Untapping the Potential of Astragaloside IV in the Battle Against Respiratory Diseases

Figures & data

Figure 1 Brief introduction and profile of AS-IV. AS-IV is a natural saponin isolated extracted from Radix astragali (Huangqi in Chinese) and possesses a wide range of pharmacological activities including respiratory diseases treatment.

Figure 2 The targets and pathways of AS-IV in treating PH. (A). AS-IV inhibits PASMCs proliferation by suppressing Notch3 and RhoA pathway. (B). AS-IV ameliorated apoptosis resistance in PASMCs by downregulating Bcl-2, phospho-ERK, and HIF-1α expressions. (C). AS-IV attenuates inflammatory response mediated by NLRP-3/calpain-1. Created with BioRender.com.

Figure 3 The targets and pathways of AS-IV in treating PF. (A). AS-IV inhibits the TGF-β1/Smads signaling pathway by suppressing MTA1 and NLRP3 expression, thereby inhibiting EMT; AS-IV also inhibits EMT by suppressing the TGF-β1/PI3K/AKT/Foxo3α signaling pathway. (B). AS-IV ameliorates oxidative stress via activation of Nrf2. (C). AS-IV alleviates inflammation by blocking NF-κB activation. (D). AS-IV blocks the differentiation of lung fibroblasts to myofibroblasts by inhibiting the TGF-β1/Smads signaling pathway. Created with BioRender.com.

