Red ginseng polysaccharide attenuates sepsis-induced acute lung injury via suppressing oxidative stress-mediated ER stress through activation of Nrf2/AMPK pathways
Main Article Content
Keywords
acute lung injury, endoplasmic reticulum stress, lipopolysaccharide, oxidative stress, red ginseng polysaccharide
Abstract
The present study elucidates the protective efficacy of red ginseng polysaccharide (RGP) against septic-associated acute lung injury (ALI), a critical condition exacerbated by oxidative stress and endoplasmic reticulum (ER) stress. Utilizing lipopolysaccharide (LPS)-induced mouse and cellular models, we assessed lung pathology through histological staining, injury scoring, and lung wet-to-dry ratios along with inflammatory cytokine levels. Cell viability and apoptosis were quantified using cell counting kit-8 and TUNEL assays, respectively, while fluorescence labeling was employed to gauge reactive oxygen species (ROS) and mitochondrial membrane potential (MMP). Our findings indicated that RGP markedly attenuated LPS-induced lung damage, inflammation, oxidative injury, ER stress, and apoptotic processes. Mechanistic insights revealed that RGP exerted its protective effects by activating the nuclear factor erythroid-2-related factor 2 (Nrf2)/adenosine monophosphate-activated protein kinase (AMPK) pathway in LPS-stressed lung tissues. Inhibition of Nrf2 or AMPK abrogated RGP’s benefits on apoptosis, ROS production, and MMP preservation in murine lung type II epithelial (MLE-12) cells, underscoring the Nrf2/AMPK-mediated mechanism of RGP’s action against LPS-induced ALI. These results underscore the potential of RGP as a novel therapeutic agent for sepsis-associated ALI.
References
Arab H.H., Khames A., Alsufyani S.E., El-Sheikh A.A.K., and Gad A.M. 2023. Targeting the endoplasmic reticulum stress-linked PERK/GRP78/CHOP pathway with magnesium sulfate attenuates chronic-restraint-stress-induced depression-like neuropathology in rats. Pharmaceuticals (Basel). 16(2):300. 10.3390/ph16020300
Chen J., Li M., Qu D., and Sun Y. 2019. Neuroprotective effects of red ginseng saponins in scopolamine-treated rats and activity screening based on pharmacokinetics. Molecules. 24(11):2136. 10.3390/molecules24112136
Chen X., Wang Y., Xie X., Chen H., Zhu Q., Ge Z., et al. 2018. Heme oxygenase-1 reduces sepsis-induced endoplasmic reticulum stress and acute lung injury. Mediators Inflamm. 2018:9413876. 10.1155/2018/9413876
Chu X., Li L., Yan W., and Ma H. 2022. 4-Octyl itaconate prevents free fatty acid-induced lipid metabolism disorder through activating Nrf2-AMPK signaling pathway in hepatocytes. Oxid Med Cell Longev. 2022:5180242. 10.1155/2022/5180242
Correia-Álvarez E., Keating J.E., Glish G., Tarran R., and Sassano M.F. 2020. Reactive oxygen species, mitochondrial membrane potential, and cellular membrane potential are predictors of E-liquid-induced cellular toxicity. Nicotine Tob Res. 22(Suppl 1):S4–S13. 10.1093/ntr/ntaa177
Dandekar A., Mendez R., and Zhang K. 2015. Cross talk between ER stress, oxidative stress, and inflammation in health and disease. Methods Mol Biol. 1292:205–214. 10.1007/978-1-4939-2522-3_15
