Gentamicin (GM) is a broad-spectrum antibiotic widely used for severe bacterial infections, but itis associated with acute nephrotoxicity. Ambrosia maritima L. is an annual herbaceous plant that has avariety of medicinal and antioxidant activities. Vitamin D3 is involved in a multitude of biological functions and essential antioxidant pathways. This study aims to investigate the protective effects of Damsissa (Ambrosia maritima) versus vitamin D3 against GM-induced nephrotoxicity using 72 male rats that were randomly divided into six groups: control, Damsissa (100 mg/kg/day), vitamin D3 (1000 IU/kg/day), GM(100 mg/kg/day for 7 days), GM + Damsissa, and GM + vitamin D3. Renal function, oxidative stress biomarkers (MDA, CAT, SOD, GSH), cytokine levels (IL-1β, IL-6, TNF-α, IL-4), and gene expression (Caspase-3, Keap1, PPARγ, Nrf2) were assessed. Histopathological and ultrastructural kidney analyses were conducted using H&E, Masson's trichrome, PCNA staining, and transmission electron microscopy. Blood samples were tested for renal and liver markers (creatinine, BUN, AST, ALT). Damsissa enhanced survival rates, returned the renal indices to near normal, and ameliorated pathological changes based on immunohistopathological and ultrastructural results. They further reduced pro-inflammatory cytokine production, optimized oxidative stress markers, and normalized gene expression levels. Both treatments exhibited abundant antioxidant and anti-inflammatory effects, which remarkably reduced GM-induced acute kidney injury. These results suggest that both Damsissa and vitamin D3 may exert protective effects against drug-induced nephrotoxicity.

Gestational diabetes mellitus (GDM) is a common metabolic complication during pregnancy that poses significant risks to both the pregnant woman and her fetus. Astragaloside IV (Ast IV) belongs to the class of triterpenoid saponins and exhibits important physiological roles in various aspects, including antidiabetic, antioxidant, and antiviral effects. The main objective of this study is to investigate the effects of Ast IV on trophoblast damage caused by high glucose (HG) and its underlying mechanism of action.

Cell viability was determined by the CCK8 assay. The levels of oxidative stress in cells were determined by lactate dehydrogenase (LDH), malondialdehyde (MDA), and reactive oxygen species (ROS) kits. Ferroptosis in cells was assessed by the iron content kit. Gene expression levels were detected by real-time quantitative reverse transcription PCR (qRT-PCR) and western blot. The protein stability of Forkhead box protein M1 (FOXM1) was determined by the cycloheximide (CHX) assay. The ubiquitination level of FOXM1 was detected by the immunoprecipitation assay.

Ast IV alleviated the inhibitory effect of HG on the proliferation of HTR-8/SVneo cells and reduced HG-induced oxidative stress and ferroptosis. Ast IV was able to decrease the ubiquitination of FOXM1, thereby ensuring the stability of its expression. The overexpression of FOXM1 significantly mitigated the inhibitory effect of HG on the viability of HTR-8/SVneo cells and concurrently decreased the occurrence of HG-induced oxidative stress and ferroptosis processes. Conversely, knockdown of FOXM1 diminished the protective effect of Ast IV on HTR-8/SVneo cells.

Ast IV ameliorates HG-induced trophoblast injury by modulating deubiquitination of FOXM1, which provides a new insight into the treatment of GDM.

Epidemiological evidence has shown that the regular ingestion of vegetables and fruits is associated with reduced risk of developing chronic diseases. The introduction of the 3Rs (replacement, reduction, and refinement) principle into animal experiments has led to the use of valid, cost-effective, and efficient alternative and complementary invertebrate animal models which are simpler and lower in the phylogenetic hierarchy. Caenorhabditis elegans (C. elegans), a nematode with a much simpler anatomy and physiology compared to mammals, share similarities with humans at the cellular and molecular levels, thus making it a valid model organism in neurotoxicology. This review explores the versatility of C. elegans in elucidating the neuroprotective mechanisms elicited by food bioactive compounds against neurotoxic effects of food- and environmental-related contaminants. Several signaling pathways linked to the molecular basis of neuroprotection exerted by bioactive compounds in chemically induced or transgenic C. elegans models of neurodegenerative diseases are also discussed. Specifically, the modulatory effects of bioactive compounds on the DAF-16/FoxO and SKN-1/Nrf2 signaling pathways, stress resistance- and autophagy-related genes, and antioxidant defense enzyme activities were highlighted. Altogether, C. elegans represent a valuable model in nutritional neuroscience for the identification of promising neuroprotective agents and neurotherapeutic targets which could help in overcoming the limitations of current therapeutic agents for neurotoxicity and neurodegenerative diseases.

Intestinal ischemia-reperfusion injury (II/RI) is a critical acute condition characterized by complex pathological mechanisms, including various modes of cell death. Among these, pyroptosis has garnered significant attention in recent years. This review explores the characteristics, molecular mechanisms, and implications of pyroptosis in II/RI, with a focus on therapeutic strategies targeting the pyroptosis pathway. Key processes such as NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation, caspase-1 activation, and gasdermin D (GSDMD)-mediated membrane pore formation are identified as central to pyroptosis. Compounds like MCC950, CY-09, metformin, and curcumin have shown promise in attenuating II/RI in preclinical studies by modulating these pathways. However, challenges remain in understanding non-canonical pyroptosis pathways, unraveling the exact mechanisms of GSDMD-induced pore formation, and translating these findings into clinical applications. Addressing these gaps will be crucial for developing innovative and effective treatments for II/RI.

Diabetic encephalopathy (DE) is a neurological complication caused by diabetes mellitus, and its underlying mechanism has not been fully clarified. Astragaloside IV (AS-IV) has been demonstrated to have treatment effects on multiple neurologic diseases. The objective of this research is to explore the role and underlying mechanism of AS-IV in the treatment of DE, utilizing the methods of network pharmacology and experimental validation.

Multiple public databases were used to search for the targets of AS-IV. Gene Expression Omnibus (GEO) dataset (GSE16135) was analyzed to identify differentially expressed genes (DEGs) in DE. The Venn diagram was employed to determine the intersecting genes. These genes were considered potential therapeutic targets of AS-IV in DE and were annotated using bioinformatics techniques. Subsequently, a protein-protein interaction (PPI) network was constructed utilizing Cytoscape software to identify the core targets of action. Additionally, molecular docking was conducted to validate the binding affinity of AS-IV to the main targets. Finally, we validated the predictive outcomes of network pharmacology in a DE rat model induced by intraperitoneal injection of streptozotocin (STZ).