Table 1 The Summary of Mechanisms of as-IV in Respiratory Diseases

Respiratory Diseases	Animal Models	Cell Lines	Targets and Mechanisms	Ref.
Pulmonary hypertension	SD rats	PASMCs	Jagged-1↓ Notch-3↓ Hes-5↓ PCNA↓ α-SMA↓; PASMCs proliferation↓	[35]
	C57BL/6 mice	PASMCs	Ki-67↓ RhoA↓ p27↓; PASMCs proliferation↓	[7]
	SD rats	PASMCs	ERK/HIF-1α pathway↓ Bcl-2↓; PASMCs apoptosis↑	[36]
	SD rats	PAECs	NLRP3 inflammasome/calpain-1 pathway↓; pulmonary vascular inflammation↓	[38]
Pulmonary fibrosis	SD rats	A549 cells	Collagen-I↓ MDA↓ SOD↑ GSH-Px↑ TNF-α↓ IL-6↓ E-cad↑ α-SMA↓ TGF‐β1↓ PI3K↓ AKT↓ FOXO3α↑; epithelial-mesenchymal transition↓	[41]
	SD rats	RLE-6TN cells	MTA1↓E-cad↑ α-SMA↓ TGF‐β1↓; epithelial-mesenchymal transition↓	[42]
	NA	Fibroblasts	NLRP3↓ TGF-β1↓ α-SMA↓ collagen-I↓ collagen-III↓ E-cad↑ N-cad↓ Smad2↓ Smad3↓; epithelial-mesenchymal transition↓	[43]
	SD rats	NA	TNF-α↓ IL-6↓ IL-1β↓ NF-κB↓; inflammation↓	[48]
	C57BL/6J mice	NA	HYP↓ TGF‐β1↓ MDA↓ SOD↑ ROS↓ Nrf-2↑ Smad3↑; oxidative stress↓	[49]
	SD rats	Fibroblasts	α-SMA↓ collagen-I↓ collagen-II↓ collagen-III↓ TGF-β1/Smad pathway↓; fibroblasts transformation to myofibroblasts↓	[50]
Lung cancer	C57BL/6 mice	NA	IDO1↓; cytotoxic T lymphocytes activities↑ regulatory T cells activities↓	[58]
	Nude mice	H460 cells	IDO1↓ GBP1↓; T-cell depletion↓	[59]
	C57BL/6 mice	A549, H1299, THP-1 cells	VEGFA↓ Arg-1↓ CD31↓ CD206↓ PPARγ↓ IL-10↓ TGF-β1↓ CCL-7↓ MMP-9↓ MMP-10↓ MMP-14↓ ICAM-1↓ IGF-1↓ CCL-2↓ AMPKα↓; M2-polarized macrophage activity↓	[63]
	C57BL/6 mice	A549 cells	PKC-α/ERK1/2/NF-κB pathway↓ integrin β1↓ MMP-2↓ MMP-9↓; cell invasion and migration↓	[64]
	NA	HCC827, H1299, A549 cells	Akt/GSK-3 pathway↓; cell proliferation↓	[65]
	NA	A549, H1299 cells	GRP78↓ Beclin1↓; ER stress and autophagy↓	[70]
	NA	HCC827, H1299, A549 cells	B7-H3↓; the sensitivity of lung cancer cells to cisplatin↑	[71]
	NA	A549 cells	P62↓ Beclin1↓ LC3I/LC3II↑ Bcl-2↓ Bax↑caspase-3↑ Akt↑ mTOR↑; autophagy↓ the sensitivity of lung cancer cells to bevacizumab↑	[25]
Lung injury	SD rats	NR8383 cells	p62↓ LC3BI/LC3BII↓ PI3K↓ AKT↓ mTOR↓ p65↓; autophagy↓	[81]
	SD rats	NA	AMPK↓ mTOR↓ Bcl-2↑ Bax↓ caspase-3↓ PARP1↓ p65↓; autophagy↓	[82]
	C57BL/6 mice	NA	MDA↓ MPO↓ SOD↑ IL-6↓ IL-1β↓ GSH↑ ROS↓ Nrf-2↑ SLC7A11↑ GPX4↑ FTH1↑ TFRC↓ COX2↓ HO-1↑; ferroptosis↓	[27]
	C57BL/6 mice	NA	NLRP3/caspase-1 pathway↓ IL-1β↓ IL-18↓; pyroptosis↓	[88]
	SD rats	NA	TNF-α↓ IL-6↓ CRP↓ MDA↓ CAT↑ SOD↑ TLR4↓ MyD88↓ NF-κB↓; inflammation↓	[89]
	BALB/C mice	NA	Rho/ROCK/NF-κB pathway↓ IL-6↓ IL-1β↓TNF-α↓; inflammation↓	[90]
	SD rats	RLE-6TN cells	Bcl-2↓ Bax↑ caspase-3↑ miR-21-5p↑ TLR4↓ NF-κB↓; inflammation↓	[91]
Asthma	BALB/c mice	NA	IL-4↓ IL-5↓ IL-13↓ JAK2↓ STAT6↓; inflammation↓	[24]
	BALB/c mice	NA	IL-4↓ IFN-γ↑ IL-10↓ Foxp3↑; inflammation↓	[94]
	BALB/c mice	NA	IL-4↓ IL-5↓I L-17↓ mTORC1 pathway↓; airway hypersensitivity and inflammation↓	[96]
	ICR mice	Human bronchial epithelial cells	IL-1β↓ TNF-α↓ IL-6↓ MDA ↓ SOD↑ JAK3↓ STAT3↓ NF-κB↓; inflammation and oxidative stress↓	[23]
COPD	Wistar rats	NA	IL-1β↓ TNF-α↓ NF-κB↓ GSH↑ NO↓; inflammation and oxidative stress↓	[102]
	BALB/c mice	NA	IL-4↓ IL-5↓I L-17↓ mTORC1 pathway↓; airway hypersensitivity and inflammation↓	[96]
	ICR mice	Human bronchial epithelial cells	IL-1β↓ TNF-α↓ IL-6↓ MDA ↓ SOD↑ JAK3↓ STAT3↓ NF-κB↓; inflammation and oxidative stress↓	[23]
COVID-19	NA	NA	Binding with ACE2 in silico	[105,106]
Obstructive sleep apnoea	NA	Beas-2B cells	MDA↓ ROS↓ IL-1β↓ IL-6↓ IL-8↓TLR4/MAPK/NF-κB pathway↓; inflammation and oxidative stress↓	[95]

