Review of the pharmacological effects of astragaloside IV and its autophagic mechanism in association with inflammation

Table 1 Protective effect of astragaloside IV on cardiovascular disease

Disease categories	Study object/model	Effect induced by autophagy	Mechanism (targets or pathways)	Ref.
Myocardial I/R injury	H2O2 in cardiomyocytes; LAD in mice	(-) Myocardial I/R injury via (-) I/R-caused autophagosome accumulation	(+) SOD2, (-) O2	Huang et al[21]
Myocardial injury	Doxorubicin in rats	(-) The heart damage of rats via (-) autophagy	(+) PI3K/Akt pathway	Luo et al[24]
Cardiac dysfunction	LPS in rats	(-) Cardiac dysfunction, reduce heart injury, (-) autophagy	(+) Calcium- and mitochondrial energy metabolism-related proteins	Wang et al[19]
Myocardial hypertrophy	The abdominal aorta narrow in rats; mechanically stretching cardiomyocytes	(+) Cardiac function, cardiomyocyte morphology; (+) Autophagy	(+) LC3 II expression, (-) p62 levels	Zhang et al[20]
Myocardial infarction	H/R injured H9C2 cells	(-) The H/R injury induced apoptosis and autophagy	(-) Autophagy related genes (Beclin 1 and LC3 II); the interactions between Bcl-2 and Beclin-1 enhanced by GATA	Yang et al[22]
Acute ischaemic heart disease	High glucose in rat cardiomyocytes H9C2	(-) Cardiomyocyte injury, (-) HG-induced oxidative stress and autophagy	Pathways [miR-34a/Bcl2/(LC3 II/LC3 I) and pAKT/Bcl2/(LC3 II/LC3 I)]	Zhu et al[23]
Atherosclerosis	High-fat diet in ApoE-/-mice; β-glycerophosphate in human VSMCs	(-) Autophagy and mineralization of VSMCs in atherosclerosis	(-) DUSP5 and autophagy-related proteins; (+) H19, p-ERK1/2 and p-mTOR	Song et al[59]
Mitochondrial dysfunction	Ang II in rat aortic VSMCs	(-) Ang II-induced mitochondrial dysfunction in rat VSMCs via (+) mitochondrial autophagy	(-) OCRs, ATP and mtDNA, the disruption of mitochondrial structural integrity	Lu et al[58]

LAD: Left anterior descending; LPS: Lipopolysaccharide; LC: Lung cancer; H/R: Hypoxia/reoxygenation; HG: High glucose; H9C2: A subclone of the original clonal cell line which exhibits many of the properties of skeletal muscle; VSMC: Vascular smooth muscle cell; OCR: Oxygen consumption rate.

Table 2 Protective effect of astragaloside IV on the brain and nervous system

Disease categories	Study object/model	Effect induced by autophagy	Mechanism (targets or pathways)	Ref.
Ischemic stroke	MCAO in SD rats; OGD/R in HT22 cells	A neuroprotective role (-) apoptosis (+) autophagy	(+) cell viability, balanced Bcl-2 and Bax expression, (-) the rate of apoptosis, (-) p62, (+) LC3 II/LC3 I	Zhang et al[27]
Acute ischaemic stroke	Acute ischaemic stroke mice	(-) The abnormal intestinal microbial; (-) ROS, homocysteine and FFA, NOX2/4, and autophagy marker	(-) Autophagy-related gene (Beclin 1, LC3 II, Atg 12	Xu et al[28]
Ischemic stroke	OGD/R in PC12 cells	(-) Excessive autophagy and damage in PC12 cells	The PI3K I/Akt/mTOR and PI3K III/Becline-1/Bcl-2 signalling pathways	Huang et al[30]
Spinal cord injury	Vascular clip to clamp the spinal cord in SD rats	(+) Functional recovery in the spinal cord; (-) apoptosis via (+) autophagy in neuronal cells	(-) mTORC1 (+) lysosomal biogenesis through TFEB	Lin et al[29]
Parkinson’s disease	MPTP-induced PD mouse model	(-) The loss of dopamine neurons and behavioural deficits; (+) mitophagy	(-) Damaged mitochondria accumulation, (-) mitochondrial ROS generation	Xia et al[31]

MCAO: Middle cerebral artery occlusion; OGD/R: Oxygen and glucose deprivation/reoxygenation; PC12: A neuron cell line; LC: Lung cancer; ROS: Reactive oxygen species; FFA: Free fatty acids; NOX: NADPH oxidases; Atg: Autophagy; MPTP: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PD: Parkinson’s disease.