Through the application of network pharmacology and bioinformatics analyses, we discovered the top two hub targets (EGFR and JAK2). Subsequent molecular docking analysis showed that AS-IV was precisely located within the binding sites of both EGFR and JAK2, with binding energies of -8.18 kJ/mol and -10.94 kJ/mol, respectively. Behavioral experiments demonstrated that the treated rats showed improvements in cognitive impairment. Following AS-IV treatment, there was a significant reduction in amyloid-β (Aβ) plaques deposition and neurofibrillary tangles in the hippocampal tissue of DE rats. Furthermore, TUNEL staining and Western blot analyses demonstrated that AS-IV suppressed neuronal apoptosis and inhibited the activation of the EGFR/JAK2/STAT3 signaling pathway.

These results demonstrated that the AS-IV has the potential to improve cognitive impairment in DE rats by mitigating neuronal apoptosis through the EGFR/JAK2/STAT3 signaling pathway, which provides important implications for the treatment of DE.

Mesenchymal stem cells (MSCs) have the potential to differentiate into various cell types, providing important sources of cells for the development of regenerative medicine. Although MSCs have various advantages, there are also various problems, such as the low survival rate of transplanted cells and poor migration and homing; therefore, determining how to reform MSCs to improve their utilization is particularly important. Although many natural bioactive compounds have shown great potential for improving MSCs, many mechanisms and pathways are involved; however, in the final analysis, natural bioactive compounds promoted MSC proliferation, migration and homing and promoted differentiation and antiaging. This article reviews the regulatory effects of natural bioactive compounds on MSCs to provide new ideas for the therapeutic effects of modified MSCs on diseases.

Peritoneal dialysis (PD) is a successful renal replacement therapy for end-stage renal disease. Continuous infiltration of bioincompatible PD fluid causes mesothelial-mesenchymal transition (MMT) of peritoneal mesothelial cells (PMCs), leading to peritoneal fibrosis (PF). DNA methylation has been characterized as an important regulatory mechanism on multiple fibrosis. However, the mechanisms by which DNA methylation regulates PF are not fully understood resulting in a lack of disease-modifying drugs. Astragalus membranaceus (Astragalus) is naturally phytomedicine that has immunoregulation properties. The study aimed to elucidate the underlying mechanisms of Astragalus in regulating DNA methylation and anti-PF capabilities. In vivo PD rat models were established by inducing with high-glucose PD fluid and Astragalus was intraperitoneal injection. Global DNA methylation sequencing was used to compare the DNA methylation status between control and PF rat models. Methylation profiles and KEGG analysis were identified a possible methylated target gene and its correlation pathway. Through real-time PCR and western blotting, candidate markers and pathways were validated in vivo and in vitro. Chromatin immunoprecipitation and luciferase assays were used to identify the prediction of DNA methyltransferase (Dnmts) binding with methylated target gene. The functions of the validated pathways were further investigated using the knockdown or overexpression strategy. In vivo and in vitro, Astragalus treatment showed a protective effect against PF and Dnmts, characterized by improving pathological manifestation, ameliorating MMT markers, and reducing Dnmt1/3a proteins. Inhibitor of DNA-binding 2 (ID2) was investigated in target gene by integrating the mRNA and methylation profiles involved in PF and Astragalus treatment. PF induced the methylation of ID2 that resulted in recruitment of the Dnmt3a and decreased ID2 expression. The increased ID2 expression in response to Astragalus is a consequence of demethylation in promoter. In addition, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway correlated with PF, knockdown or overexpression of ID2 regulated this pathway and MMT of PMCs. Astragalus ameliorated PF by targeting Dnmt3a mediated ID2 promoter via PI3K/Akt signaling pathway. The epigenetic regulation of DNA methylation existed the critical role in attenuating PF.

Inflammation is a protective mechanism that also starts the healing process. However, inflammatory reaction may cause severe tissue damage. The increased influx of phagocytic leukocytes may produce excessive amount of reactive oxygen species, which leads to additional cell injury. Inflammatory response activates the leukocytes and thus induces tissue damage and prolongs inflammation. The inflammation-induced activation of the complement system may also contribute to cell injury. Non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids are chief agents for treating inflammation associated with the diseases. However, the unwanted side effects of NSAIDs (e.g., gastrointestinal disturbances, skin reactions, adverse renal effects, cardiovascular side effects) and glucocorticoids (e.g., suppression of immune system, Cushing's syndrome, osteoporosis, hyperglycemia) limit their use in patients. Natural herbs are important sources of anti-inflammatory drugs. The ingredients extracted from natural herbs display anti-inflammatory effects to work through multiple pathways with lower risk of adverse reaction. At present, the main anti-inflammatory natural agents include saponins, flavonoids, alkaloids, polysaccharides, and so on. The present article will review the anti-inflammatory effects of saponins including escin, ginsenosides, glycyrrhizin, astragaloside, Panax notoginseng saponins, saikosaponin, platycodin, timosaponin, ophiopogonin D, dioscin, senegenin.

Civilization diseases are a growing and global health problem in modern societies. Neurological disorders, cancer, and inflammatory diseases affect a large group of patients around the world. Therefore, it is of utmost importance to search for novel drugs, lifestyle tips, and foods that can help restore balance in the living organism, promote the efficiency of the immune system, and provide satisfactory prophylactic measures. Astragaloside IV (ASIV)-a triterpenoid saponin from Astragalus species, one of the world's most widely used herbs-has been shown to have a variety of biological properties, including anti-inflammatory, antioxidant, antitumor, and neuroprotective effects. In recent years, the number of in vivo studies on this active ingredient in the scientific literature has increased considerably. The aim of this review was therefore to compile the existing knowledge on the use of this compound in the treatment of selected diseases of civilization-cancer, neurological disorders, and inflammatory diseases-in vivo.

As a highly prevalent gastrointestinal malignant tumor, colorectal cancer poses a serious challenge in terms of increasing morbidity and mortality and late diagnosis due to the invisibility of the disease. Although existing therapies are diverse but limited in efficacy, the mechanism of programmed cell death (PCD) has become a focus of research due to its central role in maintaining body homeostasis and regulating tumor progression. Multimodal cell death pathways, such as apoptosis, autophagy, pyroptosis and ferroptosis, have shown unique advantages in inhibiting the proliferation and migration of colorectal cancer cells and enhancing the sensitivity to chemotherapy by responding to internal and external environmental stimuli. In recent years, natural products have risen to prominence by virtue of their multi-target synergistic effects and chemo-sensitizing properties, and have opened up a new direction for colorectal cancer treatment by precisely regulating the PCD pathway. In this paper, we searched PubMed, Web of Science and CNKI databases for relevant studies in the last 10 years using the keywords (Colorectal cancer) and (programmed cell death) and natural products. This work retrieved 59 studies (55 from the past 5 years and 4 from the past 10 years) to reveal the mechanism of action of natural products targeting PCD, aiming to provide theoretical support and practical guidance for the optimization of clinical therapeutic strategies and the development of innovative drugs.

