| ORIGINAL ARTICLES |
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Libertellenone C attenuates oxidative stress and neuroinflammation with the capacity of NLRP3 inhibition |
| Jie Cao1, Lanqin Li2, Runge Zhang2, Zhou Shu1, Yaxin Zhang2, Weiguang Sun2, Yonghui Zhang2, Zhengxi Hu2 |
1. Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China;
2. Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China |
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Abstract Neurodegenerative diseases (NDs) are common chronic diseases arising from progressive damage to the nervous system. Here, in-house natural product database screening revealed that libertellenone C (LC) obtained from the fermentation products of Arthrinium arundinis separated from the gut of a centipede collected in our Tongji campus, showed a remarkable neuroprotective effect. Further investigation was conducted to clarify the specific mechanism. LC dose-dependently reversed glutamate-induced decreased viability, accumulated reactive oxygen species, mitochondrial membrane potential loss, and apoptosis in SH-SY5Y cells. Network pharmacology analysis predicted that the targets of LC were most likely directly related to oxidative stress and the regulation of inflammatory factor-associated signaling pathways. Further study demonstrated that LC attenuated nitrite, TNF-α, and IL-1β production and decreased inducible nitric oxide synthase and cyclooxygenase expression in lipopolysaccharide-induced BV-2 cells. LC could directly inhibit NLRP3 inflammasome activation by decreasing the expression levels of NLRP3, ASC, cleaved Caspase-1, and NF-κB p65. Our results provide a new understanding of how LC inhibits the NLRP3 inflammasome in microglia, providing neuroprotection. These findings might guide the development of effective LC-based therapeutic strategies for NDs.
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| Keywords
Neurodegenerative diseases
Narural products
Libertellenone C
NLRP3 inflammasome
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| Fund:This research was financially supported by the National Program for Support of Top-notch Young Professionals (No. 0106514050), the National Natural Science Foundation of China (Nos. 82173705, 82273811, and U22A20380), the National Key R&D Program of China (No. 2021YFA0910500), the National Natural Science Foundation for Excellent Young Scholars (No. 81922065); the Science and Technology Major Project of Hubei Province (No. 2021ACA012); the Research and Development Program of Hubei Province (No. 2020BCA058). |
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Corresponding Authors:
Weiguang Sun,E-mail:weiguang_sun@hust.edu.cn；Yonghui Zhang,E-mail:zhangyh@mails.tjmu.edu.cn；Zhengxi Hu,E-mail:huzhengxi@hust.edu.cn
E-mail: weiguang_sun@hust.edu.cn;zhangyh@mails.tjmu.edu.cn;huzhengxi@hust.edu.cn
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Issue Date: 16 May 2024
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[1] Qiao J, Wang T, Shao Z, Zhu Y, Zhang M, Huang S, Zeng P. Genetic correlation and gene-based pleiotropy analysis for four major neurodegenerative diseases with summary statistics. Neurobiol Aging. 2023;124:117-28. https://doi.org/10.1016/j.neurobiolaging.2022.12.012.
[2] Wilson DM 3rd, Cookson MR, Van Den Bosch L, Zetterberg H, Holtzman DM, Dewachter I. Hallmarks of neurodegenerative diseases. Cell. 2023;186:693-714. https://doi.org/10.1016/j.cell.2022.12.032.
[3] Simon DK, Tanner CM, Brundin P. Parkinson disease epidemiology, pathology, genetics, and pathophysiology. Clin Geriatr Med. 2020;36:1-12. https://doi.org/10.1016/j.cger.2019.08.002.
[4] Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140:918-34. https://doi.org/10.1016/j.cell.2010.02.016.
[5] Ransohoff RM. How neuroinflammation contributes to neurodegeneration. Science. 2016;353:777-83. https://doi.org/10.1126/science.aag2590.
[6] Colton CA. Heterogeneity of microglial activation in the innate immune response in the brain. J Neuroimmune Pharmacol. 2009;4:399-418. https://doi.org/10.1007/s11481-009-9164-4.
[7] Kwon HS, Koh SH. Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener. 2020;9:42. https://doi.org/10.1186/s40035-020-00221-2.
[8] Hong Y, Dong X, Chang L, Xie C, Chang M, Aguilar JS, Lin J, Lin J, Li QQ. Microglia-containing cerebral organoids derived from induced pluripotent stem cells for the study of neurological diseases. iScience. 2023;26:106267. https://doi.org/10.1186/s40035-020-00221-2.
[9] El Khoury J. Neurodegeneration and the neuroimmune system. Nat Med. 2010;16:1369-70. https://doi.org/10.1038/nm1210-1369.
[10] Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Münch AE, Chung WS, Peterson TC, Wilton DK, Frouin A, Napier BA, Panicker N, Kumar M, Buckwalter MS, Rowitch DH, Dawson VL, Dawson TM, Stevens B, Barres BA. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541:481-7. https://doi.org/10.1038/nature21029.
