Database,Uniport,PubChem,GenCards,String,and Cytoscape,to identify the active components and targets of Jiawei Jiaotai Pill,and the disease targets in DCM.Protein-protein interaction network,gene ontology,and Kyoto Encyclopedia of Genes and Genomes analyses were used to determine the mechanism of action of Jiawei Jiaotai Pill in treating DCM.Molecular docking of key active components and core targets was verified using AutoDock software.RESULTS Total 42 active ingredients and 142 potential targets of Jiawei Jiaotai Pill were identified.There were 100 common targets between the DCM and Jiawei Jiaotai Pills.Through this screening process,TNF,IL6,TP53,EGFR,INS,and other important targets were identified.These targets are mainly involved in the positive regulation of the mitogen-activated protein kinase(MAPK)MAPK cascade,response to xenobiotic stimuli,response to hypoxia,positive regulation of gene expression,positive regulation of cell proliferation,negative regulation of the apoptotic process,and other biological processes.It was mainly enriched in the AGE-RAGE signaling pathway in diabetic complications,DCM,PI3K-Akt,interleukin-17,and MAPK signaling pathways.Molecular docking results showed that Jiawei Jiaotai Pill's active ingredients had good docking activity with DCM's core target.CONCLUSION The active components of Jiawei Jiaotai Pill may play a role in the treatment of DCM by reducing oxidative stress,cardiomyocyte apoptosis and fibrosis,and maintaining metabolic homeostasis.
基金Supported by Scientific Research Project of Guangdong Provincial Administration of Traditional Chinese Medicine in 2022(20221337).
文摘[Objectives] To analyze the effect of Jiaotai acupuncture combined with Escitalopram on mild depression and its influence on inflammatory factors.[Methods] Eighty patients with mild depression admitted to Shenzhen Baoan District Central Hospital from March 2021 to March 2023 were randomly divided into observation group (40 cases) and control group (40 cases). The control group was treated with Escitalopram, and the observation group was treated with Jiaotai acupuncture on the basis of the control group. The overall efficacy, depression score before and after treatment, and the improvement of inflammation level were compared between the two groups.[Results] The total effective rate of the observation group was significantly higher than that of the control group ( P <0.05), and the improvement of depression score and inflammation level of the observation group was significantly better than that of the control group ( P <0.05).[Conclusions] Jiaotai acupuncture combined with Escitalopram can significantly reduce inflammation and improve symptoms in patients with mild depression.
基金Supported by the National Natural Science Foundation of China(No.81373871,81473637)
文摘Objective: To explore the effect and mechanism of Jiaotai Pill(交泰丸, JTW) on intestinal mucosal damage in rats with chronic partial sleep deprivation(PSD). Methods: Obesity resistant(OR) rats were selected, and underwent 4 h PSD by being exposed to environmental noise for 4 weeks. During the whole PSD period, JTW and estazolam were orally given to the rats respectively in the treating groups. Plasma concentration of lipopolysaccharide(LPS) which is the marker of gut-origin endotoxemia was examined. Intestinal morphology changes were observed by optical microscopy. The protein expression of occludin(Ocln) in the intestine was measured by immunofluorescence technique and Western blot. The expressions of circadian proteins cryptochromes(Cry1 and Cry2) in the intestine were also determined. Results: The treatment of JTW significantly decreased LPS level in OR rats with PSD(P<0.05). JTW also attenuated insomnia-induced intestinal injury like shorter, sparse and incomplete villus, wide gap between the villus, mucosal swelling and congesting(P<0.05). These changes were associated with the effect of JTW on up-regulating the expressions of Cry1 protein, Cry2 protein and Ocln protein in the intestine. Conclusions: JTW has the beneficial effect on improving intestinal mucosal damage caused by PSD. The mechanism appears to be related to the modulation of the expressions of circadian proteins and Ocln protein in the intestine, thereby attenuating inflammation and improving insulin resistance in insomnia rats.
基金the National Natural Science Foundation of China(No.81673680)。
文摘Objective To reveal the effect and mechanism of Jiaotai Pill(交泰丸,JTP)on insomniac rats.Methods The insomniac model was established by intraperitoneal injection of p-chlorophenylalanine(PCPA).In behavioral experiments,rats were divided into control,insomniac model,JTP[3.3 g/(kg•d)],and diazepam[4 mg/(kg•d)]groups.The treatment effect of JTP was evaluated by weight measurement(increasement of body weight),open field test(number of crossings)and forced swimming test(immobility time).A high performance liquid chromatography-electrochemical detection(HPLC-ECD)method was built to determine the concentration of monoamine transmitters in hypothalamus and peripheral organs from normal,model,JTP,citalopram[30 mg/(kg•d)],maprotiline[40 mg/(kg•d)]and bupropion[40 mg/(kg•d)]groups.Expressions of serotonin transporter(SERT),dopamine transporter(DAT),and norepinephrine transporter(NET)were analyzed by quantitative polymerase chain reaction(qPCR)and Western blot in normal,model and JTP groups.A high performance liquid chromatography-electrospray ionization mass spectrometry(HPLC-ESI-MS/MS)method was established to determine the pharmacokinetics,urine cumulative excretion of metformin in vivo,and tissue slice uptake in vitro,which were applied to assess the activity of organic cation transporters(OCTs)in hypothalamus and peripheral organs.Results Compared with the insomniac model group,the body weight and spontaneous locomotor were increased,and the immobility time was decreased after treatment with JTP(P<0.01).Both serotonin and dopamine contents in hypothalamus and peripheral organs were increased(P<0.01).The norepinephrine content was increased in peripheral organs and decreased in hypothalamus(P<0.05 or P<0.01).At the same time,SERT,DAT,OCT1,OCT2,and OCT3 were down-regulated in hypothalamus and peripheral organs(P<0.05).NET was down-regulated in peripheral organs and up-regulated in hypothalamus(P<0.05 or P<0.01).Moreover,the activity of OCTs in hypothalamus and peripheral organs was inhibited(P<0.05).Conclusion JTP alleviates insomnia through regulation of monoaminergic system and OCTs in hypothalamus and peripheral organs.
