The Molecular Basis of the Anti-Inflammatory Property of Astragaloside IV for the Treatment of Diabetes and Its Complications

Figures & data

Table 1 Summary of Anti-Inflammatory Activities of AS-IV on the Treatment of DM and Its Complications

Species/Cells	Model	Disease	Purification	Treatment (Conc./Time)	Effect	Star Molecule or Mechanism (Direct or Indirect)	Reference
3T3-L1 cells	Insulin resistance	Diabetic mellitus		In vitro: 100 μM for 12 h	Halt entrance of lipase to the triacylglycerol; anti-lipolysis action; promote lipogenesis	Direct: ↓Erk	[42]
HepG2 cells	Insulin resistance	Diabetic mellitus	98.05%	In vitro: 25.6, 51.2, and 102.4 μM for 24 h	Improve hepatic insulin resistance; inhibit lipogenesis	Indirect: ↓PTP1B/IR/SREBP1	[46]
C57BL/6J mice	T2DM	Diabetic mellitus	98%	In vivo: 12.5, 25, 50 mg/kg/day for 2 week	Reduce hepatic glucose production	Indirect: ↓GP/G6Pase	[49]
C2C12 cells	Insulin resistance	Diabetic mellitus		In vitro: 12.5 μM for 2 h	Promote skeletal muscle glucose transport; inhibit IR	Direct: ↓IKK/IκB/NF-κB; ↑IRS/Akt	[50]
SD rats	Metabolic syndrome	Diabetic vascular diseases		In vivo: 0.5, 2 mg/kg/day for 3 week	Improve endothelium dysfunction	Direct: ↑NO/cGMP-related pathway	[52]
SD rats; human umbilical vein endothelial cells	Vascular endothelial dysfunction	Diabetic vascular diseases		In vivo: 40, 80 mg/kg/day for 8 week; in vitro: 100 μM for 48 h	Improve vascular endothelium dysfunction	Direct: ↓TLR4/NF-κB	[53]
Human umbilical vein endothelial cells	Vascular endothelial dysfunction	Diabetic vascular diseases	Chemically pure	In vitro: 1, 10, 50, 100 μg/mL for 4 h	Reduce adhesion	Direct: ↓NF-κB	[54]
SD rats; rat aortic endothelial cells	T1DM; endothelial dysfunction	Diabetic vascular diseases		In vivo: 40, 80 mg/kg/day for 8 week; in vitro: 100 μM for 2 h	Rescue endothelial dysfunction	Direct: ↓P2X7R/p38 MAPK signaling pathway	[55]
Human umbilical vein endothelial cells	Vascular endothelial dysfunction	Diabetic vascular diseases	98%	In vitro: 25, 50, 100 μM for 48 h	Inhibit inflammation and apoptosis	Direct: ↓JNK	[56]
Human umbilical vein endothelial cells	Vascular endothelial dysfunction	Diabetic vascular diseases	98%	In vitro: 3, 10, 30 μg/mL for 3 d	Inhibit apoptosis	Indirect: ↑PPARγ	[57]
Human umbilical vein endothelial cells	Vascular endothelial dysfunction	Diabetic vascular diseases		In vitro: 100 μM for 1 h	Inhibit apoptosis	Indirect: ↓NOX4/TGF-β1/Smad2	[58]
Human umbilical vein endothelial cells	Vascular endothelial dysfunction	Diabetic vascular diseases	99.3%	In vitro: 100 μM for 24 h	Inhibit apoptosis	Indirect: ↑miR-140-3p/KLF4/PI3K/Akt	[59]
SD rats	T2DM	Diabetic cardiomyopathy	98%	In vivo: 80 mg/kg/day for 7 week	Prevent fibrosis	Direct: ↓cytokines expression	[67]
SD rats	Metabolic syndrome	Diabetic cardiomyopathy	98%	In vivo: 0.5, 2.0 mg/kg/day for 2 week	Improved cardiac diastolic function	Direct: ↑eNOS/NO/cGMP pathway	[105]
SD rats; H9c2 cells	Myocardial injury	Diabetic cardiomyopathy		In vivo: 10, 20, 40 mg/mL for 16 week; in vitro: 20, 40, 80 μM	Improve mitochondrial energy metabolism	Indirect: ↑PGC-1α/NRF1	[69]
SD rats	T1DM	Diabetic kidney disease	98%	In vivo: 5, 10 mg/kg/day for 6 week	Ameliorate the structural and functional abnormalities of the diabetic kidney	Direct: ↓NF-κB	[73]
KKAy mice	Renal interstitial fibrosis	Diabetic kidney disease		In vivo: 40 mg/kg/day for 10 week	Delay renal fibrosis process	Direct: ↓TGF-β/Smads signaling pathway	[74]
SD rats	T1DM	Diabetic kidney disease	98%	In vivo: 80 mg/kg/day for 12 week	Minimize the early kidney damages and fibrosis	Direct: ↓inflammation-related NLR signal events	[101]
SD rats	T1DM	Diabetic kidney disease		In vivo: 2.5, 5, 10 mg/kg/day for 12 week	Prevent kidney injury	Direct: ↓ERK1/2 activation	[75]
SD rats	T1DM	Diabetic kidney disease	98%	In vivo: 5 mg/kg/day for 12 week	Repress diabetic nephropathy development	Direct: ↓miR-378/TRAF5/NF-κB	[76]
SD rats; mouse podocytes	T1DM	Diabetic kidney disease	98%	In vivo: 5, 10 mg/kg/day for 10 week; in vitro: 50, 100, 200 μg/mg/day for 24 h	Podocyte apoptosis	Indirect: ↓PERK-ATF4-CHOP	[77]
SD rats; human podocytes	T1DM	Diabetic kidney disease		In vivo: 10 mg/kg/day for 2 week; in vitro: 100 μg/mL	Inhibit loss of podocytes	Indirect: ↓ER stress	[78]
Mouse podocytes	Podocyte apoptosis	Diabetic kidney disease		In vitro: 10, 20, 40 μM for 1 h	Inhibit podocyte apoptosis	Indirect: ↑calcineurin/NFAT signaling pathway	[79]
Rats; mouse podocytes	T1DM	Diabetic kidney disease	98%	In vivo: 2.5, 5, 10 mg/kg/day for 14 week; in vitro: 50, 100, 200 μg/mL for 24 h	Inhibit podocyte apoptosis	Indirect: ↓bax/bcl-2/caspase3	[40]
Human mesangial cell line	Glomerular contractile dysfunction	Diabetic kidney disease	98%	In vitro: 25, 50, 100 μM for 48 h	Inhibits mesangial cell proliferation and glomerular contractile dysfunction	Direct: ↓NADPH oxidase/ROS/Akt/NF-κB pathway	[84]
HK-2 cells	Renal fibrosis	Diabetic kidney disease		In vitro: 50, 100, 200 μg/mL	Ameliorate high glucose-mediated renal tubular EMT	Direct: ↓mTORC1/p70S6K pathway	[87]
PTCs NRK-52E	Epithelial-to-mesenchymal transition	Diabetic kidney disease		In vitro: 20, 40, 80, 100 μg/mL for 24 h	Ameliorate high glucose-mediated renal tubular EMT	Direct: ↓TGF-β1/Smads signaling pathway	[88]
SD rats; HK-2 cells	T2DM; epithelial-to-mesenchymal transition	Diabetic kidney disease		In vivo: 40, 80 mg/kg/day for 10 week; in vitro: 25, 50, 100 μM for 48 h	Reduction in EMT-related proteins and alleviation in inflammation factors release	Direct: ↓Wnt/β-catenin pathway	[88]
Tubular epithelial cell	Cells apoptosis	Diabetic kidney disease		In vitro: 25, 50, 100, 200 μg/mL for 48 h	Reverse renal tubular epithelial cell apoptosis and proliferation of fibroblasts	Direct: ↓TGF-β1 and ↓ P38MAPK	[89]
SD rats; RPE cells	T1DM	Diabetic eye disease		In vivo: 20, 40, 60 mg/kg/day for 12 week	Inhibit apoptosis of retinal pigment epithelial cells	Indirect: ↑miR-128/PI3K/Akt signaling pathway	[90]
Db/db mice	Diabetic retinopathy	Diabetic eye disease	98%	In vivo: 4.5, 9 mg/kg/day for 20 week	Improve RGC function and protected optic nerve by inhibiting RGC apoptosis and inflammation	Direct: ↓ERK1/2 and NF-κB activation	[91]

