Chinese Herbs and Repurposing Old Drugs as Therapeutic Agents in the Regulation of Oxidative Stress and Inflammation in Pulmonary Diseases

Figures & data

Figure 1 The roles of ROS, pro-inflammatory mediators, and transcription factors AP-1 and NF-κB in pulmonary inflammatory diseases. Pathogen-activated molecular patterns (PAMPs), including endotoxins (LPS or LTA), growth factors (EGF or PDGF), and cytokines (IL-1β or TNF-α), activate downstream pathways (p38 MAPK, JNK1/2, and ERK1/2) via their respective receptors (TLR, EGFR, DPGFR, IL-1R, and TNFR) to promote transcription factors NF-κB and AP-1 activities also activated by ROS, leading to genes transcription (including cytokines, chemokines, MMP-9, COX-2, iNOS, ICAM-1, VCAM-1, MUC5AC, and MUC5B) and pulmonary inflammation.

Abbreviations: LPS, lipopolysaccharides; LTA, lipoteichoic acid; EGF, epidermal growth factor; TNF-α, tumor necrosis factor α; IL-1β, interleukin 1β; PDGF, platelet-derived growth factor; TLR, Toll-like receptor; AP-1, activator protein 1; MMP-9, matrix metalloproteinases-9, NF-κB, nuclear factor-κB; ROS, reactive oxygen species; iNOS, inducible nitric oxide synthase; COX-2, cyclooxygenase-2; VCAM-1, vascular cell adhesion molecule-1; ICAM-1, intercellular adhesion molecule -1; MUC5AC, mucin 5AC; MUC5B, mucin 5B.

Figure 2 The functions of PPARs agonists in pulmonary inflammation. PPARs agonists and PPARs agonist-induced HO-1 upregulation can inhibit NF-κB activity via blocking IKK activity and IκB phosphorylation, leading to suppression of NF-κB nuclear translocation and DNA binding activity and in turn reduction of gene expression including MCP-1, iNOS, VCAM-1, ICAM-1, P-selectin, IL-1, IL-6, TNF-α, COX-2, and RANTEs.

Abbreviations: TNF-α, tumor necrosis factor α; ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; IL, interleukin; iNOS, inducible nitric oxide synthase; COX-2, cyclooxygenase-2; HO, heme oxygenase; NF-κB, nuclear factor-κB; RANTEs, regulated upon activation normal T-cell expressed and secreted; MCP-1, monocyte chemoattractant protein-1; IKK, IκB kinase.

Figure 3 The anti-inflammatory, anti-fibrotic, and anti-apoptotic mechanisms of Chinese herbs in the lungs. Herbs can target individual signal molecules including ROS, MAPKs, and NF-κB as well as pro-inflammatory mediators to block the expression of pro-inflammatory proteins, pro-fibrotic proteins, and pro-apoptotic proteins.

Abbreviations: COX-2, cyclooxygenase-2; cPLA₂, cytosolic phospholipase A₂; CTGF, connective tissue growth factor; HO, heme oxygenase; ICAM-1, intercellular adhesion molecule-1; IL-1, interleukin-1; JNKs, c-Jun NH2-terminal kinases; MAPKs, mitogen-activated protein kinases; MMP, matrix metalloproteinase; NF-κB, nuclear factor-κB; Nrf2, NF-E2-related factor 2; ROS, reactive oxygen species; SOD, superoxide dismutase; TNF-α, tumor necrosis factor-α; VCAM-1, vascular cell adhesion molecule-1.

