Astragaloside IV Research Articles

Astragaloside IV ameliorate acute alcohol-induced liver injury in mice via modulating gut microbiota and regulating NLRP3/caspase-1 signaling pathway

Purpose Astragaloside IV (AS-IV) is a natural saponin substance extracted from the plant Radix Astragali with anti-inflammatory, antioxidant, anti-apoptotic, and liver-protecting effects. This study was to evaluate the liver protection effect of AS-IV on mice after acute alcohol stimulation. Materials and Methods Mice were orally administrated with AS-IV (50, 150, and 500 mg/kg, respectively), and sodium carboxymethyl cellulose (CMC, 50 mg/kg) daily for 7 days, before giving five alcohol-intragastric injections. Results Results suggested that the levels of serum ALT and AST, liver SOD, GSH-PX, 4-HNE, and MDA, serum and liver TNF-α, IL-1β, and IL-6, serum lipopolysaccharide (LPS), lipopolysaccharide binding protein (LBP), diamine oxidase (DAO) and Myeloperoxidase (MPO), the mRNA and protein expression of hepatic NLRP3, Caspase-1, IL-1β, and IL-18 were significantly decreased in AS-IV-treated mice compared with the model group. Moreover, the effect of AS-IV on histopathology of liver tissue confirmed its protective function. Furthermore, AS-IV ameliorated the gut microbiota imbalance and adjusted the abundance of the following dysfunctional bacteria closer to the control group: Butyricicoccus, Turicibacter, Akkermansia, Anaerotruncus, and Mucispirillum. A strong correlation between intestinal bacteria and potential biomarkers was found. Conclusion Together, our findings indicated that AS-IV exert the hepatoprotective effect by modulating the gut microbiota imbalance and regulating NLRP3/Caspase-1 signaling pathway.

Astragaloside IV ameliorates radiation-induced nerve cell damage by activating the BDNF/TrkB signaling pathway.

Radiation can induce nerve cell damage. Synapse connectivity and functionality are thought to be the essential foundation of all cognitive functions. Therefore, treating and preventing damage to synaptic structure and function is an urgent challenge. Astragaloside IV (AS-IV) is a glycoside extracted from Astragalus membranaceus (Fisch.). Bunge is a widely used traditional Chinese medicine in China with various pharmacological properties, including protective effects on the central nervous system (CNS). In this study, the effect of AS-IV on synapse damage and BDNF/TrkB signaling pathway in radiated C57BL/6 mice with X-rays was investigated. PC12 cells and primary cortical neurons were exposed to UVA in vitro. Open field test and rotarod test were used to observe the effects of AS-IV on the motor and explore the abilities of radiated mice. The pathological changes in the brain were observed by hematoxylin and eosin and Nissl staining. Immunofluorescence analysis was used to detect the synapse damage. The expressions of the BDNF/TrkB pathway and neuroprotection-related molecules were detected by Western blotting and Quantitative-RTPCR, respectively. The results showed that AS-IV could improve the motor and explore abilities of radiated mice, reduce pathological damage to the cortex, enhance neuroprotection functions, and activate BDNF/TrkB pathway. In conclusion, AS-IV could relieve radiation-induced synapse damage, at least partly through the BDNF/TrkB pathway.

Astragaloside IV Attenuates High-Glucose-Induced Impairment in Diabetic Nephropathy by Increasing Klotho Expression via the NF-κB/NLRP3 Axis.

Deficiencies in klotho are implicated in various kidney dysfunctions including diabetic nephropathy (DN) related to inflammatory responses. Klotho is closely related to inflammatory responses and is a potential target for ameliorating kidney failure. Pyroptosis, an inflammatory form of programmed cell death, is reported to take part in DN pathogenesis recently. This study is aimed at exploring whether and how klotho inhibited podocyte pyroptosis and whether astragaloside IV (AS-IV) protect podocyte through the regulation of klotho. SD rat model of DN and conditionally immortalized mouse podocytes exposed to high glucose were treated with AS-IV. Biochemical assays and morphological examination, cell viability assay, cell transfection, phalloidin staining, ELISA, LDH release assay, SOD and MDA detection, MMP assay, ROS level detection, flow cytometry analysis, TUNEL staining assay, PI/Hoechst 33342 staining, immunofluorescence assay, and western blot were performed to elucidate podocyte pyroptosis and to observe the renal morphology. The treatment of AS-IV can improve renal function and protect podocytes exposed to high glucose. Klotho was decreased, and AS-IV increased klotho levels in serum and kidney tissue of DN rats as well as podocytes exposed to high glucose. AS-IV can inhibit DN glomeruli pyroptosis in vivo. In vitro, overexpressed klotho and treatment with AS-IV inhibited pyroptosis of podocytes cultured in high glucose. Klotho knockdown promoted podocyte pyroptosis, and treatment with AS-IV reversed this effect. Furthermore, the overexpression of klotho and AS-IV reduces oxidative stress levels and inhibited NF-κB activation and NLRP3-mediated podocytes' pyroptosis which was abolished by klotho knockdown. In addition, both the ROS inhibitor NAC and the NF-κB pathway inhibitor PDTC can inhibit NLRP3 inflammasome activation. NLRP3 inhibitor MCC950 can inhibit pyroptosis of podocytes exposed to high glucose. Altogether, our results demonstrate that the protective effect of AS-IV in upregulating klotho expression in diabetes-induced podocyte injury is associated with the inhibition of NLRP3-mediated pyroptosis via the NF-κB signaling pathway.

