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Decoding the chemical composition and pharmacological mechanisms of Jiedu Tongluo Tiaogan Formula using high-performance liquid chromatography coupled with network pharmacology-based investigation.

ABSTRACT: Type 2 diabetes mellitus (T2DM), a chronic low-grade inflammatory disease with high morbidity and mortality, is a serious threat to public health. Previously we demonstrated that a traditional Chinese medicine formulation, Jiedu Tongluo Tiaogan Formula (JDTL), exerted a favorable hypoglycemic effect due to unknown molecular mechanisms involving interactions among JDTL compounds and various cellular components. This study aimed to explore JDTL mechanisms for alleviating hyperglycemia using an integrated strategy incorporating system pharmacology, bioinformatics analysis, and experimental verification. This strategy entailed initial elucidation of JDTL chemical composition using fingerprint analysis via high performance liquid chromatography (HPLC). Next, functions of putative shared target genes and associated pathways were deduced using GO and KEGG pathway enrichment and molecular docking analyses. Ultimately, targets associated with JTDL anti-T2DM effects were found to be functionally associated with biological functions related to lipopolysaccharide and cytokine receptor binding. These results implicated PI3K-Akt signaling pathway involvement in JDTL anti-T2DM effects, as this pathway had been previously shown to play significant roles in glucose and lipid metabolism-related diseases. Furthermore, addition of JDTL to INS-1 and HepG2 cell cultures stimulated cellular mRNA-level and protein-level expression leading to enhanced production of IRS1, Akt, and PI3K. In summary, here JDTL bioactive ingredients, potential targets, and molecular mechanisms underlying JDTL anti-T2DM effects were identified using a multi-component, multi-target, and multi-channel analytical approach, thus providing an important scientific foundation to facilitate development of new drugs mechanistic strategies for preventing and treating T2DM.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC8610129 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Oligoasthenozoospermia is a complex disease caused by a variety of factors, and its incidence is increasing yearly worldwide. Yishen Tongluo formula (YSTLF), created by Professor Sun Zixue, has been used to treat oligoasthenozoospermia in clinical practice for several decades with a good therapeutic effect. However, the chemical and pharmacological profiles of YSTLF remain unclear and need to be elucidated. In this study, a network pharmacology approach was applied to explore the potential mechanisms of YSTLF in oligoasthenozoospermia treatment. All of the compounds in YSTLF were retrieved from the corresponding databases, and the bioactive ingredients were screened according to their oral bioavailability (OB) and drug-likeness (DL). The potential proteins of YSTLF were obtained from the traditional Chinese medicine systems pharmacology (TCMSP) database and the Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM) database, while the potential genes of oligoasthenozoospermia were obtained from the GeneCards database and the DisGeNET database. The STRING database was used to construct an interaction network according to the common targets identified by the online tool Venny for YSTLF and oligoasthenozoospermia. The topological characteristics of nodes were visualized and analyzed through Cytoscape. Biological functions and significant pathways were determined and analyzed using the Gene Ontology (GO) knowledgebase, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Metascape. Finally, the disease-formula-compound-target-pathway network was constructed by Cytoscape. A total of 106 bioactive ingredients and 134 potential targets from YSTLF were associated with oligoasthenozoospermia or considered to be therapeutically relevant. Pathway analysis indicated that the PI3K/Akt, MAPK and apoptosis signaling pathways were significant pathways involved in oligoasthenozoospermia. In conclusion, the current study expounded the pharmacological actions and molecular mechanisms of YSTLF in treating oligoasthenozoospermia from a holistic viewpoint. The potential molecular mechanisms were closely related to antioxidative stress, antiapoptosis and anti-inflammation, with TNF, CCND1, ESR1, NFKBIA, NR3C1, MAPK8, and IL6 being possible targets. This network pharmacology prediction may offer a helpful tool to illustrate the molecular mechanisms of the Chinese herbal compound YSTLF in oligoasthenozoospermia treatment.

