OBJECTIVE: Peritoneal fibrosis (PF) is an adverse event that occurs during long-term peritoneal dialysis, significantly impairing treatment efficiency and adversely affecting patient outcomes. Astragaloside IV (AS-IV), a principal active component derived from Astragalus membranaceus (Fisch.) Bunge, has exhibited anti-inflammatory and antifibrotic effects in various settings. This study aims to investigate the potential therapeutic efficacy and mechanism of AS-IV in the treatment of PF. METHODS: The PF mouse model was established by intraperitoneal injection of 4.25% peritoneal dialysis fluid (100 mL/kg). The epithelial-mesenchymal transition (EMT) of HMrSV5 cells was induced by the addition of 10 ng/mL transforming growth factor β (TGF-β). The differentially expressed genes in HMrSV5 cells treated with AS-IV were screened using transcriptome sequencing analysis. The potential targets of AS-IV were screened using network pharmacology and analyzed using molecular docking and molecular dynamics simulations. RESULTS: Administration of AS-IV at doses of 20, 40, or 80 mg/kg effectively mitigated the increase in peritoneal thickness and the development of fibrosis in mice with PF. The expression of the fibrosis marker α-smooth muscle actin in the peritoneum was significantly decreased in AS-IV-treated mice. The treatment of AS-IV (10, 20, and 40 μmol/L) significantly delayed the EMT of HMrSV5 cells induced by TGF-β, as demonstrated by the decreased number of 5-ethynyl-2'-deoxyuridine-positive cells, reduced migrated area, and decreased expression of fibrosis markers. A total of 460 differentially expressed genes were detected in AS-IV-treated HMrSV5 cells through transcriptome sequencing, with notable enrichment in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-AKT serine/threonine kinase 1 (AKT) signaling pathway. The reduced levels of phosphorylated PI3K (p-PI3K) and p-AKT were detected in HMrSV5 cells with AS-IV treatment. Epidermal growth factor receptor (EGFR) was predicted as a direct target of AS-IV, exhibiting strong hydrogen bond interactions. The activation of the PI3K-AKT pathway by the compound 740Y-P, and the activation of the EGFR pathway by NSC 228155 each partially counteracted the inhibitory effect of AS-IV on the EMT of HMrSV5 cells. CONCLUSION AS-IV delayed the EMT process in peritoneal mesothelial cells and slowed the progression of PF, potentially serving as a therapeutic agent for the early prevention and treatment of PF. Please cite this article as: Huang Y, Chu CL, Qiu WH, Chen JY, Cao LX, Ji SY, Zhu B, Wang GK, Shen QQ. Astragaloside IV delayed the epithelial-mesenchymal transition in peritoneal fibrosis by inhibiting the activation of EGFR and PI3K-AKT pathways. J Integr Med. 2025; 23(6):694-705.
Epithelial-Mesenchymal Transition/drug effects* ; Animals ; Saponins/pharmacology* ; Triterpenes/pharmacology* ; Mice ; Peritoneal Fibrosis/pathology* ; Proto-Oncogene Proteins c-akt/metabolism* ; ErbB Receptors/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Signal Transduction/drug effects* ; Male ; Humans ; Molecular Docking Simulation ; Cell Line ; Mice, Inbred C57BL

Stem-leaf saponins from Panax notoginseng (SLSP) comprise numerous PPD-type saponins with diverse pharmacological properties; however, their role in Parkinson's disease (PD), characterized by microglia-mediated neuroinflammation, remains unclear. This study evaluated the effects of SLSP on suppressing microglia-driven neuroinflammation in experimental PD models, including the 1-methyl-4-phenylpyridinium (MPTP)-induced mouse model and lipopolysaccharide (LPS)-stimulated BV-2 microglia. Our findings revealed that SLSP mitigated behavioral impairments and excessive microglial activation in models of PD, including MPTP-treated mice. Additionally, SLSP inhibited the upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2) and attenuated the phosphorylation of PI3K, protein kinase B (AKT), nuclear factor-κB (NFκB), and inhibitor of NFκB protein α (IκBα) both in vivo and in vitro. Moreover, SLSP suppressed the production of inflammatory markers such as interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α) in LPS-stimulated BV-2 cells. Notably, the P2Y2R agonist partially reversed the inhibitory effects of SLSP in LPS-treated BV-2 cells. These results suggest that SLSP inhibit microglia-mediated neuroinflammation in experimental PD models, likely through the P2Y2R/PI3K/AKT/NFκB signaling pathway. These novel findings indicate that SLSP may offer therapeutic potential for PD by attenuating microglia-mediated neuroinflammation.