Abbreviations: PASMCs, pulmonary artery smooth muscle cells; Hes-5, hes family bHLH transcription factor 5; PCNA, proliferating cell nuclear antigen; α-SMA, α-smooth muscle actin; HIF-1α, hypoxia-inducible factor-1α; NLRP3, nod-like receptor family pyrin domain-containing 3; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; IL-6, interleukin-6; TGF-β, transforming growth factor-β; PI3K, phosphatidylinositol 3-kinase; FOXO3α, forkhead Box O3; NF-κB, nuclear factor-κB; Nrf-2, nuclear factor E2-related factor; MTA1, metastasis-associated gene 1; MDA, malondialdehyde; T-AOC, total antioxidant capacity; ROS, reactive oxygen species; IDO1, indoleamine 2.3-dioxygenase 1; GBP1, guanylate binding protein 1; VEGFA, vascular endothelial growth factor A; PPARγ, proliferator-activated receptor γ; AMPKα, adenosine monophosphate (AMP)-activated protein kinase α; PKC-α, protein kinase C-alpha; ERK1/2, extracellular signal-related kinases 1 and 2; MMP-2, matrix metalloproteinase-2; Akt, protein kinase B; GSK-3β, glycogen synthase kinase-3β; mTOR, mammalian target of rapamycin; PARP1, poly(ADP-ribose) polymerase-1; GPX4, glutathione peroxidase 4; FTH1, ferritin heavy chain 1; HO-1, heme oxygenase-1; TLR4, Toll-like receptor 4; MyD88, myeloid differentiation factor 88; JAK2, Janus kinase 2; STAT6, signal transducer and activator of transcription 6; mTORC1, mechanistic target of rapamycin complex 1; ACE2 angiotensin-converting enzyme 2; MAPK, mitogen-activated protein kinase.

Figure 4 The general map of AS-IV in treating various respiratory diseases. Created with BioRender.com.

Yao J, Fang X, Zhang C, et al. Astragaloside IV attenuates hypoxia‑induced pulmonary vascular remodeling via the Notch signaling pathway. Mol Med Rep. 2021;23(1):89. doi:10.3892/mmr.2020.11726

 PubMed Web of Science ®Google Scholar

Li C, Zhu H, Zhang S, et al. Astragaloside IV ameliorates pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension by restraining the T follicular helper cell response and expanding T follicular regulatory cell response. Phytomedicine. 2022;102:154171. doi:10.1016/j.phymed.2022.154171

 PubMed Web of Science ®Google Scholar

Tian X, Zhang X, Feng Y, et al. Astragaloside IV in hypoxic pulmonary hypertension: an in vivo and in vitro experiments. Appl Biochem Biotechnol. 2022;194(12):6319–6334. doi:10.1007/s12010-022-04027-y

 PubMed Web of Science ®Google Scholar

Sun Y, Lu M, Sun T, et al. Astragaloside IV attenuates inflammatory response mediated by NLRP-3/calpain-1 is involved in the development of pulmonary hypertension. J Cell Mol Med. 2021;25(1):586–590. doi:10.1111/jcmm.15671

 PubMed Web of Science ®Google Scholar

Qian W, Cai X, Qian Q, et al. Astragaloside IV modulates TGF-β1-dependent epithelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis. J Cell Mol Med. 2018;22(9):4354–4365. doi:10.1111/jcmm.13725

 PubMed Web of Science ®Google Scholar

Qian W, Cai X, Qian Q, et al. Metastasis-associated protein 1 promotes epithelial-mesenchymal transition in idiopathic pulmonary fibrosis by up-regulating Snail expression. J Cell Mol Med. 2020;24(11):5998–6007. doi:10.1111/jcmm.15062

 PubMed Web of Science ®Google Scholar

Tian R, Zhu Y, Yao J, et al. NLRP3 participates in the regulation of EMT in bleomycin-induced pulmonary fibrosis. Exp Cell Res. 2017;357(2):328–334. doi:10.1016/j.yexcr.2017.05.028

 PubMed Web of Science ®Google Scholar

Yu WN, Sun LF, Yang H. Inhibitory effects of astragaloside IV on bleomycin-induced pulmonary fibrosis in rats via attenuation of oxidative stress and inflammation. Inflammation. 2016;39(5):1835–1841. doi:10.1007/s10753-016-0420-5

