Uncovering the key pharmacodynamic material basis and possible molecular mechanism of Xiaoke formulation improve insulin resistant through a comprehensive investigation.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiaoke formulation (XKF) has been utilized in clinical practice for decades in China as a treatment option for mild to moderate type 2 diabetes. However, there is still a need for systematic research to uncover the key pharmacodynamic material basis and mechanism of XKF. AIM OF THE STUDY: Aim of to investigate the distribution and metabolism of XKF in normal and insulin resistant (IR) mice were different, and elucidate its key pharmacodynamic material basis and mechanism of action. MATERIALS AND METHODS: Ultra performance liquid chromatography/time of flight mass spectrometry technology was employed to investigate the differences in XKF absorption, distribution, and metabolism between normal and IR mice across blood, liver, feces, and urine samples. Further, network pharmacology was used to predict target proteins and their associated signaling pathways. Then, molecular docking was utilized to validate the activity of key pharmacodynamic components and targets. Finally, IR HepG2 cells were used to detect the glucose consumption under the action of key pharmacodynamic material basis. In addition, the expression of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT) and phospho-protein kinase B (p-AKT) was determined using western blotting. RESULTS: The study demonstrates significant distinctions in plasma and liver number and abundance of alkaloids, organic acids, flavonoids, iridoids and saponins between normal and IR mice when XKF was administered. Further analysis has shown that the representative components of XKF, including berberine, chlorogenic acid, calycosin, swertiamarin and astragaloside IV have significantly different metabolic pathways in plasma and liver. Prototypes and metabolites of these components were rarely detected in the urine and feces of mice. According to the network pharmacological analysis, these differential components are predicted to improve IR by targeting key factors such as SRC, JUN, HRAS, NOS3, FGF2, etc. Additionally, the signaling pathways involved in this process include PI3K-AKT pathway, GnRH signaling pathway, and T cell receptor signaling pathway. In addition, in vitro experiments indicate that berberine and its metabolites (berberine and demethyleneberine), chlorogenic acid and its metabolites (3-O-ferulic quinic acid and 5-O-ferulic quinic acid), calycosin and swertiamarin could improve IR in IR-HepG2 cells by elevating the expression of PI3K and AKT, leading to an increase in glucose consumption. CONCLUSION: The key pharmacodynamic material basis of XKF, such as berberine and its metabolites (berberrubine and demethyleneberberine), chlorogenic acid and its metabolites (3-O-feruloylquinic acid and 5-O-feruloylquinic acid), calycosin and swertiamarin influence the glucose metabolism disorder of IR-HepG2 cells by regulating the PI3K/AKT signalling pathway, leading to an improvement in IR.

Exploring the mechanism of Jingshen Xiaoke decoction in treating T2DM mice based on network pharmacology and molecular docking.

BACKGROUND: Jingshen Xiaoke decoction (JS) was prepared by studying the classic prescriptions of famous scholars in the past dynasties to prevent and treat diabetes. The related mechanism of JS against hyperlipidemia has yet to be revealed. OBJECTIVE: To investigate the mechanism of action of JS in treating diabetes mellitus by using bioinformatics methods. METHODS: A database was used to search the active ingredients and targets of the JS and targets for type 2 diabetes mellitus (T2DM). The protein interaction between the intersection targets, and the constructed the PPI network diagram was analyzed using the STRING database. Furthermore, the gene annotation tool DAVID was used to enrich the intersecting targets for the Gene ontology (GO) function and Kyoto encyclopedia of genes and genomes (KEGG) signaling pathway. Finally, Maestro software was used for molecular docking to verify the binding ability of the active ingredients to the core target genes. RESULTS: A total of 45 active ingredients in JS were screened out corresponding to 239 effective targets, of which 64 targets were potential targets for treating T2DM. The analysis of PPI network diagram analysis revealed that the ingredients' active components are quercetin, ß-sitosterol, stigmasterol, luteolin, and 7-Methoxy-2-methyl isoflavone. GO functional enrichment analysis indicated 186 biological processes (BP), 23 molecular functions (MF) and 13 cellular components (CC). KEGG pathway enrichment analysis revealed the enrichment of 59 signal pathways. The molecular docking results demonstrated that the active ingredients and core targets had a good docking affinity with a binding activity less than -7 kcal/mol. Finally, the western blotting illustrated that JS could up-regulate the liver PI3K/AKT-signaling pathway. CONCLUSION: JS can regulate glucolipid metabolism, reduce the inflammatory response, improve insulin resistance and modulate the immune response through PI3K/AKT signaling pathway treating of T2DM and its complications effects.

