Gegen Qinlian Decoction (GGQLT) is a traditional Chinese herbal medicine that has been reported to have a significant therapeutic effect in the management of type II diabetes mellitus (T2DM). In this study, we constructed a T2DM rat model by feeding a high-fat diet and injecting streptozotocin (STZ) and tested the effects of feeding GGQLT and fecal transplantation on the physiological indices, microbiota, and metabolism of rats. The results showed that the administration of GGQLT can significantly improve the growth performance of rats and has a remarkable antihyperlipidemic effect. In addition, GGQLT altered the composition of gut microbiota by increasing beneficial bacteria such as Coprococcus, Bifidobacterium, Blautia, and Akkermansia. In addition, GGQLT elevated levels of specific bile acids by metabolomic analysis, potentially contributing to improvements in lipid metabolism. These findings suggest that GGQLT may have beneficial effects on T2DM by influencing lipid metabolism and gut microbiota. However, further studies are needed to elucidate its mechanisms and assess clinical applications.

BACKGROUND: Reynoutria multiflora (Thunb.) Moldenke (Polygonum multiflorum Thunb, PM) is a medicinal plant that was an element of traditional Chinese medicine (TCM) for centuries as a treatment for a wide range of conditions. Recent studies reported that PM suppressed prostate cancer growth in an AR-dependent manner. However, its role and mechanism in the treatment of advanced prostate cancer remain to be explored. This study aims to explore the anti-tumor role and potential mechanism of PM on prostate cancer.
METHODS: Cell viability, colony formation, fluorescence-activated cell sorting (FACS), and wound-healing assays were conducted to evaluate the tumor suppression effect of PM on lethal prostate cancer models in vitro. A xenograft mice model was established to detect the impact of PM on tumor growth and evaluate its biosafety in vivo. Integrative network pharmacology, RNA-seq, and bioinformatics were applied to determine the mechanisms of PM in prostate cancer. Molecular docking, cellular thermal shift assay (CETSA), CRISPR-Cas13, RT-qPCR, and WB were collaboratively employed to identify the potential anti-tumor ingredient derived from PM and its corresponding targets.
RESULTS: PM significantly suppressed the growth of prostate cancer and sensitized prostate cancer to AR antagonists. Mechanistically, PM induced G2/M-phase cell-cycle arrest by modulating the phosphorylation of CDK1. Additionally, polygalacic acid derived from PM and its structural analog suppress prostate cancer growth by targeting CDC25B, a master regulator of the cell cycle that governs CDK1 phosphorylation.
CONCLUSIONS: PM and its ingredient polygalacic acid suppress lethal prostate cancer growth by regulating the CDC25B-CDK1 axis to induce cell cycle arrest.

BACKGROUND: Squama Manis is a valuable traditional Chinese medicine with a long history of medicinal use in the treatment of breast-related diseases. However, owing to the excessive exploitation and utilization of the resources, Squama Manis has been included in the list of rare and endangered wild animals. The conservation of the resources of Squama Manis and continuing its clinical application has become an urgent problem, and the search for small-molecule substitutes for Squama Manis is an effective way to achieve this goal. Previous studies have identified PA3264 as a possible active ingredient in Squama Manis. In this study, we systematically investigated the pharmacological effects and mechanisms of PA3264 in the treatment of triple-negative breast cancer (TNBC), a representative breast-related disease.
METHODS: Cell viability and colony formation assays were performed after treatment with the target dipeptide PA3264 in vitro. Next, 4T1 orthotopic tumors and humanized PBMC-CDX mouse models were generated to examine the antitumor effect of PA3264 in vivo. Transcriptome sequencing and molecular docking experiments were performed to predict pathways to function. Western blotting and quantitative real-time PCR were used to validate the molecular mechanisms underlying the anticancer effects of PA3264.
RESULTS: PA3264 significantly inhibited cell viability and migration of breast cancer cells in vitro. Furthermore, PA3264 suppressed the tumor size and reduced the tumor weight in vivo. Finally, it was verified that PA3264 prevented the progression of breast cancer by inhibiting the PI3K/AKT/NF-κB pathway, causing cell cycle arrest, and promoting apoptosis.
CONCLUSIONS: This study elucidated that PA3264 derived from rare and endangered Squama Manis was a novel bioactive peptide for treating triple-negative breast cancer from a scientific research perspective.