Abbreviations: ↑, an increase in target protein; ↓, a decrease in target protein; TNF-α, tumor necrosis factor-α; Erk, extracellular regulated protein kinases; PTP1B, protein tyrosine phosphatase 1B; IR, insulin receptor; SREBP1, sterol-regulatory element binding protein 1; HFD, high frequency detection; STZ, streptozotocin; GP, glycogen phosphorylase; G6Pase, glucose-6-phosphatase; IKK, inhibitor of kappa B kinase; IκB, inhibitor of NF-κB; NF-κB, nuclear factor kappa light chain enhancer of activated B cells; IRS, insulin receptor substrate; Akt, protein kinase B; cGMP, cyclic guanosine monophosphate; HUVECs, human umbilical vein endothelial cells; TLR4, toll-like receptor 4; LPS, lipopolysaccharide; P2X7R, P2X purinoceptor7 receptor; MAPK, mitogen-activated protein kinase; JNK, c-Jun N-terminal kinases; PPARγ, peroxisome proliferators-activated receptors γ; H₂O₂, hydrogen peroxide; NOX4, nicotinamide adenine dinucleotide phosphate oxidase 4; TGF-β1, transforming growth factor-β1; Smad2, recombinant mothers against decapentaplegic homolog 2; KLF4, krüppel-like factor 4; PI3K, phosphoInositide-3 Kinase; eNOS, endothelial nitric oxide synthase; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; NRF1, nuclear respiratory factor 1; KKAy, KKay diabetic mice; Smads, sma mothers against decapentaplegic; ERK1/2, extracellular signal-regulated kinase 1/2; TRAF5, tumor-necrosis factor receptor associated factor 5; PERK, PKR-like ER kinase; ATF4, activating transcription factor 4; CHOP, cyclophosphamide, doxorubicin, oncovin, prednisone; ER, endoplasmic reticulum; NFAT, nuclear factor of activated T cells; bax, mouse Anti-Bax; bcl-2, B-cell lymphoma-2; caspase3, cysteinyl aspartate specific proteinase3; NADPH, nicotinamide adenine dinucleotide phosphate; ROS, reactive oxygen species; mTORC1, mammalian target of rapamycin C1; p70S6K, 70 kDa ribosomal protein S6 Kinase 2; EMT, epithelial-mesenchymal transition; NRK-52E, renal tubular duct epithelial cells of rat; Wnt/β-catenin pathway, canonical Wnt/β-catenin pathway; RPE, retinal pigment epithelium; RGC, retinal ganglion cells.