Construction of Evidence Body for Revision of Safety Information on Package Inserts of Chinese Patent Medicines in Post-marketing： Taking Xiaoke'an Capsules as an Example / 中国实验方剂学杂志

ObjectiveTo construct the evidence body for revision of safety information on package inserts of Chinese patent medicines in post-marketing by taking Xiaoke'an capsules as an example， so as to provide reference for the revision of instructions of Chinese patent medicines in post-marketing. MethodThe construction of the evidence body was guided by the theory of traditional Chinese medicine（TCM） and the Technical Guiding Principles for Revision of Safety Information Items in Instructions for TCMs After Marketing， and 8 categories and 25 specific items were taken as the main body of the evidence body， and information inclusion， integration， screening and improvement were carried out， then expert demonstrations were conducted， and finally modifications were made based on the opinions of the Center for Drug Evaluation to complete the revision of the safety information in the instructions of Xiaoke'an capsules. Result［Adverse reactions］ of Xiaoke'an capsules was revised to "monitoring data show that the following adverse reactions can be seen with this product：individual hypoglycemic reaction reports". ［Contraindications］ was revised to "contraindicated for those allergic to this product and its ingredients". ［Precautions］ was revised to "（1）pregnant women should use with caution， （2）elderly people should consult a physician， （3）people with spleen deficiency and dampness， spleen and stomach deficiency and cold， or those who eat less and have diarrhea should use with caution， （4）this product contains ginseng， should not be taken at the same time with TCM prescriptions or patent medicines containing veratrum and Wulingzhi， （5）pay attention to monitoring blood sugar during medication， （6）if any other discomfort occurs during medication， you should seek medical attention in time". The warning was revised to "use with caution by pregnant women， and pay attention to regular monitoring of blood sugar". ConclusionIn accordance with the content and process of the evidence body for the revision of safety information in the instructions， the revision of the safety information in the instructions of Xiaoke'an capsules has been completed， providing a strong basis for the rational and safe use of medication in the clinic.

From Xiaoke to diabetes mellitus: a review of the research progress in traditional Chinese medicine for diabetes mellitus treatment.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia resulting from insulin secretion defects or insulin resistance. The global incidence of DM has been gradually increasing due to improvements in living standards and changes in dietary habits, making it a major non-communicable disease that poses a significant threat to human health and life. The pathogenesis of DM remains incompletely understood till now, and current pharmacotherapeutic interventions are largely inadequate, resulting in relapses and severe adverse reactions. Although DM is not explicitly mentioned in traditional Chinese medicine (TCM) theory and clinical practice, it is often classified as "Xiaoke" due to similarities in etiology, pathogenesis, and symptoms. With its overall regulation, multiple targets, and personalized medication approach, TCM treatment can effectively alleviate the clinical manifestations of DM and prevent or treat its complications. Furthermore, TCM exhibits desirable therapeutic effects with minimal side effects and a favorable safety profile. This paper provides a comprehensive comparison and contrast of Xiaoke and DM by examining the involvement of TCM in their etiology, pathogenesis, treatment guidelines, and other relevant aspects based on classical literature and research reports. The current TCM experimental research on the treatment of DM by lowering blood glucose levels also be generalized. This innovative focus not only illuminates the role of TCM in DM treatment, but also underscores the potential of TCM in DM management.

Effect of modified Xiaoke Prescription on the patients with Yin deficiency and heat excessive type 2 diabetes mellitus / 国际中医中药杂志

Objective:The purpose of this study was to explore the therapeutic effect of modified Xiaoke prescription on patients with Yin deficiency and heat excessive type 2 diabetes mellitus (T2DM), and its influence on TCM syndrome scores, pancreatic islet function and oxidative stress.Methods:Randomized controlled trial. Eighty patients with Yin deficiency and heat excessive T2DM treated in the hospital between January and July 2021 were selected, and divided into observation group (41 cases) and control group (39 cases) by random number table method. Patients in the control group were treated with conventional western medicine, and patients in the observation group were treated with modified Xiaoke Prescription on the basis of the control group. Both groups were treated for 1 month. TCM syndrome scores were performed before and after treatment. Fasting plasma glucose (FPG) and 2 hPG were measured by glucose oxidase method. Serum HbA1c, malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels and SOD activity were measured by ELISA. The levels of low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and total cholesterol (TC) were detected by colorimetry.Results:The total effective rate of the observation group was 92.68% (38/41), and that of the control group was 76.92% (30/39). The difference between the two groups was statistically significant ( χ2=3.89, P=0.048). After treatment, the scores of tiredness and fatigue, thirst and appetite, overeating and hunger, redness of tongue and lack of saliva and total scores in the observation group were significantly lower than those in the control group ( t=4.46, 16.89, 13.37, 8.58, 8.38, P<0.01). After treatment, the levels of serum FPG [(7.31±0.90) mmol/L vs. (8.72±1.50) mmol/L, t=5.13], 2 hPG [(9.64±2.05) mmol/L vs. (12.85±1.20) mmol/L, t=8.49], HbA1c [(7.64±0.58)% vs. (8.11±1.35)%, t=2.04] in the observation group were significantly lower than those in the control group ( P<0.05); MDA [(3.96±1.00) mmol/L vs. (5.04±0.73) mmol/L, t=5.49], 8-OHdG [(203.41±30.70) ng/L vs. (234.50±59.00) ng/L, t=2.98] levels were significantly lower than those in the control group ( P<0.05); The activity of serum SOD [(48.64±5.05) mU/L vs. (41.75±3.58) mU/L, t=7.01] was significantly higher than that of the control group ( P<0.01); The serum LDL-C [(2.01±0.11) mmol/L vs. (2.56±0.25) mmol/L, t=12.84], TC [(4.75±0.20) mmol/L vs. (5.12±0.07) mmol/L, t=10.93] levels were significantly lower than those in the control group ( P<0.01); The serum HDL-C [(1.62±0.18) mmol/L vs. (1.24±0.42) mmol/L, t=5.31] level was significantly higher than that of the control group ( P<0.01). Conclusion:The modified Xiaoke Prescription can improve clinical symptoms, curative effect and pancreatic function, and relieve oxidative stress on the patients with T2DM.

