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Background. Danggui-Shaoyao-San (DSS) is a traditional Chinese medicine formula that has been widely used to treat a variety of disorders, including renal diseases. Despite being well-established in clinical practice, the mechanisms behind the therapeutic effects of DSS on diabetic nephropathy (DN) remain elusive. Methods. To explore the therapeutic mechanism, we explored the action mechanism of DSS on DN using network pharmacology strategies. All ingredients were selected from the relevant databases, and active ingredients were chosen on the basis of their oral bioavailability prediction and drug-likeness evaluation. The putative proteins of DSS were obtained from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, whereas the potential genes of DN were obtained from the GeneCards and OMIM databases. Enrichment analysis using gene ontology (GO) and the Kyoto encyclopedia of genes and genomes (KEGG) was performed to discover possible hub targets and gene-related pathways. Afterwards, the underlying molecular mechanisms of DSS against DN were validated experimentally in vivo against db/db mice. Results. We identified 91 phytochemicals using the comprehensive network pharmacology technique, 51 of which were chosen as bioactive components. There were 40 proteins and 20 pathways in the target-pathway network. The experimental validation results demonstrated that DSS may reduce the expression of TNF-α, IL-6, and ICAM-1, as well as extracellular matrix deposition, by blocking the JNK pathway activation, which protects against kidney injury. Conclusion. This study discovered the putative molecular mechanisms of action of DSS against diabetic kidney damage through a network pharmacology approach and experimental validation. [ABSTRACT FROM AUTHOR]

Purpose: As a formula of traditional Chinese medicine (TCM), Huoxue Jiangtang Decoction (HJD) has positive effects on diabetes mellitus (DM) through improving of the metabolism of glycolipid and the function of β-cell. Hence, this research aims to explore the potential therapeutic effects of HJD on diabetes and reveal its underlying mechanisms. Methods: Diabetic rat models induced by high-fat diet (HFD) and streptozotocin (STZ) were included in this study. Following successful modeling, diabetic rats were treated with HJD, and then its therapeutic effects in eight weeks were evaluated. In addition to biochemical indicators, two-bottle preference tests were carried out to examine the rats' preferences for fat and sugar, and 16S rRNA gene sequencing was performed to disclose the differences of oral microbiota among groups. Finally, Pearson correlation coefficient was used to explore the correlation between oral microbiota and the preferences for fat and sugar. Results: It was found that HJD significantly improved the levels of fasting blood glucose (FBG), glucose tolerance, and dyslipidemia. Additionally, HJD contributed to decreasing preferences for fat and sugar in diabetic rats, which plays an important role in food intake. Furthermore, HJD regulated the abundance, distribution, and structure of oral microbiota in diabetic rats, serving as one of the underlying mechanisms of its antidiabetic effects. Conclusion: Taken with other formulas, HJD functions to improve the metabolism of glycolipid and the function of β-cell by inhibiting preferences for fat and sugar, as well as regulating the oral microbiota of diabetic rats. Furthermore, a potential correlation between the oral micro-environment and preferences for fat and sugar in STZ-induced diabetic rats is likely to exist. [ABSTRACT FROM AUTHOR]

Introduction: Polycystic ovary syndrome (PCOS) is a common endocrine disease that is characterized by chronic inflammation. Baishao (radix paeoniae alba, RPA), classified as a top-grade herbal medicine in TCM, has anti-inflammatory, immune adjustment, and anti-oxidative activities. RPA has been used to treat PCOS in clinical practice, but its potential mechanism of action is unclear. This study aimed at exploring the potential mechanism of RPA in PCOS treatment and to investigate the anti-inflammatory constituents of RPA. Methods: The TCMSP database was used to screen the potential active compounds of RPA. On the other hand, the possible target genes of PCOS were collected from the TTD, DrugBank, GeneCard, OMIM, and PharmGKB databases. The PPI network of RPA–PCOS target genes was established by STRING, and the visual network among RPA, ingredients, disease and potential target genes was constructed in Cytoscape. The bioactivity and potential mechanism of RPA in PCOS treatment were analyzed by GO and KEGG enrichment approaches. Furthermore, molecular docking was utilized to indicate the best compounds of RPA binding with TNF-α. Results: Fifty-four potential target genes were filtered and gathered from RPA and PCOS. Visual network indicated that 8 ingredients in RPA, β-sitosterol, (+)-catechin, palbinone, sitosterol, mairin, kaempferol, paeoniflorigenone, and paeoniflorin, were closely correlated with 54 possible therapeutic target genes. The possible pathways relating the treatment of PCOS by RPA mainly contained the TNF, lipid atherosclerosis, C-type lectin receptor, and AGE-RAGE signal pathways. Paeoniflorigenone was the optimal anti-inflammatory compound of RPA to bind with TNF-α in molecular docking analysis. Conclusion: This study manifested that the most effective anti-inflammation compound of RPA was paeoniflorigenone and provided a potential therapeutic strategy for PCOS treatment. [ABSTRACT FROM AUTHOR]