Figure 1 The anti-inflammatory mechanism of AS-IV on the treatment of diabetic cardiovascular complications.

Notes: In endothelial cell, AS-IV facilitates anti-inflammatory action via inactivating TLR4, TGF-β1, P2X7R, NOX4 and upregulates miR140 expression. In vascular smooth muscle cell, AS-IV indirectly inhibits inflammation via anti-apoptosis. In cardiomyocyte, AS-IV suppresses inflammation signaling pathway via promoting PGC-1α and clearance of ROS. In cardiac fibroblast, AS-IV exhibits eliminating FFA, cytokines and inhibiting TGF-β1 to halting fibrosis.

Abbreviations: ox-LDL, oxidized low density lipoprotein; KLF4, recombinant kruppel like factor 4; ROS, reactive oxygen species; Smad, Sma mothers against decapentaplegic; AP-1, activator protein 1; ICAM-1, intercellular cell adhesion molecule-1; VCAM-1, vascular cell adhesion molecule 1; LPS, lipopolysaccharide; FFA, free fatty acid; TLR4, toll-like receptor 4; NOX4, nicotinamide adenine dinucleotide phosphate oxidase 4.

Figure 2 The anti-inflammatory mechanism of AS-IV on the treatment of diabetic kidney disease.

Notes: AS-IV blocks the progression of DKD by acting as an anti-inflammatory in renal tubular epithelial cell, podocyte, and mesangial cell. In renal tubular epithelial cell, AS-IV inhibits TGF-β and Wnt. In podocyte, AS-IV inactivates TRPC6 and downregulates miR378. In mesangial, AS-IV inactivates NOX4.

Abbreviations: mTOR, mammalian target of rapamycin; TGF-β, transforming growth factor-β; EMT, epithelial-mesenchymal transition; ECM, extracellular matrix; TRPC6, transient receptor potential cation channel 6; GBM, glomerular basement membrane; TRAF5, tumor-necrosis factor receptor associated factor 5.

Figure 3 AS-IV regulates inflammatory pathways in multiple organs, tissues and target cells.

Notes: AS-IV downregulates PTP1B/SREBP1 in hepatocyte, inactivates ERK in adipocyte, and inhibits TLR4/NF-κB signaling pathway in skeletal muscle cell to prevent DM. AS-IV inhibits ERK and NF-κB signaling pathway in retinal ganglion cell to treat DR. AS-IV regulates variety pathways in kidney, heart and vascular. AS-IV inhibits NF-κB in peripheral nervous to treat diabetic neuropathy. AS-IV halts polarization of macrophage in skin to promote diabetic wound healing.

Abbreviations: ER, endoplasmic reticulum; EMT, epithelial-mesenchymal transition; TLR4, toll-like receptor 4; NRF1, nuclear respiratory factor 1; TGF-β, transforming growth factor-β; PTP1B, protein tyrosine phosphatase 1B; SREBP1, sterol regulatory element binding protein-1; DM, diabetes mellitus; DR, diabetic retinopathy.

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