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Genistein attenuates neuroinflammation and oxidative stress and improves cognitive impairment in a rat model of sepsis-associated encephalopathy: potential role of the Nrf2 signaling pathway

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Abstract

Oxidative stress and inflammation seem to be the main factors responsible for cognitive impairment in sepsis. Genistein (GEN) is claimed to exert many beneficial effects on health, however, its possible effects on brain sepsis remains unclear. Here, we assess the influence and underling mechanisms of GEN on cognitive impairments in cecal ligation and puncture (CLP)-induced septic model. Rats were randomly divided into Sham, Sham + GEN, CLP, CLP + GEN gropus. Rats were treated with GEN (15 mg/kg at 0 and 12 h after CLP, i.p). Twenty-four hours after CLP, protein levels of cytokines, NF-kB and Nrf2, myeloperoxidase (MPO) activity, oxidative damage to lipids and proteins, the activities of antioxidant enzymes and the expression of Nrf2-target genes were evaluated in the hippocampus. At 10 days after sepsis induction, behavioral tests were conducted to evaluate cognitive impairment. The results indicate that GEN can enhance survival percentage and improve cognitive function. Genistein administration significantly reduced TNF-α and IL-1β levels, MPO activity and protein level of NF-kB in the hippocampus of septic rats. Genistein also decreased the levels of oxidative stress parameters (MDA and protein carbonyls) and elevated the activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) in septic rats. Furthermore, nuclear Nrf2 and the expression of HO-1 and NQO-1 were also elevated by GEN treatment. These findings suggest that GEN improves cognition impairment in septic rats via decreasing inflammatory responses and oxidative stress, and activation of the Nrf2 pathway.

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Data availability

The datasets generated during the current study are available from the corresponding author on reasonable request.

References

  • Aras AB, Guven M, Akman T et al (2015) Genistein exerts neuroprotective effect on focal cerebral ischemia injury in rats. Inflammation 38(3):1311–1321

    Article  CAS  Google Scholar 

  • Arnalich F, Garcia-Palomero E, López J et al (2000) “Predictive value of nuclear factor κB activity and plasma cytokine levels in patients with sepsis”. Infect Immun 68(4):1942–1945

    Article  CAS  Google Scholar 

  • Bannister JV, Calabrese L (1987) Assays for superoxide dismutase. Methods Biochem Anal 32:279–313

    CAS  Google Scholar 

  • Barichello T, Machado RA, Constantino L et al (2007) “Antioxidant treatment prevented late memory impairment in an animal model of sepsis”. Crit Care Med 35(9):2186–2190

    Article  CAS  Google Scholar 

  • Basu S, Eriksson M (1998) Oxidative injury and survival during endotoxemia. FEBS Lett 438(3):159–160

    Article  CAS  Google Scholar 

  • Byun EB, Sung NY, Yang MS et al (2014) Anti-inflammatory effect of gamma-irradiated genistein through inhibition of NF-κB and MAPK signaling pathway in lipopolysaccharide-induced macrophages. Food Chem Toxicol 74:255–264

    Article  CAS  Google Scholar 

  • Cassol-Jr OJ, Comim CM, Silva BR et al (2010) Treatment with cannabidiol reverses oxidative stress parameters, cognitive impairment and mortality in rats submitted to sepsis by cecal ligation and puncture. Brain Res 1348:128–138

    Article  Google Scholar 

  • Catalão CHR, Santos-Junior NN, da Costa LHA et al (2020) Simvastatin prevents long-term cognitive deficits in sepsis survivor rats by reducing neuroinflammation and neurodegeneration. Neurotox Res 38(4):871–886

    Article  Google Scholar 

  • Della Giustina A, Goldim MP, Danielski LG et al (2020) Fish oil-rich lipid emulsion modulates neuroinflammation and prevents long-term cognitive dysfunction after sepsis. Nutrition 70:110417

    Article  CAS  Google Scholar 

  • Della Giustina A, Goldim MP, Danielski LG et al (2017) Alpha-lipoic acid attenuates acute neuroinflammation and long-term cognitive impairment after polymicrobial sepsis. Neurochem Int 108:436–447

    Article  CAS  Google Scholar 

  • Dinkova-Kostova AT, Kostov RV, Kazantsev AG (2018) “The role of Nrf2 signaling in counteracting neurodegenerative diseases”. FEBS J 285(19):3576–3590

    Article  CAS  Google Scholar 

  • Fang J, Wang H, Zhou J et al (2018) “Baicalin provides neuroprotection in traumatic brain injury mice model through Akt/Nrf2 pathway.“ Drug design, development and therapy 12: 2497

  • Gu M, Mei X-L, Zhao Y-N (2021) Sepsis and cerebral dysfunction: BBB damage, neuroinflammation, oxidative stress, apoptosis and autophagy as key mediators and the potential therapeutic approaches. Neurotox Res 39(2):489–503