Context. Zishen Jiangtang Pill (ZJP) is a Chinese herbal compound, which has a positive therapeutic effect on diabetic osteoporosis (DOP) by regulating glucose metabolism and bone metabolism. However, its regulatory role and mechanism are still unclear. Objective. To explore the effect and mechanism of ZJP on DOP rats by proteomic analysis. Materials and Methods. After the establishment of diabetes model by Streptozocin (STZ, 60 mg/kg), 40 Wistar rats were equally divided into normal group, model group (diabetic rats), high-dose group (3.0 g/kg/d ZJP), and low-dose group (1.5 g/kg/d ZJP) and received treatment for 3 months. Histological changes in bone and pancreas tissues were observed by hematoxylin and eosin staining, electron microscopy, and immunofluorescence. Proteomic and bioinformatic analyses were performed to identify the differentially expressed proteins. The fingerprint and active ingredients of ZJP were identified via high-performance liquid chromatography (HPLC). Results. Compared with the model group, ZJP could rescue the weight, fasting blood glucose, and fasting insulin of rats in both high-dose and low-dose group. ZJP could also improve the microstructures of pancreatic islet cells, bone mass, and trabecular and marrow cavities in DOP rats. Bioinformatic analysis suggested that ZJP might influence DOP via multiple pathways, mainly including ribosomes, vitamin digestion and absorption, and fat digestion and absorption. The primary active ingredients, including notoginsenoside R1, ginsenoside Rg1, ginsenoside Re, icariin, and ginsenoside Rb1, were detected. Conclusion. ZJP could significantly improve the histomorphology and ultrastructure of bone and islets tissues and might serve as an effective alternative medicine for the treatment of DOP. [ABSTRACT FROM AUTHOR]

Background. Diabetic nephropathy (DN) is a common and serious complication of diabetes, but without a satisfactory treatment strategy till now. Liuwei Dihuang pills (LDP), an effective Chinese medicinal formula, has been used to treat DN for more than 1000 years. However, its underlying mechanism of action is still vague. Methods. Active compounds and corresponding targets of LDP were predicted from the TCMSP database. DN disease targets were extracted from the OMIM, GeneCards, TTD, DisGeNET, and DrugBank databases. Subsequently, the "herbal-compound-target" network and protein-protein interaction (PPI) network were constructed and analyzed via the STRING web platform and Cytoscape software. GO functional and KEGG pathway enrichment analyses were carried out on the Metascape web platform. Molecular docking utilized AutoDock Vina and PyMOL software. Results. 41 active components and 186 corresponding targets of LDP were screened out. 131 common targets of LDP and DN were acquired. Quercetin, kaempferol, beta-sitosterol, diosgenin, and stigmasterol could be defined as five crucial compounds. JUN, MAPK8, AKT1, EGF, TP53, VEGFA, MMP9, MAPK1, and TNF might be the nine key targets. The enrichment analysis showed that common targets were mainly associated with inflammation reaction, oxidative stress, immune regulation, and cell apoptosis. AGE-RAGE and IL-17 were the suggested two significant signal pathways. Molecular docking revealed that the nine key targets could closely bind to their corresponding active compounds. Conclusion. The present study fully reveals the multicompound's and multitarget's characteristics of LDP in DN treatment. Furthermore, this study provides valuable evidence for further scientific research of the pharmacological mechanisms and broader clinical application. [ABSTRACT FROM AUTHOR]

