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Astragalus membranaceus Bunge is widely used in Traditional Chinese Medicine to treat various cancers. Astragaloside-IV (AS-IV) is one of the major compounds isolated from A. membranaceus Bunge and has been demonstrated to have antitumor effects by inhibiting cell proliferation, invasion and metastasis in various cancer types. Numerous studies have used in vitro cell culture and in vivo animal models of cancer to explore the antitumor activities of AS-IV. In the present study, the antitumor effects and mechanisms of AS-IV reported in studies recorded in the PubMed database were reviewed. First, the antitumor effects of AS-IV on proliferation, cell cycle, apoptosis, autophagy, invasion, migration, metastasis and epithelial-mesenchymal transition processes in cancer cells and the tumor microenvironment, including angiogenesis, tumor immunity and macrophage-related immune responses to cancer cells, were comprehensively discussed. Subsequently, the molecular mechanisms and related signaling pathways associated with antitumor effects of AS-IV as indicated by in vitro and in vivo studies were summarized, including the Wnt/AKT/GSK-3β (glycogen synthase kinase-3β)/β-catenin, TGF-β/PI3K/AKT/mTOR, PI3K/MAPK/mTOR, PI3K/AKT/NF-κB, Rac family small GTPase 1/RAS/MAPK/ERK, TNF-α/protein kinase C/ERK1/2-NF-κB and Tregs (T-regulatory cells)/IL-11/STAT3 signaling pathways. Of note, several novel mechanisms of Toll-like receptor 4 (TLR4)/NF-κB/STAT3, pSmad3C/3L, nuclear factor erythroid 2-related factor (NrF2)/heme oxygenase 1, circDLST/microRNA-489-3p/eukaryotic translation initiation factor 4A1 and macrophage-related high-mobility group box 1-TLR4 signaling pathways associated with the anticancer activity of AS-IV were also included. Finally, the limitations of current studies that must be addressed in future studies were pointed out to facilitate the establishment of AS-IV as a potent therapeutic drug in cancer treatment.

Podocyte dedifferentiation and mesangial cell (MC) activation play an important role in many glomerular diseases associated with fibrosis. MicroRNA-21 (miR-21) is closely linked to renal fibrosis, but it is unknown whether and how miR-21 promotes podocyte dedifferentiation and MC activation and whether astragaloside IV (AS-IV) improves renal function and fibrosis through the regulation of miR-21. Cultured MCs, primary mouse podocytes, and diabetic KK-Ay mice were treated with AS-IV. Cell transfection, Western blot, real-time PCR, immunofluorescence assay, immunohistochemical assay, and electronic microscopy were used to detect the markers of podocyte dedifferentiation and MC activation and to observe the renal morphology. Our data showed that miR-21 expression was increased and that AS-IV decreased miR-21 levels in cells, serum, and kidney. Overexpressed miR-21 promoted podocyte dedifferentiation and MC activation, and treatment with AS-IV reversed this effect. Furthermore, the overexpression of miR-21 activated the β-catenin pathway and the transforming growth factor (TGF)-β1/Smads pathway in the process of podocyte dedifferentiation and MC activation, which was abolished by AS-IV treatment. In addition, both the Wnt/β-catenin pathway inhibitor XAV-939 and the TGF-β1/Smads pathway inhibitor SB431542 reversed the effect of AS-IV. Furthermore, AS-IV improved renal function and fibrosis in diabetic KK-Ay mice. Our results indicated that AS-IV ameliorates renal function and renal fibrosis by inhibiting miR-21 overexpression-induced podocyte dedifferentiation and MC activation in diabetic kidney disease. These findings pave way for future studies investigating AS-IV as a potential therapeutic agent in the management of glomerular diseases.