Astragaloside IV (C41H68O14, AS-IV) is a naturally occurring saponin isolated from the root of Astragalus membranaceus, a widely used traditional Chinese botanical drug in medicine. In recent years, AS-IV has attracted considerable attention for its hepatoprotective properties, which are attributed to its low toxicity as well as its anti-inflammatory, antioxidant and antitumour effects. Numerous preclinical studies have demonstrated its potential in the prevention and treatment of various liver diseases, including multifactorial liver injury, metabolic-associated fatty liver disease, liver fibrosis and liver cancer. Given the promising hepatoprotective potential of AS-IV and the growing interest in its research, this review provides a comprehensive summary of the current state of research on the hepatoprotective effects of AS-IV, based on literature available in databases such as CNKI, PubMed, ScienceDirect, Google Scholar and Web of Science. The hepatoprotective mechanisms of AS-IV are multifaceted, encompassing the inhibition of inflammatory responses, reduction of oxidative stress, improvement of insulin and leptin resistance, modulation of the gut microbiota, suppression of hepatocellular carcinoma cell proliferation and induction of tumour cell apoptosis. Notably, key molecular pathways involved in these effects include Nrf2/HO-1, NF-κB, NLRP3/Caspase-1, JNK/c-Jun/AP-1, PPARα/FSP1 and Akt/GSK-3β/β-catenin. Toxicity studies indicate that AS-IV has a high level of safety. In addition, this review discusses the sources, physicochemical properties, and current challenges in the development and clinical application of AS-IV, providing valuable insights into its potential as a hepatoprotective agent in the pharmaceutical and nutraceutical industries.

Arrhythmia, a common cardiovascular disorder, results from disturbances in cardiac impulse generation and conduction, leading to decreased cardiac output and myocardial oxygenation, with potentially life-threatening consequences. Despite advancements in therapeutic approaches, the incidence and mortality associated with arrhythmia remain high, and drug-related adverse effects continue to pose significant challenges. Traditional Chinese Medicine (TCM) has attracted considerable attention for its potential as a complementary and alternative approach in treating cardiovascular diseases, including arrhythmia. Astragalus, a prominent herb in TCM, is commonly used in clinical practice for its multi-faceted therapeutic properties, encompassing anti-arrhythmic, cardiotonic, anti-inflammatory, and immunomodulatory effects. Astragaloside IV, a primary active compound in Astragalus membranaceus, has demonstrated cardioprotective effects through mechanisms such as antioxidant, anti-inflammatory, and anti-apoptotic activities. Although evidence suggests that astragaloside IV holds promise in arrhythmia treatment, comprehensive reviews of its specific mechanisms and clinical applications in arrhythmia are scarce. This review systematically explores the pharmacological properties and underlying mechanisms of astragaloside IV in arrhythmia treatment. Utilizing a targeted search of databases including PubMed, Web of Science, Cochrane Library, Embase, CNKI, and Wanfang Data, we summarize recent findings and examine astragaloside IV's potential applications in arrhythmia prevention and treatment. Our analysis aims to provide a theoretical foundation for the development of novel arrhythmia treatment strategies, while offering insights into future research directions for clinical application.

Astragaloside IV (AS-IV) is one of the most potent components of Astragalus. It has been reported to promote bone formation and inhibit osteoclastogenesis, suggesting its potential as a candidate for the prevention and treatment of postmenopausal osteoporosis (PMOP). The gut microbiota may play a crucial role in mediating the effects of AS-IV.

To investigate the impact of gut microbiota on the efficacy of AS-IV in treating PMOP.

Mice were randomly divided into three groups: Sham, ovariectomy (OVX), and AS-IV-treated OVX group (80 mg/kg). Bone loss was evaluated using Micro-CT and histopathology. Immunohistochemistry assessed specific bone markers. Inflammatory levels were measured by enzyme-linked immunosorbent assay (ELISA). Intestinal barrier function was examined via colonic histopathology and immunohistochemistry. Gut microbiota composition was analyzed by 16S rDNA sequencing, while metabolomic profiling identified key metabolites. Correlation analysis was performed to explore relationships between differential bacteria, key metabolites, and bone loss.

AS-IV improved the femur microarchitecture and modulated bone turnover in OVX mice. AS-IV treatment strengthened the intestinal barrier function and decreased gut permeability. This compound reduced colonic oxidative stress and serum and bone marrow inflammatory cytokine production. 16S rDNA sequencing revealed that AS-IV modulated the gut microbiota composition, while metabolomic analysis showed its effects on pathways related to hormone biosynthesis, D-amino acid metabolism, and galactose metabolism.

This study provides new insights into the use of AS-IV for treating PMOP, highlighting the gut microbiota and its metabolites as key regulatory factors in AS-IV's therapeutic effects.

Astragaloside IV (AS-IV), a major bioactive component of Astragalus membranaceus, exhibits anti-cancer and anti-inflammatory properties. However, its precise role in nasopharyngeal carcinoma (NPC) remains unclear. This study investigated the effects of AS-IV on NPC progression and its relationship with Special AT-rich binding protein-2 (SATB2), a diagnostic marker for NPC. AS-IV treatment reduced NPC cell viability in a dose-dependent manner, as assessed by CCK-8 assays. Functional experiments, including transwell, immunofluorescence, and flow cytometry assays, demonstrated that AS-IV inhibited cell migration, invasion, and autophagy while promoting apoptosis. Western blot analysis showed that SATB2 expression was significantly elevated in NPC cells, particularly in C666-1 and HK-1 cells. Overexpression of SATB2 partially reversed AS-IV's inhibitory effects on NPC progression. Further analysis revealed that AS-IV suppressed the Wnt signaling pathway by downregulating SATB2 expression, while SATB2 overexpression restored Wnt pathway activation. This effect was reversed upon treatment with the Wnt pathway inhibitor DKK-1. In vivo, AS-IV administration inhibited tumor growth in a nude mouse subcutaneous xenograft model, reduced Ki-67 positivity, and lowered LC3B expression, indicating decreased proliferation and autophagy. However, these effects were diminished upon SATB2 overexpression. These findings suggest that AS-IV exerts anti-tumor effects in NPC by downregulating SATB2 and suppressing Wnt pathway activation, highlighting its potential as a therapeutic agent for NPC.

