Abstract
In vitro and in vivo models of lipopolysaccharide (LPS)-induced pulmonary injury, quercetin-3-glucuronide (Q3G) has been previously revealed the lung-protective potential via downregulation of inflammation, pyroptotic, and apoptotic cell death. However, the upstream signals mediating anti-pulmonary injury of Q3G have not yet been clarified. It has been reported that concerted dual activation of nuclear factor-erythroid 2 related factor 2 (Nrf2) and autophagy may prove to be a better treatment strategy in pulmonary injury. In this study, the effect of Q3G on antioxidant and autophagy were further investigated. Noncytotoxic doses of Q3G abolished the LPS-caused cell injury, and reactive oxygen species (ROS) generation with inductions in Nrf2-antioxidant signaling. Moreover, Q3G treatment repressed Nrf2 ubiquitination, and enhanced the association of Keap1 and p62 in the LPS-treated cells. Q3G also showed potential in inducing autophagy, as demonstrated by formation of acidic vesicular organelles (AVOs) and upregulation of autophagy factors. Next, the autolysosomes formation and cell survival were decreased by Q3G under pre-treatment with a lysosome inhibitor, chloroquine (CQ). Furthermore, mechanistic assays indicated that anti-pulmonary injury effects of Q3G might be mediated via Nrf2 signaling, as confirmed by the transfection of Nrf2 siRNA. Finally, Q3G significantly alleviated the development of pulmonary injury in vivo, which may result from inhibiting the LPS-induced lung dysfunction and edema. These findings emphasize a toxicological perspective, providing new insights into the mechanisms of Q3G’s protective effects on LPS-induced pulmonary injury and highlighting its role in dual activating Nrf2 and autophagy pathways.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
All data of this study are included in this article.
Abbreviations
- Q3G:
-
Quercetin-3-glucuronide
- LPS:
-
Lipopolysaccharide
- Nrf2:
-
Nuclear factor-erythroid 2 related factor 2
- ROS:
-
Reactive oxygen species
- AVOs:
-
Acidic vesicular organelles
- CQ:
-
Chloroquine
- SOD:
-
Superoxide dismutase
- GSH:
-
Glutathione
- GST:
-
Glutathione S-transferase
- HO-1:
-
Heme oxygenase-1
- NQO1:
-
NAD(P)H Quinone dehydrogenase 1
- MDA:
-
Malondialdehyde
- Keap1:
-
Kelch-like ECH-associated protein 1
- PI3K:
-
Phosphatidylinositol 3-kinase
- LC3:
-
Microtubule-associated protein 1A/1B-light chain 3
- Dex:
-
Dexamethasone
- HandE:
-
Hematoxylin and eosin
- MLI:
-
Mean linear intercept
- DI:
-
Destructive index
- TUNEL:
-
Terminal deoxynucleotidyl transferase dUTP nick end labeling
References
Baral S, Pariyar R, Kim J, Lee H-S, Seo J (2017) Quercetin-3-O-glucuronide promotes the proliferation and migration of neural stem cells. Neurobiol Aging 52:39–52. https://doi.org/10.1016/j.neurobiolaging.2016.12.024
Bissonnette EY, Lauzon-Joset JF, Debley JS, Ziegler SF (2020) Cross-talk between alveolar macrophages and lung epithelial cells is essential to maintain lung homeostasis. Front Immunol 11:583042. https://doi.org/10.3389/fimmu.2020.583042
Butt Y, Kurdowska A, Allen TC (2016) Acute lung injury: a clinical and molecular review. Arch Pathol Lab Med 140(4):345–350. https://doi.org/10.5858/arpa.2015-0519-RA