Project description:BackgroundAmending from ancient classic, Ziyin Tongluo Formula (ZYTLF) has been prescribed to treat postmenopausal osteoporosis (PMOP) for decades with good curative effect. However, the possible mechanisms of it are still unknown.MethodsOvariectomized rat model was established to validate the therapeutic effect of ZYTLF on PMOP by Micro-CT bone analysis and pathological observation. Subsequently, active ingredients of ZYTLF and corresponding putative targets were identified by online databases. Overlapping genes were first obtained from mining genes associated with PMOP and then overlapped them with the putative targets. Key genes were selected from the multiple constructed and analyzed networks. GO and KEGG pathway enrichment analysis were performed by importing the key genes to the DAVID database. Moreover, validation of the binding association between key targets and their corresponding active compounds were accomplished by AutoDock Tools and other software. Lastly, Enzyme linked immunosorbent assay (Elisa) detection and Western blot analysis were utilized to further explore the possible mechanism of ZYTLF on PMOP.ResultsWith 129 target genes interacting with PMOP, 92 active compounds of ZYTLF corresponded to 243 targets, and 50 key genes were chosen. Network analysis revealed the top 10 active ingredients, such as quercetin and kaempferol and the top 50 key genes, such as ERα, p38 MAPK, p-AKT and TGF-β1. Enrichment analysis uncovered multiple signaling pathways, including estrogen signaling pathway, TNF signaling pathway, PI3K-Akt signaling pathway and MAPK signaling pathway. Furthermore, our finding of the foremost active compounds was tightly bound to the core proteins, which were verified by molecular docking analysis. Through experimental studies, we confirmed that the prescription of ZYTLF could ameliorate the OVX-induced bone loss, suppress the osteoclast activity and boost osteoblast ability through experimental studies.ConclusionThe potential mechanisms and therapeutic effects of ZYTLF against PMOP may be ascribed to inhibition of osteoclast activity, boost of osteoblast activity and enhancement of the expression of ERα.

Project description:Background: The incidence of Type 2 diabetes mellitus (T2DM) combined with non-alcoholic fatty liver disease (NAFLD) has risen over the years. This comorbid condition significantly increases the probability of cirrhosis, liver cancer, and mortality compared to the disease alone. The multi-targeted, holistic treatment efficacy of traditional Chinese medicine (TCM) plays a vital role in the treatment of T2DM and NAFLD. Jiedu Tongluo Tiaogan Formula (JTTF), based on TCM theory, is widely used in clinical treatment, and its effectiveness in lowering glucose, regulating lipids, improving insulin resistance, and its pathways of action have been demonstrated in previous studies. However, the mechanism of this formula has not been investigated from a metabolomics perspective. Moreover, high-quality clinical studies on T2DM combined with NAFLD are lacking. Therefore, we aim to conduct a clinical trial to investigate the clinical efficacy, safety, and possible pathways of JTTF in the treatment of T2DM combined with NAFLD using metabolomics techniques. Methods: A total of 98 participants will be recruited to this clinical trial and randomly assigned to either a treatment group (JTTF + conventional basic treatment) or control group (conventional basic treatment) in a 1:1 ratio. Both groups will have received the same lifestyle interventions in the preceding 12 weeks. The primary outcome will be change in visceral fat area and total score on the TCM syndromes efficacy score scale. The secondary outcome will include changes in ultrasound steatosis grade, fibrosis 4 score (FIB-4), metabolic parameters, anthropometric parameters, visceral fat area. In addition, serum and urine samples collected at baseline and at the end of 12 weeks of treatment will be sequentially tested for untargeted and targeted metabolomics. Discussion: This study will evaluate the efficacy and safety of JTTF, as well as investigate the differential metabolites and possible mechanisms of JTTF treatment in T2DM combined with NAFLD. We hypothesize that patients will benefit from JTTF, which may provide strong evidence for the clinical use of JTTF in the treatment of T2DM and NAFLD, leading to the possibility of further mechanistic exploration. Clinical Trial Registration: This clinical trial has been registered in China Clinical Trial Registry (ChiCTR 2100051174).