Xiaoke Decoction in treatment of type II diabetes: A Meta-analysis.

Objective: To systematically evaluate the clinical effect of Xiaoke Decoction in the treatment of type 2 diabetes. Methods: Chinese databases such as CNKI, Wanfang, Weipu Chinese Biomedical Journal Database, and Chinese Medical Biological Literature Database, PubMed, Cochrane Library, Embase, and Web of Science were searched for English language literature from their inception until November 2019. A Meta-analysis was performed using RevMan 5.3 and Stata 12.0. Results: Thirty-eight studies were included in this study, with a total of 3757 patients. It was found that adding Xiaoke Decoction could improve total efficiency. The Xiaoke Decoction groups surpassed the western medicine groups regarding improvement in total efficiency (OR = 3.49; 95% CI: 2.78-4.39, P < 0.00001). Adding Xiaoke Decoction could lower the fasting plasma glucose (FPG) level. The Xiaoke Decoction groups surpassed the western medicine groups regarding reduction in FPG levels (MD = -1.14; 95% CI: -1.36 to 0.92, P < 0.00001). Adding Xiaoke Decoction could lower the 2 h postprandial blood glucose (2hPG) level. The Xiaoke Decoction groups surpassed the western medicine groups regarding reduction in 2hPG (MD = -1.40; 95% CI: -1.61 to 1.19, P < 0.00001). Adding Xiaoke Decoction could lower glycated hemoglobin (HbA1c). The Xiaoke Decoction groups surpassed the western medicine groups regarding reduction in HbA1c (MD = -0.77; 95% CI: -0.95 to 0.58, P < 0.00001). It was found that adding Xiaoke Decoction could lower the traditional Chinese medicine (TCM) syndrome score. The TCM syndrome scores among patients in the Xiaoke Decoction group were lower than those among patients in the control group after treatment (MD = -4.90; 95% CI: -7.22 to 2.57, P < 0.0001). At the same time, we conducted a subgroup and sensitivity analysis of age and intervention duration on the heterogeneity of total efficiency, FPG, 2hPG, HbAlc, and TCM syndrome score outcome indicators. For detecting publication bias, an egger test was conducted. Conclusion: Compared with western medicine alone, Xiaoke Decoction has more advantages for the treatment of type 2 diabetes with respect to total efficiency, FPG, 2hPG, HbAlc, and TCM syndrome score.

Integrated approach toward absorption, distribution, metabolism, and excretion of Xiaoke pills in zebrafish based on UPLC-HRMS and DESI-MS techniques.

Traditional Chinese medicine (TCM) has been used in clinical settings for over 2000 years in China. The study of the absorption, distribution, metabolism, and excretion (ADME) of TCM in vivo could be beneficial for the discovery of the active components in TCM. However, the conventional strategies used for ADME research are based on rodent models and have the characteristics of lengthy experimental periods, complex processes, and extensive data processing, which make it difficult to perform rapid analyses and high-throughput ADME screening of the medicinal components of TCM. In this study, an integrated high-throughput research strategy for the in vivo ADME analysis of TCM was established based on a zebrafish model. Accordingly, a combination of ultra-performance liquid chromatography-high-resolution mass spectrometry (UPLC-HRMS), desorption electrospray ionization-mass spectrometry (DESI-MS) imaging, and in-house non-targeted precise-and-thorough background-subtraction (PATBS) data post-processing techniques were successfully applied for the analysis of the metabolism of zebrafish exposed to Xiaoke pills. A total of 49 compounds related to Xiaoke pills (including 13 prototypical components and 36 metabolites) were detected in zebrafish. In total, 32 of them, including puerarin, daidzein, deoxyschizandrin, formononetin, and glibenclamide, which have been identified to have hypoglycemic activity in our previous studies and are phase I and phase II metabolites resulting from the hydroxylation, demethylation, glucuronidation, sulfation, and glycosylation of the prototypical components in vivo, were found in rats treated with Xiaoke pills. Furthermore, the overall distribution of the known compounds in zebrafish exposed to Xiaoke pills was explored using DESI-MS. In summary, this study provides a practical approach for the high-throughput screening of the active components of TCM using a zebrafish model.