Astragaloside IV ameliorates cognitive impairment and protects oligodendrocytes from antioxidative stress via regulation of the SIRT1/Nrf2 signaling pathway

Subcortical ischemic vascular dementia (SIVD), which is caused by chronic cerebral hypoperfusion, is a common subtype of vascular dementia, accompanied by white matter damage and cognitive impairment. Currently, there are no effective treatments for this condition. Oxidative stress is a key factor in the pathogenesis of white matter damage. Astragaloside IV (AS-IV), one of the main active components of astragaloside, has antioxidant properties and promotes cognitive improvement; however, its effect on SIVD and its potential mechanism remain unknown. We aimed to clarify whether AS-IV had a protective effect against SIVD injury caused by right unilateral common carotid artery occlusion and the underlying mechanism. The results showed that AS-IV treatment improved cognitive function and white matter damage, inhibited oxidative stress and glial cells activation, and promoted the survival of mature oligodendrocytes after chronic cerebral hypoperfusion. Moreover, the protein expression levels of NQO1, HO-1, SIRT1 and Nrf2 were increased by AS-IV treatment. However, pre-treatment with EX-527, a SIRT1-specific inhibitor, eliminated the beneficial effects of AS-IV. These results demonstrate that AS-IV plays a neuroprotective role in SIVD by suppressing oxidative stress and increasing the number of mature oligodendrocytes via the modulation of SIRT1/Nrf2 signaling. Our results support AS-IV as a potential therapeutic agent for SIVD.

Astragaloside IV for Heart Failure: Preclinical Evidence and Possible Mechanisms, A Systematic Review and Meta-Analysis.

To explore the cardioprotective effects of astragaloside IV (AS-IV) in heart failure (HF). PubMed, Excerpta Medica Database (EMBASE), Cochrane Library, Web of Science, Wanfang Database, Chinese Bio-medical Literature and Retrieval System (SinoMed), China Science and Technology Journal Database (VIP), and China National Knowledge Infrastructure (CNKI) were searched from inception to November 1, 2021 for animal experiments to explore AS-IV in treating HF in rats or mice. The left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), left ventricular weight-to-body weight (LVW/BW) and B-type brain natriuretic peptide (BNP) were recorded. The qualities of included studies were assessed by the risk of bias according to the Cochrane handbook. Meta-analysis was performed using Stata 13.0. Twenty-one articles involving 558 animals were considered. Compared with the control group, AS-IV improved cardiac function, specifically by increasing LVEF (mean difference (MD)=6.97, 95% confidence interval (CI)=5.92 to 8.03, P<0.05; fixed effects model) and LVFS (MD=7.01, 95% CI=5.84 to 8.81, P<0.05; fixed effects model), and decreasing LVEDD (MD=-4.24, 95% CI=-4.74 to -3.76, P<0.05; random effects model) and LVESD (MD=-4.18, 95% CI=-5.26 to -3.10, P<0.05; fixed effects model). In addition, the BNP and LVW/BW levels were decreased in the AS-IV treatment group (MD=-9.18, 95% CI=-14.13 to -4.22, P<0.05; random effects model; MD=-1.91, 95% CI=-2.42 to -1.39, P<0.05; random effects model). AS-IV is a promising therapeutic agent for HF. However, this conclusion needs to be clinically validated in the future.

Astragaloside IV attenuates high glucose-induced NF-κB-mediated inflammation through activation of PI3K/AKT-ERK-dependent Nrf2/ARE signaling pathway in glomerular mesangial cells.