UNASSIGNED: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related deaths globally. Current treatments often do not fully meet efficacy and quality of life expectations. Traditional Chinese medicine (TCM), particularly the Yiqi Sanjie formula, shows promise but lacks clear mechanistic understanding. This study addresses this gap by investigating the therapeutic effects and underlying mechanisms of Yiqi Sanjie formula in NSCLC.
UNASSIGNED: We utilized network pharmacology to identify potential NSCLC drug targets of the Yiqi Sanjie formula via the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Compounds with favorable oral bioavailability and drug-likeness scores were selected. Molecular docking was conducted using AutoDock Vina with structural data from the Protein Data Bank and PubChem. Molecular dynamics (MD) simulations were performed with Desmond Molecular Dynamics System, analyzing interactions up to 500 nanoseconds using the OPLS4 force field. ADMET predictions were executed using SwissADME and ADMETlab 2.0, assessing pharmacokinetic properties.
UNASSIGNED: Using network pharmacology tools, we performed Search Tool for the Retrieval of Interaction Genes/Proteins (STRING) analysis for protein-protein interaction, Kyoto Encyclopedia of Genes and Genomes (KEGG) for pathway enrichment, and gene ontology (GO) for functional enrichment, identifying crucial signaling pathways and biological processes influenced by the hit compounds bifendate, xambioona, and hederagenin. STRING analysis indicated substantial connectivity among the targets, suggesting significant interactions within the cell cycle regulation and growth factor signaling pathways as outlined in our KEGG results. The GO analysis highlighted their involvement in critical biological processes such as cell cycle control, apoptosis, and drug response. Molecular docking simulations quantified the binding efficiencies of the identified compounds with their targets-CCND1, CDK4, and EGFR-selected based on high docking scores that suggest strong potential interactions crucial for NSCLC inhibition. Subsequent MD simulations validated the stability of these complexes, supporting their potential as therapeutic interventions. Additionally, the novel identification of ADH1B as a target underscores its prospective significance in NSCLC therapy, further expanded by our comprehensive bioinformatics approach.
UNASSIGNED: Our research demonstrates the potential of integrating network pharmacology and computational biology to elucidate the mechanisms of the Yiqi Sanjie formula in NSCLC treatment. The identified compounds could lead to novel targeted therapies, especially for patients with overexpressed targets. The discovery of ADH1B as a therapeutic target adds a new dimension to NSCLC treatment strategies. Further studies, both in vitro and in vivo, are needed to confirm these computational findings and advance these compounds towards clinical trials.

BACKGROUND: Endometriosis (EMS) is a common gynecological disease that causes dysmenorrhea, chronic pelvic pain and infertility. Luoshi Neiyi Prescription (LSNYP), a traditional Chinese medicine (TCM) formula, is used to relieve EMS in the clinic.
OBJECTIVE: This study aimed to examine the active components of LSNYP and the possible mechanism involved in its treatment of EMS.
METHODS: Ultrahigh-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) was used to identify the chemical components of LSNYP. Human primary ectopic endometrial stromal cells (ecESCs) and eutopic endometrial stromal cells (euESCs) were isolated, and the expression levels of hypoxia inducible factor 1A (HIF1A), enhancer of zeste homolog 2 (EZH2) and steroidogenic factor 1 (SF-1) were detected by immunofluorescence and qPCR. Cobalt chloride (CoCl2) was utilized to construct an in vitro hypoxic environment, and lentiviruses were engineered to downregulate HIF1A and EZH2 and upregulate EZH2. Subsequently, the expression levels of HIF1A, EZH2, and SF-1 were measured using qPCR or western blotting. The binding of EZH2 to the SF-1 locus in ESCs was examined via ChIP. Furthermore, the effects of LSNYP on the HIF1A/EZH2/SF-1 pathway were evaluated both in vitro and in vivo.
RESULTS: A total of 185 components were identified in LSNYP. The protein and gene expression levels of HIF1A and SF-1 were increased, whereas those of EZH2 were decreased in ecESCs. After treating euESCs with 50 μmol L-1 CoCl2 for 24 h, cell viability and estradiol (E2) production were enhanced. Hypoxia decreased EZH2 protein expression, while si-HIF1A increased it. SF-1 was increased when EZH2 was downregulated in normal and hypoxic environments, whereas the overexpression of EZH2 led to a decrease in SF-1 expression. ChIP revealed that hypoxia reduced EZH2 binding to the SF-1 locus in euESCs. In vitro, LSNYP-containing serum decreased E2 and prostaglandin E2 (PGE2) production, inhibited cell proliferation and invasion, and reduced the expression of HIF1A, SF-1, steroidogenic acute regulatory protein (StAR), and aromatase cytochrome P450 (P450arom). In vivo, LSNYP suppressed inflammation and adhesion and inhibited the HIF1A/EZH2/SF-1 pathway in endometriotic tissues.
CONCLUSIONS: LSNYP may exert pharmacological effects on EMS by inhibiting E2 synthesis and inflammation through regulation of the HIF1A/EZH2/SF-1 pathway. These results suggest that LSNYP may be a promising candidate for the treatment of EMS.

