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Ischemic stroke (IS), as a leading cause of disability worldwide, affects intestinal bacterial communities and their metabolites, while recent discoveries have highlighted the importance of the intestinal microflora in the development of IS. Systematic investigations of complex intestinal bacterial communities and their metabolites during ischemic brain injury contribute to elucidate the promising therapeutic targets for IS. However, the associations between intestinal microbiota and related circulating metabolic processes in IS remained unclear. Hence, to identify the changed microflora and their metabolites in IS of NaoMaiTong (NMT), an effective clinical medication, we established the middle cerebral artery occlusion/reperfusion (MCAO/R) model using conventionalized and pseudo-germ-free (PGF) rats. Subsequently, we systematically screen the microflora and related metabolites changing in IS via an integrated approach of cecal 16S rRNA sequencing combined with plasma metabolomics. We found that NMT relied on intestinal flora to improve stroke outcome in conventionalized rats while the protection of NMT was reduced in PGF rats. Total 35 differential bacterial genera and 26 differential microbial metabolites were regulated by NMT. Furthermore, L-asparagine and indoleacetaldehyde were significantly negatively correlated with Lachnospiraceae_UCG.001 and significantly positively correlated with Lachnoclostridium . Indoleacetaldehyde also presented a negative correlation with Lactobacillus and Bifidobacterium . 2-Hydroxybutyric acid was strongly negatively correlated with Ruminococcus, Lachnospiraceae_UCG.001 and Lachnospiraceae_UCG.006. Creatinine was strongly negatively correlated with Akkermansia . In summary, the research provided insights into the intricate interaction between intestinal microbiota and metabolism of NMT in IS. We identified above differential bacteria and differential endogenous metabolites which could be as prebiotic and probiotic substances that can influence prognosis in stroke and have potential to be used as novel therapeutic targets or exogenous drug supplements.

Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease. Despite advances in current therapies, safer, more effective drugs are urgently needed. Traditional Chinese herbal formula Gegen Qinlian Decoction (GQD) has been used for gastrointestinal disorders, including UC, though its exact mechanisms require further clarification. This study aimed to systematically evaluate the therapeutic effects of GQD in UC mice, focusing on serum metabolomics, gut microbiota, and immunomodulatory mechanisms. A dextran sulfate sodium (DSS)-induced mouse model of UC was established. Serum metabolomics and 16S rRNA sequencing analysis of GQD's effects on metabolites and gut microbiota. Correlation analysis and network pharmacology identified potential targets and pathways of GQD. Immunofluorescence detected the expression of γδT cells, TNF-α, IFN-γ, and IL-17 proteins in the colonic tissue. Using UPLC-QE-Orbitrap-MS, 71 compounds were identified in the GQD quality control analysis. GQD markedly attenuated colonic histopathological damage and suppressed serum pro-inflammatory cytokines IFN-γ, IL-17, and TNF-α. It also modulated key serum metabolites, including succinic acid, glyoxylate, and xanthine, which are primarily involved in amino acid and purine metabolic pathways. GQD further influenced intestinal microbial diversity and composition. Joint analysis revealed GQD modulates gut microbiota, serum amino acid and purine metabolism, and inflammation pathways. Immunohistochemical results demonstrated enhanced infiltration of γδT cells following GQD treatment, accompanied by reduced protein expression levels of TNF-α, IFN-γ, and IL-17. GQD exerts therapeutic effects on UC by reshaping gut microbiota composition and metabolic activities, thereby ameliorating intestinal mucosal injury, regulating γδT cell-mediated immune responses, and influencing amino acid and purine metabolic pathways.

Background and Objectives: Diabetic hepatopathy, characterized by hepatic hypoxia and metabolic dysregulation, has a rising global incidence and prevalence, with limited effective treatments. Hepatic hypoxia activates hypoxia-inducible factor-1 alpha (HIF-1α), regulating sphingolipid metabolism and elevating ceramide, a key factor in insulin resistance. Puerarin (Pue), a flavonoid derived from Pueraria lobata, exhibits therapeutic effects in diabetes, but its effects on hypoxia-related hepatic metabolism are unclear. This study investigates Pue’s mechanisms in modulating hepatic metabolism, focusing on HIF-1α and sphingolipid metabolism. Methods: Using bioinformatics and molecular docking, HIF-1α was identified as a key target in diabetic liver disease, confirmed via drug affinity responsive target stability. In vitro experiments utilized insulin-resistant HepG2 cells to assess glucose intake and HIF-1α expression. In vivo, type 2 diabetes mellitus (T2DM) was induced in mice using a high-fat diet and streptozotocin injections. Pue administration was evaluated for its effects on fasting blood glucose, oral glucose tolerance, and hepatoprotective effects. Liver metabolomics and qPCR/Western blot analyses were conducted to assess metabolic pathways. Results: Pue increased glucose uptake in HepG2 cells and bound HIF-1α. Pue reduced HIF-1α expression in HepG2 cells, an effect attenuated by the HIF-1α stabilizer DMOG. Pue improved fasting blood glucose, oral glucose tolerance, and hepatoprotective effects in T2DM mice, which DMOG reversed. Metabolomics revealed that Pue modulates sphingolipid metabolism, decreasing ceramide content. qPCR and Western blot results confirmed that Pue dramatically decreases HIF-1α and SPTLC2 expression. Conclusions: Pue improves diabetic hepatopathy by reducing ceramide expression through the HIF-1α/SPTLC2 pathway, offering a novel therapeutic strategy for diabetes management.