Inflammation is a key contributor to diabetic kidney disease pathogenesis, including reactive oxidation stress (ROS)-mediated nuclear factor-κB (NF-κB) signaling pathway. In this study, we examined the effect of Astragaloside IV (AS-IV) on anti-inflammatory and anti-oxidative properties under high glucose (HG) condition and the potential mechanism in glomerular mesangial cells (GMCs). We showed that AS-IV concentration-dependently reduced GMCs proliferation, restrained ROS release and hydrogen peroxide content, and suppressed pro-inflammatory cytokines as well as pro-fibrotic factors expression, which were associated with the inhibition of NF-κB and nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling activation. Accordingly, both NF-κB overexpression by using RNA plasmid and Nrf2 gene silencing by using RNA interference weakened the ability of AS-IV to ameliorate HG-induced oxidative stress, inflammation, and cell proliferation. Furthermore, phosphatidylinositide 3-kinases (PI3K)/serine/threonine protein kinase (Akt) and extracellular regulated protein kinases (ERK) signaling pathway regulated the process of AS-IV-induced Nrf2 activation and antioxidant capacity, which evidenced by using PI3K inhibitor LY294002 or ERK inhibitor PD98059 that largely abolished the AS-IV efficacy. Taken together, these results indicated that AS-IV protected against HG-induced GMCs damage by inhibiting ROS/NF-kB-induced increases of inflammatory cytokines, fibrosis biomarkers, and cell proliferation via up-regulation of Nrf2-dependent antioxidant enzyme expression, which were mediated by PI3K/Akt and ERK signaling pathway activation.

Review on the protective mechanism of astragaloside IV against cardiovascular diseases.

Cardiovascular disease is a global health problem. Astragaloside IV (AS-IV) is a saponin compound extracted from the roots of the Chinese herb Astragalus. Over the past few decades, AS-IV has been shown to possess various pharmacological properties. It can protect the myocardium through antioxidative stress, anti-inflammatory effects, regulation of calcium homeostasis, improvement of myocardial energy metabolism, anti-apoptosis, anti-cardiomyocyte hypertrophy, anti-myocardial fibrosis, regulation of myocardial autophagy, and improvement of myocardial microcirculation. AS-IV exerts protective effects on blood vessels. For example, it can protect vascular endothelial cells through antioxidative stress and anti-inflammatory pathways, relax blood vessels, stabilize atherosclerotic plaques, and inhibit the proliferation and migration of vascular smooth muscle cells. Thus, the bioavailability of AS-IV is low. Toxicology indicates that AS-IV is safe, but should be used cautiously in pregnant women. In this paper, we review the mechanisms of AS-IV prevention and treatment of cardiovascular diseases in recent years to provide a reference for future research and drug development.

Insight of “Yin-Jing” medical property ofLigusticum chuanxiong Hort. via pharmacokinetics and tissue distributions by ultra-performance liquid chromatography-triple quadrupole mass spectrometry

Ethnopharmacological relevanceLigusticum chuanxiong Hort. (Chuanxiong, LC), as an important traditional Chinese medicine (TCM), can not only be used as a monarch herb but also be used as a classic “Yin-Jing” (引经) medicine in compound prescriptions, e.g., Buyang Huanwu Decoction (BHD). Although LC has the effect of guiding components into the brain in BHD, there is still a lack of scientific evidence on this “Yin-Jing” effects. Herein, we used pharmacokinetics and tissue distributions to investigate “Yin-Jing” effects of LC. To simplify the study, four major constituents in BHD, i.e., Calycosin (CA), astragaloside IV (AI), paeoniflorin (PA), and amygdalin (AM) were combined to form a simple compound (abbreviated as CAPA here) to replace the original BHD in this paper. The Yin-Jing medical property of LC was confirmed by the compatibility of CAPA with LC or its different fractions (Fr. A ∼ Fr. F). Aim of the studyTo explore the “Yin-Jing” medical property of LC via pharmacokinetics and tissue distributions by ultra-performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-QQQ-MS). Materials and methodsThe contents of CA, AI, PA, and AM were simultaneously determined by the established and validated UPLC-QQQ-MS method in different rat tissues and plasma after administration of CAPA with the combination of LC or Fr. A ∼ Fr. F. The pharmacokinetic parameters, e.g., Tmax, Cmax, AUC0–t and MRT0–t, were calculated to evaluate the efficiency of “Yin-Jing”. ResultsThe Cmax and AUC0–t of CA, AI, PA, and AM were remarkably increased in rat brain tissues compared with those of the control group after compatibility of LC. This demonstrated that LC has the Yin-Jing effects on brain tissues. Additionally, Fr. B or Fr. C might be the material basis by specifically studying the distributions of CA, AI, PA, and AM in brain tissue based on mutual compatibility. The effects of Fr. B and Fr. C on distributions of these constituents in other tissues or plasma was also studied to verify the effects of Yin-Jing of LC. The results showed that the same upward trend is found in heart, liver and plasma, but the intensity is insignificant as that in brain tissue. Furthermore, the Cmax and AUC0–t of some analytes in the rat spleen, lung, and kidney were significantly decreased compared with the control group (P < 0.05 or 0.01). ConclusionsLC has the function of Yin-Jing, especially guiding the components into the brain tissue. Moreover, Fr. B and Fr. C is suggested to be the pharmacodynamic material basis for the effect of Yin-Jing of LC. These finding explained that it was recommended to add LC into some prescriptions for treating cardiovascular and cerebrovascular diseases caused by Qi deficiency and blood stasis. This has laid a certain foundation for the research on the Yin-Jing efficacy of LC to better clarify the theory of TCM and guide the clinical application of Yin-Jing drugs.