Herbal medicines, particularly traditional Chinese medicines (TCMs), are a rich source of natural products with significant therapeutic potential. However, understanding their mechanisms of action is challenging due to the complexity of their multi-ingredient compositions. We introduced Herb-CMap, a multimodal fusion framework leveraging protein-protein interactions and herb-perturbed gene expression signatures. Utilizing a network-based heat diffusion algorithm, Herb-CMap creates a connectivity map linking herb perturbations to their therapeutic targets, thereby facilitating the prioritization of active ingredients. As a case study, we applied Herb-CMap to Suhuang antitussive capsule (Suhuang), a TCM formula used for treating cough variant asthma (CVA). Using in vivo rat models, our analysis established the transcriptomic signatures of Suhuang and identified its key compounds, such as quercetin and luteolin, and their target genes, including IL17A, PIK3CB, PIK3CD, AKT1, and TNF. These drug-target interactions inhibit the IL-17 signaling pathway and deactivate PI3K, AKT, and NF-κB, effectively reducing lung inflammation and alleviating CVA. The study demonstrates the efficacy of Herb-CMap in elucidating the molecular mechanisms of herbal medicines, offering valuable insights for advancing drug discovery in TCM.

The organic anion transporters OAT1 (SLC22A6) and OAT3 (SLC22A8) are drug transporters that are expressed in the kidney, with well-established roles in the in vivo transport of drugs and endogenous metabolites. A comparatively unexplored potential function of these drug transporters is their contribution to the in vivo regulation of natural products (NPs) and their effects on endogenous metabolism. This is important for the evaluation of potential NP interactions with other compounds at the transporter site. Here, we have analyzed the NPs present in several well-established databases from Asian (Chinese, Indian Ayurvedic) and other traditions. Loss of OAT1 and OAT3 in murine knockouts caused serum alterations of many NPs, including flavonoids, vitamins, and indoles. OAT1- and OAT3-dependent NPs were largely separable based on a multivariate analysis of chemical properties. Direct binding to the transporter was confirmed using in vitro transport assays and protein binding assays. Our in vivo and in vitro results, considered in the context of previous data, demonstrate that OAT1 and OAT3 play a pivotal role in the handling of non-synthetic small molecule natural products, NP-derived antioxidants, phytochemicals, and nutrients (e.g., pantothenic acid, thiamine). As described by remote sensing and signaling theory, drug transporters help regulate redox states by meditating the movement of endogenous antioxidants and nutrients between organs and organisms. Our results demonstrate how dietary antioxidants and other NPs might feed into these inter-organ and inter-organismal pathways.

Mechanism analysis is essential for the use and promotion of Traditional Chinese Medicine (TCM). Traditional methods of network analysis relying on expert experience lack an explanatory framework, prompting the application of deep learning and machine learning for objective identification of TCM pharmacological effects. A dataset was used to construct an interacted network graph between 424 molecular descriptors and 465 pharmacological targets to represent the relationship between components and pharmacological effects. Subsequently, the optimal identification model of pharmacological effects (IPE) was established through convolution neural networks of GoogLeNet structure. The AUC values are greater than 0.8, MCC values are greater than 0.7, and ACC values are greater than 0.85 across various test datasets. Subsequently, 18 recognition models of TCM efficacy (RTE) were created using support vector machines (SVM). Integration of pharmacological effects and efficacies led to the development of the systemic web platform for identification of pharmacological effects (SYSTCM). The platform, comprising 70,961 terms, including 636 Traditional Chinese Medicines (TCMs), 8190 components, 40 pharmacological effects, and 18 efficacies. Through the SYSTCM platform, (1) Total 100 components were predicted from TCMs with anti-inflammatory pharmacological effects. (2) The pharmacological effects of complete constituents were predicted from Coptidis Rhizoma (Huang Lian). (3) The principal components, pharmacological effects, and efficacies were elucidated from Salviae Miltiorrhizae radix et rhizome (Dan Shen). SYSTCM addresses subjectivity in pharmacological effect determination, offering a potential avenue for advancing TCM drug development and clinical applications. Access SYSTCM at http://systcm.cn.