Astragaloside IV (AS-IV) reduces nasopharyngeal carcinoma (NPC) cell vitality, suppresses cell migration, invasion and autophagy, and fosters apoptosis.SATB2 exhibits notably high levels in NPC cells.Overexpression of SATB2 counteracts the inhibition of NPC malignant progression by AS-IV.AS-IV impedes NPC progression by decreasing SATB2 and thereby hindering the Wnt pathway.AS-IV deters NPC tumor growth in nude mice.

Peripheral nerve injury is common clinically and can lead to neuronal degeneration and atrophy and fibrosis of the target muscle. The molecular mechanisms of muscle atrophy induced by denervation are complex and not fully understood. Inflammation and oxidative stress play an important triggering role in denervated muscle atrophy. Astragaloside IV (ASIV), a monomeric compound purified from astragalus membranaceus, has antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effect of ASIV on denervated muscle atrophy and its molecular mechanism, so as to provide a new potential therapeutic target for the prevention and treatment of denervated muscle atrophy. In this study, an ICR mouse model of muscle atrophy was generated through sciatic nerve dissection. We found that ASIV significantly inhibited the reduction of tibialis anterior muscle mass and muscle fiber cross-sectional area in denervated mice, reducing ROS and oxidative stress-related protein levels. Furthermore, ASIV inhibits the increase in inflammation-associated proteins and infiltration of inflammatory cells, protecting the denervated microvessels in skeletal muscle. We also found that ASIV reduced the expression levels of MAFbx, MuRF1 and FoxO3a, while decreasing the expression levels of autophagy-related proteins, it inhibited the activation of ubiquitin-proteasome and autophagy-lysosome hydrolysis systems and the slow-to-fast myofiber shift. Our results show that ASIV inhibits oxidative stress and inflammatory responses in skeletal muscle due to denervation, inhibits mitophagy and proteolysis, improves microvascular circulation and reverses the transition of muscle fiber types; Therefore, the process of skeletal muscle atrophy caused by denervation can be effectively delayed.

Natural products and their derivatives are precious resources with extensive applications in various industrial fields. Enzymatic glycosylation is an efficient approach for chemical structure diversification and biological activity alternation of natural products. Herein, we reported a stereoselective glycosylation of complex natural product glycosides catalyzed by two carbohydrate-active enzymes (CAZys). ASP OleD, a mutant of glycosyltransferase OleD from Streptomyces antibioticus, catalyzed an explicit β-1,x-linkage glycosylation of the OH group of the glycosyl moiety of the representative plant-derived complex natural product glycosides, protodioscin (1) and epimedin C (2), producing two complex glycoside derivatives. The glycoside hydrolase Δ27ThCGT, a truncated cyclodextrin glucanotransferase from Thermoanaerobacter sp., exhibited a definite α-1,x-linkage glycosylation of the OH group of the glycosyl moiety of the glycosides 1, 2, and astragaloside IV (3), generating four complex glycoside derivatives. The chemical structures and absolute configurations of these enzymatic glycosylation products were determined by analysis of their HRMS and NMR data. The present study expands the enzymatic glycosylation diversification of complex glycosides catalyzed by the CAZys.

Atherosclerosis (AS) is a major contributor to cardiovascular diseases, characterized by high morbidity and mortality rates. Long non-coding RNAs (LncRNAs), as members of non-protein coding RNAs, play a crucial role in various biological processes that maintain homeostasis and influence disease progression. Research indicates that lncRNAs are involved in the pathogenesis of AS.

In this study, we aim to explore the role of lncRNAs in the pathogenesis of AS and the latest progress in the prevention and treatment of AS by targeted regulation of lncRNAs by traditional Chinese medicine (TCM), in order to provide more new beneficial targets for the treatment of AS and expand the application of TCM in the treatment of cardiovascular diseases.

The literature was retrieved, analyzed, and collected using PubMed, Web of Science, Sci-Hub, CNKI, Elsevier, ScienceDirect, SpringerLink, and Google Scholar. Search terms include "atherosclerosis", "traditional Chinese medicine", "natural products", "active ingredient", "lncRNAs", "herbal medicine", "cardiovascular diseases", "pharmacology", "toxicology", "clinical trials", etc., and several combinations of these keywords.

This study examines the primary mechanisms through which lncRNAs induce AS, such as dysfunction in endothelial cells, abnormal proliferation of vascular smooth muscle cells, cholesterol buildup in macrophages, formation of foam cells, inflammatory responses, and imbalances in lipid metabolism. Additionally, it summarizes 16 herbal monomers and 6 Chinese herbal compounds, along with an analysis of the toxicological aspects of TCM.

The study explores the existing approaches for modulating lncRNAs and emphasizes the significance and potential of herbal monomers, extracts, and formulations in this context.

Gastric ulcer (GU) is a prevalent gastrointestinal disorder impacting millions worldwide, with complex pathogenic mechanisms that may progress to severe illnesses. Conventional therapies relying on anti-secretory agents and antibiotics are constrained by drug abuse and increased bacterial resistance, highlighting the urgent need for safer therapeutic alternatives. Natural medicinal compounds, particularly triterpenoids derived from plants and herbs, have gained significant attention in recent years due to their favorable efficacy and reduced toxicity profiles. Emerging evidence indicates that triterpenoids exhibit potent anti-ulcer properties across various experimental models, modulating key pathways involved in inflammation, oxidative stress, apoptosis, and mucosal protection. Integrating current knowledge of these bioactive compounds facilitates the development of natural triterpenoids, addresses challenges in their clinical translation, deepens mechanistic understanding of GU pathogenesis, and drives innovation of therapeutic strategies for GU. This review comprehensively evaluates the progress of research on triterpenoids in GU treatment since 2000, discussing their biological sources, structural characteristics, pharmacological activities, and mechanisms of action, the animal models employed in the studies, current limitations, and the challenges associated with their clinical application.

Autophagy is involved in the pathological changes of traumatic optic neuropathy (TON), and the regulation of autophagy mediated by the AMPK-mTOR-ULK pathway is a potential therapeutic approach. Astragaloside IV (AS-IV) can regulate autophagy and play a therapeutic role in various diseases. This study aimed to observe the therapeutic effect of astragaloside on TON and the role of AMPK-MTOR-ULK pathway-mediated autophagy in this process.

