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ASIV attenuates α-SMA expression in pulmonary arteries. (A) Immunohistochemical staining of α-SMA of pulmonary arteries (scale bar, 50 µm). (B) Quantitative analysis of the Od value of α-SMA immunoreactivity in pulmonary arteries. Values are the means ± SEM (n=6 rats/group randomly selected for this experiment). * P<0.01 compared with the control group; ## P<0.01, compared with the MCT group. ASIV, astragaloside IV; MCT, monocrotaline; ASIV10, McT + 10 mg/kg/day ASIV group; ASIV30, McT + 30 mg/kg/day group.
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Pulmonary arterial hypertension (PAH) is associated with increased inflammation and abnormal vascular remodeling. Astragaloside IV (ASIV), a purified small molecular saponin contained in the well‑know herb, Astragalus membranaceus, is known to exert anti‑inflammatory and anti‑proliferation effects. Thus, the present study investigated the possible...
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Context 1
... attenuates the increased expression of α-SMA. In the present study, the levels of α-SMA reflected the hyperplastic smooth muscularization of pulmonary arteries (Fig. 3). The integrated Od value of α-SMA in the McT group was elevated compared with that in the control group. However, both doses of ASIV inhibited the elevation of the Od value of ...
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Citations
... Research by Lan's team found that MCT can induce ferroptosis in pulmonary artery endothelial cells (PAECs), and the use of ferroptosis inhibitors significantly reverses this effect [192,193]. Astragaloside IV, a natural product, obstructs monocrotaline -induced pulmonary arterial hypertension by improving inflammation and pulmonary artery remodeling [194], but its specific mechanism of action remains unclear. Notably, studies have shown that Astragaloside IV can modulate ferroptosis and alleviate various diseases. ...
Respiratory diseases, marked by structural changes in the airways and lung tissues, can lead to reduced respiratory function and, in severe cases, respiratory failure. The side effects of current treatments, such as hormone therapy, drugs, and radiotherapy, highlight the need for new therapeutic strategies. Traditional Chinese Medicine (TCM) offers a promising alternative, leveraging its ability to target multiple pathways and mechanisms. Active compounds from Chinese herbs and other natural sources exhibit anti-inflammatory, antioxidant, antitumor, and immunomodulatory effects, making them valuable in preventing and treating respiratory conditions. Ferroptosis, a unique form of programmed cell death (PCD) distinct from apoptosis, necrosis, and others, has emerged as a key area of interest. However, comprehensive reviews on how natural products influence ferroptosis in respiratory diseases are lacking. This review will explore the therapeutic potential and mechanisms of natural products from TCM in modulating ferroptosis for respiratory diseases like acute lung injury (ALI), asthma, pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD), lung ischemia–reperfusion injury (LIRI), pulmonary hypertension (PH), and lung cancer, aiming to provide new insights for research and clinical application in TCM for respiratory health.
... For PIK3R1, SRC, PIK3CA, AKT1, PTK2, PTGS2, ESR1, ESR2, JAK2, HDAC7, ROCK1, HDAC4, TBK1 and PDK1, the active pocket's locations were built depending on the original ligands' or original peptides' positions in the 3D structures, and the size of the grid Box and the X, Y and Z centers were adjusted based on the original ligands or peptides of the receptor. For FLT1, the size of gird Box was set to 15 15 15, and the coordinates of center were set to center_x = −18.367, center_y = 13.527 and center_z = 29.601. ...
