Abstract
Sepsis, a life-threatening condition characterized by dysregulated immune responses, remains a significant clinical challenge. Myricanol, a natural compound, plays a variety of roles in regulating lipid metabolism, anti-cancer, anti-neurodegeneration, and it could act as an Sirtuin 1 (SIRT1) activator. This study aimed to explore the therapeutic potential and underlying mechanism of myricanol in the lipopolysaccharide (LPS)-induced sepsis model. In vivo studies revealed that myricanol administration significantly improved the survival rate of LPS-treated mice, effectively mitigating LPS-induced inflammatory responses in lung tissue. Furthermore, in vitro studies demonstrated that myricanol treatment inhibited the expression of pro-inflammatory cytokines, attenuated signal pathway activation, and reduced oxidative stress in macrophages. In addition, we demonstrated that myricanol selectively enhances SIRT1 activation in LPS-stimulated macrophages, and all of the protective effect of myricanol were reversed through SIRT1 silencing. Remarkably, the beneficial effects of myricanol against LPS-induced sepsis were abolished in SIRT1 myeloid-specific knockout mice, underpinning the critical role of SIRT1 in mediating myricanol’s therapeutic efficacy. In summary, this study provides significant evidence that myricanol acts as a potent SIRT1 activator, targeting inflammatory signal pathways and oxidative stress to suppress excessive inflammatory responses. Our findings highlight the potential of myricanol as a novel therapeutic agent for the treatment of LPS-induced sepsis.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The data are available from the corresponding author on reasonable request.
References
Belchamber KBR, Donnelly LE (2017) Macrophage dysfunction in respiratory disease. Results Probl Cell Differ 62:299–313. https://doi.org/10.1007/978-3-319-54090-0_12
Bonkowski MS, Sinclair DA (2016) Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nat Rev Mol Cell Biol 17:679–690. https://doi.org/10.1038/nrm.2016.93
Bosmann M, Ward PA (2013) The inflammatory response in sepsis. Trends Immunol 34:129–136. https://doi.org/10.1016/j.it.2012.09.004
Cavaillon J-M, Adib-Conquy M (2005) Monocytes/macrophages and sepsis. Crit Care Med 33:S506. https://doi.org/10.1097/01.CCM.0000185502.21012.37
Cecconi M, Evans L, Levy M, Rhodes A (2018) Sepsis and septic shock. The Lancet 392:75–87. https://doi.org/10.1016/S0140-6736(18)30696-2
Chen G-D, Yu W-D, Chen X-P (2016) SirT1 activator represses the transcription of TNF-α in THP-1 cells of a sepsis model via deacetylation of H4K16. Mol Med Rep 14:5544–5550. https://doi.org/10.3892/mmr.2016.5942
Chen P, Lin X, Yang C-H et al (2017) Study on Chemical profile and neuroprotective activity of myrica rubra leaf extract. Molecules 22:1226. https://doi.org/10.3390/molecules22071226
Ciencewicki J, Trivedi S, Kleeberger SR (2008) Oxidants and the pathogenesis of lung diseases. J Allergy Clin Immunol 122:456–468. https://doi.org/10.1016/j.jaci.2008.08.004
Crouser ED (2004) Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome. Mitochondrion 4:729–741. https://doi.org/10.1016/j.mito.2004.07.023
Dai GH, Meng GM, Tong YL et al (2014) Growth-inhibiting and apoptosis-inducing activities of Myricanol from the bark of Myrica rubra in human lung adenocarcinoma A549 cells. Phytomedicine 21:1490–1496. https://doi.org/10.1016/j.phymed.2014.04.025
Dai G, Tong Y, Chen X et al (2015) Myricanol induces apoptotic cell death and anti-tumor activity in non-small cell lung carcinoma in vivo. Int J Mol Sci 16:2717–2731. https://doi.org/10.3390/ijms16022717
Esposito S, De Simone G, Boccia G et al (2017) Sepsis and septic shock: New definitions, new diagnostic and therapeutic approaches. Journal of Global Antimicrobial Resistance 10:204–212. https://doi.org/10.1016/j.jgar.2017.06.013
Fan S, Wang C, Huang K, Liang M (2021) Myricanol inhibits platelet derived growth factor-bb-induced vascular smooth muscle cells proliferation and migration in vitro and intimal hyperplasia in vivo by targeting the platelet-derived growth factor Receptor-β and NF-κB Signaling. Front Physiol 12:790345. https://doi.org/10.3389/fphys.2021.790345
Fujihara M, Muroi M, Tanamoto K et al (2003) Molecular mechanisms of macrophage activation and deactivation by lipopolysaccharide: roles of the receptor complex. Pharmacol Ther 100:171–194. https://doi.org/10.1016/j.pharmthera.2003.08.003