Functional dyspepsia (FD) is one of the most prevalent functional gastrointestinal disorders, and more and more multicomponent drugs represented by traditional Chinese medicines have provided a favorable therapeutic effect in its treatment. However, their precise localization in the clinic, as well as corresponding mechanism, is ambiguous, thus hindering their widespread use. To meet this requirement, a precise and systematic approach based on a restriction of special disease-related molecules and the following network pharmacology analysis was developed and applied to a multicomponent conventional drug, XiaoErFuPi (XEFP) granules. Experimental verification of the results indicates that this approach can facilitate the prediction, and the precise and systematic efficacy of XEFP could be easily revealed, which shows that XEFP has an advantage over the positive control drug on lactate, gastrin, interleukin 4 and calcitonin gene-related peptide. Moreover, by the proteomics analysis, its superposition of multi-target effects was revealed and a new candidate target for the treatment of FD, striatin, was obtained and verified. This study provides a practicable precise approach for the investigation of the efficacy of multicomponent drugs against FD and offers a promising alternative for the systematical management of FD.

The occurrence and death rates of primary hepatocellular carcinoma (HCC) are increasing, and there remains a shortage of effective oral medications with minimal side effects. We aim to identify potential biomarkers and compounds from Radix Astragali (RA) and Pueraria Mirifica (PM) to treat liver cancer and improve prognosis. Differentially expressed genes (DEGs) associated with HCC were identified by bioinformatics analysis of three datasets, GSE112791, GSE101685, and GSE45114. Using public databases to predict the bioactive components and possible targets of RA and PM. Target crossover from Gene Expression Omnibus (GEO) and public databases were used to identify potential biomarkers for HCC. Subsequently, validation and prognostic value analyses were performed using the Gene Expression Profile Interaction Analysis (GEPIA) platform. The Cytoscape software created a network of “compound targets” to pinpoint compounds linked to the biomarkers. Molecular docking techniques were utilized to validate the connection between these compounds and the identified biomarkers. Ultimately, the HepG2 liver cancer cell line was chosen to assess the inhibitory effect of Hederagenin (HDG) and to confirm the expression of ADH1B through Western blot analysis. In this study, four key biomarkers (NR1I2, ADH1B, NQO1, GHR) were identified. Molecular docking showed that these four core targets could form stable conformations with the corresponding compounds. As the drug concentration decreases, the inhibitory effect on HepG2 diminishes, and the survival rate of HepG2 cells significantly declines following the administration of 100 µmol/L HDG. Compared to the control, the expression of ADH1B protein is significantly increased in HepG2 cells treated with 100 µmol/L HDG. The study identified four key biomarkers (ADH1B, GHR, NQO1, NR1I2) that have prognostic ability for HCC. This study provides biomarkers and potential targeted monomeric medicines for treating HCC.

Neuronal damage after ischemic stroke (IS) is frequently due to ferroptosis, contributing significantly to ischemic injury. However, the mechanism against ferroptosis in IS remained unclear. The aim of this study was to investigate the potential mechanism of Danhong injection (DHI) and the critical transcription factor SATB1 in preventing neuronal ferroptosis after ischemic stroke in vivo and in vitro. The results showed that DHI treatment significantly reduced the infarct area and associated damage in the brains of the pMCAO mice, and enhanced the viability of OGD-injured neurons. And several characteristic indicators of ferroptosis, such as mitochondrial necrosis and iron accumulation, were regulated by DHI after IS. Importantly, we found that the expression and activity of SATB1 were decreased in the pMCAO mice, especially in neuron cells. Meanwhile, the SATB1/SLC7A11/HO-1 signaling pathway was activated after DHI treatment in ischemic stroke and was found to improve neuronal ferroptosis. Inhibition of SATB1 significantly reduced SLC7A11-HO-1 and significantly attenuated the anti-ferroptosis effects of DHI in the OGD model. These findings indicate that neuronal ferroptosis after IS can be alleviated by DHI through SATB1/SLC7A11/HO-1 pathway, and SATB1 may be an attractive therapeutic target for treating ischemic stroke. Graphical abstract