Dhlamini Q., Wang W., Feng G., Chen A., Chong L., Li X., et al. 2022. FGF1 alleviates LPS-induced acute lung injury via suppression of inflammation and oxidative stress. Mol Med. 28(1):73. 10.1186/s10020-022-00502-8
Fukatsu M., Ohkawara H., Wang X., Alkebsi L., Furukawa M., Mori H., et al. 2022. The suppressive effects of Mer inhibition on inflammatory responses in the pathogenesis of LPS-induced ALI/ARDS. Sci Signal. 15(724):eabd2533. 10.1126/scisignal.abd2533
Guo Y., Liu Y., Zhao S., Xu W., Li Y., Zhao P., et al. 2021. Oxidative stress-induced FABP5 S-glutathionylation protects against acute lung injury by suppressing inflammation in macrophages. Nat Commun. 12(1):7094. 10.1038/s41467-021-27428-9
He R., Liu B., Xiong R., Geng B., Meng H., Lin W., et al. 2022. Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury. Cell Death Discov. 8(1):43. 10.1038/s41420-021-00807-3
He F., Ru X., and Wen T. 2020. Nrf2, a transcription factor for stress response and beyond. Int J Mol Sci. 21(13):4777. 10.3390/ijms21134777
Hong H., Lou S., Zheng F., Gao H., Wang N., Tian S., et al. 2022. Hydnocarpin D attenuates lipopolysaccharide-induced acute lung injury via MAPK/NF-κB and Keap1/Nrf2/HO-1 pathway. Phytomedicine. 101:154143. 10.1016/j.phymed.2022.154143
Huang C.Y., Deng J.S., Huang W.C., Jiang W.P., and Huang G.J. 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. 12(6):1742. 10.3390/nu12061742
Hwang J.S., Kim K.H., Park J., Kim S.M., Cho H., Lee Y., et al. 2019. Glucosamine improves survival in a mouse model of sepsis and attenuates sepsis-induced lung injury and inflammation. J Biol Chem. 294(2):608–622. 10.1074/jbc.RA118.004638
Kang J., Zhao J., He L.F., Li L.X., Zhu Z.K., and Tian M.L. 2023. Extraction, characterization and anti-oxidant activity of polysaccharide from red Panax ginseng and Ophiopogon japonicus waste. Front Nutr. 10:1183096. 10.3389/fnut.2023.1183096
Lewis A.J., Seymour C.W., and Rosengart M.R. 2016. Current murine models of sepsis. Surg Infect (Larchmt). 17(4):385–393. 10.1089/sur.2016.021
Li G., Hu C., Liu Y., and Lin H. 2023a. Ligustilide, a novel SIRT1 agonist, alleviates lipopolysaccharide-induced acute lung injury through deacetylation of NICD. Int Immunopharmacol. 121:110486. 10.1016/j.intimp.2023.110486
Li J., Lu K., Sun F., Tan S., Zhang X., Sheng W., et al. 2021. Panaxydol attenuates ferroptosis against LPS-induced acute lung injury in mice by Keap1-Nrf2/HO-1 pathway. J Transl Med. 19(1):96. 10.1186/s12967-021-02745-1
Li Y., Xiao W., and Lin X. 2023b. Long noncoding RNA MALAT1 inhibition attenuates sepsis-induced acute lung injury through modulating the miR-129-5p/PAX6/ZEB2 axis. Microbiol Immunol. 67(3):142–153. 10.1111/1348-0421.13045
Li B., Zeng M., He W., Huang X., Luo L., Zhang H., et al. 2015. Ghrelin protects alveolar macrophages against lipopolysaccharide-induced apoptosis through growth hormone secretagogue receptor 1a-dependent c-Jun N-terminal kinase and Wnt/beta-catenin signaling and suppresses lung inflammation. Endocrinology. 156(1):203–217. 10.1210/en.2014-1539
Lian Y., Zhu M., Yang B., Wang X., Zeng J., Yang Y., et al. 2022. Characterization of a novel polysaccharide from red ginseng and its ameliorative effect on oxidative stress injury in myocardial ischemia. Chin Med. 17(1):111. 10.1186/s13020-022-00669-6