Galley HF (2011) Oxidative stress and mitochondrial dysfunction in sepsis. Br J Anaesth 107:57–64. https://doi.org/10.1093/bja/aer093
García JA, Volt H, Venegas C et al (2015) Disruption of the NF-κB/NLRP3 connection by melatonin requires retinoid-related orphan receptor-α and blocks the septic response in mice. FASEB J 29:3863–3875. https://doi.org/10.1096/fj.15-273656
Hwang JS, Kim E, Hur J et al (2020) Ring finger protein 219 regulates inflammatory responses by stabilizing sirtuin 1. Br J Pharmacol 177:4601. https://doi.org/10.1111/bph.15060
Jones JR, Lebar MD, Jinwal UK et al (2011) The diarylheptanoid (+)-aR,11S-myricanol and two flavones from bayberry (Myrica cerifera) destabilize the microtubule-associated protein tau. J Nat Prod 74:38–44. https://doi.org/10.1021/np100572z
Kimura A, Kitajima M, Nishida K et al (2018) NQO1 inhibits the TLR-dependent production of selective cytokines by promoting IκB-ζ degradation. J Exp Med 215:2197–2209. https://doi.org/10.1084/jem.20172024
Kong P, Yu Y, Wang L et al (2019) circ-Sirt1 controls NF-κB activation via sequence-specific interaction and enhancement of SIRT1 expression by binding to miR-132/212 in vascular smooth muscle cells. Nucleic Acids Res 47:3580–3593. https://doi.org/10.1093/nar/gkz141
Kox WJ, Volk T, Kox SN, Volk HD (2000) Immunomodulatory therapies in sepsis. Intensive Care Med 26(Suppl 1):S124-128. https://doi.org/10.1007/s001340051129
Kumar S, Saxena J, Srivastava VK et al (2022) The interplay of oxidative stress and ROS scavenging: antioxidants as a therapeutic potential in sepsis. Vaccines (basel) 10:1575. https://doi.org/10.3390/vaccines10101575
Lee O-H, Jain AK, Papusha V, Jaiswal AK (2007) An auto-regulatory loop between stress sensors INrf2 and Nrf2 controls their cellular abundance*. J Biol Chem 282:36412–36420. https://doi.org/10.1074/jbc.M706517200
Li L, Liu M, Cao M et al (2019) Research progress on SIRT1 and sepsis. Histol Histopathol 34:1205–1215. https://doi.org/10.14670/HH-18-146
Li C, Wang W, Xie S et al (2021) The programmed cell death of macrophages, endothelial cells, and tubular epithelial cells in sepsis-AKI. Front Med (lausanne) 8:796724. https://doi.org/10.3389/fmed.2021.796724
Li T, Geng Z, Zhang J et al (2022a) BP5 alleviates endotoxemia-induced acute lung injury by activating Nrf2 via dual regulation of the Keap1-Nrf2 interaction and the Akt (Ser473)/GSK3β (Ser9)/Fyn pathway. Free Radical Biol Med 193:304–318. https://doi.org/10.1016/j.freeradbiomed.2022.10.299
Li W, Li D, Chen Y et al (2022b) Classic signaling pathways in alveolar injury and repair involved in sepsis-induced ALI/ARDS: new research progress and prospect. Dis Markers 2022:6362344. https://doi.org/10.1155/2022/6362344
Liu TF, Yoza BK, El Gazzar M et al (2011) NAD+-dependent SIRT1 deacetylase participates in epigenetic reprogramming during endotoxin tolerance. J Biol Chem 286:9856–9864. https://doi.org/10.1074/jbc.M110.196790
Lyu P, Li S, Han Y et al (2023) Affinity-based protein profiling-driven discovery of myricanol as a Nampt activator. Bioorg Chem 133:106435. https://doi.org/10.1016/j.bioorg.2023.106435
Mendes KL, de Lelis D, F, Santos SHS, (2017) Nuclear sirtuins and inflammatory signaling pathways. Cytokine Growth Factor Rev 38:98–105. https://doi.org/10.1016/j.cytogfr.2017.11.001
Murray PJ, Allen JE, Biswas SK et al (2014) Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41:14–20. https://doi.org/10.1016/j.immuni.2014.06.008
Pfalzgraff A, Weindl G (2019) Intracellular lipopolysaccharide sensing as a potential therapeutic target for sepsis. Trends Pharmacol Sci 40:187–197
Qiu P, Liu Y, Zhang J (2019) Review: the role and mechanisms of macrophage autophagy in sepsis. Inflammation 42:6–19. https://doi.org/10.1007/s10753-018-0890-8
Rajendrasozhan S, Yang S-R, Kinnula VL, Rahman I (2008) SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 177:861–870. https://doi.org/10.1164/rccm.200708-1269OC
Shapouri-Moghaddam A, Mohammadian S, Vazini H et al (2018) Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol 233:6425–6440. https://doi.org/10.1002/jcp.26429
Shen S, Xia F, Li H et al (2015) A new cyclic diarylheptanoid from the bark of Myrica rubra. Yao Xue Xue Bao 50:746–748
Shen S, Liao Q, Feng Y et al (2019a) Myricanol mitigates lipid accumulation in 3T3-L1 adipocytes and high fat diet-fed zebrafish via activating AMP-activated protein kinase. Food Chem 270:305–314. https://doi.org/10.1016/j.foodchem.2018.07.117