Astragaloside IV promotes keratinocyte proliferation and migration through upregulating lncRNA H19 recruited ILF3 to enhance the stability of CDK4 mRNA.

Skin is the first line of the body to resist pathogen invasion. A potentially fatal infection may result from problems with wound healing. Small molecule drugs like astragaloside IV (AS-IV) show pro-healing activities, but the mechanisms are not fully understood. Using real-time quantitative PCR and a western blot assay, the amount of gene expression was evaluated. The proliferation and migration of keratinocytes were determined by MTS and wound healing assay, respectively. The binding of lncRNA H19 to RBP protein ILF3 and the binding of ILF3 protein to CDK4 mRNA were confirmed by RNA immunoprecipitation. Treatment with AS-IV enhanced the expression of lncRNA H19, ILF3, and CDK4 and improved the proliferation and migration of keratinocytes HaCaT. Additionally, apoptosis of keratinocytes was attenuated by AS-IV. Further studies showed that both lncRNA H19 and ILF3 were important for AS-IV-mediated keratinocyte growth and migration. In addition, lncRNA H19 recruited ILF3 to increase CDK4 mRNA level and enhanced cell proliferation. We discovered a lncRNA H19/ILF3/CDK4 axis that is activated by AS-IV to promote keratinocyte migration and proliferation. These results elucidate the mechanism of action of AS-IV and justify its application in further application in wound healing treatment.

Astragaloside IV attenuates indoxyl sulfate-induced injury of renal tubular epithelial cells by inhibiting the aryl hydrocarbon receptor pathway.

Astragalus membranaceus Fisch. ex Bunge has long been used to treat chronic kidney disease (CKD) in China. However, the mechanism of action requires further study. Indoxyl sulfate accumulation is the key cause of CKD progression. The aryl hydrocarbon receptor (AhR) plays an essential role in the renal tubular injury induced by indoxyl sulfate (IS). We explored the effects of Astragaloside IV (AS-IV), a minor component of the flowering perennial Astragalus membranaceus Fisch. ex Bunge, on AhR activity during IS-induced injury of renal tubular epithelial cells. C57BL/6 mice fed a 0.2% adenine diet (adenine+IS) and intraperitoneally injected with IS were used to study the protective effects of AS-IV, and specifically the effect on the AhR. In addition, apoptosis (annexin/PI), oxidative stress and the AhR pathway were investigated in IS-stimulated HK-2cells treated with AS-IV. The binding of AS-IV to the AhR was assessed in a molecular docking analysis. AhR knockdown using AhR siRNA allowed determination of the effects of AS-IV in IS-stimulated HK-2cells. AS-IV inhibited tubulointerstitial injury in adenine+IS mice. While AS-IV did not reduce serum IS levels, it did inhibit AhR expression in the kidney. In IS-stimulated HK-2cells, AS-IV also dramatically reduced apoptosis, decreased oxidative stress responses and inhibited the expression of the AhR pathway. The molecular docking analysis showed surface binding of AS-IV to the AhR. Following AhR knockdown in HK-2cells, IS-induced apoptosis was reduced and could not be further reduced by AS-IV. By targeting the AhR, AS-IV may alleviate IS-induced renal tubular injury, thus offering a novel therapeutic approach to the treatment of chronic renal failure.

Effects of astragaloside IV on glucocorticoid-induced avascular necrosis of the femoral head via regulating Akt-related pathways.