Background: Diabetic coronary heart disease (DCHD), the main macrovascular complication of type 2 diabetes mellitus (T2DM), is greatly harmful to T2DM patients. Traditional Chinese medicine (TCM) is an alternative and effective therapy to delay the development of macrovascular diseases, but the existing evidence of its efficacy and safety is insufficient. The aim of this multicenter, randomized, double-blind, placebo-controlled trial is to evaluate the efficacy and safety of Chinese Medicine Fufang Zhenzhu Tiaozhi capsule (FTZ) in treating DCHD. Patients and Methods: This study includes a 2-week run-in, 52-week treatment, and 52-week post-treatment follow-up. A total of 160 participants will be recruited and randomized into two groups. The treatment group will receive FTZ and basic treatment, while the control group will receive the placebo and basic treatment. The primary outcome is the combined outcome including the major adverse cardiovascular events, coronary restenosis, and unplanned revascularization. The combined secondary outcomes include all-cause mortality, acute coronary syndrome, ischemic stroke, heart failure, unplanned re-hospitalization mainly caused by acute complications of diabetes, other thromboembolic events, and TCM symptom indicators. The safety outcomes and adverse events will also be evaluated in this trial. Discussion: This trial evaluates the clinical effectiveness and safety of FTZ in patients with DCHD. The results are important to further explore the effectiveness of the comprehensive strategy "Tiao Gan Qi Shu Hua Zhuo" (modulating Gan, trigging key metabolic system to resolve pathogenic factors such as phlegm retention and dampness) in the prevention and control of glucolipid metabolic disorders (GLMD) including DCHD and T2DM. On the other hand, this study is the first trial of FTZ to observe cardiovascular outcomes through long-term follow-up after treatment of DCHD, which is of great value. Trial Registration: This trial was registered in the Chinese Clinical Trial Registry on April 07, 2019 (No. ChiCTR1900022345). [ABSTRACT FROM AUTHOR]

Huo-Xue-Jiang-Tang Yin (HXJTY) is a Chinese medicine formulation, which has been widely used for the treatment of various lipometabolism- and glycometabolism-related diseases in clinics. Currently, HXJTY is mainly prescribed to treat patients with type 2 diabetes mellitus (T2DM), yet its chemical and pharmacologic profiles remain to be elucidated. Here, the potential bioactive compound and action mechanism were investigated using chemical and network pharmacology analysis. A rapid HPLC-MS was employed to identify and quantify the component of HXJTY. On the basis of the identified chemical markers from HXJTY, a network pharmacology study, including target gene prediction and functional enrichment, was applied to screen out the main quality markers of HXJTY and explore its potential mechanism for the treatment of T2DM. The results showed that a total of 22 components were identified and quantified from HXJTY by HPLC-MS. Furthermore, 12 active components such as astragaloside IV, calycosin-7-O-β-D-glucoside, hydroxysafflor yellow A, and others were proposed as quality markers of HXJTY for treating T2DM based on network pharmacology analysis. In addition, 125 corresponding possible therapeutic target genes of T2DM were obtained. These target genes are mainly related to peptidase activity, hydrolase activity, phosphatase activity, and cofactor binding, suggesting the involvement of PI3K-Akt, MAPK, AGE-RAGE, and Rap1 signaling pathways in HXJTY-treated T2DM. Our results may provide a useful approach to identify potential quality markers and molecular mechanism of HXJTY for treating T2DM. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a complex neurodegenerative disease characterized by cognitive dysfunction. Kai-Xin-San (KXS) is a traditional Chinese medicine (TCM) formula that has been used to treat AD patients for over a thousand years in China. However, the therapeutic mechanisms of KXS for treating AD have not been fully explored. Herein, we used a comprehensive network pharmacology approach to investigate the mechanism of action of KXS in the treatment of AD. This approach consists of construction of multiple networks and Gene Ontology enrichment and pathway analyses. Furthermore, animal experiments were performed to validate the predicted molecular mechanisms obtained from the systems pharmacology-based analysis. As a result, 50 chemicals in KXS and 39 AD-associated proteins were identified as major active compounds and targets, respectively. The therapeutic mechanisms of KXS in treating AD were primarily related to the regulation of four pathology modules, including amyloid beta metabolism, tau protein hyperphosphorylation process, cholinergic dysfunction, and inflammation. In scopolamine-induced cognitive dysfunction mice, we validated the anti-inflammatory effects of KXS on AD by determining the levels of inflammation cytokines including interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α. We also found cholinergic system dysfunction amelioration of KXS is correlated with upregulation of the cholinergic receptor CHRNB2. In conclusion, our work proposes a comprehensive systems pharmacology approach to explore the underlying therapeutic mechanism of KXS for the treatment of AD. [ABSTRACT FROM AUTHOR]

