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Deciphering the therapeutic mechanisms of Xiao-Ke-An in treatment of type 2 diabetes in mice by a Fangjiomics approach.

ABSTRACT: Xiao-Ke-An (XKA) is a traditional Chinese medicine (TCM) formula for the treatment of type 2 diabetes (T2D), and the effective ingredients and their targets as well as the mechanisms of XKA remain to be elucidated. In this study we investigated the therapeutic mechanisms of XKA in the treatment of T2D in mice using a Fangjiomics approach.KKAy mice feeding on a high-fat diet were used as models of T2D, and were orally treated with XKA (0.75 or 1.5 g · kg(-1) · d(-1)) for 32 d. Microarray mRNA expression data were obtained from the livers of the mice. Differentially expressed genes (DEGs) were identified by reverse rate analysis and ANOVA analysis. The compounds in XKA were identified by LC-MS analysis or collected from TCM databases. The relationships between the compounds and targets were established by combining the DEGs with information derived from mining literature or herb target databases. Relevant pathways were identified through a Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis using WebGestalt.The compound-target-pathway network based on compounds identified by LC-MS analysis (NCA) included 20 constituent compounds, 46 targets and 36 T2D-related pathways, whereas the compound-target-pathway network based on compounds collected from databases (NCD) consisted of 40 compounds, 68 targets and 21 pathways. In the treatment of T2D, XKA might act mainly by improving carbohydrate and lipid metabolism, as well as ameliorating insulin resistance, inflammation and diabetic vascular complications.The network-based approach reveals complex therapeutic mechanisms of XKA in the treatment of T2D in mice that involve numerous compounds, targets, and signaling pathways.

SUBMITTER: Yang ZZ

PROVIDER: S-EPMC4594179 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Deciphering the therapeutic mechanisms of Xiao-Ke-An in treatment of type 2 diabetes in mice by a Fangjiomics approach.

Yang Zhen-zhong ZZ Liu Wei W Zhang Feng F Li Zheng Z Cheng Yi-yu YY

Acta pharmacologica Sinica 20150511 6

<h4>Aim</h4>Xiao-Ke-An (XKA) is a traditional Chinese medicine (TCM) formula for the treatment of type 2 diabetes (T2D), and the effective ingredients and their targets as well as the mechanisms of XKA remain to be elucidated. In this study we investigated the therapeutic mechanisms of XKA in the treatment of T2D in mice using a Fangjiomics approach.<h4>Methods</h4>KKAy mice feeding on a high-fat diet were used as models of T2D, and were orally treated with XKA (0.75 or 1.5 g · kg(-1) · d(-1)) f ...[more]

PMID: 25960133

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Project description:BackgroundIn recent decades, the prevalence of metabolic diseases, particularly diabetes, hyperlipidemia, obesity, and non-alcoholic fatty liver disease (NAFLD), has increased dramatically, causing great public health and economic burdens worldwide. Traditional Chinese medicine (TCM) serves as an effective therapeutic choice. Xiao-Ke-Yin (XKY) is a medicine and food homology TCM formula consisting of nine "medicine and food homology" herbs and is used to ameliorate metabolic diseases, such as insulin resistance, diabetes, hyperlipidemia and NAFLD. However, despite its therapeutic potential in metabolic disorders, the underlying mechanisms of this TCM remain unclear. This study aimed to evaluate the therapeutic effectiveness of XKY on glucolipid metabolism dysfunction and explore the potential mechanisms in db/db mice.MethodsTo verify the effects of XKY, db/db mice were treated with different concentrations of XKY (5.2, 2.6 and 1.3 g/kg/d) and metformin (0.2 g/kg/d, a hypoglycemic positive control) for 6 weeks, respectively. During this study, we detected the body weight (BW) and fasting blood glucose (FBG), oral glucose tolerance test (OGTT), insulin tolerance test (ITT), daily food intake and water intake. At the end of the animal experiment, blood samples, feces, liver and intestinal tissue of mice in all groups were collected. The potential mechanisms were investigated by using hepatic RNA sequencing, 16 S rRNA sequencing of the gut microbiota and metabolomics analysis.ResultsXKY efficiently mitigated hyperglycemia, IR, hyperlipidemia, inflammation and hepatic pathological injury in a dose dependent manner. Mechanistically, hepatic transcriptomic analysis showed that XKY treatment significantly reversed the upregulated cholesterol biosynthesis which was further confirmed by RT-qPCR. Additionally, XKY administration maintained intestinal epithelial homeostasis, modulated gut microbiota dysbiosis, and regulated its metabolites. In particular, XKY decreased secondary bile acid producing bacteria (Clostridia and Lachnospircaeae) and lowered fecal secondary bile acid (lithocholic acid (LCA) and deoxycholic acid (DCA)) levels to promote hepatic bile acid synthesis by inhibiting the LCA/DCA-FXR-FGF15 signalling pathway. Furthermore, XKY regulated amino acid metabolism including arginine biosynthesis, alanine, aspartate and glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and tryptophan metabolism likely by increasing Bacilli, Lactobacillaceae and Lactobacillus, and decreasing Clostridia, Lachnospircaeae, Tannerellaceae and Parabacteroides abundances.ConclusionTaken together, our findings demonstrate that XKY is a promising "medicine food homology" formula for ameliorating glucolipid metabolism and reveal that the therapeutic effects of XKY may due to its downregulation of hepatic cholesterol biosynthesis and modulation of the dysbiosis of the gut microbiota and metabolites.