Animals ; Panax notoginseng/chemistry* ; Saponins/pharmacology* ; Microglia/immunology* ; Mice ; NF-kappa B/immunology* ; Signal Transduction/drug effects* ; Proto-Oncogene Proteins c-akt/immunology* ; Phosphatidylinositol 3-Kinases/genetics* ; Male ; Parkinson Disease/immunology* ; Mice, Inbred C57BL ; Disease Models, Animal ; Plant Leaves/chemistry* ; Neuroinflammatory Diseases/drug therapy* ; Humans

Aralia taibaiensi, widely distributed in western China, particularly in the Qinba Mountains, has been utilized as a folk medicine for treating diabetes, gastropathy, rheumatism, and cardiovascular diseases. Saponins from A. taibaiensis (sAT) have demonstrated protective effects against oxidative stress and mitochondrial dysfunction induced by ischemia/reperfusion (I/R). However, the underlying mechanisms remain unclear. In vivo, middle cerebral artery occlusion/reperfusion (MCAO/R) induced inflammatory infiltration, neuronal injury, cell apoptosis, mitochondrial dysfunction, and oxidative stress in the ischaemic penumbra, which were effectively mitigated by sAT. sAT increased the mRNA and protein expression levels of apelin and its receptor apelin/apelin receptors (ARs) both in vivo and in vitro. (Ala13)-Apelin-13 (F13A) and small interfering RNA (siRNA) abolished the regulatory effects of sAT on neuroprotection mediated by adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/protein kinase B (Akt). Furthermore, sAT induced apelin/AR expression by simultaneously inhibiting P38 mitogen-activated protein kinase (P38 MAPK)/activating transcription factor 4 (ATF4) and upregulating hypoxia-inducible factor-1α (HIF-1α). Our findings indicate that sAT regulates apelin/AR/AMPK by inhibiting P38 MAPK/ATF4 and upregulating HIF-1a, thereby suppressing oxidative stress and mitochondrial dysfunction.
Animals ; Reperfusion Injury/prevention & control* ; Aralia/chemistry* ; Saponins/administration & dosage* ; AMP-Activated Protein Kinases/genetics* ; Male ; Apelin/genetics* ; Signal Transduction/drug effects* ; Neuroprotective Agents/administration & dosage* ; Brain Ischemia/genetics* ; Rats, Sprague-Dawley ; Rats ; Oxidative Stress/drug effects* ; Apelin Receptors/genetics* ; Humans ; Apoptosis/drug effects* ; Mice

Osteosarcoma (OS) is the most prevalent primary malignant bone tumor affecting children and adolescents. Despite ongoing research efforts, the 5-year survival rate has remained stagnant for many years, highlighting the critical need for novel drug development to enhance current treatment protocols. Ziyuglycoside II (ZYG II), a triterpenoid saponin extracted from S. officinalis, has recently demonstrated antitumor properties. This study evaluates the antitumor effect of ZYG II on osteosarcoma and elucidates its mechanism of action through the co-regulation of p53 and estrogen-related receptor gamma (ESRRG), which inhibits disease progression. The research employs in vitro experiments using multiple established osteosarcoma cell lines, as well as in vivo studies utilizing a nude mouse model of orthotopic xenograft osteosarcoma. Additionally, ESRRG shRNA was used to construct stable ESRRG-reducing OS cell lines to investigate the molecular mechanism by which ZYG II exerts its anti-osteosarcoma effects through the co-regulation of ESRRG and p53. Results indicate that ZYG II administration led to decreased OS cell viability and reduced tumor volumes. Furthermore, cell cycles were arrested at the G₀/G₁ phase, while the proportion of apoptotic cells increased. Expression of p53, ESRRG, p21, Bax, Cleaved Caspase-9, and Cleaved Caspase-3 proteins increased, while expression of CDK4, Cyclin D1, and Bcl-2 proteins decreased. Multiple ZYG II and ESRRG docking patterns were simulated through molecular docking. Comparing the pharmacodynamic response of ZYG II to OS cell lines with reduced ESRRG and normal expression demonstrated that ZYG II inhibits osteosarcoma progression, induces cell cycle arrest, and promotes cell apoptosis through the coordination of p53 and ESRRG. In conclusion, ZYG II inhibits osteosarcoma progression, leads to cell cycle arrest, and promotes cell apoptosis through synergistic regulation of p53 and ESRRG.