Glioma treatment in traditional Chinese medicine has a lengthy history. Astragalus membranaceus, a traditional Chinese herb that is frequently utilized in therapeutic practice, is a component of many Traditional Chinese Medicine formulas that have been documented to have anti-glioma properties. Uncertainty persists regarding the molecular mechanism behind the therapeutic effects. Based on results from network pharmacology and molecular docking, we thoroughly identified the molecular pathways of Astragalus membranaceus’ anti-glioma activities in this study. According to the findings of the enrichment analysis, 14 active compounds and 343 targets were eliminated from the screening process. These targets were mainly found in the pathways in cancer, neuroactive ligand–receptor interaction, protein phosphorylation, inflammatory response, positive regulation of phosphorylation, and inflammatory mediator regulation of Transient Receptor Potential (TRP) channels. The results of molecular docking showed that the active substances isoflavanone and 1,7-Dihydroxy-3,9-dimethoxy pterocarpene have strong binding affinities for the respective targets ESR2 and PTGS2. In accordance with the findings of our investigation, Astragalus membranaceus active compounds exhibit a multicomponent and multitarget synergistic therapeutic impact on glioma by actively targeting several targets in various pathways. Additionally, we propose that 1,7-Dihydroxy-3,9-dimethoxy pterocarpene and isoflavanone may be the main active ingredients in the therapy of glioma.
... AS-IV is the most active triterpenoid glycoside of Astragalus membranaceus, and has a variety of pharmacological effects, including anti-oxidation, anti-atherosclerosis, anti-cancer and enhancing immune function, etc. [8]. Recent research found that AS-IV has protective effect on PAH, such as attenuating hypoxia-induced inflammation and pulmonary vascular remodeling [9,10]. However, the protective mechanism of AS-IV in PAH has not been fully understood. ...
Background
Astragaloside (AS)-IV, extracted from traditional Chinese medicine Astragalus mongholicus , has been widely used in the anti-inflammatory treatment for cardiovascular disease. However, the mechanism by which AS-IV affects pulmonary artery hypertension (PAH) development remains largely unknown.
Methods
Monocrotaline (MCT)-induced PAH model rats were administered with AS-IV, and hematoxylin-eosin staining and Masson staining were performed to evaluate the histological change in pulmonary tissues of rats. Pulmonary artery smooth muscle cells (PASMCs) were treated by hypoxia and AS-IV. Pyroptosis and fibrosis were assessed by immunofluorescence, western blot and enzyme-linked immunosorbent assay.
Results
AS-IV treatment alleviated pulmonary artery structural remodeling and pulmonary hypertension progression induced by MCT in rats. AS-IV suppressed the expression of pyroptosis-related markers, the release of pro-inflammatory cytokine interleukin (IL)-1β and IL-18 and fibrosis development in pulmonary tissues of PAH rats and in hypoxic PAMSCs. Interestingly, the expression of prolyl-4-hydroxylase 2 (PHD2) was restored by AS-IV administration in PAH model in vivo and in vitro, while hypoxia inducible factor 1α (HIF1α) was restrained by AS-IV. Mechanistically, silencing PHD2 reversed the inhibitory effect of AS-IV on pyroptosis, fibrosis trend and pyroptotic necrosis in hypoxia-cultured PASMCs, while the HIF1α inhibitor could prevent these PAH-like phenomena.
Conclusion
Collectively, AS-IV elevates PHD2 expression to alleviate pyroptosis and fibrosis development during PAH through downregulating HIF1α. These findings may provide a better understanding of AS-IV preventing PAH, and the PHD2/HIF1α axis may be a potential anti-pyroptosis target during PAH.
... (locally known as "mojia huangqi", ME), two perennial leguminous plants with wide distribution, belong to the same traditional Chinese medicine (TCM) named "Huangqi" in Chinese Pharmacopoeia (2020 edition). Generally, MO and ME are widely applied for immunity improvement [1], cardiotonic enhancement [2], anti-hypertension [3], anti-cancer [4], antivirus [5] and anti-diabetes [6][7][8] treatments. Our previous study proved that the chemical components of MO and ME were obviously different [9]. ...
Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) P. K. Hsiao (MO) and Astragalus membranaceus (Fisch.) Bug. (ME) are two primary sources of the Astragalus herb, also known as “Huangqi” in China, which is widely applied to treat hypertension, glomerulonephritis, ischemic heart disease, and diabetes mellitus. As two different sources of the Astragalus herb, the chemical profiles of MO and ME may be different. Previous studies showed abundant differences in chemical composition between MO and ME. Therefore, the by-products of MO and ME, such as Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) P. K. Hsiao flower (MOF) and Astragalus membranaceus (Fisch.) Bug. flower (MEF), may have different phytochemical profiles. In this paper, a metabolomics method combined with ultra-high-performance liquid chromatography and electrospray ionization/quadrupole time-of-flight mass spectrometry (UHPLC−Q−TOF−MS/MS) was employed to analyze the components of MOF and MEF. Consequently, the results of principal component analysis (PCA) showed that MOF and MEF could be separated clearly. In total, 31 chemical markers differentiating MOF and MEF were successfully identified, including 22 flavonoids, 8 isoflavones and 1 benzopyran. Among them, the contents of 18 components, including Calycosin, Cyanidin-3-O-glucoside, Quercetin, Rutin, Kaempferol, Formononetin, Isomucronulatol and Prim-O-glucosylcimifugin in MEF, were significantly higher than in MOF. In turn, the contents of another 13 components, covering Biochanin A, Tectoridin, Isomucronulatol-7-O-glucoside, Liquiritin, Rhamnetin, etc., were lower in the MEF group than that in the MOF group. It is worth noting that flavonoids, especially flavonoid glycosides, were the primary active chemical ingredients in MOF and MEF. The 18 ingredients in MEF with a higher level carried out diverse activities, like anti-oxidant, anti-inflammatory, anti-bacterial and anti-tumor activities, which led us to speculate that MEF may have greater pharmacological effects and potential development prospects than MOF. The present results displayed that the contents of ingredients in the two different species of plants were radically different, and there was significant uniqueness to the components of MOF and MEF. Our study not only provides helpful chemical information for further quality assessment and active mechanism research of MOF and MEF but also offers scientific support for the resource utilization of MOF and MEF.
... Additionally, factors such as hypoxia-inducible factor-1 (HIF-1α), which has an important role in PH, can regulate ET production and EC migration [24]. After a period of hypoxemia, a number of hypoxia-sensitive inflammatory responses and proliferative pathways are activated, leading to increased vascular resistance and even pulmonary vascular remodeling [25,26]. The exposure of pulmonary artery ECs to hypoxia in humans can cause an increase in HIF-1 expression, and the heterozygous expression of HIF-1 and HIF-2 in mice can have a protective effect against PH [27,28]. ...
Pulmonary hypertension (PH) is a disease which affects the cardiopulmonary system; it is defined as a mean pulmonary artery pressure (mPAP) > 20 mmHg as measured by right heart catheterization at rest, and is caused by complex and diverse mechanisms. In response to stimuli such as hypoxia and ischemia, the expression and synthesis of endothelin (ET) increase, leading to the activation of various signaling pathways downstream of it and producing effects such as the induction of abnormal vascular proliferation during the development of the disease. This paper reviews the regulation of endothelin receptors and their pathways in normal physiological processes and disease processes, and describes the mechanistic roles of ET receptor antagonists that are currently approved and used in clinical studies. Current clinical researches on ET are focused on the development of multi-target combinations and novel delivery methods to improve efficacy and patient compliance while reducing side effects. In this review, future research directions and trends of ET targets are described, including monotherapy and precision medicine.
... An imbalance in the lung inflammatory response leads to the occurrence of many major lung diseases, such as pulmonary hypertension , acute lung injury (Zhai et al., 2022), pneumoconiosis , chronic obstructive pulmonary disease (Kim et al., 2023), and lung cancer (Ahmad et al., 2022). 3-Bromopyruvic acid, fucoidan oligosaccharide and astragaloside IV alleviate monocrotaline-induced pulmonary hypertension in rats through an anti-inflammatory pathway Jin et al., 2021); The downregulation of miR-let-7e suppresses lung inflammation by targeting the SCOS1/ OPEN ACCESS EDITED BY NFκB signaling pathway, thereby reducing acute lung injury induced by lipopolysaccharide (LPS) in mice (Li W. et al., 2021). Ghrelin protects rats from pulmonary vascular dysfunction caused by acute lung injury by inhibiting pulmonary inflammatory response (Li G. et al., 2021); LPS promotes pulmonary fibrosis in silicosis by aggravating the inflammatory response of alveolar macrophages (Tan et al., 2020). ...