Project description:BackgroundInfertility affects approximately 15% of couples around the world, and male factors are accounted for 40-50%. Oligoasthenozoospermia is the most common reason for male infertility. Unfortunately, effective drug therapy is still lacking except for assisted reproductive technology (ART). Previous researchers found that Wuzi Ershen decoction (WZESD) can increase sperm count, enhance sperm vitality, and improve semen quality. However, the pharmacological mechanisms remain unclear.MethodsIn this study, we screened compounds and predicted the targets of WZESD based on the TCMSP and BATMAN-TCM database combined with literature searching in the PubMed database. We obtained proteins related to oligoasthenozoospermia through GeneCards and submitted them to STRING to obtain the protein-protein interaction (PPI) network. Potential targets of WZESD were mapped to the network, and the hub targets were screened by topology. We used online platform Metascape and Enrichr for GO and KEGG enrichment analyses. AutoDock Vina was utilized for further verification of the binding mode between compounds and targets.ResultsTotally, 276 bioactive compounds were obtained and targeted 681 proteins. 446 oligoasthenozoospermia disease-specific proteins were acquired, and further bioinformatics analysis found that they were mainly involved in the formation of gametes, meiosis, and sperm differentiation. Protein interaction network analysis revealed that target proteins of WZESD were associated with oligoasthenozoospermia disease-specific proteins. The 79 targets of disease-specific proteins, which were anchored by WZESD, mainly participate in the cellular response to the organic cyclic compound, regulation of the apoptotic process, nitricoxide biosynthetic and metabolic process, oxidative stress, and protein phosphorylation regulation, which are the causes for oligoasthenozoospermia. Molecular docking simulation further validated that bioactive compounds originated from WZESD with targeted proteins showed high binding efficiency.ConclusionsThis study uncovers the therapeutic mechanisms of WZESD for oligoasthenozoospermia treatment from the perspective of network pharmacology and may provide a valuable reference for further experimental research studies and clinical applications.

Project description:BackgroundXiao-Ke-An (XKA) is a Chinese medicine widely used for treating type 2 diabetes mellitus (T2D). It is composed of eight herbal medicines traditionally used for T2D, including Rehmannia glutinosa Libosch, Anemarrhena asphodeloides Bunge, Coptis chinensis Franch, etc. The aim of the present study was to investigate the antidiabetic effects of XKA with both conventional and holistic omics approaches.MethodsThe antidiabetic effect of XKA was first investigated in 3T3-L1 cells to study the effect of XKA on adipogenesis in vitro. Oil Red O staining was performed to determine the lipid accumulation. The intracellular total cholesterol (TC) and triglyceride (TG) contents in XKA treated 3T3-L1 cells were also evaluated. The therapeutic effects of XKA was further evaluated in KKAy mice with both conventional and holistic omics approaches. Body weight, fasting and non-fasting blood glucose, and oral glucose tolerance were measured during the experiment. At the time of sacrifice, serum was collected for the measurement of TG, TC, high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c). The liver, kidney, spleen, pancreas, heart and adipose tissues were harvested and weighted. The liver was used for further microarray experiment. Omics approaches were adopted to evaluate the holistic rebalancing effect of XKA at molecular network level.ResultsXKA significantly inhibited adipogenic differentiation, lowered the intracellular TC and TG contents in 3T3-L1 cells. XKA improved the glucose homeostasis and lipid metabolism, ameliorated insulin resistance in KKAy mice. Furthermore, XKA also exhibited effective therapeutic effects by reversing the molecular T2D disease network from an unbalanced state.ConclusionsThis study investigated the antidiabetic effects of XKA with both conventional and holistic omics approaches, providing both phenotypic evidence and underlying action mechanisms for the clinical use of XKA treating T2D.

Project description:Despite the availability of a great variety of medications, a significant proportion of people with type 2 diabetes mellitus (T2DM) are not able to achieve or maintain adequate glycemic control. Beyond improved glucose control, novel treatments would ideally provide a reduction of cardiovascular risk, with a favorable impact on excess weight, and a low intrinsic hypoglycemia risk, as well as a synergistic mechanism of action for broad combination therapy. With the development of sodium glucose cotransporter 2 (SGLT2) inhibitors, an antidiabetic pharmacologic option has recently become available that comes close to meeting these requirements. For the first time, SGLT2 inhibitors offer a therapeutic approach acting directly on the kidneys without requiring insulin secretion or action. Canagliflozin, dapagliflozin, and empagliflozin are the SGLT2 inhibitors approved to date. Taken once a day, these medications can be combined with all other antidiabetic medications including insulin, due to their insulin-independent mechanism of action, with only a minimal risk of hypoglycemia. SGLT2 inhibitors provide additional reductions in body weight and blood pressure due to the therapeutically induced excretion of glucose and sodium through the kidneys. These "concomitant effects" are particularly interesting with regard to the increased cardiovascular risk in T2DM. In many cases, T2DM treatment requires a multidimensional approach where the treatment goals have to be adapted to the individual patient. While there is a consensus on the use of metformin as a first-line drug therapy, various antidiabetics are used for treatment intensification. New mechanisms of action like that of SGLT2 inhibitors such as canagliflozin, which can be used both in early and late stages of diabetes, are a welcome addition to expand the treatment options for patients at every stage of T2DM. The efficacy and tolerability of canagliflozin have been tested in an extensive clinical trial program described in this review article.

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Deciphering the therapeutic mechanisms of Xiao-Ke-An in treatment of type 2 diabetes in mice by a Fangjiomics approach.

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Deciphering the therapeutic mechanisms of Xiao-Ke-An in treatment of type 2 diabetes in mice by a Fangjiomics approach.

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