TABLE 2

The mediating roles of polyphenols and flavonoids on the amelioration of cigarette smoke (CS)-induced inflammasome in COPD

Active substancesInduction modelKey findingsRef.
Astragalin (kaempferol-3-glucoside), a flavonoid from leaves of persimmon and green tea seedsCS exposure: BALB/c mice
CSE treatment: A549 cells
Astragalin may interrupt the smoking-induced oxidative stress–MAPK signalling–inflammation axis via disconnection between alveolar PAR activation and pulmonary thromboembolism.[164]
CurcuminCS exposure: male SD rats
CSE treatment: BEAS-2B cells
Curcumin attenuated CS-induced inflammation in vivoand in vitro, by modulating the PPARγ–NF-κB pathway.[106]
Fisetin, a flavone from apples strawberries and onionCS exposure: male Wistar ratsFisetin blunted CS-induced oxidative stress and inflammation in the lungs and prevented tissue damage via the Nrf2-mediated upregulation of antioxidant gene expression.[165]
Hesperidin, a flavanone glycosideCSE injection: C57BL/6 mice male and female mixedHesperidin alleviated inflammation and oxidative stress responses in CSE-induced COPD mice, associated with SIRT1/PGC-1α/NF-κB signalling axis.[166]
Icariin, a flavonoid from Epimedium brevicornum Maxim (Berberidaceae)CSE treatment: BEAS-2B cellsDecreased CSE-induced inflammation, airway remodelling and ROS production by mitigating GC resistance. Icariin combination with GC can potentially increase therapeutic efficacy and reduce GC resistance in COPD.[167]
ISOF, a flavonoid from Coleus forskohliiCS exposure: mice and infected with influenza virus A/Puerto Rico/8/34 (H1N1), Th17 cellsThe levels of inflammatory mediators (TNF-α, IL-1β, IL-6, IL-17A, MCP-1, MIG, IP-10 and CRP) in the lung homogenate were reduced after ISOF treatment. ISOF alleviated AECOPD by improving pulmonary function and attenuating inflammation via the downregulation of pro-inflammatory cytokines, Th17–IL-17A and NF-κB–NLRP3 pathways.[149]
Isoliquiritigenin, a polyphenol from Glycyrrhizae radixCS exposure: male C57BL/6N miceIsoliquiritigenin protected against CS-induced COPD by inhibiting inflammatory and oxidative stress via the regulation of the Nrf2 and NF-κB signalling pathways.[168]
Isorhapontigenin, a polyphenol from Belamcanda chinensisCS exposure: SD rats
CSE treatment: primary HAECs (healthy and COPD), A549 cells
Isorhapontigenin reduced the activation of NF-κB and AP-1 and notably the PI3 K–Akt–FoxO3A pathway was insensitive to dexamethasone.[101]
Liquiritin apioside, a flavonoid from Glycyrrhiza uralensisCS exposure: ICR mice
CSE treatment: A549 cells
The protective role of liquiritin apioside on CS-induced the lung epithelial cell injury and are mediated by inhibiting TGF-β and TNF-α expression and increasing anti-oxidative levels of GSH.[129]
MgIGCS exposure: male Wistar rats with endotracheal-atomized LPSMgIG might be an alternative for COPD treatment, and the suppression of NLRP3 inflammasome.[80]
Oroxylin A, a flavonoid from Scutellaria baicalensis GeorgiCS exposure: male C57BL/6 mice
CSE treatment: BEAS-2B, RAW264.7 cells
Oroxylin A attenuated oxidative stress and lung inflammation by CS-induced via activating the Nrf2 signalling pathway.[169]
Phloretin, a polyphenol from Prunus mandshuricaCS exposure: male BALB/c mice
CSE treatment: NCI-H292 cells
The protective effect of phloretin on CS-related airway mucus hypersecretion and inflammation, where EGFR, ERK and P38 might be involved.[170]
Sal-B, a polyphenol of danshenPPE endotracheal treatment: male SD rats