Table 3 Protective effect of astragaloside IV on lung disease

Disease categories	Study object/model	Effect induced by autophagy	Mechanism (targets or pathways)	Ref.
Lung injury	PM2.5-induced lung toxicity in rats	(-) PM2.5-induced lung toxicity; (+) autophagic flux	(+) AMPK/mTOR pathway	Wang et al[36]
Lung injury	PM2.5 in rats and rat alveolar macrophages	(-) Severe inflammation and oxidative stress, (+) autophagic flux mainly via autophagosome degradation	(-) The PI3K/Akt/mTOR pathway to (+) autophagy and (-) inflammation	Pei et al[37]
Lung injury	LPS in pulmonary epithelial cell	(-) Apoptosis in cell model, (-) autophagy initiation	(-) The oxidative stress and inflammatory response	Liu et al[34]
Lung adenocarcinoma	Bevacizumab in A549 cells	(-) Proliferation inhibition and apoptosis promotion (-) inhibiting autophagy pathway	Autophagy-related proteins (p62, LC3 II/LC3 I), p-AKT and p-Mtor	Li et al[57]
NSCLC	Cisplatin-resistant the NSCLC cell lines	(-) Chemoresistance to cisplatin in NSCLC cells via (-) inhibition of ER stress or autophagy	Autophagy-related proteins (Beclin1, LC3 II/I)	Lai et al[35]

AMPK: AMP-activated protein kinase; LPS: Lipopolysaccharide; LC: Lung cancer; NSCLC: Non-small cell lung cancer; ER: Endoplasmic reticulum

Table 4 Protective effect of astragaloside IV on diabetes

Disease categories	Study object/model	Effect induced by autophagy	Mechanism (targets or pathways)	Ref.
Diabetic peripheral neuropathy	A high-glucose medium in Schwann cells	Antioxidant activity via (-) the autophagy overactivation of Schwann cells	(-) Reactive oxygen species and (-) autophagy-related proteins (LC3, PINK and Parkin); protective effect (mitochondrial morphology and membrane potential)	Wei et al[38]
Diabetic peripheral neuropathy	High-fat diet in rats; high glucose in Schwann RSC96 cells	(-) The myelin sheath injury by the apoptosis of Schwann cells via (+) autophagy	(-) The activation of the PI3K/Akt/mTOR signalling pathway by (+) miR-155 expression	Yin et al[41]
DN	KK-Ay diabetic mice; immortalized mouse podocytes	(-) Glucose-induced podocyte EMT and (+) enhanced autophagy	The SIRT1–NF-κB pathway	Wang et al[40]
DN	STZ diabetic mice; high glucose in podocytes	(-) The progression of DN via (+) autophagy induction	AMPKα-promoted autophagy induction	Guo et al[39]
Liver injury in diabetics	Highfat diets + lowdose STZ in diabetic liver injury rats	(+) Autophagy in the liver of T2DM rats; (-) IR, dyslipidaemia, oxidative stress and inflammation	The promotion of AMPK/mTORmediated autophagy	Zhu et al[42]

LC: Lung cancer; PINK: PTEN-induced putative kinase 1; RSC: Rat Schwann cells; KK-Ay: Spontaneous diabetes; EMT: Epithelial-mesenchymal transition; STZ: Streptozotocin; DN: Diabetic nephropathy; IR: Immunoreactive; T2DM: Type 2 diabetes mellitus.

Table 5 Protective effect of astragaloside IV on organ injury

Disease categories	Study object/model	Effect induced by autophagy	Mechanism (targets or pathways)	Ref.
Liver injury	Iron overload (iron dextran) in LO2 cells	(-) Damage to hepatocytes, excessive autophagy, autophagosomes and apoptosis of hepatocytes by the iron overload	(-) LC3 II/I, (+) p62	Xie et al[43]
Liver and kidney injury	Cisplatin in rats	Protected against cisplatin-induced injury by (+) autophagy	(-) Autophagy-mediated NLRP3	Qu et al[44]

LO2: Human normal embryonic hepatocytes; LC: Lung cancer; NLRP3: NLR family, pyrin domain containing 3.

Table 6 Protective effect of astragaloside IV on kidney disease

Disease categories	Study object/model	Effect induced by autophagy	Mechanism (targets or pathways)	Ref.
Chronic glomerular nephritis	Cationic bovine serum in rats	(+) Kidney function, (-) kidney lesion, (-) inflammatory, (+) autophagy	(-) The activation of PI3K/AKT/AS160 pathway	Lu et al[46]
Diabetic kidney disease	A high-fat diet in the diabetic KK-Ay mice	(+) Renal function and morphology by (+) autophagy	(-) MC activation through the SIRT1-NF-κB pathway	Wang et al[47]

KK-Ay: Spontaneous diabetes; MC: Mesangial cell.