BACKGROUND: Chronic inflammation is the major pathological feature of Atherosclerosis(As). Inflammation may accelerate plaque to develop, which is a key factor resulting in the thinning of the fibrous cap and the vulnerable rupture of plaque. Presently, clinical treatments are still lacking. It is necessary to find a safe and effective treatment for As inflammation. Simiaoyongan Decoction (SMYA) has potential anti-inflammatory and plaque protection effects. This protocol aims to evaluate the efficacy, safety, and mechanism of SMYA for patients with carotid atherosclerotic plaque.
METHODS: The assessment of SMYA clinical trial is designed as a randomized, double-blind, placebo-controlled study. The sample size is 86 cases in total, with 43 participants in the intervention group and the control group respectively. The intervention group takes SMYA, while the control group takes SMYA placebo. The medication lasts for 14 days every 10 weeks, with a total of 50 weeks. We will use carotid artery high resolution magnetic resonance imaging (HR-MRI) to measure plaque. The plaque minimum fiber cap thickness (PMFCT) is adopted as the primary outcome. The secondary outcomes include plaque fiber cap volume, volume percentage of fiber cap, lipid-rich necrotic core (LRNC) volume, volume percentage of LRNC, internal bleeding volume of plaque, internal bleeding volume percentage of plaque, plaque calcification volume, volume percentage of plaque calcification, lumen stenosis rate, average and a maximum of vessel wall thickness, vessel wall volume, total vessel wall load, carotid atherosclerosis score, hs-CRP, IL-1β and IL-6, the level of lipid profiles and blood glucose, blood pressure, and body weight.
CONCLUSIONS: We anticipate that patients with As plaque will be improved from SMYA by inhibiting inflammation to enhance plaque stability. This study analyzes plaque by using HR-MRI to evaluate the clinical efficacy and safety of SMYA. Moreover, we conduct transcriptome analysis, proteomic analysis, and metagenomic analysis of blood and stool of participants to study the mechanism of SMYA against As plaque. This is the first prospective TCM trial to observe and treat As plaque by inhibiting inflammatory reaction directly. If successful, the finding will be valuable in the treatment of As plaque and drug development, especially in the \"statin era\".
BACKGROUND: This trial is registered on Chinese Clinical Trials.gov with number ChiCTR2000039062 on October 15, 2020 ( http://www.chictr.org.cn ).

Naoxintong Capsule (NXT), a renowned traditional Chinese medicine (TCM) formulation, has been broadly applied in China for more than 30 years. Over decades, accumulating evidences have proven satisfactory efficacy and safety of NXT in treating cardiovascular and cerebrovascular diseases (CCVD). Studies have been conducted unceasingly, while this growing latest knowledge of NXT has not yet been interpreted properly and summarized comprehensively. Hence, we systematically review the advancements in NXT research, from its chemical constituents, quality control, pharmacokinetics, to its profound pharmacological activities as well as its clinical applications in CCVD. Moreover, we further propose specific challenges for its future perspectives: 1) to precisely clarify bioactivities of single compound in complicated mixtures; 2) to evaluate the pharmacokinetic behaviors of NXT feature components in clinical studies, especially drug-drug interactions in CCVD patients; 3) to explore and validate its multi-target mechanisms by integrating multi-omics technologies; 4) to re-evaluate the safety and efficacy of NXT by carrying out large-scale, multicenter randomized controlled trials. In brief, this review aims to straighten out a paradigm for TCM modernization, which help to contribute NXT as a piece of Chinese Wisdom into the advanced intervention strategy for CCVD therapy.