CSE intraperitoneal treatment: male SD rats
Sal-B as one of the first anti-emphysema agents enabling reversal of alveolar structural destruction and loss via local lung treatment by STAT3 activation and VEGF stimulation.[98]
EGCGCSE treatment: NHBE cellsEGCG sequestered 4-hydroxynonenal and inhibited NF-κB activation, antioxidative and anti-inflammatory effects of EGCG in CSE-treatment AECs.[73]
EC, flavonoidCS exposure: male Wistar rats
CSE treatment: BEAS-2B cells
The protective effect of EC on experimental COPD rats and elucidated the mechanism of EC promoting Nrf2 activity.[171]
Baicalin, a polyphenol of Scutellaria baicalensisCS exposure: male SD rats, CSE treatment: HBEpCsBaicalin ameliorated CS-induced airway inflammation in rats, and these effects were partially attributed to the modulation of HDAC2–NF-κB–PAI-1 signalling.[81]
CS exposure: male BALB/c mice
CSE treatment: A549 cells
Anti-inflammatory effects in CS-induced inflammatory models in mice and A549 cells, achieved by modulating HDAC2.[172]
Casticin, a flavonoid from Vitex species (Vitex rotundifolia, Vitex agnus-castus)CS exposure: male Wistar ratsCasticin protected lungs against COPD via improving lung function and inhibition of oxidative stress and inflammation via the reduction of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6).[173]
CS exposure: female C57BL/6 miceCasticin had significant effects on the lung inflammation induced by CS in a COPD mouse model.[174]
Naringenin, a flavanone from grapefruitCS exposure: male BALB/c mice
CSE treatment: A549 cells
Naringenin inhibited the production of pro-inflammatory cytokines such as IL-8, TNF-α, and MMP9 in the BALF and serum of CS-induced animals.[175]
Naringin, a flavonoid glycoside from grapefruit and citrus fruitsCS exposure: male and female guinea pigsNaringin exhibited antitussive, anti-AHR and anti-inflammation effects on chronic CS exposure-induced chronic bronchitis of guinea pigs.[125]
CS exposure: male and female SD ratsNaringin prevented CS-induced infiltration of neutrophils and activation of MPO and MMP-9, in parallel with suppression of the release of cytokines, TNF-α, IL-8 and IL-10.[128]
Quercetin, a flavonoidCSE treatment: J774A.1 cells CSE injection: male C57BL/6 miceAn effective adjuvant effects from quercetin for treating CS exposure.[176]
CSE treatment: U937 cells, COPD patient PBMCQuercetin restored corticosteroid sensitivity, to be a novel treatment in combination with corticosteroids in COPD.[85]
ResveratrolCS exposure: male Wistar ratsResveratrol inhibited oxidative stress and inflammatory response via the activation and upgrading of the SIRT1/PGC-1α signalling pathways.[120]
CS exposure: male Kunming mice with LPSResveratrol has a therapeutic effect on mouse CS-induced COPD and reduced the production of the beclin1 protein.[124]
CSE treatment: HBEpCA protective effect against CSE-induced apoptosis, and a molecular pathway involving SIRT1 and ORP150 may be associated with the anti-apoptotic functions, caspase-3 and caspase-4 of resveratrol in HBEpC.[122]
PPE endotracheal treatment: female C57BL/6JNarl mice
CSE treatment: MSC cells
cis-Resveratrol-regulated VEGFA expression in HSP–VEGFA–MSC significantly improved the therapeutic effects in the treatment of a COPD mouse, avoiding side effects associated with constitutive VEGFA expression.[123]
CS exposure: male SD rats with LPSCo-administered with sirtinol, a SIRT1 inhibitor. The combination therapy may serve as a potential approach for treating lung inflammatory conditions like COPD.[119]