Chen X, Tang J, Shuai W, Meng J, Feng J, Han Z (2020) Macrophage polarization and its role in the pathogenesis of acute lung injury/acute respiratory distress syndrome. Inflamm Res 69(9):883–895. https://doi.org/10.1007/s00011-020-01378-2
Chen J-H, Wu P-T, Chyau C-C, Wu P-H, Lin H-H (2023) The nephroprotective effects of hibiscus sabdariffa leaf and ellagic acid in vitro and in vivo models of hyperuricemic nephropathy. J Agric Food Chem 71(1):382–397. https://doi.org/10.1021/acs.jafc.2c05720
Cho HY, Kleeberger SR (2010) Nrf2 protects against airway disorders. Toxicol Appl Pharmacol 244(1):43–56. https://doi.org/10.1016/j.taap.2009.07.024
Cho HY, Kleeberger SR (2015) Association of Nrf2 with airway pathogenesis: lessons learned from genetic mouse models. Arch Toxicol 89(11):1931–1957. https://doi.org/10.1007/s00204-015-1557-y
Cho HY, Reddy SP, Kleeberger SR (2006) Nrf2 defends the lung from oxidative stress. Antioxid Redox Signal 8(1–2):76–87. https://doi.org/10.1089/ars.2006.8.76
Chow CW, Herrera Abreu MT, Suzuki T, Downey GP (2003) Oxidative stress and acute lung injury. Am J Respir Cell Mol Biol 29(4):427–431. https://doi.org/10.1165/rcmb.F278
D’Andrea G (2015) Quercetin: a flavonol with multifaceted therapeutic applications? Fitoterapia 106:256–271. https://doi.org/10.1016/j.fitote.2015.09.018
Domscheit H, Hegeman MA, Carvalho N, Spieth PM (2020) Molecular dynamics of lipopolysaccharide-induced lung injury in rodents. Front Physiol 11:36. https://doi.org/10.3389/fphys.2020.00036
Fan D, Zhou X, Zhao C, Chen H, Zhao Y, Gong X (2011) Anti-inflammatory, antiviral and quantitative study of quercetin-3-O-β-D-glucuronide in Polygonum perfoliatum L. Fitoterapia 82(6):805–810. https://doi.org/10.1016/j.fitote.2011.04.007
Ganesan S, Faris AN, Comstock AT, Chattoraj SS, Chattoraj A, Burgess JR, Curtis JL, Martinez FJ, Zick S, Hershenson MB, Sajjan US (2010) Quercetin prevents progression of disease in elastase/LPS-exposed mice by negatively regulating MMP expression. Respir Res 11(1):131. https://doi.org/10.1186/1465-9921-11-131
Ghani MA, Barril C, Bedgood DR Jr, Prenzler PD (2017) Measurement of antioxidant activity with the thiobarbituric acid reactive substances assay. Food Chem 230:195–207. https://doi.org/10.1016/j.foodchem.2017.02.127
Ha AT, Rahmawati L, You L, Hossain MA, Kim JH, Cho JY (2021) Anti-inflammatory, antioxidant, moisturizing, and antimelanogenesis effects of quercetin 3-O-β-D-glucuronide in human keratinocytes and melanoma cells via activation of NF-κB and AP-1 pathways. Int J Mol Sci. https://doi.org/10.3390/ijms23010433
Hansen M, Rubinsztein DC, Walker DW (2018) Autophagy as a promoter of longevity: insights from model organisms. Nat Rev Mol Cell Biol 19(9):579–593. https://doi.org/10.1038/s41580-018-0033-y
He F, Ru X, Wen T (2020) NRF2, a transcription factor for stress response and beyond. Int J Mol Sci. https://doi.org/10.3390/ijms21134777
He YQ, Zhou CC, Yu LY, Wang L, Deng JL, Tao YL, Zhang F, Chen WS (2021) Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms. Pharmacol Res 163:105224. https://doi.org/10.1016/j.phrs.2020.105224
Hogg JC, Timens W (2009) The pathology of chronic obstructive pulmonary disease. Annu Rev Pathol 4:435–459. https://doi.org/10.1146/annurev.pathol.4.110807.092145
Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Landray MJ (2021) Dexamethasone in hospitalized patients with covid-19. N Engl J Med 384(8):693–704. https://doi.org/10.1056/NEJMoa2021436
Hu Y, Luo Y, Zheng Y (2022) Nrf2 pathway and autophagy crosstalk: new insights into therapeutic strategies for ischemic cerebral vascular diseases. Antioxidants (Basel). https://doi.org/10.3390/antiox11091747
Huang CY, Deng JS, Huang WC, Jiang WP, Huang GJ (2020) Attenuation of lipopolysaccharide-induced acute lung injury by hispolon in mice, through regulating the TLR4/PI3K/Akt/mTOR and keap1/Nrf2/HO-1 pathways, and suppressing oxidative stress-mediated ER stress-induced apoptosis and autophagy. Nutrients. https://doi.org/10.3390/nu12061742
Janbazacyabar H, van Bergenhenegouwen J, Verheijden KAT, Leusink-Muis T, van Helvoort A, Garssen J, Folkerts G, Braber S (2019) Non-digestible oligosaccharides partially prevent the development of LPS-induced lung emphysema in mice. PharmaNutrition 10:100163. https://doi.org/10.1016/j.phanu.2019.100163
Jomova K, Raptova R, Alomar SY, Alwasel SH, Nepovimova E, Kuca K, Valko M (2023) Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging. Arch Toxicol 97(10):2499–2574. https://doi.org/10.1007/s00204-023-03562-9
Lamontagne F, Briel M, Guyatt GH, Cook DJ, Bhatnagar N, Meade M (2010) Corticosteroid therapy for acute lung injury, acute respiratory distress syndrome, and severe pneumonia: a meta-analysis of randomized controlled trials. J Crit Care 25(3):420–435. https://doi.org/10.1016/j.jcrc.2009.08.009
Laskin DL, Malaviya R, Laskin JD (2019) Role of macrophages in acute lung injury and chronic fibrosis induced by pulmonary toxicants. Toxicol Sci 168(2):287–301. https://doi.org/10.1093/toxsci/kfy309
Liao Y-R, Lin J-Y (2015) Quercetin intraperitoneal administration ameliorates lipopolysaccharide-induced systemic inflammation in mice. Life Sci 137:89–97. https://doi.org/10.1016/j.lfs.2015.07.015
Liao SX, Sun PP, Gu YH, Rao XM, Zhang LY, Ou-Yang Y (2019) Autophagy and pulmonary disease. Ther Adv Respir Dis 13:1753466619890538. https://doi.org/10.1177/1753466619890538
Liebers V, Raulf-Heimsoth M, Brüning T (2008) Health effects due to endotoxin inhalation (review). Arch Toxicol 82(4):203–210. https://doi.org/10.1007/s00204-008-0290-1
Liu WJ, Ye L, Huang WF, Guo LJ, Xu ZG, Wu HL, Yang C, Liu HF (2016) p62 links the autophagy pathway and the ubiqutin-proteasome system upon ubiquitinated protein degradation. Cell Mol Biol Lett 21:29. https://doi.org/10.1186/s11658-016-0031-z
Liu Q, Gao Y, Ci X (2019) Role of Nrf2 and its activators in respiratory diseases. Oxid Med Cell Longev 2019:7090534. https://doi.org/10.1155/2019/7090534
Liu B, He R, Zhang L, Hao B, Jiang W, Wang W, Geng Q (2021) Inflammatory caspases drive pyroptosis in acute lung injury. Front Pharmacol 12:631256. https://doi.org/10.3389/fphar.2021.631256
Long ME, Mallampalli RK, Horowitz JC (2022) Pathogenesis of pneumonia and acute lung injury. Clin Sci 136(10):747–769. https://doi.org/10.1042/cs20210879
Lv X, Lu X, Zhu J, Wang Q (2020) Lipopolysaccharide-induced acute lung injury is associated with increased ran-binding protein in microtubule-organizing center (RanBPM) molecule expression and mitochondria-mediated apoptosis signaling pathway in a mouse model. Med Sci Monit 26:e923172. https://doi.org/10.12659/msm.923172