Diabetic osteoporosis (DO) is a complication of diabetes. Zishen Jiangtang Pill (ZJP) is a Chinese herbal product which has been used in clinic to maintain blood glucose level and bone density for decades. However, the evidence about its mechanism on diabetes and osteoporosis is still unknown. The aim of this study is to investigate therapeutic effect of ZJP on DO in streptozotocin- (STZ-) induced rats. Rats were randomly assigned to 4 groups: one control group (CON), one model group (MOD), and two ZJP treatment groups (1.5 and 3.0 g/kg/d). All rats were treated for 8 weeks. Results showed that ZJP decreased the blood glucose level during OGTT and prevented the changes of FBG and Fins. Similarly, ZJP inhibited the changes of BCa, P, TRACP-5b, CTX-1, BALP, and BGP and the reduction of BMD. In parallel, 1H-NMR metabolomic studies showed that ZJP significantly altered the metabolic fingerprints of blood and urine level. These findings suggest that ZJP can effectively improve glucose metabolism, abnormal bone metabolism, and metabolic disorders in DO rats, which may be a useful alternative medicine for DO therapy. [ABSTRACT FROM AUTHOR]

α-Glucosidase inhibitors have been used for the management of type 2 diabetes mellitus (T2DM) for a long time. The natural α-glucosidase inhibitors from Chinese herbal medicine have become an attractive therapeutic approach for treating T2DM due to their low toxicity. The assays for the discovery of compounds in natural product extracts, however, mostly needed labor-intensive and time-consuming purification. In the current study, the screening of α-glucosidase inhibitors from Coptidis-Rehmanniae herb couple which was composed of Rhizoma Coptidis and Radix Rehmanniae, was investigated by ultrafiltration liquid chromatography/mass spectrometry (UF-LC/MS). As a result, four compounds binding to α-glucosidase were observed and identified to be jatrorrhizine, coptisine, palmatine, and berberine. Subsequently, the sustained off-resonance irradiation collision-induced dissociation Fourier transform mass spectrometry was performed for validation. In addition, the specific binding of ligands to α-glucosidase was demonstrated using UF-LC/MS and the ligands were ranked in order of affinity for α-glucosidase. The relative affinity order for the ligands was coptisine > jatrorrhizine > palmatine ≈ berberine, which indicated that coptisine and jatrorrhizine exhibited more potent α-glucosidase inhibitory activity compared to palmatine and berberine. Therefore, UF-LC/MS might provide not only a powerful tool for screening α-glucosidase inhibitors in complex samples but also a useful platform for bioactive compounds discovery of the efficient anti-diabetic drugs. [ABSTRACT FROM PUBLISHER]