After the TON model was established, varying doses of AS-IV were administered as an intervention. Additionally, compound C (an AMPK inhibitor) or 3-methyladenine (an autophagy inhibitor) was administered intraperitoneally in conjunction with AS-IV. Samples were collected following a 7-day intervention period. Western blot analysis was conducted to measure the protein and phosphorylation levels of AMPK, mTOR, and ULK proteins. Moreover, western blot and quantitative reverse transcription PCR assays were used to quantify LC3 levels in retinal tissue. LC3 immunofluorescence was performed to examine autophagy levels in the ganglion cell layer (GCL), while transmission electron microscopy was employed to observe autophagosomes. Additionally, BRN3A immunofluorescence was used to label retinal ganglion cells (RGCs) in the GCL, and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining was used to assess apoptosis within the GCL. Finally, optic nerve conduction function was evaluated using flash visual evoked potentials.

After 7 days, the phosphorylation levels of AMPK, mTOR, and ULK proteins in retinal tissue exhibited significant changes following TON. AS-IV treatment enhanced LC3 messenger RNA and protein levels in TON model rats, and the autophagy-promoting effect of AS-IV was reversed by 3-methyladenine. Moreover, AS-IV elevated P-AMPK and P-ULK levels while decreasing P-mTOR levels. AS-IV also improved the survival rate of RGCs and reduced the P2 peak latency of flash visual evoked potentials. These effects were attenuated by the AMPK inhibitor compound C. Additionally, AS-IV increased the levels of AKT1 and P-AKT1 while decreasing P-S6RP levels in the retinal tissue of TON model rats.

AS-IV can increase the survival rate of RGCs and improve visual function after TON, which may be related to the improvement of autophagy by regulating the AMPK-MTORC1-ULK pathway.

Angiotensin II (Ang II)-triggered endothelial inflammation is a critical mechanism contributing to Ang II-related cardiovascular diseases. The inflammation is highly correlated with mitochondrial function. Although astragaloside IV (AS-IV), a primary bioactive ingredient extracted from the traditional Chinese medicine Astragalus membranaceus Bunge that can effectively treat numerous cardiovascular diseases, posses the actions of antiinflammation and antioxidation in vivo, limited data are made available on the impacts of AS-IV on mitochondrial function in endothelial inflammation triggered by Ang II. This study was performed to evaluate the in vitro actions of AS-IV on Ang II-triggered inflammatory responses in endothelial cells, and to further clarify the potential role of mitochondria in the actions.

Human umbilical vein endothelial cells (HUVECs) were preincubated with AS-IV and then exposed to Ang II for 12 h.

The exposure of HUVECs to Ang II triggered cytokine and chemokine production, the upregulation of adhesive molecules, monocyte attachment, and nuclear factor-kappa B activation. Additionally, our results showed that the inflammatory responses triggered by Ang II were associated with the impairment of mitochondrial function, as evidenced by the reductions of mitochondrial membrane potential, ATP synthesis, and mitochondrial complexes I and III activities. Moreover, the concentrations of malondialdehyde, cellular reactive oxygen species, and mitochondrial superoxide enhanced after HUVECs challenged with Ang II, which were concurrent with the decreases in total superoxide dismutase (SOD) and its isoenzyme activities such as Mn-SOD. These Ang II-induced alterations were reversed by preincubation with AS-IV.

Our data indicate that AS-IV attenuates Ang II-triggered endothelial inflammation possibly via ameliorating mitochondrial function.

Hyperuricemia, a prevalent chronic metabolic disorder caused by purine metabolism disturbances, is characterized by elevated serum uric acid (UA) levels. Prolonged hyperuricemia can cause severe complications such as gout or kidney damage. However, the toxic side effects of and adverse reactions to UA-lowering drugs are becoming increasingly prominent. Therefore, new targets and drugs for hyperuricemia are needed.

This review aims to summarize recent research progress on the prevention and treatment mechanisms for gut microbiota-hyperuricemia from the perspective of plant-derived natural products.

Data from PubMed, Web of Science, ScienceDirect, and the CNKI databases spanning from January 2020 to December 2024 were reviewed. The aim of this study is to categorize and summarize the relevant mechanisms through which natural products improve hyperuricemia via the gut microbiota. The retrieved data followed PRISMA criteria (Preferred Reporting Items for Systematic reviews and Meta-Analyses).

Regulating gut microbiota as a treatment for hyperuricemia. Targeting the gut microbiota could reduce host UA levels by promoting purine degradation, reducing UA production, and increasing UA excretion. Moreover, the gut microbiota also exerts anti-inflammatory and antioxidant effects that alleviate complications such as renal damage caused by hyperuricemia. Due to their diverse sources, multicomponent synergy, multitarget effects, and minimal side effects, plant-derived natural products have been extensively utilized in the management of hyperuricemia. Especially, utilizing natural products from plants to regulate the gut microbiota has become a new strategy for reducing UA levels.

This review comprehensively summarizes recent advances in understanding the preventive and therapeutic mechanisms of plant-derived natural products in ameliorating hyperuricemia and its comorbidities through gut microbiota modulation. This review contributes a novel perspective for the development of safer and more efficacious UA-lowering products.

Doxorubicin (DOX) is a principal chemotherapeutic agent in the domain of oncological intervention. However, its clinical application is constrained due to its severe and irreversible side effects, particularly heart damage. Ferroptosis, characterized by iron accumulation and redox system imbalance, serves a key role in DOX‑induced cardiotoxicity. Ophiopogon japonicus polysaccharide (OJP) exhibits diverse pharmacological activities, including cardiovascular protection, and anti‑inflammatory, anti‑oxidative and immune regulatory effects. However, the role and mechanism of OJP in DOX‑mediated ferroptosis‑triggered injury in cardiomyocytes remain elusive. The present study aimed to assess the effect of OJP on DOX‑induced myocardial ferroptosis injury and to reveal its underlying anti‑ferroptosis mechanism. The detection of myocardial injury markers, such as LDH, indicated that OJP can ameliorate myocardial damage. Additionally, western blot analyses reveal that OJP decreases the expression levels of the ferroptosis‑related marker transferrin receptor 1 (TFR1) while simultaneously increasing expression levels of glutathione peroxidase 4 (GPX4) in a concentration‑dependent manner. Furthermore, fluorescence probe assays demonstrate that OJP not only reduces iron accumulation and oxidative stress but also inhibits the production of lipid peroxidation, as evidenced by a decrease in malondialdehyde (MDA) levels measured. In addition, OJP simultaneously decreased ferroptosis by enhancing mitochondrial function. Mechanistically, OJP attenuated ferroptosis by upregulating the endogenous key antioxidant factor nuclear factor erythroid 2‑related factor 2 (Nrf2), which in turn increased the expression of the downstream signaling molecule GPX4 and reduced the accumulation of the labile iron pool. Therefore, OJP may be a novel therapeutic intervention for DOX‑induced ferroptosis‑triggered myocardial injury.