We investigated the role of astragaloside IV (AS-IV) in preventing glucocorticoid-induced avascular necrosis of the femoral head (ANFH) and the underlying molecular mechanisms. Network pharmacology was used to predict the molecular targets of AS-IV. Molecular dynamic simulations were performed to explore the binding mechanism and interaction mode between AS-IV and Akt. Rat models of glucocorticoid-induced ANFH with AS-IV intervention were established, and osteogenesis, angiogenesis, apoptosis and oxidative stress were evaluated before and after blocking the PI3K/Akt pathway with LY294002. The effects of glucocorticoid and AS-IV on bone marrow mesenchymal stem cells and human umbilical vein endothelial cells incubated with and without LY294002 were determined. Downregulated p-Akt expression could be detected in the femoral heads of glucocorticoid-induced ANFH patients and rats. AS-IV increased trabecular bone integrity and vessel density of the femoral head in the model rats. AS-IV increased Akt phosphorylation and upregulated osteogenesis-, angiogenesis-, apoptosis- and oxidative stress-related proteins and mRNA and downregulated Bax, cleaved caspase-3 and cytochrome c levels. AS-IV promoted human umbilical vein endothelial cell migration, proliferation and tube formation ability; bone marrow mesenchymal stem cell proliferation; and osteogenic differentiation under glucocorticoid influence. AS-IV inhibited apoptosis. LY294002 inhibited these effects. AS-IV prevented glucocorticoid-induced ANFH by promoting osteogenesis and angiogenesis via the Akt/Runx2 and Akt/HIF-1α/VEGF pathways, respectively, and suppressing apoptosis and oxidative stress via the Akt/Bad/Bcl-2 and Akt/Nrf2/HO-1 pathways, respectively.

Systems pharmacology reveals the mechanism of Astragaloside IV in improving immune activity on cyclophosphamide-induced immunosuppressed mice

Ethnopharmacological relevanceMyelosuppression, also known as bone marrow suppression (BMS), is a pathological phenomenon of the decrease in the production of blood cells and further lead to immune homeostasis disorder. Astragalus mongholicus Bunge (AM, checked with The World Flora Online, http://www.worldfloraonline.org, updated on January 30, 2023) is a traditional Chinese medicine with efficacy of tonifying Qi and strengthening body immunity in thousands of years of clinical practice in China. Astragaloside IV (AS-IV) is a major active ingredient of AM, which plays an important role in regulating immune system through different ways. Aim of the studyThis study was aimed to investigate the protective effect and mechanism of AS-IV on macrophages in vitro and cyclophosphamide (CTX)-induced immunosuppressive mice in vivo, and to provide experimental basis for the prevention and treatment of AS-IV in myelosuppression. Materials and methodsBased on network pharmacology and molecular docking technology, the core targets and signaling pathways of saponins of AM against myelosuppression were screened. And then, the immunoregulatory effect of AS-IV on RAW264.7 cells was investigated by cellular immune activity and cellular secretion analysis in vitro. In this way, the effects of AS-IV on the main potential targets of HIF-1α/NF-κB signaling pathway were analyzed by qRT-PCR and Western blot methods. Furthermore, comprehensive analysis of the effects of AS-IV against CTX-induced mice were conducted on the basis of immune organs indices analysis, histopathological analysis, hematological analysis, natural killer cell activity analysis and spleen lymphocyte transformation activity analysis. In order to further verify the relationship between active ingredients and action targets, drug inhibitor experiments were finally conducted. ResultsAS-IV, as a potential anti-myelosuppressive compound, was screened by systematic pharmacological methods to act on target genes including HIF1A and RELA together with the HIF-1α/NF-κB signaling pathway. Further studies by molecular docking technology showed that AS-IV had good binding activity with HIF1A, RELA, TNF, IL6, IL1B and other core targets. Besides, cellular and animal experiments validation results showed that AS-IV could enhance the migration and phagocytosis of RAW264.7 cells, and protect the immune organs such as spleen and thymus together with bone tissues from damage. By this means, immune cell function including spleen natural killer cell and lymphocyte transformation activity were also enhanced. In addition, white blood cells, red blood cells, hemoglobin, platelets and bone marrow cells were also significantly improved in the suppressed bone marrow microenvironment (BMM). In kinetic experiments, the secretion of cytokines such as TNF-α, IL-6 and IL-1β were increased, and IL-10, TGF-β1 were decreased. The key regulatory proteins such as HIF-1α, NF-κB, PHD3 in HIF-1α/NF-κB signaling pathway were also regulated in the results of upregulated expression of HIF-1α, p–NF–κB p65 and PHD3 at the protein or mRNA level. Finally, the inhibition experiment results suggested that AS-IV could significantly improve protein response in immunity and inflammation such as HIF-1α, NF-κB and PHD3. ConclusionAS-IV could significantly relieve CTX-induced immunosuppressive and might improve the immune activity of macrophages by activating HIF-1α/NF-κB signaling pathway, and provide a reliable basis for the clinical application of AS-IV as a potentially valuable regulator of BMM.

