Simultaneous determination of 8 components in Jinqi jiangtang tablets by ion mobility mass spectrometry method / 中国药房

OBJECTIVE To establish the ion mobility mass spectrometry method for simultaneous determination of epiberberine， berberine， coptisine， palmatine， calycosin-7-glucoside， 3，5-O-dicaffeoylquinic acid， 4，5-O-dicaffeoylquinic acid and chlorogenic acid in Jinqi jiangtang tablets. METHODS Ion mobility mass spectrometry method was used. The determination was performed on Waters ACQUITY UPLC HSS T3 （2.1 mm×50 mm， 1.8 μm） with mobile phase consisted of 0.1% formic acid solution-acetonitrile （gradient elution） at the flow rate of 0.3 mL/min. The column temperature was 40 ℃， and the injection volume was 5 μL. The contents of 8 components in Jinqi jiangtang tablets were determined by scanning detection under positive and negative ion modes with an electric spray ion source， and setting ion mobility mass parameters according to the peak response of each component. RESULTS The results showed that the linear relationship of the eight components was good within their respective ranges （r≥0.999）； RSDs of precision， repeatability and stability （24 h） tests were not more than 4.0%； average recoveries were 94.6%-101.2% ， RSDs were 2.6%-3.9% （n＝9）. The contents of the above eight components in three batches of Jinqi jiangtang tablets were 3.060-3.545， 24.50-26.74， 2.795-4.149， 1.437-2.501， 0.204-0.242， 0.950-1.281， 2.272-2.828， 7.314- 7.960 mg/g， respectively. CONCLUSIONS The established method has high sensitivity and good reproducibility， and can provide reference for the quality control of the preparation.

The Hypoglycemic Effect of JinQi Jiangtang Tablets Is Partially Dependent on the Palmatine-Induced Activation of the Fibroblast Growth Factor Receptor 1 Signaling Pathway.

JinQi Jiangtang tablet (JQJTT) is a Chinese patent medicine that has been shown to be beneficial for patients with diabetes both preclinically and clinically; however, the molecular mechanism underlying the effects of JQJTT remains unclear. In this study, surface plasmon resonance fishing was employed to identify JQJTT constituent molecules that can specifically bind to fibroblast growth factor receptor 1 (FGFR1), leading to the retrieval of palmatine (PAL), a key active ingredient of JQJTT. In vivo and in vitro experiments demonstrated that PAL can significantly stimulate FGFR1 phosphorylation and upregulate glucose transporter type 1 (GLUT-1) expression, thereby facilitating glucose uptake in insulin resistance (IR) HepG2 cells as well as alleviating hyperglycemia in diabetic mice. Our results revealed that PAL functions as an FGFR1 activator and that the hypoglycemic effect of JQJTT is partially dependent on the PAL-induced activation of the FGFR1 pathway. In addition, this study contributed to the understanding the pharmacodynamic basis and mechanism of action of JQJTT and provided a novel concept for future research on PAL.

Refined-JinQi-JiangTang tablet ameliorates hypertension through activation of FGF21/FGFR1 axis in fructose-fed rats.

The aim of this study was to investigate the therapeutic effect of JQ-R on metabolic hypertension and its correlation with Fibroblast growth factor 21/Fibroblast growth factor receptors 1(FGF21/FGFR1) pathway. In this study, fructose-induced metabolic hypertension rats were used as hypertension models to detect the regulation effect of JQ-R on hypertension. The effects of JQ-R on blood glucose, blood lipids, serum insulin levels and other metabolic indicators of rats were also measured. The effects of JQ-R on FGF21/FGFR1 signaling pathway in model animals were detected by Real-time quantitative PCR and Western blotting. The results showed that JQ-R significantly reduce the blood pressure of model rats in a dose-dependent manner. Meanwhile, fasting insulin, fasting blood glucose, insulin resistance index, total cholesterol and triglyceride levels were significantly decreased, and glucose and lipid metabolism abnormalities were also significantly improved. JQ-R induces these changes along with FGFR1 phosphorylation, which was also detected in JQ-R treated FGF21 knockout mice. These results suggest that JQ-R can reduce blood pressure and improve glucose and lipid metabolism in fructose-induced hypertension rats. Activation of FGF21/FGFR1 signaling pathway to regulate downstream blood pressure and glucolipid metabolism-related pathways may be one of the important mechanisms of JQ-R in regulating blood pressure.