基金supported by the National Natural Science Foundation of China(No.81473319 and No.81473540)the Key Projects of Guangdong Natural Science Foundation(No.2017A030311022)+3 种基金the Guangdong Science and Technology Program(No.2015A030401031,2014A020209026)the Guangdong Natural Science Foundation(No.2015A030313123)the Zhongshan Science and Technology Program(No.2016C1015)the Science Program for Overseas Scholar of Guangzhou University of Chinese Medicine(Torch Program)(No.XH20170111)
文摘Objective:To compare the brain pharmacokinetics of five protoberberine-type alkaloids(i.e.berberine,palmatine,coptisine,epiberberine,and jatrorrhizine),which were the main bioactive constituents of Jiaotai Pills(JTP),in normal and insomnic rats orally administrated with JTP.Methods:The detection was conducted by a fully validated liquid chromatography-tandem mass spectrometry combinated with brain microdialysis method.Brain microdialysis probes were inserted into the hippocampus of rats.JTP extracts were administrated intragastrically and then brain microdialysates were collected at 30 min time intervals for 10 h.The separation of the five protoberberine-type alkaloids was carried out on a BDS Hypersilusing a mobile phase consisting of acetonitrile and water(containing 5 mmol ammonium acetate adjusted to p H 5.0)within 4 min.The quantification was performed by multiple reaction monitoring with the transitions of m/z 336.0-320.1 for berberine,m/z 352.0-336.1for palmatine,m/z 338.0-322.1 for jatrorrhizine,m/z 336.0-320.1 for epiberberine,m/z 320.0-292.1 for coptisine and m/z 356.4-192.1 for IS.Results:The lower limit of quantification for five protoberberine-type alkaloids was 0.05 ng/m L.Linearity,accuracy,precision,stability and matrix effect of five analytes were all satisfactory.Five protoberberinetype alkaloids were quickly distributed in the brain.Moreover,significant differences in the principal pharmacokinetic parameters such as AUC andthe analytes were observed between two groups.Conclusion:The LC-MS/MS method combinated with microdialysis is useful in the brain pharmacokinetic study of five protoberberine-type alkaloids.The results indicated that the rates of analytes absorption in insomnic rats were significantly higher than those in normal rats.Besides,the protoberberine-type alkaloids could bring a direct effect on the neuron in the hippocampus.
文摘目的通过网络药理学和分子对接技术对交泰丸治疗失眠的作用机制进行研究。方法交泰丸活性成分由中药系统药理学数据库与分析平台(Traditional Chinese Medicine Systems Pharmacology Database andAnalysis Platform,TCMSP)、中医药整合药理学研究平台(Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine,TCMIP)整合获得,SwissTargetPrediction数据库预测作用靶点,整合DisGeNET、DrugBank疾病基因数据库中失眠的靶点基因。采用Venny 2.1在线软件作图工具平台,获取活性成分与失眠靶点的交集靶,Cytoscape 3.9.1作图软件构建交泰丸活性成分的交集靶点网络,分析得到交泰丸核心成分。蛋白互作网络、核心靶点由STRING12.0数据库获得,DAVID数据进行基因本体(gene ontology,GO)功能注释和京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)通路富集分析,采用AutoDockTools1.5.7 Pymol软件对关键靶点与成分进行分子对接、可视化处理。结果筛选得到交泰丸中治疗失眠的5个核心成分依次为小檗碱、柠檬苦素、黄柏酮、N-反式阿魏酰酪胺、黄藤素,筛选出5-羟色胺(5-hydroxy tryptamine,5-HT)转运体(solute carrier family 6 member,SLC6A4)、多巴胺受体(dopamine receptor D2,DRD2)、烟碱乙酰胆碱受体(cholinergic receptor nicotinic alpha 4 subunit,CHRNA4)、肿瘤坏死因子(tumor necrosis factor,TNF)、前列腺素内过氧化物合酶(prostaglandin-endoperoxide synthase 2,PTGS2)等核心靶点。交泰丸治疗失眠的信号通路主要富集于调节5-HT能突触、多巴胺能突触等。分子对接显示核心成分小檗碱、柠檬苦素、黄柏酮等与核心靶点SLC6A4、DRD2、CHRNA4、TNF、PTGS2等对接程度良好。结论交泰丸中小檗碱、柠檬苦酸、黄柏酮等成分通过影响SLC6A4、DRD2、TNF、CHRNA4、PTGS2等蛋白的表达,多作用机制治疗失眠。