 PubMed Web of Science ®Google Scholar

Tong J, Wu Z, Wang Y, et al. Astragaloside IV synergizing with ferulic acid ameliorates pulmonary fibrosis by TGF-β1/Smad3 signaling. Evid Based Complement Alternat Med. 2021;2021:8845798. doi:10.1155/2021/8845798

 PubMed Web of Science ®Google Scholar

Li N, Feng F, Wu K, et al. Inhibitory effects of astragaloside IV on silica-induced pulmonary fibrosis via inactivating TGF-β1/Smad3 signaling. Biomed Pharmacother. 2019;119:109387. doi:10.1016/j.biopha.2019.109387

 PubMed Web of Science ®Google Scholar

Zhang A, Zheng Y, Que Z, et al. Astragaloside IV inhibits progression of lung cancer by mediating immune function of Tregs and CTLs by interfering with IDO. J Cancer Res Clin Oncol. 2014;140(11):1883–1890. doi:10.1007/s00432-014-1744-x

 PubMed Web of Science ®Google Scholar

Meng Y, Wang W, Chen M, et al. GBP1 facilitates indoleamine 2,3-dioxygenase extracellular secretion to promote the malignant progression of lung cancer. Front Immunol. 2020;11:622467. doi:10.3389/fimmu.2020.622467

 PubMed Web of Science ®Google Scholar

Xu F, Cui WQ, Wei Y, et al. Astragaloside IV inhibits lung cancer progression and metastasis by modulating macrophage polarization through AMPK signaling. J Exp Clin Cancer Res. 2018;37(1):207. doi:10.1186/s13046-018-0878-0

 PubMed Web of Science ®Google Scholar

Cheng X, Gu J, Zhang M, et al. Astragaloside IV inhibits migration and invasion in human lung cancer A549 cells via regulating PKC-α-ERK1/2-NF-κB pathway. Int Immunopharmacol. 2014;23(1):304–313. doi:10.1016/j.intimp.2014.08.027

 PubMed Web of Science ®Google Scholar

Jia L, Lv D, Zhang S, et al. Astragaloside IV inhibits the progression of non-small cell lung cancer through the Akt/GSK-3β/β-Catenin pathway. Oncol Res. 2019;27(4):503–508. doi:10.3727/096504018X15344989701565

 PubMed Web of Science ®Google Scholar

Lai ST, Wang Y, Peng F. Astragaloside IV sensitizes non-small cell lung cancer cells to cisplatin by suppressing endoplasmic reticulum stress and autophagy. J Thorac Dis. 2020;12(7):3715–3724. doi:10.21037/jtd-20-2098

 PubMed Web of Science ®Google Scholar

He CS, Liu YC, Xu ZP, et al. Astragaloside IV enhances cisplatin chemosensitivity in non-small cell lung cancer cells through inhibition of B7-H3. Cell Physiol Biochem. 2016;40(5):1221–1229. doi:10.1159/000453175

 PubMedGoogle Scholar

Li L, Li G, Chen M, et al. Astragaloside IV enhances the sensibility of lung adenocarcinoma cells to bevacizumab by inhibiting autophagy. Drug Dev Res. 2022;83(2):461–469. doi:10.1002/ddr.21878

 PubMed Web of Science ®Google Scholar

Pei C, Wang F, Huang D, et al. Astragaloside IV protects from PM2.5-induced lung injury by regulating autophagy via inhibition of PI3K/Akt/mTOR signaling in vivo and in vitro. J Inflamm Res. 2021;14:4707–4721. doi:10.2147/JIR.S312167

 PubMed Web of Science ®Google Scholar

Wang Z, Wu Y, Pei C, et al. Astragaloside IV pre-treatment attenuates PM2.5-induced lung injury in rats: impact on autophagy, apoptosis and inflammation. Phytomedicine. 2022;96:153912. doi:10.1016/j.phymed.2021.153912

 PubMed Web of Science ®Google Scholar

Wang X, Wang Y, Huang D, et al. Astragaloside IV regulates the ferroptosis signaling pathway via the Nrf2/SLC7A11/GPX4 axis to inhibit PM2.5-mediated lung injury in mice. Int Immunopharmacol. 2022;112:109186. doi:10.1016/j.intimp.2022.109186