Astragaloside IV (ATS) is an active component of Astragalus membranaceus, which has immune regulation and anti-inflammatory effects. However, owing to its large molecular weight and poor solubility in water, the therapeutic effects of ATS are limited. We aimed to prepare ATS-chitosan (ATS-CS) nanoparticles and determine their anti-inflammatory effect and mechanism of action on RAW264.7 cells using metabolomics. The size of the ATS-CS nanoparticles was 200.3 nm with a zeta potential of 30.5 mV, and the encapsulation rate and drug loading were 69% and 13%, respectively. ATS-CS nanoparticles not only significantly decreased the increase of nitric oxide, interleukin-6, and tumor necrosis factor-α levels induced by lipopolysaccharide, but also exerted an anti-inflammatory effect by acting on arginine and proline, glutathione, sphingolipid, glycerophospholipid, glycine, serine, and threonine metabolism. Our findings confirmed that ATS-CS nanoparticles had good anti-inflammatory activity and showed that the activity of high molecular weight could be increased by producing nanoparticles. Our study paves the way for exploring the mechanism of nanoparticles through metabolomics.

Acute hepatic injury (AHI) is associated with poor prognosis in sepsis patient; however, to date, no specific therapeutic approach has been established for this disease. Therefore, we aimed to explore the effects and action mechanisms of Astragaloside IV (AS) on AHI. C57BL/6 mice, RAW264.7 cells, and bone marrow-derived macrophages were used in this study. Sepsis-associated AHI model mice were established using lipopolysaccharide + D-galactosamine. Pathological examination of liver tissues and serum alanine aminotransferase/aspartate aminotransferase was performed to evaluate the liver function. Moreover, inflammatory cytokine levels, proportion of M1/M2 macrophages and their marker levels, and cell pyroptosis-related indicator levels were determined in the liver of the AHI model mice with or without AS treatment. AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) expression was determined after AS treatment. Additionally, inflammatory cytokine levels, liver injury, and macrophage polarization were evaluated after inhibiting the AMPK/SIRT1 pathway. AS alleviated lipopolysaccharide + D-galactosamine-induced AHI and inhibited inflammatory reactions in the blood and liver of mice. AS also promoted the M1-to-M2 phenotypic transformation of macrophages in the liver of AHI model mice and in vitro, thereby decreasing the pro-inflammatory cytokine levels and increasing the anti-inflammatory cytokine levels. AS increased AMPK and SIRT1 levels in the liver and macrophages. Furthermore, AS improved liver injury by elevating the expression of the AMPK/SIRT1 signaling pathway and inhibiting pyroptosis in macrophages. Overall, AS alleviated AHI by promoting M1-to-M2 macrophage transformation and inhibiting macrophage pyroptosis via activation of the AMPK/SIRT1 signaling pathway.

Atherosclerosis is a chronic inflammatory disease mainly characterized by the activation of endothelial cells and recruitment of macrophages, leading to plaque formation. Astragaloside IV (AS-IV), a natural saponin derived from Astragalus mongholicus Bunge, has been shown to confer protective effects against cardiovascular diseases.

The purpose of this study is to explore the role of AS-IV on atherosclerosis and the underlying mechanism.

Mice with atherosclerosis were administered with AS-IV by oral gavage. Atherosclerotic plaques and blood lipid profiles of these mice were assessed. Endothelial cell activation and macrophage infiltration were examined by immunofluorescent or immunohistochemical staining. The effects of AS-IV on endothelial cell activation, macrophage migration and adhesion were determined by transwell experiments, RT-qPCR, and Western blot.

Mice treated with AS-IV exhibited a dose-dependent reduction in atherosclerotic plaque size, with no concomitant change in blood lipid levels. It significantly suppressed endothelial cell activation and macrophage infiltration in the vasculature. AS-IV inhibited TNF-α-induced endothelial cell activation and macrophage migration and adhesion in vitro. Furthermore, AS-IV reduced the phosphorylation of key kinases in the MAPK pathways and their upstream regulator TAK1 in endothelial cells. The inhibitory effects of AS-IV on MAPK pathways and endothelial cell activation were counteracted by TAK1 deficiency or overexpression of TAK1. Molecular docking analysis suggested AS-IV binds to TAK1 with high affinity.

AS-IV exhibits anti-atherosclerotic effects by targeting TAK1 in endothelial cells, thereby inhibiting endothelial cell activation, and the subsequent adhesion and migration of macrophages, providing a prospective therapeutic strategy for the management of atherosclerosis.

The widely used Radix Astragali (RA) has significant therapeutic effects on cognitive impairment (CI) caused by type 2 diabetes (T2DM). However, the effective active ingredients and the precise mechanism underly RA alleviation of T2DM-induced CI still require further study. In this study, we aim to elucidate whether and how jaranol, a key effective active ingredient in RA, influences CI in db/db mice. We used various online databases and Cytoscape to screen jaranol as the most active ingredient of RA in the treatment of T2DM-induced CI. The fear conditioning experiment, new object recognition (NOR) test, and Morris water maze (MWM) test were conducted to assess the improvement effect of jaranol on CI in diabetic mice. The protein-protein interaction (PPI) network, Cytoscape, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to identify key genes. The levels of AKT and caspase-3 were determined by Western blotting. The number of surviving hippocampal neurons was verified through Nissl staining. AutoDock was utilized for predicting potential binding sites between jaranol and key genes.As a result, jaranol attenuated CI in db/db mice probably through activation of PI3K-AKT signaling pathway by inhibiting cell apoptosis in hippocampus. Furthermore, A329 near the active site of AKT1 had hydrogen bond with jaranol. In conclusion, we suggest that jaranol may have therapeutic applications in T2DM-induced CI by targeting the PI3K-AKT signaling pathway directly via key sites. Our study provides alternative drugs and potential therapeutic targets for the prevention and treatment of T2DM-induced CI.

Cerebral ischemia-reperfusion injury (CIRI) usually occurs during the treatment phase of ischemic disease, which is closely related to high morbidity and mortality. Promoting neurogenesis and synaptic plasticity are effective neural recovery strategies for CIRI. Astragaloside IV (AS-IV) has been shown to play a neuroprotective role in some neurological diseases. In the current study, we evaluated the effect and possible mechanism of AS-IV in CIRI rats.

The middle cerebral artery occlusion reperfusion (MCAO/R) model was established in rats to simulate the occurrence of human CIRI. First, we determined the cerebral injury on the 1st, 3rd, 5th and 7th day after cerebral ischemia-reperfusion (I/R) surgery by neurological deficit detection, TTC staining, TUNEL staining and Western blot analysis. Furthermore, rats were pre administered with AS-IV and then subjected to cerebral I/R surgery. Brains were collected on the 3rd day to evaluate the neuroprotective effect of AS-IV.

