Resveratrol Cải Thiện Tổn Thương Thiếu Máu - Tưới Máu Lại Ở Võng Mạc Bằng Cách Điều Chỉnh Đường Dẫn NLRP3 Inflammasome Và Keap1/Nrf2/HO-1

Jiazhen Feng1,2, Kaibao Ji2,1, Yiji Pan1,2, Pingping Huang2, Tao He2, Yiqiao Xing1,2
1Eye Institute of Wuhan University, Hubei, China
2Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, China

Tóm tắt

Glaucoma, như một bệnh lý tổn thương thiếu máu - tưới máu lại (I/R), dẫn đến mù lòa không hồi phục thông qua sự mất mát tế bào hạch võng mạc (RGCs), được trung gian bởi nhiều con đường khác nhau. Resveratrol (Res) là một hợp chất polyphenolic có tác dụng bảo vệ chống lại tổn thương I/R ở nhiều mô. Bài báo này nhằm giải thích các cơ chế ẩn giấu qua đó Res bảo vệ RGCs và giảm rối loạn thị giác in vivo. Một mô hình glaucoma thí nghiệm được tạo ra bằng cách sử dụng chuột đực C57BL/6J hoang dã từ 6-8 tuần tuổi. Res đã được tiêm vào khoang phúc mạc trong 5 ngày. Các con chuột sau đó được phân nhóm dựa trên số ngày sau phẫu thuật và việc điều trị bằng Res. Chúng tôi đã áp dụng nhuộm miễn dịch huỳnh quang gắn Brn3a và điện sinh lý võng mạc (ERG) để đánh giá sự sống sót của RGCs và chức năng thị giác. Sự biểu hiện của các thành phần của protein 3 (NLRP3) inflammasome, interleukin-1-beta (IL-1β), và các chỉ số quan trọng của con đường protein 1 (Keap1)/yếu tố liên quan hồng cầu 2 (Nrf2)/heme-oxygenase 1 (HO-1) ở mức độ protein và RNA được phát hiện tương ứng. Sự sống sót của RGCs bị giảm sau phẫu thuật so với nhóm chứng, trong khi ứng dụng Res đã cứu sống RGCs và cải thiện rối loạn thị giác. Tóm lại, kết quả của chúng tôi cho thấy rằng việc sử dụng Res đã cho thấy tác dụng bảo vệ thần kinh thông qua việc ức chế đường dẫn NLRP3 inflammasome và kích hoạt đường dẫn Keap1/Nrf2/HO-1. Do đó, chúng tôi đã làm sáng tỏ tiềm năng của Res trong liệu pháp điều trị glaucoma.