[11] Nayak D, Roth TL, McGavern DB. Microglia development and function. Annu Rev Immunol. 2014;32:367-402. https://doi.org/10.1146/annurev-immunol-032713-120240.
[12] Zhu T, Guo J, Wu Y, Lei T, Zhu J, Chen H, Kala S, Wong KF, Cheung CP, Huang X, Zhao X, Yang M, Sun L. The mechanosensitive ion channel Piezo1 modulates the migration and immune response of microglia. iScience. 2023;26:105993. https://doi.org/10.1016/j.isci.2023.105993.
[13] Venigalla M, Sonego S, Gyengesi E, Sharman MJ, Münch G. Novel promising therapeutics against chronic neuroinflammation and neurodegeneration in Alzheimer’s disease. Neurochem Int. 2016;95:63-74. https://doi.org/10.1016/j.neuint.2015.10.011.
[14] Zhang WJ, Li KY, Lan Y, Zeng HY, Chen SQ, Wang H. NLRP3 inflammasome: a key contributor to the inflammation formation. Food Chem Toxicol. 2023;174:113683. https://doi.org/10.1016/j.fct.2023.113683.
[15] Wang T, Xu H, Dong R, Wu S, Guo Y, Wang D. Effectiveness of targeting the NLRP3 inflammasome by using natural polyphenols: a systematic review of implications on health effects. Food Res Int. 2023;165:112567. https://doi.org/10.1016/j.foodres.2023.112567.
[16] Afonina IS, Zhong Z, Karin M, Beyaert R. Limiting inflammation-the negative regulation of NF-κB and the NLRP3 inflammasome. Nat Immunol. 2017;18:861-9. https://doi.org/10.1038/ni.3772.
[17] Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA, Hornung V, Latz E. Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009;183:787-91. https://doi.org/10.4049/jimmunol.0901363.
[18] Simard JC, Cesaro A, Chapeton-Montes J, Tardif M, Antoine F, Girard D, Tessier PA. S100A8 and S100A9 induce cytokine expression and regulate the NLRP3 inflammasome via ROS-dependent activation of NF-κB1. PLoS ONE. 2013;8:e72138. https://doi.org/10.1371/journal.pone.0072138.
[19] Thapa P, Upadhyay SP, Singh V, Boinpelly VC, Zhou J, Johnson DK, Gurung P, Lee ES, Sharma R, Sharma M. Chalcone: a potential scaffold for NLRP3 inflammasome inhibitors. Eur J Med Chem Rep. 2023;7:100100. https://doi.org/10.1016/j.ejmcr.2022.100100.
[20] Liu X, Zhang Z, Ruan J, Pan Y, Magupalli VG, Wu H, Lieberman J. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature. 2016;535:153-8. https://doi.org/10.1038/nature18629.
[21] Porte Alcon S, Gorojod RM, Kotler ML. Kinetic and protective role of autophagy in manganese-exposed BV-2 cells. Biochim Biophys Acta Mol Cell Res. 2020;1867:118787. https://doi.org/10.1016/j.bbamcr.2020.118787.
[22] Shao QH, Zhang XL, Chen Y, Zhu CG, Shi JG, Yuan Y, Chen NH. Anti-neuroinflammatory effects of 20C from Gastrodia elata via regulating autophagy in LPS-activated BV-2 cells through MAPKs and TLR4/Akt/mTOR signaling pathways. Mol Immunol. 2018;99:115-23. https://doi.org/10.1016/j.molimm.2018.04.014.
[23] Costantino V, Fattorusso E, Mangoni A, Perinu C, Cirino G, De Gruttola L, Roviezzo F. Tedanol: a potent anti-inflflammatory ent-pimarane diterpene from the Caribbean Sponge Tedania ignis. Bioorg Med Chem. 2009;17:7542-7. https://doi.org/10.1016/j.bmc.2009.09.010.
[24] Maitra U, Stephen C, Ciesla LM. Drug discovery from natural products—old problems and novel solutions for the treatment of neurodegenerative diseases. J Pharm Biomed Anal. 2022;210:114553. https://doi.org/10.1016/j.jpba.2021.114553.
[25] Joyner PM, Cichewicz RH. Bringing natural products into the fold—exploring the therapeutic lead potential of secondary metabolites for the treatment of protein-misfolding-related neurodegenerative diseases. Nat Prod Rep. 2011;28:26-47. https://doi.org/10.1039/c0np00017e.
[26] Chib S, Singh S. Manganese and related neurotoxic pathways: a potential therapeutic target in neurodegenerative diseases. Neurotoxicol Teratol. 2022;94:107124. https://doi.org/10.1016/j.ntt.2022.107124.
[27] Javaid HMA, Ko E, Joo EJ, Kwon SH, Park JH, Shin S, Cho KW, Huh JY. TNFα-induced NLRP3 inflammasome mediates adipocyte dysfunction and activates macrophages through adipocyte-derived lipocalin 2. Metabolism. 2023;142:155527. https://doi.org/10.1016/j.metabol.2023.155527.