 PubMed Web of Science ®Google Scholar

Huang D, Shi S, Wang Y, et al. Astragaloside IV alleviates PM2.5-caused lung toxicity by inhibiting inflammasome-mediated pyroptosis via NLRP3/caspase-1 axis inhibition in mice. Biomed Pharmacother. 2022;150:112978. doi:10.1016/j.biopha.2022.112978

 PubMed Web of Science ®Google Scholar

Wu Y, Xiao W, Pei C, et al. Astragaloside IV alleviates PM2.5-induced lung injury in rats by modulating TLR4/MyD88/NF-κB signalling pathway. Int Immunopharmacol. 2021;91:107290. doi:10.1016/j.intimp.2020.107290

 PubMed Web of Science ®Google Scholar

Chen T, Wang R, Jiang W, et al. Protective effect of astragaloside IV against paraquat-induced lung injury in mice by suppressing Rho signaling. Inflammation. 2016;39(1):483–492. doi:10.1007/s10753-015-0272-4

 PubMed Web of Science ®Google Scholar

Li H, Yao C, Shi K, et al. Astragaloside IV attenuates hypoxia/reoxygenation injury-induced apoptosis of type II alveolar epithelial cells through miR-21-5p. Bioengineered. 2021;12(1):7747–7754. doi:10.1080/21655979.2021.1982845

 PubMed Web of Science ®Google Scholar

Yang X, Wang F. The effect of astragaloside IV on JAK2-STAT6 signalling pathway in mouse model of ovalbumin-induced asthma. J Anim Physiol Anim Nutr (Berl). 2019;103(5):1578–1584. doi:10.1111/jpn.13114

 PubMed Web of Science ®Google Scholar

Huang X, Tang L, Wang F, et al. Astragaloside IV attenuates allergic inflammation by regulation Th1/Th2 cytokine and enhancement CD4(+)CD25(+)Foxp3 T cells in ovalbumin-induced asthma. Immunobiology. 2014;219(7):565–571. doi:10.1016/j.imbio.2014.03.005

 PubMed Web of Science ®Google Scholar

Jin H, Wang L, Li B, et al. Astragaloside IV ameliorates airway inflammation in an established murine model of asthma by inhibiting the mTORC1 signaling pathway. Evid Based Complement Alternat Med. 2017;2017:4037086. doi:10.1155/2017/4037086

 PubMed Web of Science ®Google Scholar

Meiqian Z, Leying Z, Chang C. Astragaloside IV inhibits cigarette smoke-induced pulmonary inflammation in mice. Inflammation. 2018;41(5):1671–1680. doi:10.1007/s10753-018-0811-x

 PubMed Web of Science ®Google Scholar

Chen L, Sun BB, Wang T, et al. Cigarette smoke enhances {beta}-defensin 2 expression in rat airways via nuclear factor-{kappa}B activation. Eur Respir J. 2010;36(3):638–645. doi:10.1183/09031936.00029409

 PubMed Web of Science ®Google Scholar

Ge C, He Y. In silico prediction of molecular targets of astragaloside IV for alleviation of COVID-19 hyperinflammation by systems network pharmacology and bioinformatic Gene Expression Analysis. Front Pharmacol. 2020;11:556984. doi:10.3389/fphar.2020.556984

 PubMed Web of Science ®Google Scholar

Ye M, Luo G, Ye D, et al. Network pharmacology, molecular docking integrated surface plasmon resonance technology reveals the mechanism of Toujie Quwen Granules against coronavirus disease 2019 pneumonia. Phytomedicine. 2021;85:153401. doi:10.1016/j.phymed.2020.153401

 PubMed Web of Science ®Google Scholar

Chen JK, Guo MK, Bai XH, et al. Astragaloside IV ameliorates intermittent hypoxia-induced inflammatory dysfunction by suppressing MAPK/NF-κB signalling pathways in Beas-2B cells. Sleep Breath. 2020;24(3):1237–1245. doi:10.1007/s11325-019-01947-8

 PubMed Web of Science ®Google Scholar