[Mechanism of Jinqi Jiangtang Tablets in treatment of pancreatic ß cell dysfunction based on network pharmacology and molecular docking technology].

The present study investigated the therapeutic efficacy and potential mechanism of Jinqi Jiangtang Tablets(JQJT) on pancreatic ß cell dysfunction based on network pharmacology and molecular docking technology. TCMSP platform was used to retrieve the chemical components and targets of the three Chinese herbal medicines of JQJT. The genes were converted to gene symbol by the UniProt, and its intersection with targets related to pancreatic ß cell function in GeneCards and CTD databases was obtained. The drugs, active components and common targets were imported into Cytoscape 3.8.2 to plot the drug-component-target network. The main effective components and targets were obtained by software analysis. The drug targets and targets related to pancreatic ß cell function were imported separately into the STRING platform for the construction of protein-protein interaction(PPI) networks. The two PPI networks were merged by Cytoscape 3.8.2 and the key targets were obtained by plug-in CytoNCA. The targets obtained from drug-component-target network and PPI networks were imported into DAVID for GO analysis and KEGG enrichment analysis. AutoDock was used to carry out molecular docking of main active components and core targets and Pymol was used to plot the molecular docking diagram. The results showed that there were 371 active components and 203 targets related to JQJT and 2 523 targets related to pancreatic ß cell damage, covering 136 common targets. The results revealed core targets(such as PTGS2, PTGS1, NOS2, ESR1 and RXRA) and effective key components(such as quercetin, kaempferol, luteolin, ß-carotene and ß-sitosterol). KEGG enrichment analysis indicated that apoptosis, inflammation, and other signaling pathways were mainly involved. Molecular docking results showed that the main active components could spontaneously bind to the targets. This study preliminarily revealed the mechanism of JQJT in improving pancreatic ß cell damage through multi-component, multi-target and multi-pathway, and provided a theoretical basis for JQJT in the treatment of pancreatic ß cell dysfunction.

Mechanism of Jinqi Jiangtang Tablets in treatment of pancreatic β cell dysfunction based on network pharmacology and molecular docking technology / 中国中药杂志

The present study investigated the therapeutic efficacy and potential mechanism of Jinqi Jiangtang Tablets(JQJT) on pancreatic β cell dysfunction based on network pharmacology and molecular docking technology. TCMSP platform was used to retrieve the chemical components and targets of the three Chinese herbal medicines of JQJT. The genes were converted to gene symbol by the UniProt, and its intersection with targets related to pancreatic β cell function in GeneCards and CTD databases was obtained. The drugs, active components and common targets were imported into Cytoscape 3.8.2 to plot the drug-component-target network. The main effective components and targets were obtained by software analysis. The drug targets and targets related to pancreatic β cell function were imported separately into the STRING platform for the construction of protein-protein interaction(PPI) networks. The two PPI networks were merged by Cytoscape 3.8.2 and the key targets were obtained by plug-in CytoNCA. The targets obtained from drug-component-target network and PPI networks were imported into DAVID for GO analysis and KEGG enrichment analysis. AutoDock was used to carry out molecular docking of main active components and core targets and Pymol was used to plot the molecular docking diagram. The results showed that there were 371 active components and 203 targets related to JQJT and 2 523 targets related to pancreatic β cell damage, covering 136 common targets. The results revealed core targets(such as PTGS2, PTGS1, NOS2, ESR1 and RXRA) and effective key components(such as quercetin, kaempferol, luteolin, β-carotene and β-sitosterol). KEGG enrichment analysis indicated that apoptosis, inflammation, and other signaling pathways were mainly involved. Molecular docking results showed that the main active components could spontaneously bind to the targets. This study preliminarily revealed the mechanism of JQJT in improving pancreatic β cell damage through multi-component, multi-target and multi-pathway, and provided a theoretical basis for JQJT in the treatment of pancreatic β cell dysfunction.

[Meta-analysis of effect of Jinqi Jiangtang Tablets on treating insulin resistance in type 2 diabetes].