[28] Xu Z, Ji R, Zha X, Zhao H, Zhou S. The aqueous extracts of Ageratum conyzoides inhibit inflammation by suppressing NLRP3 inflammasome activation. J Ethnopharmacol. 2023;309:116353. https://doi.org/10.1016/j.jep.2023.116353.
[29] Duan Y, Wang J, Cai J, Kelley N, He Y. The leucine-rich repeat (LRR) domain of NLRP3 is required for NLRP3 inflammasome activation in macrophages. J Biol Chem. 2022;298:102717. https://doi.org/10.1016/j.jbc.2022.102717.
[30] Singh L, Singh S. Neuroprotective potential of Honokiol in ICV-STZ induced neuroinflammation, Aβ (1-42) and NF-kB expression in experimental model of rats. Neurosci Lett. 2023;799:137090. https://doi.org/10.1016/j.neulet.2023.137090.
[31] Xu Z, Zhou X, Hong X, Wang S, Wei J, Huang J, Ji L, Yang Y, Efferth T, Hong C, Li C. Essential oil of Acorus tatarinowii Schott inhibits neuroinflammation by suppressing NLRP3 inflammasome activation in 3×Tg-AD transgenic mice. Phytomedicine. 2023;112:154695. https://doi.org/10.1016/j.phymed.2023.154695l.
[32] Anderson FL, Biggs KE, Rankin BE, Havrda MC. NLRP3 inflammasome in neurodegenerative disease. Transl Res. 2023;252:21-33. https://doi.org/10.1016/j.trsl.2022.08.006.
[33] Tejera D, Mercan D, Sanchez-Caro JM, Hanan M, Greenberg D, Soreq H, Latz E, Golenbock D, Heneka MT. Heneka, systemic inflammation impairs microglial Aβ clearance through NLRP3 inflammasome. EMBO J. 2019;38:e101064. https://doi.org/10.15252/embj.2018101064.
[34] Jayaraj RL, Azimullah S, Parekh KA, Ojha SK, Beiram R. Effect of citronellol on oxidative stress, neuroinflammation and autophagy pathways in an in vivo model of Parkinson’s disease. Heliyon. 2022;8:e11434. https://doi.org/10.1016/j.heliyon.2022.e11434.
[35] Deng Z, Dong Y, Zhou X, Lu JH, Yue Z. Pharmacological modulation of autophagy for Alzheimer’s disease therapy: opportunities and obstacles. Acta Pharm Sin B. 2022;12:1688-706. https://doi.org/10.1016/j.apsb.2021.12.009.
[36] Minchev D, Kazakova M, Sarafian V. Neuroinflammation and autophagy in Parkinson’s disease—novel perspectives. Int J Mol Sci. 2022;23:14997. https://doi.org/10.3390/ijms232314997.
[37] Wang X, Feng L, Xin M, Hao Y, Wang X, Shang P, Zhao M, Hou S, Zhang Y, Xiao Y, Ma D, Feng J. Mechanisms underlying astrocytic connexin-43 autophagy degradation during cerebral ischemia injury and the effect on neuroinflammation and cell apoptosis. Biomed Pharmacother. 2020;127:110125. https://doi.org/10.1016/j.biopha.2020.110125.
[38] Cui M, Yoshimori T, Nakamura S. Autophagy system as a potential therapeutic target for neurodegenerative diseases. Neurochem Int. 2022;155:105308. https://doi.org/10.1016/j.neuint.2022.105308.
[39] Wang ZY, Liu J, Zhu Z, Su CF, Sreenivasmurthy SG, Iyaswamy A, Lu JH, Chen G, Song JX, Li M. Traditional Chinese medicine compounds regulate autophagy for treating neurodegenerative disease: a mechanism review. Biomed Pharmacother. 2021;13:110968. https://doi.org/10.1016/j.biopha.2020.110968.
[40] Schiøtz BL, Roos N, Rishovd AL, Gjøen T. Formation of autophagosomes and redistribution of LC3 upon in vitro infection with infectious salmon anemia virus. Virus Res. 2010;151:104-7. https://doi.org/10.1016/j.virusres.2010.03.013.
[41] Rebhan M, Chalifa-Caspi V, Prilusky J, Lancet D. GeneCards: integrating information about genes, proteins and diseases. Trends Genet. 1997;13:163. https://doi.org/10.1016/s0168-9525(97)01103-7.
[42] Bauer-Mehren A, Rautschka M, Sanz F, Furlong LI. DisGeNET: a cytoscape plugin to visualize, integrate, search and analyze gene-disease networks. Bioinformatics. 2010;26:2924-6. https://doi.org/10.1093/bioinformatics/btq538.
[43] Yuan Q, Zhang X, Wei W, Furlong LI. Lycorine improves peripheral nerve function by promoting Schwann cell autophagy via AMPK pathway activation and MMP9 downregulation in diabetic peripheral neuropathy. Pharmacol Res. 2022;26:105985. https://doi.org/10.1016/j.phrs.2021.105985.
[44] Huang DW, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4:44-57. https://doi.org/10.1038/nprot.2008.211. |
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