Ma Q (2013) Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 53:401–426. https://doi.org/10.1146/annurev-pharmtox-011112-140320
Menon MB, Dhamija S (2018) Beclin 1 phosphorylation - at the center of autophagy regulation. Front Cell Dev Biol 6:137. https://doi.org/10.3389/fcell.2018.00137
Mokra D, Mikolka P, Kosutova P, Mokry J (2019) Corticosteroids in acute lung injury: the dilemma continues. Int J Mol Sci. https://doi.org/10.3390/ijms20194765
Nakahira K, Choi AM (2013) Autophagy: a potential therapeutic target in lung diseases. Am J Physiol Lung Cell Mol Physiol 305(2):L93-107. https://doi.org/10.1152/ajplung.00072.2013
Ni Y-L, Shen H-T, Su C-H, Chen W-Y, Huang-Liu R, Chen C-J, Chen S-P, Kuan Y-H (2019) Nerolidol suppresses the inflammatory response during lipopolysaccharide-induced acute lung injury via the modulation of antioxidant enzymes and the AMPK/Nrf-2/HO-1 pathway. Oxid Med Cell Longev 2019:9605980. https://doi.org/10.1155/2019/9605980
Rahman I, Adcock IM (2006) Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J 28(1):219–242. https://doi.org/10.1183/09031936.06.00053805
Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma SS, Kensler TW, Yamamoto M, Petrache I, Tuder RM, Biswal S (2004) Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Invest 114(9):1248–1259. https://doi.org/10.1172/jci21146
Rojo de la Vega M, Dodson M, Gross C, Mansour HM, Lantz RC, Chapman E, Wang T, Black SM, Garcia JG, Zhang DD (2016) Role of Nrf2 and autophagy in acute lung injury. Curr Pharmacol Rep 2(2):91–101. https://doi.org/10.1007/s40495-016-0053-2
Ryter SW, Choi AMK (2015) Autophagy in lung disease pathogenesis and therapeutics. Redox Biol 4:215–225. https://doi.org/10.1016/j.redox.2014.12.010
Saetta M, Shiner RJ, Angus GE, Kim WD, Wang NS, King M, Ghezzo H, Cosio MG (1985) Destructive index: a measurement of lung parenchymal destruction in smokers. Am Rev Respir Dis 131(5):764–769. https://doi.org/10.1164/arrd.1985.131.5.764
Sichelstiel A, Yadava K, Trompette A, Salami O, Iwakura Y, Nicod LP, Marsland BJ (2014) Targeting IL-1β and IL-17A driven inflammation during influenza-induced exacerbations of chronic lung inflammation. PLoS One 9(2):e98440–e98440. https://doi.org/10.1371/journal.pone.0098440
Swenson KE, Swenson ER (2021) Pathophysiology of acute respiratory distress syndrome and COVID-19 lung injury. Crit Care Clin 37(4):749–776. https://doi.org/10.1016/j.ccc.2021.05.003
Tanida I, Ueno T, Kominami E (2008) LC3 and autophagy. Methods Mol Biol 445:77–88. https://doi.org/10.1007/978-1-59745-157-4_4
Terao J (2009) Dietary flavonoids as antioxidants. Forum Nutr 61:87–94. https://doi.org/10.1159/000212741
Thiam F, Yazeedi SA, Feng K, Phogat S, Demirsoy E, Brussow J, Abokor FA, Osei ET (2023) Understanding fibroblast-immune cell interactions via co-culture models and their role in asthma pathogenesis. Front Immunol 14:1128023. https://doi.org/10.3389/fimmu.2023.1128023
Thurlbeck WM (1967) Measurement of pulmonary emphysema. Am Rev Respir Dis 95(5):752–764. https://doi.org/10.1164/arrd.1967.95.5.752