To systematically assess the efficacy and safety of Jinqi Jiangtang Tablets for patients with insulin resistance in type 2 diabetes, literatures were retrieved in 7 databases: PubMed, EMbase, Cochrane Library, Chinese National Knowledge Infrastructure(CNKI), WanFang database, Chinese BioMedical Database(CBM), VIP Chinese Science and Technique Journals Database, from the date of its inception up to November 2018. Review Manager 5.3 software was used for risk bias assessment, data synthesis and subgroup analysis. Begg's and Egger's tests were performed for assessing symmetries of funnel plot by software Stata 14.0. GRADE system was used to assess the quality of evidence. A total of 10 trials involving 797 participants were eligible. Compared with Western medicine alone, Jinqi Jiangtang Tablets showed a statistical significance in FBG(WMD=-0.63, 95%CI[-1.00,-0.26]). Jinqi Jiangtang Tablets showed a significant decrease in 2 h BG combined with Western medicine compared with Western medicine alone(WMD=-1.46, 95%CI[-1.71,-1.21], P<0.000 01). Jinqi Jiangtang Tablets combined with Western medicine showed a significant decrease in HbA1 c(WMD=-0.75, 95%CI[-0.97,-0.53], P<0.000 01), FINS(WMD=-0.65, 95%CI[-0.80,-0.50], P<0.000 01), 2 h INS(SMD=-1.67, 95%CI[-2.26,-1.09], P<0.000 01) and HOMA-IR(WMD=-1.22, 95%CI[-1.67,-0.76], P<0.000 01). Jinqi Jiangtang Tablets combined with Western medicine was beneficial for ISI(WMD=1.00, 95%CI[0.84, 1.17], P<0.000 01). Egger's and Begg's test showed no publication bias(P=0.379). Sensitivity analysis showed no impact on the overall results. The GRADE quality of the evidence was low. Despite of the apparently positive results, we cannot draw a rational conclusion that Jinqi Jiangtang Tablets has a positive effect in patients with IR, because of the low evidence grade.

Meta-analysis of effect of Jinqi Jiangtang Tablets on treating insulin resistance in type 2 diabetes / 中国中药杂志

To systematically assess the efficacy and safety of Jinqi Jiangtang Tablets for patients with insulin resistance in type 2 diabetes, literatures were retrieved in 7 databases: PubMed, EMbase, Cochrane Library, Chinese National Knowledge Infrastructure(CNKI), WanFang database, Chinese BioMedical Database(CBM), VIP Chinese Science and Technique Journals Database, from the date of its inception up to November 2018. Review Manager 5.3 software was used for risk bias assessment, data synthesis and subgroup analysis. Begg's and Egger's tests were performed for assessing symmetries of funnel plot by software Stata 14.0. GRADE system was used to assess the quality of evidence. A total of 10 trials involving 797 participants were eligible. Compared with Western medicine alone, Jinqi Jiangtang Tablets showed a statistical significance in FBG(WMD=-0.63, 95%CI[-1.00,-0.26]). Jinqi Jiangtang Tablets showed a significant decrease in 2 h BG combined with Western medicine compared with Western medicine alone(WMD=-1.46, 95%CI[-1.71,-1.21], P<0.000 01). Jinqi Jiangtang Tablets combined with Western medicine showed a significant decrease in HbA1 c(WMD=-0.75, 95%CI[-0.97,-0.53], P<0.000 01), FINS(WMD=-0.65, 95%CI[-0.80,-0.50], P<0.000 01), 2 h INS(SMD=-1.67, 95%CI[-2.26,-1.09], P<0.000 01) and HOMA-IR(WMD=-1.22, 95%CI[-1.67,-0.76], P<0.000 01). Jinqi Jiangtang Tablets combined with Western medicine was beneficial for ISI(WMD=1.00, 95%CI[0.84, 1.17], P<0.000 01). Egger's and Begg's test showed no publication bias(P=0.379). Sensitivity analysis showed no impact on the overall results. The GRADE quality of the evidence was low. Despite of the apparently positive results, we cannot draw a rational conclusion that Jinqi Jiangtang Tablets has a positive effect in patients with IR, because of the low evidence grade.