    Article  CAS  Google Scholar 

  • Hsu BG, Lee RP, Yang FL, Harn HJ, Chen HI (2006) “Post-treatment with N-acetylcysteine ameliorates endotoxin shock-induced organ damage in conscious rats. " Life Sci 79(21):2010–2016

    Article  CAS  Google Scholar 

  • Hu Q-p, Huang X-y, Feng W et al (2021) “Genistein Protects Epilepsy-Induced Brain Injury Through Regulating The JAK2/STAT3 and Keap1/Nrf2 Signaling Pathways in The Developing Rats.“

  • Huang Y-H, Zhang Q-H (2010) Genistein reduced the neural apoptosis in the brain of ovariectomised rats by modulating mitochondrial oxidative stress. Br J Nutr 104(9):1297–1303

    Article  CAS  Google Scholar 

  • Ibrahim AS, El-Shishtawy MM, Peña A Jr, Liou GI (2010) Genistein attenuates retinal inflammation associated with diabetes by targeting of microglial activation. Mol Vis 16:2033–2042

    CAS  Google Scholar 

  • Kawai T, Akira S (2007) Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med 13(11):460–469

    Article  CAS  Google Scholar 

  • Lee YW, Lee WH (2008) Protective effects of genistein on proinflammatory pathways in human brain microvascular endothelial cells. J Nutr Biochem 19(12):819–825

    Article  CAS  Google Scholar 

  • Liu H, Zhong H, Yin Y, Jiang Z (2017) Genistein has beneficial effects on hepatic steatosis in high fat-high sucrose diet-treated rats. Biomed Pharmacother 91:964–969

    Article  CAS  Google Scholar 

  • Liu SF, Malik AB (2006) NF-κB activation as a pathological mechanism of septic shock and inflammation. Am J Physiology-Lung Cell Mol Physiol 290(4):L622–L645

    Article  CAS  Google Scholar 

  • Ma Q (2013) Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 53:401–426

    Article  CAS  Google Scholar 

  • Nguyen T, Nioi P, Pickett CB (2009) “The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress”. J Biol Chem 284(20):13291–13295

    Article  CAS  Google Scholar 

  • Oeckinghaus A, Hayden MS, Ghosh S (2011) “Crosstalk in NF-κB signaling pathways”. Nat Immunol 12(8):695–708

    Article  CAS  Google Scholar 

  • Prauchner CA (2017) Oxidative stress in sepsis: Pathophysiological implications justifying antioxidant co-therapy. Burns 43(3):471–485

    Article  Google Scholar 

  • Qian L, Weng X-W, Chen W, Sun C-H, Wu J (2014) TREM-1 as a potential therapeutic target in neonatal sepsis. Int J Clin Exp Med 7(7):1650

    Google Scholar 

  • Reis PA, Alexandre PC, D’Avila JC et al (2017) “Statins prevent cognitive impairment after sepsis by reverting neuroinflammation, and microcirculatory/endothelial dysfunction.“ Brain, behavior, and immunity. 60:293–303

  • Ritter C, Andrades ME, Reinke A, Menna-Barreto S, Moreira JC, Dal-Pizzol F (2004) “Treatment with N-acetylcysteine plus deferoxamine protects rats against oxidative stress and improves survival in sepsis”. Crit Care Med 32(2):342–349

    Article  CAS  Google Scholar 

  • Schwalm MT, Pasquali M, Miguel SP et al (2014) Acute brain inflammation and oxidative damage are related to long-term cognitive deficits and markers of neurodegeneration in sepsis-survivor rats. Mol Neurobiol 49(1):380–385

    Article  CAS  Google Scholar 

  • Sener G, Toklu H, Ercan F, Erkanli G (2005) Protective effect of beta-glucan against oxidative organ injury in a rat model of sepsis. Int Immunopharmacol 5(9):1387–1396

    Article  CAS  Google Scholar 

  • Soltani Z, Khaksari M, Jafari E, Iranpour M, Shahrokhi N (2015) “Is genistein neuroprotective in traumatic brain injury?“ Physiology & behavior 152:26–31

    CAS  Google Scholar 

  • Suzuki K, Ota H, Sasagawa S, Sakatani T, Fujikura T (1983) Assay method for myeloperoxidase in human polymorphonuclear leukocytes. Anal Biochem 132(2):345–352

    Article  CAS  Google Scholar 

  • Tang G, Yang H, Chen J et al (2017) Metformin ameliorates sepsis-induced brain injury by inhibiting apoptosis, oxidative stress and neuroinflammation via the PI3K/Akt signaling pathway. Oncotarget 8(58):97977

    Article  Google Scholar 

  • Tuon L, Comim CM, Petronilho F et al (2008) Time-dependent behavioral recovery after sepsis in rats. Intensive Care Med 34(9):1724–1731

    Article  CAS  Google Scholar 

  • Van Gool WA, Van de Beek D, Eikelenboom P (2010) “Systemic infection and delirium: when cytokines and acetylcholine collide”. The Lancet 375(9716):773–775