• HQS reversed the abnormal hormone increasing, ameliorated insulin resistance and improved histopathological changes of the ovary tissue. • HQS decreased the production of TNF-α and IL-6, and inhibited the activation of NF-κB to further prohibited the macrophage M1 polarization in vivo and in vitro. • After HQS treatment, the apoptosis positive cells and the expression of BAX, Cleaved-caspase3 were decreased, and the expression of Bcl2 was increased in vivo. The co-culture experiments also verified that HQS could prevented the apoptosis of KGN cells. • HQS increased the abundance of bifldobacterium and parasutterella and decreased the abundance of lachnoclostridium. Polycystic ovary syndrome (PCOS) is a common and complex endocrine disease in women, with a prevalence of 5% to 18% worldwide. HeQi San (HQS) is a Chinese medicine compound prescription, which has been applied to treat various endocrine and metabolic diseases. The study was intended to investigate the effect of HQS on PCOS, and clarify the potential mechanism via in vivo and in vitro experiments. The PCOS mouse model was established by injecting the dehydroepiandrosterone (DHEA) subcutaneously and fading high-fat diet for 3 weeks. After making model, PCOS mice were treated with HQS (8.75 g/kg and 17.5 g/kg, ig.) for 4 weeks. Firstly, we assessed the histopathological changes in ovary tissues and detected the hormone level. Subsequently, the study evaluated the capability of anti-inflammatory and regulating macrophage polarization of HQS in vivo and in vitro. The secretion of inflammation indicators was measured with Elisa kits, and the expression level of phosphorylated nuclear factor kappa-B (P-NFκB) and B-lymphocyte activation antigen B7 (CD80) was measured by immunofluorescence and Western blot. Meanwhile, the apoptosis of ovarian granulosa cells was detected via tunel staining and Western blot. The co-culture model in vitro was utilized to assess the effect between macrophage polarization and human ovarian granulosa cells (KGN cells) apoptosis. Furthermore, 16S rDNA sequencing was utilized to elevate gut microbiota change in PCOS mice. HQS reversed the abnormal hormone increase, ameliorated insulin resistance, and improved histopathological changes of the ovary tissue to exert the therapeutic effect. HQS inhibited the expression of P-NF-κB and decreased the production of interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) to further prohibit the macrophage M1 polarization in ovary tissues and macrophages. The apoptosis-positive cells, Bcl-2 Assaciated X protein (BAX), and cleaved-caspase 3 expression were also decreased in the treatment group. The B-cell lymphoma-2 (Bcl2) expression was enhanced after HQS treatment in vivo. The co-culture experiments also verified that HQS could prevent the apoptosis of KGN cells. Furthermore, HQS mediated the abundance of gut flora. The abundance of bifldobacterium and parasutterella was increased and the abundance of lachnoclostridium was decreased. The study verified that HQS has the effect of anti-inflammation and inhibits macrophage M1 polarization. Besides, HQS could mediate the abundance of gut microbiota in mice with PCOS. Thus, this study would provide more reasonable basis of HQS for clinical use. In conclusion, HQS might be a potential candidate for PCOS treatment. [ABSTRACT FROM AUTHOR]

Eight nonaromatic acylphloroglucinol-terpenoid adducts including 7 new compounds were isolated from H. japonicum. Among them, compounds 1 – 4 showed significant PXR agonistic activity. [Display omitted] • Seven novel nonaromatic acylphloroglucinol-terpenoid adducts were isolated. • Compounds 1 − 4 showed significant PXR agonistic activity in dual-luciferase reporter gene model. • Compounds 1 − 4 can upregulate the expression of PXR-targeted gene in mice primary hepatocyte model. • Compounds 1 − 4 efficiently promoted PXR nuclear translocation at 10 μM. • The binding models of active compounds and PXR were elucidated. Pregnane X receptor (PXR) has been considered as a promising therapeutic target for cholestasis due to its crucial regulation in bile acid biosynthesis and metabolism. To search promising natural PXR agonists, the PXR agonistic activities of five traditional Chinese medicines (TCMs) with hepatoprotective efficacy were assayed, and Hypericum japonicum as the most active one was selected for subsequent phytochemical investigation, which led to the isolation of eight nonaromatic acylphloroglucinol-terpenoid adducts including seven new compounds (1 − 4 , 5a , 5b and 6). Their structures including absolute configurations were determined by comprehensive spectroscopic, computational and X-ray diffraction analysis. Meanwhile, the PXR agonistic activities of aplenty compounds were evaluated via dual-luciferase reporter assay, RT-qPCR and immunofluorescence. Among them, compounds 1 − 4 showed more potent activity than the positive drug rifampicin. Furthermore, the molecular docking revealed that 1 − 4 were docked well on the PXR ligand binding domain and formed hydrogen bonds with amino acid residues Gln285, Ser247 and His409. This investigation revealed that H. japonicum may serve as a rich source of natural PXR agonists. [ABSTRACT FROM AUTHOR]