Table 7 Protective effect of astragaloside IV on gynaecological diseases

Disease categories	Study object/model	Effect induced by autophagy	Mechanism (targets or pathways)	Ref.
Triple-negative breast cancer	The MDA-MB-231 orthotopic mammary tumour in BALB/c nude mice	(-) Cancer cells' proliferation and migration, (+) autophagy flux	(+) The ATG16L1, ATG9B, ATG4D via SANT; (-) TMEM74 and TNF gene expressions	Li et al[48]
Cervical cancer	A SiHa cell in the nude mice	(-) Cervical cancer invasion, (+) autophagy	(+) Atg12 and (+) cancer cell autophagy via DCP1A and TMSB4X	Xia et al[49]
Vulvar squamous cell carcinoma	The human VSCC cell line SW962	(-) Cell proliferation, (+) apoptosis and autophagy	The TGF-β/Smad signalling pathway; (+) Beclin 1 and LC3 II, (-) p62	Zhao et al[50]

LC: Lung cancer; MDA-MB-231: Human breast cancer cell line; BALB/c: The white mutant laboratory mouse; Atg: Autophagy; VSCC: Vulvar squamous cell carcinoma; SW962: Human vulva phosphorous cancer cell line; SANT: A novel Chinese herbal monomer combination; DCP1A: mRNA-decapping enzyme 1A; TMSB4X: Thymosin beta-4; TNF: Tumour necrosis factor.