Role of simulated in vitro gastrointestinal digestion on biotransformation and bioactivity of astragalosides from Radix Astragali

Radix Astragali (RA) is commonly used in Asian herbal therapy or food supply, and astragalosides and flavonoids are its major components with diverse pharmaceutical effects. To provide new information on the potential cardiovascular benefits of RA administered orally, the bioaccessibility of these compounds with relevant in vitro digestion parameters was determined for four digestion phases (oral, gastric, small and large intestines) by ultrahigh-performance liquid chromatography quadrupole time-of-flight-mass spectrometry (UPLC-Q-TOF/MS). Meanwhile, we compared the effects of digestion products on advanced glycation end products (AGEs)-induced intracellular reactive oxygen species (ROS) levels in a human arterial endothelial cells (HAECs) model, and studied the potential of RA against oxidative stress-related cardiovascular disease. The changes of saponins and flavonoids composition and antioxidant activity after digestion in intestines were mainly due to the astragaloside IV (AS-IV) biosynthesis involving saponins acetyl isomerization and deacetylation, and the flavonoid glycosides converted to aglycone by deglycosylation processes. All these results suggest that acetyl biotransformation of RA in small intestine directly influenced the response to oxidative stress, and might provide a reference for elucidation of the multi-component action after oral RA in cardiovascular health care.

Astragaloside IV suppresses the migration and EMT progression of cervical cancer cells by inhibiting macrophage M2 polarization through TGFβ/Smad2/3 signaling

Cervical cancer (CC) is a gynecological malignant tumor worldwide. Astragaloside IV (AS-IV) has been found to exert antitumor effects on CC. In addition, M2-polarized macrophages, known as tumor-associated macrophages (TAMs), play an important role in promoting cancer cell growth and angiogenesis. Thus, we explored the association between the antitumor effect of AS-IV and macrophage polarization in CC. Flow cytometry, ELISA, and RT‒qPCR assays were applied to detect the levels of CD163, IL-10, TGFβ, and CD206 in M2 macrophages with or without AS-IV treatment. In addition, conditioned medium (CM) was collected from these M2 macrophages, and CC cells were then cultured in various CMs. Wound healing and transwell assays were used to assess the migratory ability of CC cells. In this study, we found that AS-IV significantly inhibited M2 polarization of macrophages, as shown by decreased CD163, IL-10, TGFβ, and CD206 expression. In addition, compared with CM from M2 macrophages, CM from AS-IV-treated M2 macrophages notably inhibited angiogenesis, migration, and epithelial-mesenchymal transition (EMT) in CC cells. Furthermore, compared with CM from M2 macrophages, CM from AS-IV-treated M2 macrophages markedly reduced p-Smad2 and p-Smad3 protein expression in CC cells, and these changes were reversed by TGF-β treatment. Collectively, suppression of M2-like polarization of macrophages by AS-IV could prevent the migration and EMT of CC cells by inactivating TGF-β/Smad2/3 signaling. These findings might provide some theoretical support for exploring novel treatments for CC.

A novel microbial and hepatic biotransformation-integrated network pharmacology strategy explores the therapeutic mechanisms of bioactive herbal products in neurological diseases: the effects of Astragaloside IV on intracerebral hemorrhage as an example

BackgroundThe oral bioavailability and blood–brain barrier permeability of many herbal products are too low to explain the significant efficacy fully. Gut microbiota and liver can metabolize herbal ingredients to more absorbable forms. The current study aims to evaluate the ability of a novel biotransformation-integrated network pharmacology strategy to discover the therapeutic mechanisms of low-bioavailability herbal products in neurological diseases.MethodsA study on the mechanisms of Astragaloside IV (ASIV) in treating intracerebral hemorrhage (ICH) was selected as an example. Firstly, the absorbed ASIV metabolites were collected by a literature search. Next, the ADMET properties and the ICH-associated targets of ASIV and its metabolites were compared. Finally, the biotransformation-increased targets and biological processes were screened out and verified by molecular docking, molecular dynamics simulation, and cell and animal experiments.ResultsThe metabolites (3-epi-cycloastragenol and cycloastragenol) showed higher bioavailability and blood–brain barrier permeability than ASIV. Biotransformation added the targets ASIV in ICH, including PTK2, CDC42, CSF1R, and TNF. The increased targets were primarily enriched in microglia and involved in cell migration, proliferation, and inflammation. The computer simulations revealed that 3-epi-cycloastragenol bound CSF1R and cycloastragenol bound PTK2 and CDC42 stably. The In vivo and in vitro studies confirmed that the ASIV-derived metabolites suppressed CDC42 and CSF1R expression and inhibited microglia migration, proliferation, and TNF-α secretion.ConclusionASIV inhibits post-ICH microglia/macrophage proliferation and migration, probably through its transformed products to bind CDC42, PTK2, and CSF1R. The integrated strategy can be used to discover novel mechanisms of herbal products or traditional Chinses medicine in treating diseases.Graphical

Fufang shenhua tablet, astragali radix and its active component astragaloside IV: Research progress on anti-inflammatory and immunomodulatory mechanisms in the kidney.