Establishment of fingerprint ，chemical pattern recognition and content determination for Qingshen tiaozhi xiaoke tablets / 中国药房

OBJECTIVE To e stablish the fingerprint of Qings hen tiaozhi xiaoke tablets （QTXT）and carry out the analysis of chemical pattern recognition ，and determine the contents of seven active components simultaneously. METHODS Using coptisine hydrochloride as reference ，the Similarity Evaluation System for Chromatographic Fingerprint of TCM （2012 edition）was utilized to establish the HPLC fingerprints of 13 batches of QTXT and analyze their similarity. The common peaks were confirmed by comparing with the chromatogram of the mixed control ；the attribution of the common peak was determined by comparing the chromatograms of the sample solutions of single decoction pieces and negative sample solutions ；using SPSS 22.0 and SIMCA 14.1 software，cluster analysis （CA），principal component analysis （PCA）and orthogonal partial least squares-discriminant analysis （OPLS-DA）were carried out ，and the markers affecting the quality of QTXT were screened ，using the variable importance in projection（VIP）value greater than 1 as the standard. Using coptisine hydrochloride as internal reference ，the contents of naringin ， hesperidin，neohesperidin，berberine hydrochloride ，palmatine hydrochloride and lovastatin were determined by quantitative analysis of multicomponents by single marker （QAMS），and then compared wi th the result s（except for coptisine hydrochloride ） of external standard method. RESULTS There were 17 Δ 基金项目：江苏省“双创团队”项目[No.（2018）2024号] ＊硕士研究生。研究方向：中药新药药学。E-mail：2769544062@ common peaks in 13 batches of QTXT ，and the similarity was qq.com 0.987-0.999. Seven chromatographic peaks were identified ， # 通信作者：副研究员，硕士生导师，博士。研究方向：中药药剂 namely naringin （peak 4）， hesperidin （peak 5）， 学。E-mail：tsliur411@sina.com neohesperidin（peak 6），coptisine hydrochloride （peak 8）， ·1204· China Pharmacy 2022Vol. 33 No. 10 中国药房 2022年第33卷第10期 palmatine hydrochloride （peak 9），berberine hydrochlo ride（peak 10），lovastatin（peak 14）. Peaks 7-10 were the exclusive peaks of Coptis chinensis ；peaks 3-6 and 11-13 were the exclusive peaks of bran-fried Fructus aurantii ；peak 14 was the exclusive peak of Monascus purpureus ；peak 1 was the common peak of C. chinensis and M. purpureus . Peak 2 and 15 were the common peak of bran-fried F. aurantii and M. purpureus ；peaks 16 and 17 were the common peaks of 6 traditional Chinese medicines. The results of CA showed that 13 batches of QTXT could be divided into three categories ，S2 was clustered into one category ，S1，S9，S10 were clustered into one category ，S3-S8 and S 11-S13 were clustered into one category. The results of PCA showed that accumulative variance contribution of the first three principal components was 85.120％. Compared with CA ，S1 was further distinguished from S9 and S 10 by PCA. OPLS-DA showed that 7 common peaks with VIP value greater than 1（from large to small ）were peak 10 （berberine hydrochloride ），peak 9（palmatine hydrochloride ），peak 5（hesperidin），peak 11 and peak 8（coptisine hydrochloride ）， peak 12 and peak 6（neohesperidin）. The contents of naringin ，hesperidin，neohesperidin，berberine hydrochloride ，palmatine hydrochloride and lovastatin measured by QAMS were 40.198-77.552，6.138-13.413，71.823-125.868，11.274-49.951，3.303- 5.367，1.821-3.185 mg/g，respectively. The contents of naringin ，hesperidin，neohesperidin，berberine hydrochloride ，coptisine hydrochloride，palmatine hydrochloride and lovastatin measured by external reference method were 41.454-79.976，6.404-13.993， 74.068-129.081，11.627-51.512，5.922-12.020，3.158-5.131 and 1.901-3.325 mg/g，respectively. The deviations of the two methods （except for coptisine hydrochloride ）were all less than 3.00％. CONCLUSIONS The established HPLC fingerprint and the method of QAMS are simple ，accurate and reproducible. Combined with chemical pattern recognition analysis ，it can be used for the quality evaluation of QTXT. Berberine hydrochloride ，palmatine hydrochloride and other components may be the markers affecting the quality of the drug.