Wang Q, **ao L (2019) Isochlorogenic acid A attenuates acute lung injury induced by LPS via Nf-κB/NLRP3 signaling pathway. Am J Transl Res 11(11):7018–7026
Wang W, Sun C, Mao L, Ma P, Liu F, Yang J, Gao Y (2016) The biological activities, chemical stability, metabolism and delivery systems of quercetin: a review. Trends Food Sci Technol 56:21–38. https://doi.org/10.1016/j.tifs.2016.07.004
Wang Y, Zhao S, Jia N, Shen Z, Huang D, Wang X, Wu Y, Pei C, Shi S, He Y, Wang Z (2023) Pretreatment with rosavin attenuates PM25-induced lung injury in rats through antiferroptosis via PI3K/Akt/Nrf2 signaling pathway. Phytother Res 37(1):195–210. https://doi.org/10.1002/ptr.7606
Ward PA (2010) Oxidative stress: acute and progressive lung injury. Ann NY Acad Sci 1203:53–59. https://doi.org/10.1111/j.1749-6632.2010.05552.x
Wu X, Kong Q, Zhan L, Qiu Z, Huang Q, Song X (2019) TIPE2 ameliorates lipopolysaccharide-induced apoptosis and inflammation in acute lung injury. Inflamm Res 68(11):981–992. https://doi.org/10.1007/s00011-019-01280-6
**e W, Wang H, Wang L, Yao C, Yuan R, Wu Q (2013) Resolvin D1 reduces deterioration of tight junction proteins by upregulating HO-1 in LPS-induced mice. Lab Invest 93(9):991–1000. https://doi.org/10.1038/labinvest.2013.80
Yamazaki S, Miyoshi N, Kawabata K, Yasuda M, Shimoi K (2014) Quercetin-3-O-glucuronide inhibits noradrenaline-promoted invasion of MDA-MB-231 human breast cancer cells by blocking β2-adrenergic signaling. Arch Biochem Biophys 557:18–27. https://doi.org/10.1016/j.abb.2014.05.030
Yorimitsu T, Klionsky DJ (2005) Autophagy: molecular machinery for self-eating. Cell Death Differ 12(Suppl 2):1542–1552. https://doi.org/10.1038/sj.cdd.4401765
Yu PR, Hsu JY, Tseng CY, Chen JH, Lin HH (2023) The inhibitory effect of quercetin-3-glucuronide on pulmonary injury in vitro and in vivo. J Food Drug Anal 31(2):254–277. https://doi.org/10.38212/2224-6614.3453
Zhang W, Feng C, Jiang H (2021) Novel target for treating Alzheimer’s diseases: crosstalk between the Nrf2 pathway and autophagy. Ageing Res Rev 65:101207. https://doi.org/10.1016/j.arr.2020.101207
Acknowledgements
This study was supported by the grant from the National Science and Technology Council (NSTC111-2320-B-040-020), Taiwan.
Funding
This study was supported by the grant from the National Science and Technology Council (NSTC111-2320-B-040-020), Taiwan.
Author information
Authors and Affiliations
Contributions
Conceptualization: HHL and JHC; Methodology: PRY, CYT and CCH; Investigation: PRY and CYT; Software: CYT and CCH; Visualization: CCH and JHC; Data curation: PRY, HHL and JHC; Funding acquisition: HHL and JHC; Resources: HHL and JHC; Supervision: HHL and JHC; Writing–original draft: PRY; Writing–review and editing: PRY and HHL.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflict of interest.
Ethical approval
Not applicable.
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Yu, PR., Tseng, CY., Hsu, CC. et al. In vitro and in vivo protective potential of quercetin-3-glucuronide against lipopolysaccharide-induced pulmonary injury through dual activation of nuclear factor-erythroid 2 related factor 2 and autophagy. Arch Toxicol 98, 1415–1436 (2024). https://doi.org/10.1007/s00204-024-03691-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-024-03691-9