Osteosarcoma/physiopathology* ; Tumor Suppressor Protein p53/genetics* ; Humans ; Animals ; Saponins/chemistry* ; Bone Neoplasms/physiopathology* ; Signal Transduction/drug effects* ; Cell Line, Tumor ; Mice, Nude ; Mice ; Apoptosis/drug effects* ; Receptors, Estrogen/genetics* ; Mice, Inbred BALB C ; Female ; Male ; Xenograft Model Antitumor Assays

Fibrosis is characterized as an aberrant reparative process involving the direct replacement of damaged or deceased cells with connective tissue, leading to progressive architectural remodeling across various tissues and organs. This condition imposes a substantial burden, resulting in considerable morbidity and mortality. Ginseng (Panax ginseng C. A. Meyer), renowned for its medicinal properties, has been incorporated as a key component in Chinese patent medicines to mitigate fibrotic diseases. Ginsenosides, the primary bioactive compounds in ginseng, have garnered significant attention. Over the past five years, extensive research has explored the pharmaceutical potential of ginsenosides in diverse organ fibrosis conditions, including liver, myocardial, renal, and pulmonary fibrosis. Studies have elucidated that ginsenosides demonstrate potential effects on inflammatory responses stemming from parenchymal cell damage, myofibroblast activation leading to extracellular matrix (ECM) production, and myofibroblast apoptosis or inactivation. Additionally, potential downstream targets and pathways associated with these pathological processes have been identified as being influenced by ginsenosides. This review presents a comprehensive overview of the efficacious treatments utilizing ginsenosides for various tissue fibrosis types and their potential anti-fibrotic mechanisms. Furthermore, it offers a reference for the development of novel candidate drugs for future organ fibrosis therapies.
Ginsenosides/pharmacology* ; Humans ; Fibrosis/drug therapy* ; Animals ; Panax/chemistry* ; Drugs, Chinese Herbal/therapeutic use*

Saponins associated with Panax notoginseng (P. notoginseng) demonstrate significant therapeutic efficacy across multiple diseases. However, certain high-yield saponins face limited clinical applications due to their reduced pharmacological efficacy. This study synthesized and evaluated 36 saponin-1,2,3-triazole derivatives of ginsenosides Rg1/Rb1 and notoginsenoside R1 for anti-adipogenesis activity in vitro. The research revealed that the ginsenosides Rg1-1,2,3-triazole derivative a17 demonstrates superior adipogenesis inhibitory effects. Structure-activity relationships (SARs) analysis indicates that incorporating an amidyl-substituted 1,2,3-triazole into the saponin side chain via Click reaction enhances anti-adipogenesis activity. Additionally, several other derivatives exhibit general adipogenesis inhibition. Compound a17 demonstrated enhanced potency compared to the parent ginsenoside Rg1. Mechanistic investigations revealed that a17 exhibits dose-dependent inhibition of adipogenesis in vitro, accompanied by decreased expression of preadipocytes. Peroxisome proliferator-activated receptor γ (PPARγ), fatty acid synthase (FAS), and fatty acid binding protein 4 (FABP4) adipogenesis regulators. These findings establish the ginsenoside Rg1-1,2,3-triazole derivative a17 as a promising adipocyte differentiation inhibitor and potential therapeutic agent for obesity and associated metabolic disorders. This research provides a foundation for developing effective therapeutic approaches for various metabolic syndromes.