Background: Given the limited treatment options available for kidney disease, a significant number of patients turn to alternative therapies, including traditional Chinese medicine. Among these therapies, the Fufang Shenhua tablet (SHT) has garnered attention for its effectiveness in addressing the most common deficiency of Qi and Yin in chronic glomerulonephritis. Notably, the sovereign drug of SHT is Astragali Radix (AR), with the most abundant and effective component being Astragaloside IV (AS-IV). AS-IV has been shown to possess anti-inflammatory and immunomodulatory properties, and it is extensively used in treating kidney diseases. Nevertheless, the molecular mechanisms underlying its action are numerous and intricate, and a comprehensive understanding is yet to be achieved. Aim of the review: Thus, we have thoroughly examined the existing research and outlined the advancements made in investigating the anti-inflammatory and immunomodulatory mechanisms of SHT, AR and its active component AS-IV, in relation to kidney health. This serves as a dependable foundation for conducting more comprehensive investigations, evaluating efficacy, and making further improvements in the future. Materials and methods: We conducted a comprehensive literature search utilizing multiple globally recognized databases, including Web of Science, Google Scholar, PubMed, ScienceDirect, Wiley, ACS, Springer, and CNKI. The search keywords used in this study were "Fufang Shenhua tablet," "Astragali Radix," "Astragaloside IV," and "Anti-inflammatory" or "Immunity." Results: The mechanism of inflammation inhibition by SHT, AR and its active component AS-IV is mainly related to the signaling pathways such as NF-κB, TLRs, PI3K/AKT, Wnt/β-catenin, and JAK-STAT. Immunomodulation exerts not only activating, stimulating, and regulating effects on macrophages and dendritic cells, but also on immune organs, T-lymphocytes, B-lymphocytes, and a myriad of cytokines. Moreover, the SHT, AR and its active component AS-IV also demonstrate regulatory effects on renal cells, including glomerular mesangial cells, tubular epithelial cells, and podocytes. Conclusion: To summarize, SHT, AR and its active component AS-IV, exhibit notable therapeutic effects in kidney-related ailments, and their molecular mechanisms for anti-inflammatory and immunomodulatory effects have been extensively explored. However, further standard clinical trials are necessary to evaluate their safety and efficacy in the adjunctive treatment of kidney-related diseases. Moreover, in-depth studies of unverified chemical components and regulatory mechanisms in SHT are required. It is our belief that with continued research, SHT, AR and its active component AS-IV are poised to pave the way for enhancing therapeutic outcomes in kidney-related ailments.

Astragaloside IV attenuates lipopolysaccharide induced liver injury by modulating Nrf2-mediated oxidative stress and NLRP3-mediated inflammation

Aims and objectivesSepsis-associated liver injury is a common public health problem in intensive care units. Astragaloside IV (AS-IV) is an active component extracted from the Chinese herb Astragalus membranaceus, and has been shown to have anti-oxidation, anti-inflammation, and anti-apoptosis properties. The research aimed to investigate the protective effect of AS-IV in lipopolysaccharide (LPS)-induced liver injury. MethodsMale C57BL/6 wild-type mice (6-8 week-old) were intraperitoneally injected with 10 mg/kg LPS for 24 h and AS-IV (80 mg/kg) 2 h before the LPS injection. Biochemical and histopathological analyses were carried out to assess liver injury. The RT-qPCR analyzed the mRNA expression of IL-1β, TNF-α, and IL-6. The mRNA and protein expression of SIRT1, nuclear Nrf2, Nrf2, and HO-1 were measured by Western blotting. ResultsSerum alanine/aspartate aminotransferases (ALT/AST) analysis, malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) were showed that AS-IV protected against LPS-induced hepatotoxicity. The protection afforded by AS-IV was confirmed by pathological examination of the liver. Pro-inflammatory cytokines, including interleukin- 1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6), were observed to be reversed by AS-IV after exposure to LPS. Western blot analysis demonstrated that AS-IV enhanced the expression levels of Sirtuin 1 (SIRT1), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase 1 (HO-1). ConclusionsAS-IV protects against LPS-induced Liver Injury and Inflammation by modulating Nrf2-mediated oxidative stress and NLRP3-mediated inflammation.

A novel Nanocellulose-Gelatin-AS-IV external stent resists EndMT by activating autophagy to prevent restenosis of grafts.