Xiaoke Decoction in treatment of type II diabetes: A Meta-analysis / 中草药·英文版

Objective: To systematically evaluate the clinical effect of Xiaoke Decoction in the treatment of type 2 diabetes. Methods: Chinese databases such as CNKI, Wanfang, Weipu Chinese Biomedical Journal Database, and Chinese Medical Biological Literature Database, PubMed, Cochrane Library, Embase, and Web of Science were searched for English language literature from their inception until November 2019. A Meta-analysis was performed using RevMan 5.3 and Stata 12.0. Results: Thirty-eight studies were included in this study, with a total of 3757 patients. It was found that adding Xiaoke Decoction could improve total efficiency. The Xiaoke Decoction groups surpassed the western medicine groups regarding improvement in total efficiency (OR = 3.49; 95% CI: 2.78–4.39, P < 0.00001). Adding Xiaoke Decoction could lower the fasting plasma glucose (FPG) level. The Xiaoke Decoction groups surpassed the western medicine groups regarding reduction in FPG levels (MD = −1.14; 95% CI: −1.36 to 0.92, P < 0.00001). Adding Xiaoke Decoction could lower the 2 h postprandial blood glucose (2hPG) level. The Xiaoke Decoction groups surpassed the western medicine groups regarding reduction in 2hPG (MD = −1.40; 95% CI: −1.61 to 1.19, P < 0.00001). Adding Xiaoke Decoction could lower glycated hemoglobin (HbA1c). The Xiaoke Decoction groups surpassed the western medicine groups regarding reduction in HbA1c (MD = −0.77; 95% CI: −0.95 to 0.58, P < 0.00001). It was found that adding Xiaoke Decoction could lower the traditional Chinese medicine (TCM) syndrome score. The TCM syndrome scores among patients in the Xiaoke Decoction group were lower than those among patients in the control group after treatment (MD = −4.90; 95% CI: −7.22 to 2.57, P < 0.0001). At the same time, we conducted a subgroup and sensitivity analysis of age and intervention duration on the heterogeneity of total efficiency, FPG, 2hPG, HbAlc, and TCM syndrome score outcome indicators. For detecting publication bias, an egger test was conducted. Conclusion: Compared with western medicine alone, Xiaoke Decoction has more advantages for the treatment of type 2 diabetes with respect to total efficiency, FPG, 2hPG, HbAlc, and TCM syndrome score.

Effects of angelica lactone combined with Xiaoke pill on regulation of vascular endothelial growth factor signal pathway and on renal protection in diabetic nephropathy rats / 解剖学报

Objective To investigate the effects of angelica lactone combined with Xiaoke pill on blood glucose regulation, renal protection and vascular endothelial growth factor signal pathway in diabetic nephropathy rats. Methods Totally 75 rats were randomly divided into control group, model group, Xiaoke pill group, angelica lactone group and angelica lactone combined with Xiaoke pill group, with 15 rats in each group. Except for the control group, the rest of the rats established diabetic nephropathy model. Rats in Xiaoke pill group, angelica lactone group and angelica lactone combined with Xiaoke pill group were given Xiaoke pill (0.8 g/kg), angelica lactone (20 mg/kg), Xiaoke pill (0.8 g/kg) combined with angelica lactone (20 mg/kg), respectively, once for 8 weeks. The levels of 24-hour urinary protein, fasting and postprandial blood glucose, glycosylated serum albumin and glycosylated hemoglobin, fasting insulin and insulin sensitivity index, serum creatinine (SCr) and urea nitrogen (BUN) were measured. The levels of insulin (INS) and glucose-6-phosphatase (G6Pase) mRNA in islet tissue were measured by Real-time PCR. Renal histopathological changes were detected by HE staining. The levels of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) in rat kidney were detected by Western blotting and immunohistochemistry. Results Compared with the model group, 24-hour urinary protein, fasting and postprandial blood glucose, glycosylated serum albumin and glycosylated hemoglobin, fasting insulin, SCr and BUN, VEGF and VEGFR2 protein levels and relative integral absorbance of kidney tissue in angelica lactone combined with Xiaoke pill group were significantly lower than those in model group(P<0.05). The insulin sensitivity index, the levels of INS and G6Pase mRNA in islet tissue were significantly increased (P < 0.05), and the renal histopathology of diabetic nephropathy rats was significantly improved. Conclusion Angelica lactone combined with Xiaoke pill can reduce blood glucose level, increase insulin sensitivity index, and its mechanism may be related to the regulation of VEGF signal pathway.

Quality evaluation of compound Chinese medicines as related to clinical efficacy / 药学学报

The quality evaluation of compound Chinese medicines is an important but challenging issue in this research field, which has been paid much controversial due to the constrained association with clinical efficacy. Developing a methodology for quality evaluation of compound Chinese medicines related to clinical efficacy is an important measure in research on Chinese material medica quality to ensure clinical effectiveness and safety. Therefore, based on the research concept that "originating from clinic-testing in experiment-returning to clinic", and taking Xiaoke prescription as an example, the characteristic information of metabolome, proteome and microbiome are discussed from the clinical aspect, and the integrated markers associated with clinical efficacy constructed with artificial intelligence technology. Taking the integrated markers as the link and indication are connecting the clinical and basic, the main pharmacodynamic substances and key targets of Xiaoke prescription that are related to clinical efficacy are explained. Clinical samples are used for validation. Based on the main pharmacodynamic substances and key targets, methods and key technologies for chemical and biological evaluation of the quality of Xiaoke prescription are established, providing a methodology for quality evaluation of compound Chinese medicines, including clinical efficacy response indicators (related to clinic), main pharmacodynamic substances (chemical evaluation), and key targets (biological evaluation), to provide new ideas and methods for improving the quality evaluation of compound Chinese medicines.

[Expert consensus statement on treatment of type 2 diabetes with Xiaoke Pills in clinical practice].