Project description:ObjectiveTo elucidate the pharmacological mechanisms of Qubi Formula (QBF), a traditional Chinese medicine (TCM) formula which has been demonstrated as an effective therapy for psoriasis in China.MethodsThe Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, BATMAN-TCM database, and literature search were used to excavate the pharmacologically active ingredients of QBF and to predict the potential targets. Psoriasis-related targets were obtained from Therapeutic Target Database (TTD), DrugBank database (DBD), MalaCards database, and DisGeNET database. Then, we established the network concerning the interactions of potential targets of QBF with well-known psoriasis-related targets by using protein-protein interaction (PPI) data in String database. Afterwards, topological parameters (including DNMC, Degree, Closeness, and Betweenness) were calculated to excavate the core targets of Qubi Formula in treating psoriasis (main targets in the PPI network). Cytoscape was used to construct the ingredients-targets core network for Qubi Formula in treating psoriasis, and ClueGO was used to perform GO-BP and KEGG pathway enrichment analysis on these core targets.ResultsThe ingredient-target-disease core network of QBF in treating psoriasis was screened to contain 175 active ingredients, which corresponded to 27 core targets. Additionally, enrichment analysis suggested that targets of QBF in treating psoriasis were mainly clustered into multiple biological processes (associated with nuclear translocation of proteins, cellular response to multiple stimuli (immunoinflammatory factors, oxidative stress, and nutrient substance), lymphocyte activation, regulation of cyclase activity, cell-cell adhesion, and cell death) and related pathways (VEGF, JAK-STAT, TLRs, NF-κB, and lymphocyte differentiation-related pathways), indicating the underlying mechanisms of QBF on psoriasis.ConclusionIn this work, we have successfully illuminated that Qubi Formula could relieve a wide variety of pathological factors (such as inflammatory infiltration and abnormal angiogenesis) of psoriasis in a "multicompound, multitarget, and multipathway" manner by using network pharmacology. Moreover, our present outcomes might shed light on the further clinical application of QBF on psoriasis treatment.

Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic respiratory disease with high incidence, morbidity, and mortality rates. Jinshui Huanxian formula (JHF) is an empirical formula that targets the pathogenesis of lung-kidney qi deficiency and phlegm-blood stasis in pulmonary fibrosis (PF). The purpose of this study was to explore JHF's potential pharmacological mechanisms in IPF therapy using network intersection analysis. JHF's primary active components and corresponding target genes were predicted using various databases. Two sets of IPF disease genes were obtained from the DisGeNET and GEO databases and two sets of IPF drug targets were collected. The disease and drug target genes were analyzed. The JHF target genes that intersected with IPF's differentially expressed genes were identified to predict JHF's targets of action in IPF. The functions and pathways of predicted targets acting on IPF were analyzed using the DAVID and KEGG pathway databases. Finally, the resulting drug target mechanisms were validated in a rat model of PF. The initial analyses identified 494 active compounds and 1,304 corresponding targets for JHF. The intersection analysis revealed four common genes for the JHF targets, IPF disease, and anti-IPF drugs in the KEGG database. Furthermore, these genes were targeted by several JHF compounds. Seventy-two JHF targets were closely related to IPF, which suggests that they are therapeutically relevant. Target screening revealed that they regulate IPF through 18 pathways. The targets' molecular functions included regulation of oxidoreductase activity, kinase regulator activity, phosphotransferase activity, and transmembrane receptor protein kinase activity. In vivo experiments showed that JHF alleviated the degree of PF, including decreases in collagen deposition and epithelial-mesenchymal transition. This study systematically explored JHF's mechanisms to identify the specific target pathways involved in IPF. The generated pharmacological network, paired with in vivo validation, elucidates the potential roles and mechanisms of JHF in IPF therapy.

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Decoding the chemical composition and pharmacological mechanisms of Jiedu Tongluo Tiaogan Formula using high-performance liquid chromatography coupled with network pharmacology-based investigation.

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