Vein grafts are widely used for coronary artery bypass grafting and hemodialysis access, but restenosis remains the "Achilles' heel" of these treatments. An extravascular stent is one wrapped around the vein graft and provides mechanical strength; it can buffer high arterial pressure and secondary vascular dilation of the vein to prevent restenosis. In this study, we developed a novel Nanocellulose-gelatin hydrogel, loaded with the drug Astragaloside IV (AS-IV) as an extravascular scaffold to investigate its ability to reduce restenosis. We found that the excellent physical and chemical properties of the drug AS-IV loaded Nanocellulose-gelatin hydrogel external stent limit graft vein expansion and make the stent biocompatible. We also found it can prevent restenosis by resisting endothelial-to-mesenchymal transition (EndMT) in vitro. It does so by activating autophagy, and AS-IV can enhance this effect both in vivo and in vitro. This study has added to existing research on the mechanism of extravascular stents in preventing restenosis of grafted veins. Furthermore, we have developed a novel extravascular stent for the prevention and treatment of restenosis. This will help optimize the clinical treatment plan of external stents and improve the prognosis in patients with vein grafts.

Mechanism exploration and prognosis study of Astragali Radix-Spreading hedyotis herb for the treatment of lung adenocarcinoma based on bioinformatics approaches and molecular dynamics simulation.

Background: Herb pair of Astragali Radix (AR) and Spreading Hedyotis Herb (SH) has been frequently prescribed in clinical for the treatment of lung cancer owing to its favorable efficacy. Yet, the mechanism under the therapeutic effects remained unveiled, which has limited its clinical applications, and new drug development for lung cancer. Methods: The bioactive ingredients of AR and SH were retrieved from the Traditional Chinese Medicine System Pharmacology Database, with the targets of obtained components predicted by Swiss Target Prediction. Genes related to lung adenocarcinoma (LUAD) were acquired from GeneCards, OMIM and CTD databases, with the hub genes of LUAD screened by CTD database. The intersected targets of LUAD and AR-SH were obtained by Venn, with David Database employed to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Survival analysis of the hub genes of LUAD was carried out using TCGA-LUAD dataset. Molecular docking of core proteins and active ingredients was performed by Auto-Dock Vina software, followed by molecular dynamics simulations of protein-ligand complexes with well-docked conformations. Results: 29 active ingredients were screened out with 422 corresponding targets predicted. It is revealed that AR-SH can act on various targets such as EGFR, MAPK1, and KARS by ursolic acid (UA), Astragaloside IV(ASIV), and Isomucronulatol 7,2'-di-O-glucoside (IDOG) to alleviate the symptoms of LUAD. Biological processes involved are protein phosphorylation, negative regulation of apoptotic process, and pathways involved are endocrine resistance, EGFR tyrosine kinase inhibitor resistance, PI3K-Akt, and HIF-1 pathway. Molecular docking analysis indicated that the binding energy of most of the screened active ingredients to proteins encoded by core genes was less than -5.6kcal/mol, with some active ingredients showing even lower binding energy to EGFR than Gefitinib. Three ligand-receptor complexes including EGFR-UA, MAPK1-ASIV, and KRAS-IDOG were found to bind relatively stable by molecular dynamics simulation, which was consistent with the results of molecule docking. Conclusion: We suggested that the herb pair of AR-SH can act on targets like EGFR, MAPK1 and KRAS by UA, ASIV and IDOG, to play a vital role in the treatment and the enhancement of prognosis of LUAD.

Astragaloside IV induces the protective effect of bone marrow mesenchymal stem cells derived exosomes in acute myocardial infarction by inducing angiogenesis and inhibiting apoptosis

ABSTRACT Bone marrow mesenchymal stem cells (BMECs)-derived exosomes (MSC-Exo) can improve acute myocardial infarction (AMI). Astragaloside IV (AS-IV) has also been reported to have cardioprotective pharmacological effects. However, it is not entirely clear whether AS-IV can improve AMI by inducing MSC-Exo. BMSCs and MSC-Exo were isolated and identified, and we also established the AMI rat model and the OGD/R model with H9c2 cells. After MSC-Exo or AS-IV-mediated MSC-Exo treatment, cell angiogenesis, migration, and apoptosis were evaluated by tube formation, wound healing, and TUNEL staining. The cardiac function of the rats was measured by echocardiography. The pathological changes and collagen deposition in rats were also assessed with Masson and Sirius red staining. The levels of α-SMA, CD31 and inflammatory factors were determined by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). In vitro, AS-IV-mediated MSC-Exo can significantly enhance the angiogenesis and migration of H9c2 cells induced by OGD/R, and significantly reduce their apoptosis. In vivo, AS-IV-mediated MSC-Exo can improve the cardiac function of rats, and attenuate pathological damage and collagen deposition in AMI model rats. In addition, AS-IV-mediated MSC-Exo can also promote angiogenesis and reduce inflammatory factors in rats with AMI. AS-IV-stimulated MSC-Exo can improve myocardial contractile function, myocardial fibrosis and angiogenesis, reduce inflammatory factors and induce apoptosis in rats after AMI.