Pharmacodynamic Basis of Jinqi Jiangtang Tablets in Treatment of Type 2 Diabetes Based on LC-MS and Molecular Docking Strategy / 中国实验方剂学杂志

Objective::Based on LC-MS and molecular docking strategy, to study the pharmacodynamic material basis of Jinqi Jiangtang tablets in the treatment of type 2 diabetes mellitus(T2DM). Method::UPLC-Q-TOF-MS was used to identify the chemical constituents of Jinqi Jiangtang tablets. On this basis, the disease targets were screened based on the online disease target database and protein-protein interaction(PPI). The molecular docking technology was used to verify the relationship between the chemical constituents and disease targets in Jinqi Jiangtang tablets, so as to find out the potential pharmacodynamic basis of Jinqi Jiangtang tablets in the treatment of T2DM. Result::Based on UPLC-Q-TOF-MS, 51 chemical constituents were identified in Jinqi Jiangtang tablets, including 31 astragalus, 16 coptis and 4 honeysuckle. The key targets of catalase from micrococcus lysodeiktic(CAT) receptor, peroxisome proliferative actived receptor(PPARG) receptor and insulin(INS) receptor were identified by CTD database, topological analysis and related literature. Based on LC-MS and molecular docking technology, we found that magnoflorine, coptisine, epiberberine, astragaloside Ⅳ, caffeic acid, palmatine, berberine, jateorhizine, berberubine, berberastine, groenlandne, lycoranine B, demethyleneberberine, isomucrontolula-7-O-glucoside and calycosin-7-O-glucoside were used to treat type 2 diabetes potential pharmacodynamic material basis of urinary diseases. Conclusion::Protein interaction and network topology analysis are helpful for the rapid localization of core targets. In addition, molecular docking technology can realize large-scale virtual screening of potential candidate compounds. The integration of LC-MS and molecular docking technology can facilitate and quickly find the potential pharmacodynamic substance basis in traditional Chinese medicine prescriptions, and provide a reference for subsequent drug activity screening experiments.

Development and Validation of an UPLC-MS/MS Method for Pharmacokinetic Comparison of Five Alkaloids from JinQi Jiangtang Tablets and Its Monarch Drug Coptidis Rhizoma.

JinQi Jiangtang (JQJT) tablets, a Chinese patent medicine approved by the State Food and Drug Administration, are composed of Coptidis Rhizoma, Astragali Radix, and Lonicerae Japonicae Flos, and have a significant effect on diabetes. Coptidis Rhizoma is monarch drug in the prescription. The aim of the present study was to investigate and compare the pharmacokinetics of multiple ingredients from JQJT tablets and Coptidis Rhizoma extract (CRE) following oral administration in rats. Five alkaloids: coptisine chloride, epiberberine chloride, berberine chloride, jatrorrhizine chloride, and palmatine chloride, were simultaneously determined in rat plasma using established and validated ultra-high performance liquid chromatography mass spectrometry (UPLC-MS/MS). Significant pharmacokinetic differences were observed for the five alkaloids after a single administration of CRE and JQJT tablets. Compared with CRE, the Cmax values of palmatine chloride and jatrorrhizine chloride were decreased significantly, the AUC0-t values of four alkaloids (all except jatrorrhizine chloride) were notably decreased, and the mean residence times of all five alkaloids were significantly decreased after administration of JQJT tablets. The results indicated that the absorption characteristics of the five alkaloids from Coptidis Rhizoma would be influenced by the compatibility of Astragali Radix or Lonicerae Japonicae Flos from JQJT tablets, such that absorption was inhibited and elimination was accelerated. In conclusion, the developed strategy was suitable for the comparison of five alkaloids from JinQi Jiangtang tablets and its monarch drug, which could be valuable for compatibility studies of traditional Chinese medicines.

The effect of Jinqi Jiangtang tablet on expressions of IL-17 and IL-23 in kidney of diabetic rats / 天津医药