Xiaoke Pills are Chinese and Western medicine compound preparations with effects of nourishing kidney and Yin,and supplementing Qi and promoting fluid. It is widely used in clinical treatment of type 2 diabetes( Qi and Yin deficiency syndrome),and continuously included in 2010,2013 and 2017 editions of Chinese prevention guide for type 2 diabetes. For the purpose of accurate positioning and rational use in clinic,it is necessary to further define the curative effect,indications,medication precautions and contraindications of Xiaoke Pills,in order to improve medication safety. This consensus was reached by reference of international clinical guidelines and expert consensus approach based on clinical evidence-based evidence,expert experience and standard specification. The evidence-based evaluation was oriented to clinical problems summarized by no less than 200 front-line clinical physicians in two rounds.GRADE system was adopted for quality classification and evaluation of the evidences,and then the nominal group method was used to form consensus recommendations or suggestions. This consensus defined the curative effect advantages,target users,dosage,administration method,contraindications and precautions of Xiaoke Pills,and provided valuable reference for the clinical use of the drug. Thisconsensus still needs to be updated and revised based on new clinical problems and evidence-based evidence in practical application in the future.

Expert consensus statement on treatment of type 2 diabetes with Xiaoke Pills in clinical practice / 中国中药杂志

Xiaoke Pills are Chinese and Western medicine compound preparations with effects of nourishing kidney and Yin,and supplementing Qi and promoting fluid. It is widely used in clinical treatment of type 2 diabetes( Qi and Yin deficiency syndrome),and continuously included in 2010,2013 and 2017 editions of Chinese prevention guide for type 2 diabetes. For the purpose of accurate positioning and rational use in clinic,it is necessary to further define the curative effect,indications,medication precautions and contraindications of Xiaoke Pills,in order to improve medication safety. This consensus was reached by reference of international clinical guidelines and expert consensus approach based on clinical evidence-based evidence,expert experience and standard specification. The evidence-based evaluation was oriented to clinical problems summarized by no less than 200 front-line clinical physicians in two rounds.GRADE system was adopted for quality classification and evaluation of the evidences,and then the nominal group method was used to form consensus recommendations or suggestions. This consensus defined the curative effect advantages,target users,dosage,administration method,contraindications and precautions of Xiaoke Pills,and provided valuable reference for the clinical use of the drug. Thisconsensus still needs to be updated and revised based on new clinical problems and evidence-based evidence in practical application in the future.

Application value of pungent herbs in treatment of “Xiaoke syndrome” and thinking of modern research on five-flavor theory of Chinese materia medica / 中草药

“Pungent flavor” is one content of the Chinese medicine five-flavor theory, and generally speaking, pungent herbs have the functions of “dispersing”, “moving qi” as well as “activating blood”, which possessed a larger proportion of clinical applications in traditional Chinese medicine (TCM). The relationship of pungent herbs with the treatment of Xiaoke syndrome was discussed based on TCM efficacy of pungent herbs and the understanding of Xiaoke syndrome in TCM theory in this article. The therapeutic significance and value of pungent herbs were summarized. Furthermore, some thoughts based on the current trend and direction of the Chinese medicine five-flavor theory were investigated to provide references for peer study.

Mechanism of Chinese Medicine Ingredients Combined with Glibenclamide from Xiaoke Pill for the Treatment of Diabetes Mellitus Based on Biomolecules Network / 中国药学杂志

OBJECTIVE: To explore the synergistic molecular network mechanism of Chinese medicine ingredients and glibenclamide from Xiaoke pill for the treatment of diabetes mellitus. METHODS: After obtained diabetic-related genes of Xiaoke pill, STRING software was used to construct biomolecular network, DAVID software was used to identify KEGG pathways, Cytoscape software was used to construct the network for Xiaoke pill ingredients-key target-disease related pathway. RESULTS: The results showed that Xiaoke pill targeted 123 diabetic-related genes. Glibenclamide mainly affected pathways involved in type 2 diabetes, whereas Chinese medicine ingredients from Xiaoke pill was associated with inflammatory-related pathways such as TNF, Jak-STAT, NF-kB and cytokine pathway, islet β cell-related pathways such as PI3K/Akt, mTOR and MAPK pathway, AGE-RAGE and metabolic pathways. By combining Chinese medicine ingredients and glibenclamide, Xiaoke pill widely targeted diabetic-related pathways. CONCLUSION: It indicates that Xiaoke pill, a combination of traditional Chinese and Western medicine, can prevente diabetes and diabetic syndrome possibly by improving insulin resistance and protecting β cells and inhibiting inflammatory response.

[Study on relevance mining of "core drug action target" in Dictionary of Traditional Chinese Medicine Prescriptions].