Silibinin, a flavonoid from the milk thistle Silybum marianumCSE treatment: NCI-H292 cells
CS exposure: male C57BL/6 N mice with LPS
Silibinin effectively suppressed the neutrophilic airway inflammation provoked by treatment with LPS and CS, which was associated with downregulation of ERK phosphorylation.[177]
CS exposure: male C57BL/6N mice with LPSSilibinin effectively inhibited the fibrotic response induced by CS+LPS exposure, via suppression of TGF-β1/Smad 2/3 signalling, resulting in reduced collagen deposition.[178]
Silymarin, a flavonoid from the seeds and fruits of milk thistleCS exposure: male BALB/c miceSilymarin attenuated inflammation and oxidative stress induced by CS. The anti-inflammatory effect might partly act through the MAPK pathway.[103]
CSE treatment: BEAS-2B cellsSilymarin could attenuate inflammatory responses through intervening in the crosstalk between autophagy and the ERK–MAPK pathway.[102]
HSYA, a polyphenol from edible plant safflowerCS exposure: male Wistar rats with LPSHSYA inhibited the phosphorylation of p38 MAPK in the lung tissue of rat. HSYA can attenuate experimentally induced airway remodelling and was attributed to suppression of TGF-β1 expression.[179]
CS exposure: male Wistar ratsHSYA alleviated inflammatory cell infiltration and inhibited inflammatory cytokine expression and increased phosphorylation of p38 MAPK and p65 NF-κB in the lungs of COPD rats.[180]
Jaboticabin and related polyphenols from jaboticaba (Myrciaria cauliflora)CSE treatment: SAE cells, Caco-2 cellsThe polyphenols, jaboticabin and 3,3'-dimethyellagic acid-4-O-sulphate from jaboticaba both exhibited anti-inflammatory activities.[88]
Apple polyphenolCS exposure: female ICR miceApple polyphenol may be a potential dietary nutrient supplement agent to improve quality of life of COPD patients by inhibiting CS-induced ALI via the p38 MAPK signalling pathway.[115]
DRIAsCS exposure: male C57BL/6 miceDRIAs significantly attenuated the pathological changes of COPD via suppression of neutrophilic inflammation.[104]
Anthocyanins delphinidin and cyanidin from the edible fruits of Eugenia brasiliensisCSE treatment: SAE cellsDelphinidin inhibited IL-8 in the CSE-treated cells in a dose-dependent manner.[181]
Flower buds of Tussilago farfara L.CS exposure: miceFTF-EtOH effectively attenuated lung inflammation in vitroand in vivo. The protection of FTF-EtOH against inflammation was produced by activation of Nrf2 and inhibitions of NF-κB and NLRP3 inflammasome.[90]
Glycyrrhiza glabra, Agastache rugosaCoal fly ash, diesel-exhaust particle exposure: male BALB/c miceHerbal combinational mixture more effectively inhibited neutrophilic airway inflammation by regulating the expression of inflammatory cytokines and CXCL-2 by blocking the IL-17/STAT3 pathway.[182]
Pomegranate juiceCS exposure: male C57BL/6J mice
CSE treatment: A549 cells
The expression of inflammatory mediators and the emphysematous changes noted with chronic CS exposure were reduced with pomegranate juice supplementation. In vitro, pomegranate juice attenuated the damaging effects of CSE on cultured human alveolar cells.[97]
Total flavonoids from sea buckthornCSE/LPS treatment: HBE16 cells
CS exposure: male ICR mice with LPS
Total flavonoids from sea buckthorn including quercetin and isorhamnetin showed potent binding affinities to MAPK1 and PIK3CG, two upstream kinases of ERK and Akt, respectively. Against LPS/CS-induced airway inflammation through inhibition of ERK, PI3 K/Akt and PKCα pathways.[183]