In recent years, the unique and diverse physicochemical properties of nanoparticles have brought about their wide use in many fields; however, it is necessary to better understand the possible human health risks caused by their release in the environment. Although the adverse health effects of nanoparticles have been proposed and are still being clarified, their effects on lung health have not been fully studied. In this review, we focus on the latest research progress on the pulmonary toxic effects of nanoparticles, and we summarized their disturbance of the pulmonary inflammatory response. First, the activation of lung inflammation by nanoparticles was reviewed. Second, we discussed how further exposure to nanoparticles aggravated the ongoing lung inflammation. Third, we summarized the inhibition of the ongoing lung inflammation by nanoparticles loaded with anti-inflammatory drugs. Forth, we introduced how the physicochemical properties of nanoparticles affect the related pulmonary inflammatory disturbance. Finally, we discussed the main gaps in current research and the challenges and countermeasures in future research.
... 30 mg/kg/day) reduced MCT-induced pulmonary artery pressure increases and inhibited pulmonary artery remodeling in SD rats. In vitro studies, AS-IV (10-80 µM) inhibited hypoxia-induced proliferation and anti-apoptosis of human PASMCs and inhibited HIF-1α and p-ERK1/2 protein expression enhancement in human PASMCs (Jin et al., 2021). In another study, AS-IV (2 mg/kg) was shown to mitigate pulmonary artery remodeling in rats with PAH. ...
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.
... Inflammation plays an important role in PAH development according to a growing number of studies. [3,4] As a biomarker for clinical diagnosis of PAH, [5] inflammatory cytokines expression is abnormally elevated in PAH model rats [6] and PAH patients [7] and involved in the proliferation of PASMCs [8] and pulmonary vascular remodelling. [9] Nobiletin, a flavonoid that can be obtained from the peel of citrus fruits, [10] has been proved by many studies to have extensive pharmacological activities, such as anti-inflammatory, [11,12] antioxidant, [13][14][15] inhibits cell proliferation and migration. ...
Objectives:
Nobiletin is a flavonoid found in the peel of Citrus sinensis (oranges). The purpose of this study is to investigate whether Nobiletin can alleviate the monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and explore the underlying mechanisms.
Methods:
The PAH rat model was replicated by subcutaneous injection of MCT. Nobiletin (1, 5 and 10 mg/kg) was administered by gavage from day 1 to day 21. After 21 days of MCT injection, the mean pulmonary artery pressure, pulmonary vascular resistance, Fulton Index, pulmonary artery remodelling, blood routine parameters, liver and kidney functions was measured. The level of inflammatory cytokines and PI3K/Akt/STAT3 were detected by qPCR, ELISA and western blot, the proliferation of pulmonary artery smooth muscle cells (PASMCs) was evaluated by CCK-8.
Key findings:
Nobiletin (10 mg/kg) inhibited the MCT-induced increase in mean pulmonary artery pressure and pulmonary vascular resistance, right ventricular hypertrophy and pulmonary artery remodelling in rats. Nobiletin decreased the levels of inflammatory cytokines and phosphorylation level of PI3K/Akt/STAT3 in lungs of MCT-treated rats. Nobiletin inhibited the proliferation and lowered the inflammatory cytokines level induced by PDGF-BB in PASMCs.
Conclusion:
Nobiletin attenuates MCT-induced PAH, and the potential mechanism is to inhibit inflammation through PI3K/Akt/STAT3 pathway.