Astragaloside (AST) is derived from the Chinese herb Astragalus membranaceus, and studies have demonstrated that it promotes differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). To the best of our knowledge, however, the functions of the component AST-IV in osteogenesis have not previously been elucidated. The present study aimed to verify the effects of AST-IV in osteogenesis. First, the proliferation and differentiation status of human BMSCs incubated with AST-IV were analysed and compared with a control (no AST-IV treatment). In order to determine the involvement of the glycogen synthase kinase (GSK)3β signalling pathway in AST-IV, overexpression and inhibition of GSK3β was induced during incubation of BMSCs with AST-IV. In order to investigate how neuronal growth factor (NGF) contributes to BMSCs differentiation, BMSCs were co-incubated with an anti-NGF antibody and AST IV, and then levels of osteogenesis markers were assessed. The results demonstrated for the first time that AST-IV contributed to BMSCs differentiation. Furthermore, the GSK3β/β-catenin signalling pathway was revealed to be involved in AST-IV-induced osteogenesis; moreover, AST-IV accelerated differentiation by enhancing the expression levels of NGF. In summary, the present study demonstrated that AST-IV promotes BMSCs differentiation, thus providing a potential target for the treatment of osteoporosis.

[This corrects the article DOI: 10.3389/fphar.2020.610102.].

Background: Ischemia/reperfusion (I/R) caused by ischemic stroke treatments leads to brain injury, and autophagy plays a role in the pathology. Astragaloside IV is a potential neuroprotectant, but its underlying mechanism on cerebral I/R injury needs to be explored. The objective of this study is to investigate the neuroprotective mechanism of Astragaloside IV against cerebral I/R injury. Methods: Middle cerebral artery occlusion method (MCAO) and oxygen and glucose deprivation/reoxygenation (OGD/R) method were used to simulate cerebral I/R injury in Sprague-Dawley (SD) rats and HT22 cells, respectively. The neurological score, 2,3,5-Triphe-nyltetrazolium chloride (TTC) staining, and transmission electron microscope were used to detect cerebral damage in SD rats. Cell viability and cytotoxicity assay were tested in vitro. Fluorescent staining and flow cytometry were applied to detect the level of apoptosis. Western blotting was conducted to examine the expression of proteins associated with autophagy. Results: This study found that Astragaloside IV could decrease the neurological score, reduce the infarct volume in the brain, and alleviate cerebral I/R injury in MCAO rats. Astragaloside IV promoted cell viability and balanced Bcl-2 and Bax expression in vitro, reduced the rate of apoptosis, decreased the expression of P62, and increased the expression of LC3II/LC3I in HT22 cells after OGD/R. Conclusions: These data suggested that Astragaloside IV plays a neuroprotective role by down-regulating apoptosis by promoting the degree of autophagy.

Astragaloside IV (AS-IV) is one of the main active components extracted from the Chinese medicinal herb Astragali and serves as a marker for assessing the herb’s quality. AS-IV is a tetracyclic triterpenoid saponin in the form of lanolin ester alcohol and exhibits various biological activities. This review article summarizes the chemical structure of AS-IV, its pharmacological effects, mechanism of action, applications, future prospects, potential weaknesses, and other unexplored biological activities, aiming at an overall analysis. Papers were retrieved from online electronic databases, such as PubMed, Web of Science, and CNKI, and data from studies conducted over the last 10 years on the pharmacological effects of AS—IV as well as its impact were collated. This review focuses on the pharmacological action of AS-IV, such as its anti-inflammatory effect, including suppressing inflammatory factors, increasing T and B lymphocyte proliferation, and inhibiting neutrophil adhesion-associated molecules; antioxidative stress, including scavenging reactive oxygen species, cellular scorching, and regulating mitochondrial gene mutations; neuroprotective effects, antifibrotic effects, and antitumor effects.