Bioelectrical impedance technology (EBI) offers a non-invasive, cost-effective method for body composition assessment, showing promise in diagnosing and managing musculoskeletal disorders, particularly osteoarthritis (OA). OA is a major global health concern, notably affecting the knee and hip joints. Conventional imaging techniques like X-rays and MRI have limitations in early detection, as they cannot capture microscopic cartilage changes. Phase angle (PhA), an essential EBI parameter, is widely applied in evaluating sarcopenia, tumors, and body fluids, and is increasingly valuable in OA research. PhA reflects cellular health through cell membrane impedance, with studies showing that lower PhA levels correlate with OA severity and predict OA-related degeneration, supporting its role in early screening. Additionally, EBI holds potential for monitoring OA progression and evaluating treatment efficacy. This review summarizes recent advances in OA diagnosis with EBI, focusing on the applications of PhA and other bioimpedance parameters in screening, monitoring, and evaluation. Through systematic analysis, this review provides theoretical support for EBI’s clinical use, highlighting its potential in OA prevention, diagnosis, and intervention. With continued technological progress, EBI is poised to become a critical tool in OA management, particularly for early diagnosis and personalized treatment.

Inflammation is a key mediator in the progression of atherosclerosis (AS). Benzoinum, a resin secreted from the bark of Styrax tonkinensis, has been widely used as a form of traditional Chinese medicine in clinical settings to enhance cardiovascular function, but the active components of the resin responsible for those pharmaceutical effects remain unclear. To better clarify these components, a new phenylpropane derivative termed stybenpropol A was isolated from benzoinum and characterized via comprehensive spectra a nalysis. We further assessed how this phenylpropane derivative affected treatment of human umbilical vein endothelial cells (HUVECs) with tumor necrosis factor-α (TNF-α). Our results revealed that stybenpropol A reduced soluble intercellular cell adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), interleukin-8 (IL-8), and interleukin-1β (IL-1β) expression by ELISA, inhibited apoptosis, and accelerated nitric oxide (NO) release in TNF-α-treated HUVECs. We further found that stybenpropol A decreased VCAM-1, ICAM-1, Bax, and caspase-9 protein levels, and increased the protein levels of Bcl-2, IKK-β, and IκB-α. This study identified a new, natural phenylpropane derivative of benzoinum, and is the first to reveal its cytoprotective effects in the context of TNF-α-treated HUVECs via regulation of the NF-κB and caspase-9 signaling pathways.

Systematic investigations of complex pathological cascades during ischemic brain injury help to elucidate novel therapeutic targets against cerebral ischemia. Although some transcription factors (TFs) involved in cerebral ischemia, systematic surveys of their changes during ischemic brain injury have not been reported. Moreover, some multi-target agents effectively protected against ischemic stroke, but their mechanisms, especially the targets of TFs, are still unclear. Therefore, a comprehensive approach by integrating network pharmacology strategy and a new concatenated tandem array of consensus transcription factor response elements method to systematically investigate the target TFs critical in the protection against cerebral ischemia by a medication was first reported and then applied to a multi-target drug, Danhong injection (DHI). High-throughput nature and depth of coverage, as well as high quantitative accuracy of the developed approach, make it more suitable for analyzing such multi-target agents. Results indicated that pre-B-cell leukemia transcription factor 1 and cyclic AMP-dependent transcription factor 1, along with six other TFs, are putative target TFs for DHI-mediated protection against cerebral ischemia. This study provides, for the first time, a systematic investigation of the target TFs critical to DHI-mediated protection against cerebral ischemia, as well as reveals more potential therapeutic targets for ischemic stroke.

Background. NaoMaiTong (NMT) is widely used in the treatment of cerebral ischemia but the molecular details of its beneficial effects remain poorly characterized. Materials and Methods. In this study, we used iTRAQ using 2D LC-MS/MS technology to investigate the cellular mechanisms governing the protective effects of NMT. The transient middle cerebral artery occlusion (MCAO) rat model was established and evaluated. The degree of cerebral ischemia was assessed through scoring for nerve injury symptoms and through the assessment of the areas of cerebral infarction. Brain tissues were subjected to analysis by iTRAQ. High-pH HPLC and RSLC-MS/MS analysis were performed to detect differentially expressed proteins (DEPs) between the treatment groups (Sham, MCAO, and NMT). Bioinformatics were employed for data analysis and DEPs were validated by western blot. Results. The results showed that NMT offers protection to the neurological damage caused by MCAO and was found to reduce the areas of cerebral infarction. We detected 3216 DEPs via mass spectrometry. Of these proteins, 21 displayed altered expression following NMT intervention. These included DEPs involved in translation, cell cycle regulation, cellular nitrogen metabolism, and stress responses. Pathway analysis revealed seven key DEPs that were enriched in ribosomal synthesis pathways, tight junction formation, and regulation of the actin cytoskeleton. According to protein-protein interaction analysis, RPL17, Tuba, and Rac1 were affected by NMT treatment, which was validated by western blot analysis. Discussion. We therefore identify new pharmacodynamic mechanisms of NMT for the prevention and treatment of ischemic stroke. These DEPs reveal new targets to prevent ischemic stroke induced neuronal damage.