Liu D., Huang S.Y., Sun J.H., Zhang H.C., Cai Q.L., Gao C., et al. 2022a. Sepsis-induced immunosuppression: mechanisms, diagnosis and current treatment options. Mil Med Res. 9(1):56. 10.1186/s40779-022-00422-y
Liu J., Yao S., Jia J., Chen Z., Yuan Y., He Y., et al. 2022b. Loss of MBD2 ameliorates LPS-induced alveolar epithelial cell apoptosis and ALI in mice via modulating intracellular zinc homeostasis. FASEB J. 36(2):e22162. 10.1096/fj.202100924RR
Lv H., Liu Q., Wen Z., Feng H., Deng X., and Ci X. 2017. Xanthohumol ameliorates lipopolysaccharide (LPS)-induced acute lung injury via induction of AMPK/GSK3β-Nrf2 signal axis. Redox Biol. 12:311–324. 10.1016/j.redox.2017.03.001
Men L., Guo J., Cao Y., Huang B., Wang Q., Huo S., et al. 2023. IL-6/GP130/STAT3 signaling contributed to the activation of the PERK arm of the unfolded protein response in response to chronic beta-adrenergic stimulation. Free Radic Biol Med. 205:163–174. 10.1016/j.freeradbiomed.2023.06.005
Qian Q., Cao X., Wang B., Dong X., Pei J., Xue L., et al. 2020. Endoplasmic reticulum stress potentiates the autophagy of alveolar macrophage to attenuate acute lung injury and airway inflammation. Cell Cycle. 19(5):567–576. 10.1080/15384101.2020.1718851
Qiu Y.L., Cheng X.N., Bai F., Fang L.Y., Hu H.Z., and Sun D.Q. 2018. Aucubin protects against lipopolysaccharide-induced acute pulmonary injury through regulating Nrf2 and AMPK pathways. Biomed Pharmacother. 106:192–199. 10.1016/j.biopha.2018.05.070
Rehfeldt S.C.H., Laufer S., and Goettert M.I. 2021. A highly selective in vitro JNK3 inhibitor, FMU200, restores mitochondrial membrane potential and reduces oxidative stress and apoptosis in SH-SY5Y cells. Int J Mol Sci. 22(7):3701. 10.3390/ijms22073701
Sang A., Wang Y., Wang S., Wang Q., Wang X., Li X., et al. 2022. Quercetin attenuates sepsis-induced acute lung injury via suppressing oxidative stress-mediated ER stress through activation of SIRT1/AMPK pathways. Cell Signal. 96:110363. 10.1016/j.cellsig.2022.110363
Schwarz D.S., and Blower M.D. 2016. The endoplasmic reticulum: structure, function and response to cellular signaling. Cell Mol Life Sci (CMLS). 73(1):79–94. 10.1007/s00018-015-2052-6
Tang Y., Wa Q., Peng L., Zheng Y., Chen J., Chen X., et al. 2022. Salvianolic acid B suppresses ER stress-induced NLRP3 inflammasome and pyroptosis via the AMPK/FoxO4 and syndecan-4/Rac1 signaling pathways in human endothelial progenitor cells. Oxid Med Cell Longev. 2022:8332825. 10.1155/2022/8332825
Trefts E., and Shaw R.J. 2021. AMPK: restoring metabolic homeostasis over space and time. Mol Cell. 81(18):3677–3690. 10.1016/j.molcel.2021.08.015
Wang F., Ma J., Wang J., Chen M., Xia H., Yao S., et al. 2022a. SIRT1 ameliorated septic associated-lung injury and macrophages apoptosis via inhibiting endoplasmic reticulum stress. Cell Signal. 97:110398. 10.1016/j.cellsig.2022.110398
Wang Y., Wang X., Li Y., Xue Z., Shao R., Li L., et al. 2022b. Xuanfei Baidu decoction reduces acute lung injury by regulating infiltration of neutrophils and macrophages via PD-1/IL17A pathway. Pharmacol Res. 176:106083. 10.1016/j.phrs.2022.106083
Wang S., Zhao Y., Yang J., Liu S., Ni W., Bai X., et al. 2023. Ginseng polysaccharide attenuates red blood cells oxidative stress injury by regulating red blood cells glycolysis and liver gluconeogenesis. J Ethnopharmacol. 300:115716. 10.1016/j.jep.2022.115716