Astragaloside IV (AsIV), an active ingredient isolated from traditional Chinese medicine astragalus membranaceus, is beneficial to cardiovascular health. This study aimed to characterize the functional role of AsIV against adriamycin (ADR)-induced cardiomyopathy. Here, healthy rats were treated with ADR and/or AsIV for 35 days. We found that AsIV protected the rats against ADR-induced cardiomyopathy characterized by myocardial fibrosis and cardiac dysfunction. Meanwhile, ADR increased type I and III collagens, TGF-β, NOX2, and NOX4 expression and SMAD2/3 activity in the left ventricles of rats, while those effects were countered by AsIV through suppressing oxidative stress. Moreover, ADR was found to promote cardiac ferroptosis, whereas administration of AsIV attenuated the process via activating Nrf2 signaling pathway and the subsequent GPx4 expression increasing. These results suggest that AsIV might play a protective role against ADR-induced myocardial fibrosis, which may partly attribute to its anti-ferroptotic action by enhancing Nrf2 signaling.

Osteoarthritis (OA) is a chronic joint disease characterized by articular cartilage damage. Astragaloside IV (AS-IV), a cyclic triterpenoid saponin extracted from Astragalus membranaceus, exhibits antioxidant and cartilage-protective activities. However, its mechanism of action in OA remains unclear. To study the efficacy and mechanism of action of AS-IV in the treatment of OA. In the SW1353 cell model treated with IL-1β, cell viability was detected by CCK-8, and the ultrastructure of mitochondria was observed by transmission electron microscopy. Multiple methods such as flow cytometry, immunofluorescence, Western blotting, and fluorescent probe method were used to evaluate the effects of AS-IV on chondrocyte ferroptosis and extracellular matrix degradation, and the results were verified by rescue experiments. An OA rat model was established, and multiple methods such as histopathology were used to evaluate the therapeutic effect of AS-IV on OA cartilage injury. In vitro experiments have shown that IL-1β can induce ferroptosis in chondrocytes. Overexpression of p53 promotes ferroptosis in chondrocytes and exacerbates the progression of OA. AS-IV can downregulate the expression of p53 and MMP13, while upregulating the expression of SLC7A11, GPX4, SOX9, Col II, and GSH. Additionally, AS-IV reduces intracellular levels of ROS, MDA, and Fe . In an OA rat model, AS-IV significantly reduces the Osteoarthritis Research Society International (OARSI) score and Mankin score, alleviating cartilage damage. Furthermore, AS-IV inhibits extracellular matrix degradation and lipid peroxidation in cartilage tissue. AS-IV inhibits chondrocyte ferroptosis by modulating the p53/SLC7A11/GPX4 axis, thereby alleviating cartilage damage and OA. This suggests that AS-IV has therapeutic potential for OA treatment.

Inflammation induced by angiotensin II (Ang II) is a key event in the progression of numerous cardiovascular diseases. Astragaloside IV (AS-IV), a glycoside extracted from Astragalus membranaceus Bunge, has been shown to inhibit Ang II-induced inflammatory responses in vivo. However, the mechanisms underlying the beneficial effects are still unclear. This study investigated whether AS-IV attenuates endothelial inflammation induced by Ang II via the activation of endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) pathway. Human umbilical vein endothelial cells (HUVECs) were cultured in the presence of AS-IV with or without the specific inhibitor of NOS or Ca[sup.2+]- and phosphatidylinositol 3-kinase (PI3K)/Akt-dependent cascade prior to Ang II exposure. Incubation of HUVECs with AS-IV enhanced NO production and eNOS[sup.ser1177] phosphorylation. These responses were abrogated by the inhibition of NOS or Ca[sup.2+]- and PI3K/Akt-dependent pathway. In addition, preincubation of HUVECs with AS-IV inhibited Ang II-induced cytokine and chemokine production, adhesion molecule expression, monocyte adhesion, and nuclear factor kappa B (NF-κ B) activation as evidenced by the attenuation of inhibitor of kappa B alpha phosphorylation and subsequent NF-κ B DNA binding. These effects of AS-IV were abolished by the suppression of NOS or Ca[sup.2+]- and PI3K/Akt-dependent cascade. Our findings indicate that AS-IV attenuates inflammatory responses triggered by Ang II possibly via the activation of Ca[sup.2+]/PI3K/Akt/eNOS/NO pathway in endothelial cells.

[This corrects the article DOI: 10.3389/fphar.2022.895696.].