Adipogenesis/drug effects* ; Triazoles/chemical synthesis* ; Ginsenosides/chemical synthesis* ; Saponins/chemical synthesis* ; Animals ; Mice ; Structure-Activity Relationship ; PPAR gamma/genetics* ; 3T3-L1 Cells ; Adipocytes/metabolism* ; Panax notoginseng/chemistry* ; Drug Design ; Molecular Structure ; Humans ; Cell Differentiation/drug effects* ; Fatty Acid-Binding Proteins/genetics*

Coptis chinensis Franch. and Panax ginseng C. A. Mey. are traditional herbal medicines with millennia of documented use and broad therapeutic applications, including anti-diabetic properties. However, the synergistic effect of total alkaloids from Coptis chinensis and total ginsenosides from Panax ginseng on type 2 diabetes mellitus (T2DM) and its underlying mechanism remain unclear. The research demonstrated that the optimal ratio of total alkaloids from Coptis chinensis and total ginsenosides from Panax ginseng was 4∶1, exhibiting maximal efficacy in improving insulin resistance and gluconeogenesis in primary mouse hepatocytes. This combination demonstrated significant synergistic effects in improving glucose tolerance, reducing fasting blood glucose (FBG), the weight ratio of epididymal white adipose tissue (eWAT), and the homeostasis model assessment of insulin resistance (HOMA-IR) in leptin receptor-deficient (db/db) mice. Subsequently, a T2DM liver-specific network was constructed based on RNA sequencing (RNA-seq) experiments and public databases by integrating transcriptional properties of disease-associated proteins and protein-protein interactions (PPIs). The network recovery index (NRI) score of the combined treatment group with a 4∶1 ratio exceeded that of groups treated with individual components. The research identified that activated adenosine 5'-monophosphate-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) signaling in the liver played a crucial role in the synergistic treatment of T2DM, as verified by western blot experiment in db/db mice. These findings demonstrate that the 4∶1 combination of total alkaloids from Coptis chinensis and total ginsenosides from Panax ginseng significantly improves insulin resistance and glucose and lipid metabolism disorders in db/db mice, surpassing the efficacy of individual treatments. The synergistic mechanism correlates with enhanced AMPK/ACC signaling pathway activity.
Animals ; Panax/chemistry* ; Ginsenosides/administration & dosage* ; Diabetes Mellitus, Type 2/metabolism* ; Mice ; Male ; Alkaloids/pharmacology* ; Coptis/chemistry* ; Drug Synergism ; Insulin Resistance ; Mice, Inbred C57BL ; Humans ; Transcriptome/drug effects* ; Blood Glucose/metabolism* ; Hypoglycemic Agents/administration & dosage* ; Drugs, Chinese Herbal/administration & dosage* ; Hepatocytes/metabolism*

Cancer multidrug resistance (MDR) impairs the therapeutic efficacy of various chemotherapeutics. Novel approaches, particularly the development of MDR reversal agents, are critically needed to address this challenge. This study demonstrates that tenacissoside I (TI), a compound isolated from Marsdenia tenacissima (Roxb.) Wight et Arn, traditionally used in clinical practice as an ethnic medicine for cancer treatment, exhibits significant MDR reversal effects in ABCB1-mediated MDR cancer cells. TI reversed the resistance of SW620/AD300 and KBV200 cells to doxorubicin (DOX) and paclitaxel (PAC) by downregulating ABCB1 expression and reducing ABCB1 drug transport function. Mechanistically, protein arginine methyltransferase 1 (PRMT1), whose expression correlates with poor prognosis and shows positive association with both ABCB1 and EGFR expressions in tumor tissues, was differentially expressed in TI-treated SW620/AD300 cells. SW620/AD300 and KBV200 cells exhibited elevated levels of EGFR asymmetric dimethylarginine (aDMA) and enhanced PRMT1-EGFR interaction compared to their parental cells. Moreover, TI-induced PRMT1 downregulation impaired PRMT1-mediated aDMA of EGFR, PRMT1-EGFR interaction, and EGFR downstream signaling in SW620/AD300 and KBV200 cells. These effects were significantly reversed by PRMT1 overexpression. Additionally, TI demonstrated resistance reversal to PAC in xenograft models without detectable toxicities. This study establishes TI's MDR reversal effect in ABCB1-mediated MDR human cancer cells through inhibition of PRMT1-mediated aDMA of EGFR, suggesting TI's potential as an MDR modulator for improving chemotherapy outcomes.