Wu Y.X., Zeng S., Wan B.B., Wang Y.Y., Sun H.X., Liu G., et al. 2021. Sophoricoside attenuates lipopolysaccharide-induced acute lung injury by activating the AMPK/Nrf2 signaling axis. Int Immunopharmacol. 90:107187. 10.1016/j.intimp.2020.107187
Xiao K., He W., Guan W., Hou F., Yan P., Xu J., et al. 2020. Mesenchymal stem cells reverse EMT process through blocking the activation of NF-kappaB and hedgehog pathways in LPS-induced acute lung injury. Cell Death Dis. 11(10):863. 10.1038/s41419-020-03034-3
Xu P., Zhang W.Q., Xie J., Wen Y.S., Zhang G.X., and Lu S.Q. 2020. Shenfu injection prevents sepsis-induced myocardial injury by inhibiting mitochondrial apoptosis. J Ethnopharmacol. 261:113068. 10.1016/j.jep.2020.113068
Yang H., Song Z., and Hong D. 2020. CRBN knockdown mitigates lipopolysaccharide-induced acute lung injury by suppression of oxidative stress and endoplasmic reticulum (ER) stress associated NF-kappaB signaling. Biomed Pharmacother. 123:109761. 10.1016/j.biopha.2019.109761
Yang R., Yang H., Wei J., Li W., Yue F., Song Y., et al. 2021. Mechanisms underlying the effects of Lianhua Qingwen on sepsis-induced acute lung injury: a network pharmacology approach. Front Pharmacol. 12:717652. 10.3389/fphar.2021.717652
Yang Y., Zhong Z.T., Xiao Y.G., and Chen H.B. 2022. The activation of AMPK/NRF2 pathway in lung epithelial cells is involved in the protective effects of kinsenoside on lipopolysaccharide-induced acute lung injury. Oxid Med Cell Longev. 2022:3589277. 10.1155/2022/3589277
Yimam M., Horm T., O’Neal A., Jiao P., Hong M., and Jia Q. 2023. UP360, a standardized composition from extracts of Aloe barbadense, Poria cocos, and Rosemary officinalis protected against sepsis and mitigated acute lung injury in murine models. J Med Food. 26(7):489–499. 10.1089/jmf.2022.0136
Zeng M., Sang W., Chen S., Chen R., Zhang H., Xue F., et al. 2017. 4-PBA inhibits LPS-induced inflammation through regulating ER stress and autophagy in acute lung injury models. Toxicol Lett. 271:26–37. 10.1016/j.toxlet.2017.02.023
Zeng T., Zhou Y., Yu Y., Wang J.W., Wu Y., Wang X., et al. 2023. rmMANF prevents sepsis-associated lung injury via inhibiting endoplasmic reticulum stress-induced ferroptosis in mice. Int Immunopharmacol. 114:109608. 10.1016/j.intimp.2022.109608
Zhai F.G., Liang Q.C., Wu Y.Y., Liu J.Q., and Liu J.W. 2022. Red ginseng polysaccharide exhibits anticancer activity through GPX4 downregulation-induced ferroptosis. Pharm Biol. 60(1):909–914. 10.1080/13880209.2022.2066139
Zhang M.Q., and Li C.S. 2023. Therapeutic effects of Shenfu injection in shock. Chin J Integr Med. 29(12):1142–1146. 10.1007/s11655-023-3631-2
Zheng G., Ren H., Li H., Li X., Dong T., Xu S., et al. 2019. Lycium barbarum polysaccharide reduces hyperoxic acute lung injury in mice through Nrf2 pathway. Biomed Pharmacother. 111:733–739. 10.1016/j.biopha.2018.12.073
Zhou X., and Liao Y. 2021. Gut-lung crosstalk in sepsis-induced acute lung injury. Front Microbiol. 12:779620. 10.3389/fmicb.2021.779620
Zhou J., Peng Z., and Wang J. 2021. Trelagliptin alleviates lipopolysaccharide (LPS)-induced inflammation and oxidative stress in acute lung injury mice. Inflammation. 44(4):1507–1517. 10.1007/s10753-021-01435-w