Based on the database of "Dictionary of Traditional Chinese Medicine Prescriptions", high-frequency herbs of Xiaoke disease is mined by traditional Chinese medicine inheritance support system, and core herbs and combinations are discovered through association rules and cluster analysis. On this basis, based on the integrative pharmacology of traditional Chinese medicine to explore the herb-disease relationship, the "herb-compound-target" network is constructed and enriched for the analysis of key target gene functions, metabolic pathways, and their "core herb-target interactions". In order to explore the molecular mechanism of its prevention and treatment of diabetes, 341 diabetes prescriptions are collected, organized, and tapped in the Dictionary of Traditional Chinese Medicine Prescriptions. Herb frequency statistics show that Licorice was the most commonly used, followed by Ophiopogonis Radix, Poria, Ginseng Radix et Rhizoma, Coptidis Rhizoma, etc., the medicinal properties are mostly cold, warm and ping, and the medicinal taste tends to be pungent, bitter, and sour, and they were attributed to lung meridian, stomach meridian, spleen meridian, etc. Among them, the 17 herbs were closely related. Ginseng Radix et Rhizoma, Ophiopogonis Radix, Poria and Glycyrrhizae Radix et Rhizoma were the core Chinese herbs. Ophiopogonis Radix was the key node of Coptidis Rhizoma, Trichosanthis Radix and core Chinese medicine, and Ophiopogonis Radix was the key node for the connection between Coptidis Rhizoma and Trichosanthis Radix and the core Chinese herbs. Using integrated pharmacology platform analysis, 10 crucial core targets for the prevention and treatment of diabetes were obtained, including the known disease targets (PLCD1, PIK3R1, ENPP1), and potential herb targets(GNB1, ADCY1, AKT1, RAC1, PRKAA1, RHOA) , common target (GCK). There were seven similar targets in the 10 crucial core targets predicted with the combination of "Ophiopogonis Radix, Coptidis Rhizoma and Trichosanthis Radix", including PLCD1, PIK3R1, ENPP1, ADCY1, AKT1, PRKAA1, GCK. These genes were mainly located in the cytosol, plasma membrane, etc., involved in adenosine triphosphate binding, protein binding, platelet activation, etc., mainly involved in the endocrine system, signal transduction, chemokine signaling pathway, cancer pathway, and other metabolic pathways, and it is speculated that these genes were potentially associated with diabetes. In this study, Traditional Chinese Medicine Inheritance Support System and Integrative Pharmacology of Traditional Chinese Medicine are used to analyze the prescription law of Xiaoke prescription, and the correlation of "core herbs-functionary targets" is excavated, which provided the basis and reference for the screening and development of TCM prescriptions for the prevention and treatment of diabetes.

Jiangtang Xiaoke granule attenuates glucose metabolism disorder via regulating endoplasmic reticulum stress in the liver of type 2 diabetes mellitus mice.

OBJECTIVE: To observe the effect of Jiangtang Xiaoke (JTXK) granule on endoplasmic reticulum (ER) stress in high fat diet (HFD)-induced type 2 diabetes mellitus (T2DM) KK-Ay mice. METHODS: KK-Ay mice were fed with HFD to induce the T2DM model, while normal control C57BL/6J mice were given standard feed. Fasting blood glucose (FBG) in all mice was measured weekly and oral glucose tolerance tests (OGTTs) were performed at 4 and 10 weeks after start of treatment to determine glucose metabolism. Serum fasting insulin (FINS) and insulin sensitivity index (ISI) were measured to determine insulin sensitivity. mRNA expressions of eukaryotic initiation factor-2 alpha (eIF2¦Á), glucose regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), and C/EBP homology protein (CHOP) were assessed by reverse transcription polymerase chain reaction and the protein expressions of p-eIF2¦Á, GRP78, and CHOP were assessed by Western blotting. RESULTS: JTXK granule significantly reduced FBG and free fatty acid levels and improved OGTT at the 120 min of the 10-week treatment in T2DM KK-Ay mice. FINS and HbAlc levels were reduced and insulin sensitivities were increased in KK-Ay diabetic mice, which were improved with the treatment of JTXK granule, especially at the 7 and 3.5 g/kg doses. JTXK granule at the 3.5 g/kg dose was most effective in reducing both gene and protein expressions of eIF2¦Á, GRP78, and CHOP. CONCLUSION: ER stress response is increased in T2DM KK-Ay mice. Treatment with JTXK granule attenuates glucose disorders, improves insulin sensitivity, and reduces serum FFA in T2DM KK-Ay mice. The mechanisms may be attributed to regulation of the signaling ER stress pathway via decreasing eIF2¦Á phosphorylation and suppressing eIF2¦Á- ATF4-CHOP activation.

Study on relevance mining of "core drug action target" in Dictionary of Traditional Chinese Medicine Prescriptions / 中国中药杂志