Table 8 The autophagy promotion or inhibition effects of astragaloside IV

Autophagy effects (+, -) and inflammation (R, NR)	Diseases or study model	Effect induced by autophagy	Mechanism (targets or pathways)	Ref.
"+; R"	Lung injury rats induced by PM2.5	(-) GM-CSF, ICAM-1, IFN-γ, TNF-α, IL-6, IL-18 and CRP	The AMPK/mTOR; PI3K/Akt/mTOR pathway	Wang et al[36], Pei et al[37]
"+; R"	Liver injury in T2DM rats	(-) TNFα and IL6	The AMPK/mTOR signalling pathway	Zhu et al[42]
"+; R"	Liver and kidney injury in rats induced by cisplatin	(-) The NLRP3 inflammasome	(+) LC3 II/I and (-) p62	Qu et al[44]
"+; R"	Acute spinal cord injury	(-) neuroinflammation; (-) iNOS, COX-2 and TNF-α	Polarize towards an M2 phenotype in microglial cells	Lin et al[29]
"+; R"	Myocardial hypertrophy by mechanical stress	(-) NLRP3 and IL-1β in cardiomyocytes	(+) LC3 II/I and (-) p62	Zhang et al[20]
"+; R"	H1N1 infection	(-) IL-1β	(+) Autophagosome formation, (+) autolysosomes, (+) the fusion of autophagosome and lysosome	Zhang et al[53]
"+; R"	The rat "McFarlane flap" model	Skin flap survival; (-) TNF-α, IL-1β and IL6 and (-) leukocyte infiltration	(+) Autophagosome formation related protein, Beclin 1 and LC3 II/I	Lin et al[52]
"+; NR"	Lung cancer	Favourable in lung cancer	The p53/AMPK/mTOR signalling pathway	Yang et al[32]
"+; NR"	Lung adenocarcinoma cells	(-) The viability and promote the apoptosis of A549 cells	The AKT and mTOR pathways	Li et al[57]
"+; NR"	Vulvar squamous cell carcinoma	(-) Cell proliferation	The TGF-β/Smad pathway	Zhao et al[50]
"+; NR"	The gastric mucosa	A beneficial effect on gastric mucosa in vivo	(+) Beclin1, p62, ATG5, and ATG12	Cai et al[51]
"+; NR"	Diabetic KK-Ay mice	Improve renal fibrosis and function	The SIRT1–NF-κB pathway; (-) mesangial cell activation through the SIRT1-NF-κB pathway	Wang et al[40,47]
"+; NR"	DPN induced by Schwann cell apoptosis	(-) Myelin sheath injury	(-) The PI3K/Akt/mTOR signalling pathway	Yin et al[41]
"+; NR"	Diabetic rats	(-) Liver injury and insulin resistance	The AMPK/mTOR pathway	Zhu et al[42]
"+; NR"	Nervous system diseases	(-) Parkinson's disease	(-) Astrocyte senescence	Xia et al[31]
"+; NR"	Nervous system diseases	(-) Brain injury caused by ischaemic stroke	Further (+) LC3II/LC3 I	Zhang et al[27]
"+; NR"	Cardiovascular diseases; rat VSMCs induced by Ang II	Favourable effects on mitochondrial dysfunction	Drp1 and parkin are vital to mitochondrial autophagy	Lu et al[58]
"-; R"	Acute respiratory distress syndrome; the pulmonary endothelial ARDS cell model stimulated by LPS	(-) Inflammation and apoptosis	(-) Autophagy proteins	Liu et al[34]
"-; R"	Kidney disease; CGN rats	(-) Kidney injury and (-) inflammation	(-) The PI3K/AKT/AS160 pathway	Lu et al[46]
"-; R"	Graves' orbitopathy	Protect against Graves' orbitopathy; (-) IL-6, IL-8, TNF-α, and MCP-1	(-) Beclin 1, Atg 5 and LC3 II/LC3 I	Li et al[56]
"-; R"	Thermal injury in vitro and in vivo	(-) Inflammatory responses	The PERK-eIF2α pathway	Dong et al[54]
"-; NR"	Heart diseases	(-) The cardiotoxicity of rats; (-) H/R-injured H9C2 cells	PI3K/Akt pathway activation	Huang et al[21]
"-; NR"	Heart diseases	Improve heart dysfunction induced by LPS	(-) Calcium-mediated apoptosis and autophagy by targeting miR-1	Wang et al[19]
"-; NR"	Atherosclerosis; VSMCs in thoracic aorta of mice and in vitro VSMCs model	(-) Mineralization in vitro and in vivo models	(-) DUSP5 and autophagy-related proteins and (+) H19, p-ERK1/2 and p-mTOR	Song et al[59]
"-; NR"	Nerve injury; PC12 cells in response to OGD/R	(-) Excessive autophagy injury	(-) The number of autophagosomes; (-) LC3 II/LC3 I, (+) p62; PI3K I/Akt/mTOR pathway	Huang et al[30]
"-; NR"	Nerve injury; Schwann cells induced by high glucose	(-) Mitophagy and excessive autophagy	(-) Autophagy markers Beclin-1, Atg12, and LC3 II	Wei et al[38]
"-; NR"	Liver injury; L02 hepatocytes induced by iron overload	(-) The damage to L02 hepatocytes	(-) Autophagosome formation; (+) p62, (-) LC3II/LC3 I	Xie et al[43]
"-; NR"	Lung injury caused by PM2.5 in vivo and in vitro	(-) Lung injury	Degraded autophagosomes	Pei et al[37]
"-; NR"	Cancer; NSCLC cells treated with cisplatin	Counteract chemoresistance	(-) Autophagy (Beclin 1) and ER stress (GPR78)	Lai et al[35]
"-; NR"	Cancer	(-) Invasion of cervical cancer	(-) Atg7/Atg12, (-) DCP1A and TMSB4X	Li et al[48]

Autophagy effects (+, -): “+” Indicates autophagy promotion, “-” indicates autophagy inhibition. Inflammation (R, NR): “R” indicates “related”, “NR” indicates “not related”. LC: Lung cancer; GM-CSF: Granulocyte-macrophage colony-stimulating factor; ICAM: Intercellular adhesion molecule; IFN: Inborn errors of interferon; TNF: Tumour necrosis factor; IL: Interleukin; Atg: Autophagy; NLRP3: NLR family, pyrin domain containing 3; H1N1: Influenza A; CRP: C-reactive protein; T2DM: Type 2 diabetes mellitus; iNOS: Inducible nitric oxide synthases; COX-2: Cyclooxygenase-2; KK-Ay: Spontaneous diabetes; DPN: Diabetic peripheral neuropathy; VSMC: Vascular smooth muscle cell; ARDS: Acute respiratory distress syndrome; LPS: Lipopolysaccharide; CGN: Chronic glomerular nephritis; MCP-1: Monocyte chemotactic protein-1; H9C2: A subclone of the original clonal cell line which exhibits many of the properties of skeletal muscle; PC12: A neuron cell line; H/R: Hypoxia/reoxygenation; OGD/R: Oxygen and glucose deprivation/reoxygenation; NSCLC: Non-small cell lung cancer; DCP1A: mRNA-decapping enzyme 1A; TMSB4X: Thymosin beta-4.