Shen S, Liao Q, Liu J et al (2019b) Myricanol rescues dexamethasone-induced muscle dysfunction via a sirtuin 1-dependent mechanism. J Cachexia Sarcopenia Muscle 10:429–444. https://doi.org/10.1002/jcsm.12393
Sica A, Erreni M, Allavena P, Porta C (2015) Macrophage polarization in pathology. Cell Mol Life Sci 72:4111–4126. https://doi.org/10.1007/s00018-015-1995-y
Singh CK, Chhabra G, Ndiaye MA et al (2018) The role of sirtuins in antioxidant and redox signaling. Antioxid Redox Signal 28:643–661. https://doi.org/10.1089/ars.2017.7290
Song Y, Lin W, Zhu W (2023) Traditional Chinese medicine for treatment of sepsis and related multi-organ injury. Front Pharmacol 14:1003658. https://doi.org/10.3389/fphar.2023.1003658
Vachharajani VT, Liu T, Brown CM et al (2014) SIRT1 inhibition during the hypoinflammatory phenotype of sepsis enhances immunity and improves outcome. J Leukoc Biol 96:785–796. https://doi.org/10.1189/jlb.3MA0114-034RR
van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG (2017) The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol 17:407–420. https://doi.org/10.1038/nri.2017.36
Wang X, Buechler NL, Woodruff AG et al (2018) Sirtuins and immuno-metabolism of sepsis. Int J Mol Sci 19:2738. https://doi.org/10.3390/ijms19092738
Wang YL, Zhang Y, Liu T, Cui J (2021) 3,5-Dimethoxy-4-hydroxy myricanol attenuated oxidative stress-induced toxicity on cardiomyoblast cells. Hum Exp Toxicol 40:1485–1495. https://doi.org/10.1177/0960327121997977
Xu S, Gao Y, Zhang Q et al (2016) SIRT1/3 Activation by Resveratrol Attenuates Acute Kidney Injury in a Septic Rat Model. Oxid Med Cell Longev 2016:7296092. https://doi.org/10.1155/2016/7296092
Xue F, Huang J-W, Ding P-Y et al (2016) Nrf2/antioxidant defense pathway is involved in the neuroprotective effects of Sirt1 against focal cerebral ischemia in rats after hyperbaric oxygen preconditioning. Behav Brain Res 309:1–8. https://doi.org/10.1016/j.bbr.2016.04.045
Yeung F, Hoberg JE, Ramsey CS et al (2004) Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 23:2369–2380. https://doi.org/10.1038/sj.emboj.7600244
Yoshimura M, Yamakami S, Amakura Y, Yoshida T (2012) Diarylheptanoid sulfates and related compounds from Myrica rubra bark. J Nat Prod 75:1798–1802. https://doi.org/10.1021/np300212c
Yoshizaki T, Milne JC, Imamura T et al (2009) SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes. Mol Cell Biol 29:1363–1374. https://doi.org/10.1128/MCB.00705-08
Yu T, Tang Y, Zhang F, Zhang L (2023) Roles of ginsenosides in sepsis. J Ginseng Res 47:1–8. https://doi.org/10.1016/j.jgr.2022.05.004
Zhang J, Zhang M, Huo X-K et al (2023) Macrophage inactivation by small molecule wedelolactone via targeting sEH for the treatment of LPS-induced acute lung injury. ACS Cent Sci 9:440–456. https://doi.org/10.1021/acscentsci.2c01424
Acknowledgements
Not applicable.
Funding
This study was supported by the National Natural Science Foundation of China (No: 81900519), Natural Science Foundation of Hubei Province (2020CFB429, 2022BEC027 and 2022ACA005), Wuhan East Lake High-Tech Development Zone (2022KJB119), and Key project of Hubei Provincial Health Commission (WJ2023Z004).
Author information
Authors and Affiliations
Contributions
K.H. and M.L. conceived of and designed the experiments. K.L. and L.Y. conducted the experiments, prepared the manuscript, and analyzed the data for the work. L.Y., P.W., J.Z. and F.L. analyzed the data of the work. K.H., M.L. and J.P. prepared and revised the manuscript. All authors gave final approval. The authors declare that all data were generated in-house and that no paper mill was used.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Ethical approval and consent to participate
This animal experiment was approved by Institutional Animal Care and Use Committee, Huazhong University of Science and Technology.
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
Liu, K., Yang, L., Wang, P. et al. Myricanol attenuates sepsis-induced inflammatory responses by nuclear factor erythroid 2-related factor 2 signaling and nuclear factor kappa B/mitogen-activated protein kinase pathway via upregulating Sirtuin 1. Inflammopharmacol (2024). https://doi.org/10.1007/s10787-024-01448-5
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s10787-024-01448-5