Our results showed that on the 3rd day after I/R, the neurological impairment score and infarct volume were highest, the levels of apoptosis and expression of Caspase3 and Bax reached the peak. AS-IV treatment apparently attenuated neurological dysfunction, reduced infarct volume and pathological damage, promoted the neurogenesis, and alleviated the pathological damage caused by cerebral I/R involved in thickening and blurring of synaptic membranes, reduction of microtubules and synaptic vesicles, and loss of synaptic cleft. Our study also showed that AS-IV promoted the transcription and expression of the peroxisome proliferators-activated receptors γ (PPARγ) and brain-derived neurotrophic factor (BDNF), increased the expression of phosphorylation of tyrosine kinase receptor B (TrkB) and downstream PI3K/Akt/mTOR pathway proteins. Notably, when GW9662, an inhibitor of PPARγ was administered with AS-IV, the neuroprotective effect of AS-IV was reduced.

These findings suggested that AS-IV has neuroprotective function in CIRI rats, and its molecular mechanism may depend on the phosphatidylinositide 3-kinase (PI3K)/protein kinase B (PKB)/Akt signalling pathway activated by PPARγ. AS-IV could be an effective therapeutic drug candidate for CIRI treatment.

Astragaloside IV (AS-IV) has been shown to have a curative effect on non-small cell lung cancer (NSCLC). This study aimed to elucidate the role of AS-IV in NSCLC cell anlotinib resistance (AR).

The NSCLC/AR cells, resistant to anlotinib, have been produced. The role of AS-IV in the AR of NSCLC cells about the miR-181a-3p/unfolded protein response (UPR)- endoplasmic reticulum associated degradation (ERAD) pathway was then discussed by treating the cells with anlotinib or AS-IV, or by manipulating them with inhibitors or mimics of miR- 181a-3p, HRD1 or Derlin-1 overexpression plasmids.

We found that AS-IV could suppress the AR of NSCLC cells. In addition, miR-181a- 3p was elevated in NSCLC/AR cells. Functionally, AS-IV limited the AR of NSCLC cells by reducing miR-181a-3p. Further, activation of the UPR-ERAD pathway was correlated with AR in NSCLC cells. Increased sensitivity of NSCLC cells to anlotinib caused by miR-181a-3p inhibitor could be reversed by overexpression of HRD1 or Derlin-1.

This research revealed a promising NSCLC/AR treatment approach by showing that AS-IV exposed NSCLC cells to anlotinib by inhibiting the miR-181a-3p/UPR-ERAD axis.

The term "Diabetic neuropathy" refers to a collection of clinical and subclinical symptoms caused by problems with the peripheral nervous system. Diabetes, which affects approximately 381 million people worldwide, is the source of dysfunction due to the emergence of microvascular complications. It is anticipated that in the next ten years, Diabetic neuropathy will manifest in about 50% of patients who are currently diagnosed with diabetes. Clinical diagnosis can be established by getting a thorough patient history and exploring the symptoms to rule out alternative causes. Although distal symmetrical polyneuropathy, or just, is the most common and well-researched variant of the disorder, this review will concentrate on it. The multifactorial pathogenesis is linked to various inflammatory, vascular, metabolic, and neurodegenerative illnesses. The three fundamental molecular alterations that lead to the development of diabetic neuropathic pain are oxidative stress, endothelial dysfunction, and chronic inflammation. These three elements are crucial in the development of polyneuropathy because their combination might result in direct axonal damage and nerve ischemia. The purpose of this article was to provide a narrative review of diabetic neuropathy. We provide an overview of the most recent data on biomarkers, the pathogenesis of the illness, the most recent epidemiology of diabetic neuropathy, and the existing screening and diagnosis outcome measures used in both clinical and research contexts.

Doxorubicin (DOX) is a chemotherapy drug widely used in clinical settings, acting as a first-line treatment for various malignant tumors. However, its use is greatly limited by the cardiotoxicity it induces, including doxorubicin-induced cardiomyopathy (DIC). The mechanisms behind DIC are not fully understood, but its potential biological mechanisms are thought to include oxidative stress, inflammation, energy metabolism disorders, mitochondrial damage, autophagy, apoptosis, and ferroptosis. Recent studies have shown that cardiac injury induced by DOX is closely related to ferroptosis. Due to their high efficacy, availability, and low side effects, natural medicine treatments hold strong clinical potential. Currently, natural medicines have been shown to mitigate DOX-induced ferroptosis and ease DIC through various functions such as antioxidation, iron ion homeostasis correction, lipid metabolism regulation, and mitochondrial function improvement. Therefore, this review summarizes the mechanisms of ferroptosis in DIC and the regulation by natural plant products, with the expectation of providing a reference for future research and development of inhibitors targeting ferroptosis in DIC. This review explores the mechanisms of ferroptosis in doxorubicin-induced cardiomyopathy (DIC) and summarizes how natural plant products can alleviate DIC by inhibiting ferroptosis through reducing oxidative stress, correcting iron ion homeostasis, regulating lipid metabolism, and improving mitochondrial function.

Chronic hyperglycemia in diabetes induces oxidative stress, leading to damage to the vascular system. In this study, we aimed to evaluate the effects and mechanisms of AS-IV-Exos in alleviating endothelial oxidative stress and dysfunction caused by high glucose (HG).

Histopathological changes were observed using HE staining, and CD31 expression was assessed through immunohistochemistry (IHC). Cell proliferation was evaluated through CCK8 and EDU assays. The levels of ROS, SOD, and GSH-Px in the skin tissues of each group were measured using ELISA. Cell adhesion, migration, and tube formation abilities were assessed using adhesion, Transwell, and tube formation experiments. ROS levels in HUVEC cells were measured using flow cytometry. The levels of miR-210 and Nox2 were determined through quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The expression of Nox2, SOD, GSH-Px, CD63, and CD81 was confirmed using WB.

The level of miR-210 was reduced in diabetes-induced skin damage, while the levels of Nox2 and ROS increased. Treatment with AS-IV increased the level of miR-210 in EPC-Exos. Compared to Exos, AS-IV-Exos significantly reduced the proliferation rate, adhesion number, migration speed, and tube-forming ability of HGdamaged HUVEC cells. AS-IV-Exos also significantly decreased the levels of SOD and GSH-Px in HG-treated HUVEC cells and reduced the levels of Nox2 and GSH-Px. However, ROS levels and Nox2 could reverse this effect.

AS-IV-Exos effectively alleviated endothelial oxidative stress and dysfunction induced by HG through the miR-210/Nox2/ROS pathway.