Humans ; Protein-Arginine N-Methyltransferases/antagonists & inhibitors* ; Drug Resistance, Neoplasm/drug effects* ; ErbB Receptors/genetics* ; Animals ; Cell Line, Tumor ; Drug Resistance, Multiple/drug effects* ; Methylation/drug effects* ; Saponins/administration & dosage* ; Mice ; Mice, Nude ; Mice, Inbred BALB C ; ATP Binding Cassette Transporter, Subfamily B/genetics* ; Doxorubicin/pharmacology* ; Paclitaxel/pharmacology* ; Female ; Repressor Proteins

Astragali Radix (AR), a traditional Chinese medicine (TCM), has demonstrated therapeutic efficacy against various diseases, including cardiovascular conditions, over centuries of use. While doxorubicin serves as an effective chemotherapeutic agent against multiple cancers, its clinical application remains constrained by significant cardiotoxicity. Research has indicated that AR exhibits protective properties against doxorubicin-induced cardiomyopathy (DIC); however, the specific bioactive components and underlying mechanisms responsible for this therapeutic effect remain incompletely understood. This investigation seeks to identify the protective bioactive components in AR against DIC and elucidate their mechanisms of action. Through network medicine analysis, astragaloside IV (AsIV) and formononetin (FMT) were identified as potential cardioprotective agents from 129 AR components. In vitro experiments using H9c2 rat cardiomyocytes revealed that the AsIV-FMT combination (AFC) effectively reduced doxorubicin-induced cell death in a dose-dependent manner, with optimal efficacy at a 1∶2 ratio. In vivo, AFC enhanced survival rates and improved cardiac function in both acute and chronic DIC mouse models. Additionally, AFC demonstrated cardiac protection while maintaining doxorubicin's anti-cancer efficacy in a breast cancer mouse model. Lipidomic and metabolomics analyses revealed that AFC normalized doxorubicin-induced lipid profile alterations, particularly by reducing fatty acid accumulation. Gene knockdown studies and inhibitor experiments in H9c2 cells demonstrated that AsIV and FMT upregulated peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α) and PPARα, respectively, two key proteins involved in fatty acid metabolism. This research establishes AFC as a promising therapeutic approach for DIC, highlighting the significance of multi-target therapies derived from natural herbals in contemporary medicine.