    Article  Google Scholar 

  • Wang S, Wei H, Cai M et al (2014) Genistein attenuates brain damage induced by transient cerebral ischemia through up-regulation of ERK activity in ovariectomized mice. Int J Biol Sci 10(4):457

    Article  CAS  Google Scholar 

  • Widmann CN, Heneka MT (2014) “Long-term cerebral consequences of sepsis”. Lancet Neurol 13(6):630–636

    Article  Google Scholar 

  • Xin X, Chen C, Hu Y-Y, Feng Q (2019) Protective effect of genistein on nonalcoholic fatty liver disease (NAFLD). Biomed Pharmacother 117:109047

    Article  CAS  Google Scholar 

  • Xiong C-q, Zhou H-c, Wu J, Guo N-Z (2019) The protective effects and the involved mechanisms of tanshinone IIA on sepsis-induced brain damage in mice. Inflammation 42(1):354–364

    Article  CAS  Google Scholar 

  • Xu X-e, Li M-z, Yao E-s et al (2020) Morin exerts protective effects on encephalopathy and sepsis-associated cognitive functions in a murine sepsis model. Brain Res Bull 159:53–60

    Article  CAS  Google Scholar 

  • Xu X-e, Liu L, Wang Y-c et al (2019) Caspase-1 inhibitor exerts brain-protective effects against sepsis-associated encephalopathy and cognitive impairments in a mouse model of sepsis. Brain Behav Immun 80:859–870

    Article  CAS  Google Scholar 

  • Yi L, Chang M, Zhao Q et al (2020) Genistein-3’-sodium sulphonate protects against lipopolysaccharide-induced lung vascular endothelial cell apoptosis and acute lung injury via BCL-2 signalling. J Cell Mol Med 24(1):1022–1035

    Article  CAS  Google Scholar 

  • Zamani-Garmsiri F, Emamgholipour S, Rahmani Fard S, Ghasempour G, Jahangard Ahvazi R, Meshkani R (2021a) “Polyphenols:Potential anti-inflammatory agents for treatment of metabolic disorders.“ Phytother Res

  • Zamani-Garmsiri F, Hashemnia SMR, Shabani M, Bagherieh M, Emamgholipour S, Meshkani R (2021b) Combination of metformin and genistein alleviates non-alcoholic fatty liver disease in high-fat diet-fed mice. J Nutr Biochem 87:108505

    Article  CAS  Google Scholar 

  • Zarbato GF, de Souza Goldim MP, Della Giustina A et al (2018) Dimethyl fumarate limits neuroinflammation and oxidative stress and improves cognitive impairment after polymicrobial sepsis. Neurotox Res 34(3):418–430

    Article  CAS  Google Scholar 

  • Zhang N, Zhao W, Hu Z-J et al (2021) “Protective effects and mechanisms of high-dose vitamin C on sepsis-associated cognitive impairment in rats”. Sci Rep 11(1):1–10

    Google Scholar 

Download references

Funding

This study was supported by the Health Commission of Hubei Province scientific research project (WJ2021M184).

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Authors and Affiliations

  1. Department of Pediatric Intensive Care Unit (PICU), Maternal and Child Health Hospital of Hubei Province (Women and Children’s Hospital of Hubei Province), NO.745 Wuluo Road, Hongshan District, 430070, Wuhan City, Hubei Province, China

    Buyun Shi, Zhi Xia, Wen Tang, Yong Li, Chenguang Qin, Chengjiao Huang & Hui Xu

  2. Department of Dermatology, Maternal and Child Health Hospital of Hubei Province (Women and Children’s Hospital of Hubei Province), NO.745 Wuluo Road, Hongshan District, Wuhan City, China

    Ming Chen

  3. Department of Pharmacy and Molecular Sciences, Faculty of Sciences, University of Shiraz, Shiraz, Iran

    Amir Ahmadi

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  1. Buyun Shi
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  2. Ming Chen
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  3. Zhi Xia
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  4. Wen Tang
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  5. Yong Li
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Contributions

S.B: Performed the experiments, wrote the manuscript.

C.M: Performed the experiments, wrote the manuscript.

X.Z; analyzed the data.

T.W: analyzed the data.

L.Y: contributed to the interpretation of the results.

Q.C: contributed to the interpretation of the results.

A.A: Performed the experiments, contributed to the interpretation of the results, wrote the paper.

H.C: revised the manuscript.

X.H: Conceived and designed the study.

Corresponding author

Correspondence to Hui Xu.

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Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Maternal and Child Health Hospital of Hubei Province (Date 22/2/2021/No 1GW22012).

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This study is on animal model and therefore informed consent is not applicable.

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Shi, B., Chen, M., Xia, Z. et al. Genistein attenuates neuroinflammation and oxidative stress and improves cognitive impairment in a rat model of sepsis-associated encephalopathy: potential role of the Nrf2 signaling pathway. Metab Brain Dis 38, 339–347 (2023). https://doi.org/10.1007/s11011-022-01076-4

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