Từ khóa

#Glaucoma #Resveratrol #RGCs #NLRP3 inflammasome #Keap1 #Nrf2 #HO-1

Tài liệu tham khảo

Schuster AK, Erb C, Hoffmann EM, Dietlein T, Pfeiffer N (2020) The diagnosis and treatment of glaucoma. Dtsch Arztebl Int 117(13):225–234. https://doi.org/10.3238/arztebl.2020.0225 Kang JM, Tanna AP (2021) Glaucoma. Med Clin North Am 105(3):493–510. https://doi.org/10.1016/j.mcna.2021.01.004 Stein JD, Khawaja AP, Weizer JS (2021) Glaucoma in adults-screening, diagnosis, and management: a review. JAMA 325(2):164–174. https://doi.org/10.1001/jama.2020.21899 Huang Y, Xu W, Zhou R (2021) NLRP3 inflammasome activation and cell death. Cell Mol Immunol 18(9):2114–2127. https://doi.org/10.1038/s41423-021-00740-6 Wang L, Hauenstein AV (2020) The NLRP3 inflammasome: mechanism of action, role in disease and therapies. Mol Aspects Med 76:100889. https://doi.org/10.1016/j.mam.2020.100889 Wang M, Pan W, Xu Y, Zhang J, Wan J, Jiang H (2022) Microglia-mediated neuroinflammation: a potential target for the treatment of cardiovascular diseases. J Inflamm Res 15:3083–3094. https://doi.org/10.2147/JIR.S350109 Shen S, Wang Z, Sun H, Ma L (2022) Role of NLRP3 inflammasome in myocardial ischemia-reperfusion injury and ventricular remodeling. Med Sci Monit 28:e934255. https://doi.org/10.12659/MSM.934255 8, Minutoli L, Puzzolo D, Rinaldi M, Irrera N, Marini H, Arcoraci V, Bitto A, Crea G et al (2016) ROS-mediated NLRP3 inflammasome activation in brain, heart, kidney, and testis ischemia/reperfusion injury. Oxid Med Cell Longev 2016:2183026. https://doi.org/10.1155/2016/2183026 Toldo S, Abbate A (2018) The NLRP3 inflammasome in acute myocardial infarction. Nat Rev Cardiol 15(4):203–214. https://doi.org/10.1038/nrcardio.2017.161 Ulasov AV, Rosenkranz AA, Georgiev GP, Sobolev AS (2022) Nrf2/Keap1/ARE signaling: towards specific regulation. Life Sci 291:120111. https://doi.org/10.1016/j.lfs.2021.120111 Saha S, Buttari B, Panieri E, Profumo E, Saso L (2020) An overview of Nrf2 signaling pathway and its role in inflammation. Molecules 25(22). https://doi.org/10.3390/molecules25225474 Panisello-Roselló GBR, Sanchez-Nuno A, Alva S, Roselló-Catafau N, Carbonell J T (2022) Nrf2 and oxidative stress in liver ischemia/reperfusion injury. Febs J 289(18):5463–5479. https://doi.org/10.1111/febs.16336 Yu C, Xiao JH (2021) The Keap1-Nrf2 system: a mediator between oxidative stress and aging. Oxid Med Cell Longev 2021:6635460. https://doi.org/10.1155/2021/6635460 Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J (2016) Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci 73(17):3221–3247. https://doi.org/10.1007/s00018-016-2223-0 Zhang Q, Liu J, Duan H, Li R, Peng W, Wu C (2021) Activation of Nrf2/HO-1 signaling: an important molecular mechanism of herbal medicine in the treatment of atherosclerosis via the protection of vascular endothelial cells from oxidative stress. J Adv Res 34:43–63. https://doi.org/10.1016/j.jare.2021.06.023 Zhang C, Zhao M, Wang B, Su Z, Guo B, Qin L, Zhang W, Zheng R (2021) The Nrf2-NLRP3-caspase-1 axis mediates the neuroprotective effects of celastrol in Parkinson’s disease. Redox Biol 47:102134. https://doi.org/10.1016/j.redox.2021.102134 Bian H, Wang G, Huang J, Liang L, Zheng Y, Wei Y, Wang H, Xiao L et al (2020) Dihydrolipoic acid protects against lipopolysaccharide-induced behavioral deficits and neuroinflammation via regulation of Nrf2/HO-1/NLRP3 signaling in rat. J Neuroinflammation 17(1):166. https://doi.org/10.1186/s12974-020-01836-y Wu Y, Qiu G, Zhang H, Zhu L, Cheng G, Wang Y, Li Y, Wu W (2021) Dexmedetomidine alleviates hepatic ischaemia-reperfusion injury via the PI3K/AKT/Nrf2-NLRP3 pathway. J Cell Mol Med 25(21):9983–9994. https://doi.org/10.1111/jcmm.16871 Xiao L, Dai Z, Tang W, Liu C, Tang B (2021) Astragaloside IV alleviates cerebral ischemia-reperfusion injury through NLRP3 inflammasome-mediated pyroptosis inhibition via activating Nrf2. Oxid Med Cell Longev 2021:9925561. https://doi.org/10.1155/2021/9925561 Cheng Y, Cheng L, Gao X, Chen S, Wu P, Wang C, Liu Z (2021) Covalent modification of