Animals ; Doxorubicin/adverse effects* ; Saponins/administration & dosage* ; Isoflavones/pharmacology* ; Rats ; Cardiomyopathies/prevention & control* ; Mice ; Fatty Acids/metabolism* ; Myocytes, Cardiac/metabolism* ; Triterpenes/administration & dosage* ; Male ; Drugs, Chinese Herbal/administration & dosage* ; Humans ; Cardiotonic Agents/administration & dosage* ; Mice, Inbred C57BL ; Cell Line ; Astragalus Plant/chemistry* ; Astragalus propinquus

OBJECTIVES: To explore the promoting effect of ginsenoside Rb3 (Rb3) on osteogenesis in periodontitis environment, and to explain its mechanism. METHODS: Human periodontal ligament stem cells (hPDLSCs) were cultured by tissue block method and identified by flow cytometry. Cell counting kit-8 (CCK8) method and calcein acetoxymethyl ester/propidium iodide staining were used to detect the effect of Rb3 on the viability of hPDLSCs cells. In vitro cell experiments were divided into control group, 10 μg/mL lipopolysaccharides (LPS) group, 10 μg/mL LPS+100 μmol/L Rb3 group and 10 μg/mL LPS+200 μmol/L Rb3 group. Alkaline phosphatase (ALP) staining was used to detect the ALP activity of hPDLSCs in each group after osteogenesis induction. The expression of hPDLSCs interleukin-6 (IL-6), interleukin-8 (IL-8), runt-related transcription factor 2 (RUNX2) and transforming growth factor-β (TGF-β)genes in each group after osteogenesis was detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR) method. Western blot was used to detect the protein expression of hPDLSCs phosphorrylated extracellular signal-regulated kinase (p-ERK) in each group. Sprague-Dawley rats were randomly divided into the control group, ligation group and ligation+Rb3 group. The left molar-maxillary tissue was subjected to micro-computed tomography (micro-CT) scanning. After the scanning, the left molar-maxilla was made into periodontal tissue sections. Hematoxylin-eosin (HE) staining was used to detect the infiltration and loss of adhesion of inflammatory cells. Masson staining was used to detect the destruction of gingival collagen fibers. Immunofluorescence staining was used to detect the protein expression of RUNX2 and p-ERK. The expression of TGF-β in rat gingival tissue was detected by qRT-PCR. The protein expression of IL-6 in peripheral serum of rats was detected by enzyme-linked immunosorbent assay (ELISA). Flow cytometry was used to detect the proportion of Treg cells in rat heart blood. The experimental data were statistically analyzed by Graph Pad Prism10.1.2 software. RESULTS: Rb3 had no effect on the cell activity of hPDLSCs. The results of qRT-PCR and ALP staining showed that Rb3 could inhibit the gene expression of IL-6 and IL-8 in inflammatory hPDLSCs, promote TGF-β gene and promote the osteogenic differentiation of inflammatory hPDLSCs. Western blot showed that Rb3 inhibited the protein expression of inflammatory hPDLSCs p-ERK. The results from micro-CT, Masson staining, and HE staining demonstrated that Rb3 promotes alveolar bone formation in rats with periodontitis, while simultaneously inhibiting the destruction of periodontal fibrous tissue, reducing attachment loss, and suppressing inflammatory cell infiltration. The results of flow cytometry showed that Rb3 could promote the differentiation of Treg cells in peripheral blood of periodontitis rats. The results of ELISA and qRT-PCR showed that Rb3 could inhibit the protein expression of IL-6 and promote the gene expression of TGF-β in periodontitis rats. Immunofluorescence results showed that Rb3 could promote the protein expression of RUNX2 and inhibit the protein expression of p-ERK in periodontitis rats. CONCLUSIONS Rb3 can reduce the inflammatory reaction of periodontal tissues in periodontitis rats, and promote the osteogenic differentiation of hPDLSCs by regulating p-ERK pathways.
Animals ; Ginsenosides/pharmacology* ; Osteogenesis/drug effects* ; Periodontitis/metabolism* ; Rats ; Periodontal Ligament/cytology* ; Humans ; Core Binding Factor Alpha 1 Subunit/metabolism* ; Stem Cells/drug effects* ; Interleukin-6/metabolism* ; Rats, Sprague-Dawley ; Interleukin-8/metabolism* ; Cells, Cultured ; MAP Kinase Signaling System/drug effects* ; Transforming Growth Factor beta/metabolism* ; Signal Transduction ; Male ; Phosphorylation ; Lipopolysaccharides ; Extracellular Signal-Regulated MAP Kinases/metabolism* ; Alkaline Phosphatase/metabolism*