... Astragaloside IV can alleviate PH by reducing inflammation and PASMC proliferation in vivo and in vitro experiments [88]. In HPAECs, astragaloside IV normalizes hypoxia-induced inflammatory cytokine release, HIF-1α levels, and VEGF [89]. Astragaloside IV also attenuates inflammatory responses mediated by NLRP-3/calpain-1 in the development of PH [90]. ...
... Hypoxia significantly reduced the levels of the pro-apoptotic proteins Bax, cleaved caspase-3, and cleaved caspase-9, while it in-creased the expression of the antiapoptotic protein Bcl-2 in HPASMCs. Astragaloside IV, puerarin, baicalein, and many other natural products can inhibit apoptotic resistance in PVSMCs by modulating apoptotic proteins [74,89,145]. Mitochondria balance cell apoptosis by regulating a family of apoptotic proteins [146]. Apigenin is a widely distributed natural dietary flavonoid that can induce mitochondrial-dependent apoptosis in PASMCs by inhibiting the HIF-1α-KV1.5 channel pathway [147]. ...
... TIIA, ligustrazine, and resveratrol are also adept at regulating ion channels [33,49,62]. STS, astragaloside IV, salidroside, and apigenin can regulate cell apoptosis [38,89,147,148]. Baicalin and chrysin may reduce collagen deposition [68,153]. ...
Pulmonary hypertension (PH) is a lethal disease due to the remodeling of pulmonary vessels. Its pathophysiological characteristics include increased pulmonary arterial pressure and pulmonary vascular resistance, leading to right heart failure and death. The pathological mechanism of PH is complex and includes inflammation, oxidative stress, vasoconstriction/diastolic imbalance, genetic factors, and ion channel abnormalities. Currently, many clinical drugs for the treatment of PH mainly play their role by relaxing pulmonary arteries, and the treatment effect is limited. Recent studies have shown that various natural products have unique therapeutic advantages for PH with complex pathological mechanisms owing to their multitarget characteristics and low toxicity. This review summarizes the main natural products and their pharmacological mechanisms in PH treatment to provide a useful reference for future research and development of new anti-PH drugs and their mechanisms.
... Specifically, the effects of AS-IV mentioned above may be achieved by down-regulating the expression of Jagged-1/Notch-3/Hes-5 both in rat lungs and cultured PASMCs exposed to hypoxia. Recently, astragaloside IV has been found to attenuate MCT-induced PH as indicated by reduction of RVSP and medial wall thickness through improving inflammation response, pulmonary endothelial dysfunction, PASMCs proliferation, and resistance to cell apoptosis [166]. To be Specifical, AS-IV inhibited the increase of TNF-α and IL-1β concentrations and gene expression in serum and lung tissues of rats, respectively; it also reduced the expression of HIF-1α, p-ERK, and B-cell lymphoma-2 (Bcl-2) proteins but increased the expression of p27, p21, Bcl-2 associated X (Bax), caspase-9 and caspase-3 proteins in hPASMCs; meanwhile, AS-IV normalized hypoxia-induced elevation of inflammatory factors, HIF-1α, and VEGF protein in human pulmonary artery endothelial cells (PAECs). ...
Pulmonary hypertension (PH) is a complex multifactorial disease characterized by increased pulmonary vascular resistance and pulmonary vascular remodeling (PVR), with high morbidity, disability, and mortality. The abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) is the main pathological change causing PVR. At present, clinical treatment drugs for PH are limited, which can only improve symptoms and reduce hospitalization but cannot delay disease progression and reduce survival rate. In recent years, numerous studies have shown that traditional Chinese medicine monomers (TCMs) inhibit excessive proliferation of PASMCs resulting in alleviating PVR through multiple channels and multiple targets, which has attracted more and more attention in the treatment of PH. In this paper, the experimental evidence of inhibiting PASMCs proliferation by TCMs was summarized to provide some directions for the future development of these mentioned TCMs as anti-PH drugs in clinical.