Table 1 The Effects of Herbal Compounds in Pulmonary Inflammation

Compound	Action	references
Salvianolic acid A/B	↑Nrf2 translocation, ↑HO-1, ↓pulmonary vascular remodeling via inhibiting EndMT	[87,237,238]
	↓pulmonary fibrosis, ↓cyclin D1, ↓cyclin E1, ↓cyclin B1, ↓Bcl-2 protein, ↑p53, ↑p21, ↑cleaved caspase-3 protein	[234]
	repress the adhesion of bacteria	[235]
	↑SOD, ↑catalase, ↑glutathione peroxidase ↓ type I collagen I, ↓endogenous TGF-β1, ↓α-SMA	[236,238]
	↓MAPK and NF-κB signaling pathways	[40,237]
	↓TNF-α, ↓IL-6, ↓IL-1β, ↓MCP-1	[237]
Asiatic acid	↓pulmonary fibrosis	[241,242]
	↓TGF-β1, ↓collagen I, ↓collagen III, ↓α-SMA, ↓TIMP-1, ↓NLRP3 inflammasome, ↓Smads and ERK1/2	[242–244]
	↓ROS, ↓neutrophil elastase (NE) activity, ↓MCP-1, ↓recruitment of inflammatory cells, ↓MAPKs, ↓NF-kB, ↑Nrf2, ↑HO- 1, ↑SOD3, ↓catalase	[41,243,244]
Celastrol	↓NF-κB signaling pathway, ↓NLRP3 activity	[245–246]
	↓IL-8, ↓TNFα, ↓MCP -1, ↑SOD, ↑catalase, ↓Ednrb/Kng 1 signaling pathway	[248]
	↓MMP 2/9, ↑Nrf2, ↑HO-1, ↑GSTs, ↑NQO1	[88]
	↓Bax, ↓caspase-3	[249]
Fisetin	↓TNFα, ↓PARP-1	[253]
	↓neutrophils and macrophage infiltration, ↓MPO activity, ↓TLR4 expression, ↑NF-κB	[254,255]
	↑Nrf2, ↑HO-1, ↑glutathione peroxidase-2, ↑reduced glutathione, ↑SOD	[89]
Galangin	↓TGF-β1-ROS-MAPK pathway, ↓goblet cell hyperplasia, ↓collagen deposition, ↓α-SMA expression, ↓VEGF, ↓MMP-9	[257]
	↓IL-4, 5, 13, 17, ↓TNF-α, ↓NO, ↓ROS, ↓EPO, ↓IgE, ↑IFN-γ, ↑PPARγ activity	[258]
Kaempferol	↓TAK1, ↓NF-κB, ↓MAPK, ↓cytokine production	[45,262,264,265]
	↓ROS	[262]
	↓cyclooxygenase-2	[133]
Luteolin	↓NF-κB signaling pathway, ↓miR-132	[269]
	↓TGF-β1, ↓α-SMA, ↓type I collagen, ↓vimentin, ↓neutrophil infiltration, ↓TNF-R, ↓IL-6, ↓lung fibrosis	[270]
	↓MPO, ↓Inflammatory cytokines, ↓MDA, ↑SOD, ↑glutathione, ↓NFκ-B activation, ↑AKT/Nrf2 pathway	[271,272]
Madecassoside	↓pulmonary fibrosis, ↓oxidative stress ↓α-SMA, ↓TGF-β1, ↓phosphorylations of Smad2 and Smad3, ↓MPO, ↓MDA, ↑SOD, ↑glutathione level	[276]
Oleanolic acid	↓GATA-3 and RORγt pathways	[280]
	↓ROS, ↑reduced glutathione/oxidized glutathione ratio, ↑catalase, ↓TNF-α, ↓macrophage migration inhibitory factor, ↓IL-6, ↓Interferon-γ, ↓TGF-β	[48,281]
	↓iNOS, ↑SOD	[282]
	↑NF-κB	[272,284,285]
	↓cytokines, ↓NLRP3 inflammasome	[283]
	↑SIRT1	[285]
Saikosaponin A	↓cell infiltration, ↓NO, ↓TNF-α, ↓IL-1β, ↓MPO, ↓MDA, ↓NF-KB, ↑Nrf2 and HO-1	[101]
CDDO-Me	↓NO, ↓TNF-α, ↓IL-1β, ↓IL-6, ↓NF-κB, ↓Akt, ↓MAPK pathways	[288–291]
	↑Nrf2 activity	[289]
	↓TGFβ, and ↓α-SMA, ↓fibronectin, ↓fibrosis	[290,291]
Pristimerin	↓TNF-α, ↓IL-6, ↓Bax, ↓caspase-3,↑Bcl2	[298]

Abbreviations: NE, neutrophil elastase; TGF-β1, transforming growth factor-βI; αSMA, α-smooth muscle actin; SOD, superoxide dismutase; MDA, Malondialdehyde; MPO, myeloperoxidase; RORγt, retinoic acid receptor-related orphan receptor gamma-t; iNOS, inducible nitric oxide synthase; , decrease; , increase.

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