Extracts of Ximenia americana L.CS exposure: male and female ratsThe aqueous extract of X. americana presents itself as a new option for CS-COPD treatment.[184]
MelatoninCS exposure: male Swiss albino mice
CSE treatment: L-132 cells
Activated the intracellular antioxidant thioredoxin-1 (thereby suppressing the TXNIP–NLRP3 pathway) and inhibited the impaired the mitophagy mediated inflammasome activation (upregulating PINK-1, Parkin, LC3B-II expression). Also improved the overall antioxidant status of the COPD lung via Nrf2–HO-1 axis restoration.[142]
CSE treatment: HAECsMelatonin effectively protected against smoking-induced vascular injury and atherosclerosis through the Nrf2–ROS–NLRP3 signalling pathway.[185]
CS exposure: male Wistar rats with LPSMelatonin attenuated airway inflammation via SIRT1-dependent inhibition of NLRP3 inflammasome and IL-1β in COPD rats.[143]
TFEBCSE treatment: RAW 264.7 cellsTFEB acted as autophagy-inducing drugs in restoring of CS-impaired phagocytosis.[186]

16HBE: human airway epithelial cells; A549: alveolar epithelial cell; AEC: airway epithelial cell; AECOPD: acute exacerbations of COPD; AHR: airway hyper-responsiveness; ALI: acute lung injury; AP-1: activator protein 1; BALF: bronchoalveolar lavage fluid; BEAS-2B: human bronchial epithelial cell; Caco-2: human intestinal cells; CSE: cigarette smoke extract; CRP: C-reactive protein; CXCL-2: chemokine (C-X-C motif) ligand 2; DRIA: daidzein-rich soy isoflavone aglycone; EC: (-)-epicatechin; EGCG: epigallocatechin gallate; EGFR: epidermal growth factor receptor; ERK: extracellular signal-regulated kinases; FTF-EtOH: ethanol extract of the flower buds of T. farfara L.; GC: glucocorticoid; GSH: glutathione; HAEC: human aortic endothelial cell; HBEpC: human bronchial epithelial cell; HDAC2: histone deacetylase 2; HO-1: haem oxygenase-1; HSP: heat shock protein; HSYA: hydroxysafflor yellow A; IL: interleukin; IP-10: interferon gamma-induced protein 10; ISOF: isoforskolin; J774A.1: mouse macrophage cells; LPS: lipopolysaccharide; MAPK: mitogen-activated protein kinase; MCP-1: monocyte chemoattractant protein-1; MgIG: magnesium isoglycyrrhizinate; MIG: monokine induced by interferon-γ; MMP9: matrix metalloproteinase-9; MPO: myeloperoxidase; MSC: human mesenchymal stem cell; NCI-H292: human lung mucoepidermoid carcinoma cell; NF-κB: nuclear factor-κB; NHBE: normal human bronchial epithelial cell; NLRP3: nucleotide-binding oligomerisation domain-like receptor family, pyrin domain containing protein-3; Nrf2: nuclear factor erythroid 2-related factor 2; ORP150: oxygen-regulated protein 150; PAI1: plasminogen activator inhibitor type-1; PAR: protease-activated receptor; PBMC: human peripheral blood mononuclear cell; PGC-1α: peroxisome proliferator-activated receptor-gamma coactivator-1α; PINK-1: PTEN-induced kinase 1; PKCα: protein kinase C alpha; PPARγ: peroxisome proliferator-activated receptor γ; PPE: porcine pancreatic elastase; RAW 264.7: mouse macrophage; ROS: reactive oxygen species; SAE: human small airway epithelial cell; Sal-B: salvianolic acid B; SD: Sprague Dawley; SIRT1: sirtuin 1; STAT3: signal transducer and activator of transcription 3; TFEB: transcription factor EB; TGF-β: transforming growth factor-β; Th17: T-helper cell 17; TNF-α: tumour necrosis factor-α; TXNIP: thioredoxin interacting protein; U937: human monocyte cells; VEGF: vascular endothelial growth factor; VEGFA: vascular endothelial growth factor A.