Based on the database of "Dictionary of Traditional Chinese Medicine Prescriptions", high-frequency herbs of Xiaoke disease is mined by traditional Chinese medicine inheritance support system, and core herbs and combinations are discovered through association rules and cluster analysis. On this basis, based on the integrative pharmacology of traditional Chinese medicine to explore the herb-disease relationship, the "herb-compound-target" network is constructed and enriched for the analysis of key target gene functions, metabolic pathways, and their "core herb-target interactions". In order to explore the molecular mechanism of its prevention and treatment of diabetes, 341 diabetes prescriptions are collected, organized, and tapped in the Dictionary of Traditional Chinese Medicine Prescriptions. Herb frequency statistics show that Licorice was the most commonly used, followed by Ophiopogonis Radix, Poria, Ginseng Radix et Rhizoma, Coptidis Rhizoma, etc., the medicinal properties are mostly cold, warm and ping, and the medicinal taste tends to be pungent, bitter, and sour, and they were attributed to lung meridian, stomach meridian, spleen meridian, etc. Among them, the 17 herbs were closely related. Ginseng Radix et Rhizoma, Ophiopogonis Radix, Poria and Glycyrrhizae Radix et Rhizoma were the core Chinese herbs. Ophiopogonis Radix was the key node of Coptidis Rhizoma, Trichosanthis Radix and core Chinese medicine, and Ophiopogonis Radix was the key node for the connection between Coptidis Rhizoma and Trichosanthis Radix and the core Chinese herbs. Using integrated pharmacology platform analysis, 10 crucial core targets for the prevention and treatment of diabetes were obtained, including the known disease targets (PLCD1, PIK3R1, ENPP1), and potential herb targets(GNB1, ADCY1, AKT1, RAC1, PRKAA1, RHOA) , common target (GCK). There were seven similar targets in the 10 crucial core targets predicted with the combination of "Ophiopogonis Radix, Coptidis Rhizoma and Trichosanthis Radix", including PLCD1, PIK3R1, ENPP1, ADCY1, AKT1, PRKAA1, GCK. These genes were mainly located in the cytosol, plasma membrane, etc., involved in adenosine triphosphate binding, protein binding, platelet activation, etc., mainly involved in the endocrine system, signal transduction, chemokine signaling pathway, cancer pathway, and other metabolic pathways, and it is speculated that these genes were potentially associated with diabetes. In this study, Traditional Chinese Medicine Inheritance Support System and Integrative Pharmacology of Traditional Chinese Medicine are used to analyze the prescription law of Xiaoke prescription, and the correlation of "core herbs-functionary targets" is excavated, which provided the basis and reference for the screening and development of TCM prescriptions for the prevention and treatment of diabetes.

Therapeutic Efficacy of Xiaoke Formula in the Treatment of Type 2 Diabetes Mellitus with Qi and Yin Deficiency:A Meta-analysis / 中国药房

OBJECTIVE:To systematically evaluate therapeutic efficacy of Xiaoke formula in the treatment of type 2 diabetes mellitus (T2DM) with Qi and Yin deficiency,and to provide evidence-based reference in clinic. METHODS:Retrieved from PubMed,Embase,Cochrane Library,CBM and CNKI,randomized controlled trials(RCTs)about modified Xiaoke formula(trial group) with Qi and Yin deficiency versus Metformin tablet or insulin(control group) in the treatment of T2DM were included. After literature screening and data extraction,the qualities of included studies were evaluated by modified Jadad scoring scale. Meta-analysis was performed by using Rev Man 5.3 statistical software. RESULTS:Totally 18 RCTs were included,involving 2 065 patients. Meta-analysis showed that response rate of trial group [OR＝2.89,95%CI(2.16,3.86),P＜0.001] was significantly higher than that of control group,while fasting blood glucose [SMD＝－0.72,95%CI(－0.96,－0.47),P＜0.001],2 h postprandial blood glucose [SMD＝ －0.72,95%CI(－0.96,－0.47),P＜0.001],glycosylated hemoglobin [MD＝－0.65,95%CI (－0.88,－0.42),P＜0.001] and TCM syndrome score [MD＝－5.77,95%CI(－7.46,－4.08),P＜0.001] were significantly lower than control group. Totally 18 RCTs were included,involving 18 formula and 66 ingredients. The sum of use frequency of various medicinal materials was 218. Trichosanthes,Coptis chinensis,Ophiopogon japonicus and so on were used most frequently. CONCLUSIONS:Xiaoke formula shows significant therapeutic efficacy for T2DM with Qi and Yin deficiency,and reduces related index levels and TCM syndrome score effectively.

Simultaneous determination of eight constituents in Yuye Xiaoke Granules by QAMS / 中成药

AIM To establish a quantitative analysis of multi-components by single-marker (QAMS) method for the simultaneous content determination of 3'-hydroxy puerarin,puerarin,3'-methoxy puerarin,neomangiferin,mangiferin,calycosin-7-O-β-D-glucoside,astragaloside Ⅳ and batatasin Ⅰ in Yuye Xiaoke Granules (Astragali Radix,Dioscoreae Rhizoma,Puerariae lobatae Radix,etc.).METHODS The analysis of methanol extract of this drug was performed on a 30℃ thermostatic Kromasil C1scolumn (4.6 mm ×250 mm,5 μm),with the mobile phase comprising of methanol-acetonitrile (1 ∶ 1) and 0.4％ glacial acetic acid flowing at 0.9 mL/min in a gradient elution manner,and the detection wavelengths were set at 210,250,254,274 nm.With astragaloside Ⅳ as an internal standard,the relative correction factors of the other seven constituents were calculated,after which the con tent determination was made.RESULTS Eight constituents showed good linear relationships within their own ranges (r ＞ 0.999 0),whose average recoveries were 97.06％-99.95％ with the RSDs of 0.54％-1.44％.The results obtained by QAMS approximated those obtained by external standard method.CONCLUSION This stable and reliable method can be used for the quality control of Yuye Xiaoke Granules.