Astragalus membranaceus (AM) herb is a component of traditional Chinese medicine used to treat various cancers. Herein, we demonstrate a strong anti-leukemic effect of AM injected (Ai) into the mouse model of erythroleukemia induced by Friend virus. Chemical analysis combined with mass spectrometry of AM/Ai identified the compounds Betulinic acid, Kaempferol, Hederagenin, and formononetin, all major mediators of leukemia inhibition in culture and in vivo. Docking analysis demonstrated binding of these four compounds to FLI1, resulting in downregulation of its targets, induction of apoptosis, differentiation, and suppression of cell proliferation. Chemical composition analysis identified other compounds previously known having anti-tumor activity independent of the FLI1 blockade. Among these, Astragaloside-A (As-A) has marginal effect on cells in culture, but strongly inhibits leukemogenesis in vivo, likely through improvement of anti-tumor immunity. Indeed, both IDO1 and TDO2 were identified as targets of As-A, leading to suppression of tryptophane-mediated Kyn production and leukemia suppression. Moreover, As-A interacts with histamine decarboxylase (HDC), leading to suppression of anti-inflammatory genes TNF, IL1B/IL1A, TNFAIP3, and CXCR2, but not IL6. These results implicate HDC as a novel immune checkpoint mediator, induced in the tumor microenvironment to promote leukemia. Functional analysis of AM components may allow development of combination therapy with optimal anti-leukemia effect.

Astragalus mongholicus Bunge [Fabaceae; Astragali radix] (AM), a traditional Chinese medicinal (TCM) botanical drug, has been used for centuries and is gaining growing recognition in medical research for its therapeutic potential. The currently accepted scientific name is Astragalus mongholicus Bunge, with Astragalus membranaceus Fisch. ex Bunge recognized as a taxonomic synonym. This review explores the most relevant scientific studies on AM, focusing on its chemical composition, mechanisms of action, and associated health benefits.

AM is commonly used in clinical practice to treat diabetes mellitus, cardiovascular diseases, oncological processes, lipid metabolism disorders, and ulcerative colitis. Recent research has investigated its potential as a product for anti-aging purposes. These therapeutic effects are attributed to the interactions of bioactive metabolites such as Astragaloside IV, Formononetin, and polysaccharides, with various signaling pathways, leading to the activation or inhibition of gene expression. This review aims to map the signaling pathways affected by these metabolites and their effects on different pathologies. Studies suggest that these metabolites act on signaling pathways such as TLR4/MyD88/NF-κB, PI3K/AKT, RNA expression, and tumor receptors. However, further research is necessary to validate the findings in human trials with better methodological quality.

AM is rich in bioactive metabolites that interact with various signaling pathways, modulating diseases such as diabetes mellitus type 2, cardiovascular diseases, cancer, lipid metabolism disorders, and ulcerative colitis. Although promising, the majority of the studies are conducted in vitro and animal models, and more rigorous human trials are needed to determine the therapeutic potential of AM.

Cardiovascular diseases (CVDs) are major public health problems that threaten the lives and health of individuals. The article has reviewed recent progresses about ferroptosis and ferroptosis-related intervention approaches for the treatment of CVDs and provided more references and strategies for targeting ferroptosis to prevent and treat CVDs.

A comprehensive review was conducted using the literature researches.

Many ferroptosis-targeted compounds and ferroptosis-related genes may be prospective targets for treating CVDs and our review provides a solid foundation for further studies about the detailed pathological mechanisms of CVDs.

There are challenges and limitations about the translation of ferroptosis-targeted potential therapies from experimental research to clinical practice. It warrants further exploration to pursure safer and more effective ferroptosis-targeted thereapeutic approaches for CVDs.

Chronic stress affects intestinal microbiota. Astragaloside IV (AS), called super Astragalus polysaccharide, is a monomer component of traditional herbs Astragalus membranaceus which belongs to medicinal food homology (MFH), exerts a neuroprotection effect, but the underlying mechanism has not yet been elucidated. Intestinal flora is also involved in the biotransformation of the active ingredients of MFH species, thus affecting their physiological and pharmacological properties. In this study, we found that AS improved CUMS-induced cognitive impairment, inhibited neuroinflammation, and restored intestinal barrier damage, but the improvement was suppressed by the elimination of gut microbiota, suggesting a key regulatory role for the microbiota. The results of 16S rDNA sequencing showed that AS treatment significantly increased the relative abundance of Lactobacillus reuteri (L. reuteri) and Bacteroides acidifaciens. Furthermore, supplementation of L. reuteri rather than Lactobacillus plantarum restored the effect of AS-supplied dysbiosis mice via inhibition of inflammatory repose and the maintenance of the intestinal epithelial barrier, indicating that dietary AS requires L. reuteri to ameliorate cognitive injury. These findings provide evidence for new therapeutic strategies to treat chronic stress and support the role of specific bacteria in the intestinal environment that metabolizes the AS.

The pathogenesis of membranous nephropathy (MN) involves podocyte injury that is attributed to inflammatory responses induced by local immune deposits. Astragaloside IV (AS-IV) is known for its robust anti-inflammatory properties. Here, we investigated the effects of AS-IV on passive Heymann nephritis (PHN) rats and TNF-α-induced podocytes to determine the underlying molecular mechanisms of MN. Serum biochemical parameters, 24-h urine protein excretion and renal histopathology were evaluated in PHN and control rats. The expression of tumor necrosis factor receptor associated factor 6 (TRAF6), the phosphorylation of nuclear factor kappa B (p-NF-κB), the expression of associated proinflammatory cytokines (TNF-α, IL-6 and IL-1β) and the ubiquitination of TRAF6 were measured in PHN rats and TNF-α-induced podocytes. We detected a marked increase in mRNA expression of TNF-α, IL-6 and IL-1β and in the protein abundance of p-NF-κB and TRAF6 within the renal tissues of PHN rats and TNF-α-induced podocytes. Conversely, there was a reduction in the K48-linked ubiquitination of TRAF6. Additionally, AS-IV was effective in ameliorating serum creatinine, proteinuria, and renal histopathology in PHN rats. This effect was concomitant with the suppression of NF-κB pathway activation and decreased expression of TNF-α, IL-6, IL-1β and TRAF6. AS-IV decreased TRAF6 levels by promoting K48-linked ubiquitin conjugation to TRAF6, which triggered ubiquitin-mediated degradation. In summary, AS-IV averted renal impairment in PHN rats and TNF-α-induced podocytes, likely by modulating the inflammatory response through the TRAF6/NF-κB axis. Targeting TRAF6 holds therapeutic promise for managing MN.