Objective To investigate the effect of Jinqi Jiangtang tablet on the activation of T helper type 17 (Th17) and the expressions of interleukin (IL)-17 and IL-23 in kidney of diabetic rats. Methods A total of 45 male SD rats were randomly divided into normal control group (NC, n=15) and experimental group (n=30). Diabetes was induced by tail vein injection with streptozotocin (STZ, 45 mg/kg). The well-established 28 diabetic model rats were then randomly divided into diabetes group (DM, n=14) and Jinqi Jiangtang tablet administration group (Jinqi, n=14). The rats in Jinqi group were given Jinqi Jiangtang tablet solution by gavage at a single dose of 2.1 g·kg-1·d-1 for 18 weeks, while NC group and DM group were given 0.9%NaCl in the same way. All rats were sacrificed after 18 weeks. The circulating Th17 frequencies were assessed using flow cytometry. Serum IL-17 and IL-23 levels were measured by enzyme-linked immunosorbent assay. The pathological changes in kidney were studied by electron microscope. The expressions of IL-17 and IL-23 in kidney were detected using immunohistochemistry. Results (1) Compared with the group NC, the circulating Th17 frequencies were significantly increased in group DM and group Jinqi. The circulating Th17 frequencies were significantly lower in group Jinqi than those in group DM. (2) Compared with the group NC, the serum IL-17 and IL-23 levels were significantly increased in group DM and group Jinqi. The serum IL-17 and IL-23 levels were significantly lower in group Jinqi than those in group DM. (3) In group DM, irregular thickening of glomerular basement membrane, fusion of epithelial cell foot processes and mesangial expansion were observed by electron microscope. The above-mentioned pathological changes were improved inthe group Jinqi. (4) Compared with the group NC, the expressions of IL-17 and IL-23 in the renal cortex were significantly increased in group DM and group Jinqi, and those were significantly lower in group Jinqi than those in group DM. Conclusion The activation of Th17 and the increased expressions of IL-17 and IL-23 in kidney play a potential role in diabetic nephropathy. Jinqi Jiangtang tablet can improve diabetic nephropathy through inhibiting the activating Th 17 and decreasing the expression of IL-17 and IL-23 in kidney.

Protective effects of Jinqi Jiangtang tablets on diabetic complications of cardiovascular diseases in Drosophila / 中国药科大学学报

@#This study was to investigate the protective effects of Jinqi Jiangtang tablets on diabetic complications of cardiovascular disease in Drosophila. The effects of Jinqi Jiangtang tablets on hypolipidemia and hypoglycemia by high fat diet(HFD)induced model organism Drosophila with the content of triglyceride and trehalose in Drosophila as indexes, were investigated. And the Drosophila heart function was detected by high speed EM-CCD; cell signaling pathways were detected by Western blot and RT-PCR. The results showed that high fat diet could induce the appearance of hyperglycemia and hyperlipidemia on Drosophila model. Jinqi Jiangtang tablets could significantly reduce triglyceride and trehalose and protect heart function of Drosophila induced by high fat diet. Jinqi Jiangtang tablets could also increase the expression of 4ebp mRNA, while decreasing p-4EBP protein and pepck mRNA expression. This study demonstrated that Jinqi Jiangtang tablets have a protective effect on HFD-induced dyslipidemic-diabetic and cardiac dysfunction, which may be related to mTOR/4EBP pathway.

Chemical profiling of Jinqi Jiangtang tablets by HPLC-ESI-Q-TOF/MS.

AIM: To profile the chemical constituents in Jinqi Jiangtang tablets. METHOD: Based on the chromatographic retention behavior, fragmentation patterns of chemical components, and published literatures, a high-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (HPLC-ESI-Q-TOF/MS) method was established to characterize and identify components in Jinqi Jiangtang tablets. RESULTS: A total of 52 chemical compounds, including eight iridoid glycosides, seven phenolic acids, twelve alkaloids, six flavonoids, and nineteen saponins, were identified in Jinqi Jiangtang tablets. CONCLUSION: The established method could serve as a powerful tool for structural characterization and quality control of this Chinese herbal preparation.

Chemical profiling of Jinqi Jiangtang tablets by HPLC-ESI-Q-TOF/MS / 中国天然药物

AIM@#To profile the chemical constituents in Jinqi Jiangtang tablets.@*METHOD@#Based on the chromatographic retention behavior, fragmentation patterns of chemical components, and published literatures, a high-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (HPLC-ESI-Q-TOF/MS) method was established to characterize and identify components in Jinqi Jiangtang tablets.@*RESULTS@#A total of 52 chemical compounds, including eight iridoid glycosides, seven phenolic acids, twelve alkaloids, six flavonoids, and nineteen saponins, were identified in Jinqi Jiangtang tablets.@*CONCLUSION@#The established method could serve as a powerful tool for structural characterization and quality control of this Chinese herbal preparation.