Keap1 at Cys77 and Cys434 by pubescenoside a suppresses oxidative stress-induced NLRP3 inflammasome activation in myocardial ischemia-reperfusion injury. Theranostics 11(2):861–877. https://doi.org/10.7150/thno.48436 Qi Y, Zhao M, Bai Y, Huang L, Yu W, Bian Z, Zhao M, Li X (2014) Retinal ischemia/reperfusion injury is mediated by toll-like receptor 4 activation of NLRP3 inflammasomes. Invest Ophthalmol Vis Sci 55(9):5466–5475. https://doi.org/10.1167/iovs.14-14380 Su CF, Jiang L, Zhang XW, Iyaswamy A, Li M (2021) Resveratrol in rodent models of Parkinson’s disease: a systematic review of experimental studies. Front Pharmacol 12:644219. https://doi.org/10.3389/fphar.2021.644219 Hecker A, Schellnegger M, Hofmann E, Luze H, Nischwitz SP, Kamolz LP, Kotzbeck P (2022) The impact of resveratrol on skin wound healing, scarring, and aging. Int Wound J 19(1):9–28. https://doi.org/10.1111/iwj.13601 Khorshidi F, Poljak A, Liu Y, Lo JW, Crawford JD, Sachdev PS (2021) Resveratrol: a miracle drug in neuropsychiatry or a cognitive enhancer for mice only? A systematic review and meta-analysis. Ageing Res Rev 65:101199. https://doi.org/10.1016/j.arr.2020.101199 Mahdavi A, Bagherniya M, Mirenayat MS, Atkin SL, Sahebkar A (2021) Medicinal plants and phytochemicals regulating insulin resistance and glucose homeostasis in type 2 diabetic patients: a clinical review. Adv Exp Med Biol 1308:161–183. https://doi.org/10.1007/978-3-030-64872-5_13 Sun ZM, Guan P, Luo LF, Qin LY, Wang N, Zhao YS, Ji ES (2020) Resveratrol protects against CIH-induced myocardial injury by targeting Nrf2 and blocking NLRP3 inflammasome activation. Life Sci 245:117362. https://doi.org/10.1016/j.lfs.2020.117362 Ji K, Li Z, Lei Y, Xu W, Ouyang L, He T, Xing Y (2021) Resveratrol attenuates retinal ganglion cell loss in a mouse model of retinal ischemia reperfusion injury via multiple pathways. Exp Eye Res 209:108683. https://doi.org/10.1016/j.exer.2021.108683 Sun YY, Zhu HJ, Zhao RY, Zhou SY, Wang MQ, Yang Y, Guo ZN (2023) Remote ischemic conditioning attenuates oxidative stress and inflammation via the Nrf2/HO-1 pathway in MCAO mice. Redox Biol 66:102852. https://doi.org/10.1016/j.redox.2023.102852 Li J, Xu P, Hong Y, Xie Y, Peng M, Sun R, Guo H, Zhang X et al (2023) Lipocalin-2-mediated astrocyte pyroptosis promotes neuroinflammatory injury via NLRP3 inflammasome activation in cerebral ischemia/reperfusion injury. J Neuroinflammation 20(1):148. https://doi.org/10.1186/s12974-023-02819-5 Hu R, Luo H, Ji Y, Wang Z, Zheng P, Ouyang H, Wang X, Wang Y et al (2023) Activation of NLRP3 signaling contributes to cadmium-induced bone defects, associated with autophagic flux obstruction. Sci Total Environ 893:164787. https://doi.org/10.1016/j.scitotenv.2023.164787 Yang J, Yang N, Luo J, Cheng G, Zhang X, He T, Xing Y (2020) Overexpression of S100A4 protects retinal ganglion cells against retinal ischemia-reperfusion injury in mice. Exp Eye Res 201:108281. https://doi.org/10.1016/j.exer.2020.108281 Franke M, Bieber M, Kraft P, Weber A, Stoll G, Schuhmann MK (2021) The NLRP3 inflammasome drives inflammation in ischemia/reperfusion injury after transient middle cerebral artery occlusion in mice. Brain Behav Immun 92:223–233. https://doi.org/10.1016/j.bbi.2020.12.009 Tang TT, Lv LL, Pan MM, Wen Y, Wang B, Li ZL, Wu M, Wang FM et al (2018) Hydroxychloroquine attenuates renal ischemia/reperfusion injury by inhibiting cathepsin mediated NLRP3 inflammasome activation. Cell Death Dis 9(3):351. https://doi.org/10.1038/s41419-018-0378-3 Qin Q, Yu N, Gu Y, Ke W, Zhang Q, Liu X, Wang K, Chen M (2022) Inhibiting multiple forms of cell death optimizes ganglion cells survival after retinal ischemia reperfusion injury. Cell Death Dis 13(5):507. https://doi.org/10.1038/s41419-022-04911-9 Kong P, Cui ZY, Huang XF, Zhang DD, Guo RJ, Han M (2022) Inflammation and atherosclerosis: signaling pathways and therapeutic intervention. Signal Transduct Target Ther 7(1):131. https://doi.org/10.1038/s41392-022-00955-7 Madhu LN, Kodali M, Attaluri S, Shuai B, Melissari L, Rao X, Shetty AK (2021) Melatonin improves brain function in a model of chronic Gulf War illness with modulation of oxidative stress, NLRP3 inflammasomes, and BDNF-ERK-CREB pathway in the hippocampus. Redox Biol 43:101973. https://doi.org/10.1016/j.redox.2021.101973 Sharma BR, Kanneganti TD (2021) NLRP3 inflammasome in cancer and metabolic diseases. Nat Immunol 22(5):550–559. https://doi.org/10.1038/s41590-021-00886-5 Chen H, Deng Y, Gan X, Li Y, Huang W, Lu L, Wei L, Su L et al (2020) NLRP12 collaborates with NLRP3 and NLRC4 to promote pyroptosis inducing ganglion cell death of acute glaucoma. Mol Neurodegener 15(1):26. https://doi.org/10.1186/s13024-020-00372-w Liu M, Li H, Yang R, Ji D, Xia X (2022) GSK872 and necrostatin-1 protect retinal ganglion cells against necroptosis through inhibition of RIP1/RIP3/MLKL pathway in glutamate-induced retinal excitotoxic model of glaucoma. J Neuroinflammation 19(1):262. https://doi.org/10.1186/s12974-022-02626-4 Liu J, Zhang N, Zhang M, Yin H, Zhang X, Wang X, Wang X, Zhao Y (2021) N-acetylserotonin alleviated the expression of interleukin-1β in retinal ischemia-reperfusion rats via the TLR4/NF-κB/NLRP3 pathway. Exp Eye Res 208:108595. https://doi.org/10.1016/j.exer.2021.108595 Zhao W, Huang X, Han X, Hu D, Hu X, Li Y, Huang P, Yao W (2018) Resveratrol suppresses gut-derived NLRP3 inflammasome partly through stabilizing mast cells in a rat model. Mediators Inflamm 2018:6158671. https://doi.org/10.1155/2018/6158671 He Q, Li Z, Wang Y, Hou Y, Li L, Zhao J (2017) Resveratrol alleviates cerebral ischemia/reperfusion injury in rats by inhibiting NLRP3 inflammasome activation through Sirt1-dependent autophagy induction. Int Immunopharmacol 50:208–215. https://doi.org/10.1016/j.intimp.2017.06.029 Li H, Zheng F, Zhang Y, Sun J, Gao F, Shi G (2022) Resveratrol, novel application by preconditioning to attenuate myocardial ischemia/reperfusion injury in mice through regulate AMPK pathway and autophagy level. J Cell Mol Med 26(15):4216–4229. https://doi.org/10.1111/jcmm.17431 Rojo DLVM, Chapman E, Zhang DD (2018) NRF2 and the hallmarks of cancer. Cancer Cell 34(1):21–43. https://doi.org/10.1016/j.ccell.2018.03.022 Qin X, Li N, Zhang M, Lin S, Zhu J, Xiao D, Cui W, Zhang T et al (2019) Tetrahedral framework nucleic acids prevent retina ischemia-reperfusion injury from oxidative stress via activating the Akt/Nrf2 pathway. Nanoscale 11(43):20667–20675. https://doi.org/10.1039/c9nr07171g Arioz BI, Tastan B, Tarakcioglu E, Tufekci KU, Olcum M, Ersoy N, Bagriyanik A, Genc K et al (2019) Melatonin attenuates LPS-induced acute depressive-like behaviors and microglial NLRP3 inflammasome activation through the SIRT1/Nrf2 pathway. Front Immunol 10:1511. https://doi.org/10.3389/fimmu.2019.01511 Yang H, Lv H, Li H, Ci X, Peng L (2019) Oridonin protects LPS-induced acute lung injury by modulating Nrf2-mediated oxidative stress and Nrf2-independent NLRP3 and NF-κB pathways. Cell Commun Signal 17(1):62. https://doi.org/10.1186/s12964-019-0366-y Lin Y, Luo T, Weng A, Huang X, Yao Y, Fu Z, Li Y, Liu A et al (2020) Gallic acid alleviates gouty arthritis by inhibiting NLRP3 inflammasome activation and pyroptosis through enhancing Nrf2 signaling. Front Immunol 11:580593. https://doi.org/10.3389/fimmu.2020.580593 Satoh T, Trudler D, Oh CK, Lipton SA (2022) Potential therapeutic use of the rosemary diterpene carnosic acid for Alzheimer’s disease, Parkinson’s disease, and Long-COVID through NRF2 activation to counteract the NLRP3 inflammasome. Antioxid (Basel) 11(1). https://doi.org/10.3390/antiox11010124 Dai Y, Zhang J, Xiang J, Li Y, Wu D, Xu J (2019) Calcitriol inhibits ROS-NLRP3-IL-1β signaling axis via activation of Nrf2-antioxidant signaling in hyperosmotic stress stimulated human corneal epithelial cells. Redox Biol 21:101093. https://doi.org/10.1016/j.redox.2018.101093 Liu Q, Zhang F, Zhang X, Cheng R, Ma JX, Yi J, Li J (2018) Fenofibrate ameliorates diabetic retinopathy by modulating Nrf2 signaling and NLRP3 inflammasome activation. Mol Cell Biochem 445(1–2):105–115. https://doi.org/10.1007/s11010-017-3256-x