Keap1/Nrf2 Signaling Pathway

Sykiotis, Gerasimos P.

doi:10.3390/antiox10060828

Cited by 15 publications

(8 citation statements)

References 38 publications

(69 reference statements)

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“…We further investigate the effects of Lf on the antioxidant system. By Lf pretreatment, not only the hepatic Nrf2 protein level was increased but also its inhibitor Keap1 expression was downregulated . Meanwhile, hepatic CAT activity was significantly higher in the HLf group than in the EtOH group.…”

Section: Discussionsupporting

confidence: 87%

Lactoferrin Alleviates Acute Alcoholic Liver Injury by Improving Redox-Stress Response Capacity in Female C57BL/6J Mice

Liu

Qian

et al. 2021

J. Agric. Food Chem.

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Lactoferrin (Lf) can attenuate alcoholic liver injury (ALI) in male mice; however, the effects of Lf on acute ALI in female mice are still unknown. Female C57BL/6J mice were randomly divided into four groups and fed with different diets for 4 weeks: an AIN-93G diet for control (CON) and ethanol (EtOH) groups; an AIN-93G diet with 0.4 and 4% casein replaced by Lf for low-dose Lf (LLf) and high-dose Lf (HLf) groups. Acute ALI was induced by intragastric administration of ethanol (4.8 g/kgbw) every 12 h continuously for three times. HLf had obvious alleviating effects on acute ALI. Lf pretreatment did not affect hepatic alcohol metabolism key enzymes. Meanwhile, the ethanol-induced hepatic reactive oxygen species level increase was not ameliorated by Lf. Metabolomics and bioinformatics analysis results suggested an important role of redox-stress response capacity (RRC). Western blots showed HLf-promoted AKT and AMP-activated protein kinase activations and upregulated Nrf2 and LC3-II expressions, which was associated with RRC improvement. In summary, HLf could prevent acute ALI in female mice, and RRC likely played an important role.

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Section: Discussionsupporting

confidence: 87%

Lactoferrin Alleviates Acute Alcoholic Liver Injury by Improving Redox-Stress Response Capacity in Female C57BL/6J Mice

Liu

Qian

et al. 2021

J. Agric. Food Chem.

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“…Keap1-Nrf2 signaling pathway is a master regulator of the antioxidant system [ 31 ]. Keap1 is a negative regulator of Nrf2, and it can degrade Nrf2.…”

Section: Discussionmentioning

confidence: 99%

Lactoferrin Prevents Chronic Alcoholic Injury by Regulating Redox Balance and Lipid Metabolism in Female C57BL/6J Mice

Liu

et al. 2022

Antioxidants

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This study aimed to investigate the preventive effects of lactoferrin (Lf) on chronic alcoholic liver injury (ALI) in female mice. Female C57BL/6J mice were randomly divided into four groups: control group (CON), ethanol administration group (EtOH), low-dose Lf treatment group (LLf), and high-dose Lf group (HLf). In the last three groups, chronic ALI was induced by administering 20% ethanol ad libitum for 12 weeks. Mice in the CON and EtOH groups were fed with AIN-93G diet. Meanwhile, 0.4% and 4% casein in the AIN-93G diet were replaced by Lf as the diets of LLf and HLf groups, respectively. HLf significantly reduced hepatic triglyceride content and improved pathological morphology. HLf could inhibit cytochrome P450 2E1 overexpression and promote alcohol dehydrogenase-1 expression. HLf activated protein kinase B and AMP-activated protein kinase (AMPK), as well as upregulating nuclear-factor-erythroid-2-related factor-2 expression to elevate hepatic antioxidative enzyme activities. AMPK activation also benefited hepatic lipid metabolism. Meanwhile, HLf had no obvious beneficial effects on gut microbiota. In summary, Lf could alleviate chronic ALI in female mice, which was associated with redox balance and lipid metabolism regulation.

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“…Under oxidative stress, KEAP1 is detached from its complex with NRF2. Therefore, NRF2 is accumulated in the nucleus and binds to a DNA sequence called antioxidant response element (ARE), thus activating the upregulation of cytoprotective antioxidative genes, including NAD(P)H quinone dehydrogenase 1 ( Nqo1 ), Hmox1 , which expresses the hemoxygenase-1 (HO-1) protein, and previously known as heat shock protein 32 (HSP32), glutathione S-transferases ( Gsts ), catalase ( Cat ), Gpx1 , and Sod1 , among others (reviewed in [ 13 , 14 , 15 ]). As reviewed by Matzinger et al in obesity models using Nfe2l2 -knockout ( Nfe2l2 -KO) mice, ROS levels and blood glucose levels augment, and insulin signaling is impaired [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, NRF2 overexpression by phytochemical intake decreases diastolic dysfunction in hypertensive Dahl salt-sensitive rats with heart failure and preserved ejection fraction (HFpEF) (reviewed in [ 20 ]). Geraniol is another phytochemical that activates NRF2 and has protective effects on oxidative, inflammatory, and apoptotic alterations in isoproterenol-induced myocardial infarction (reviewed in [ 15 ]). The pharmacological activation of NRF2 using the synthetic triterpenoid CDDO-Im (2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide) results in the prevention of high fat diet (HFD)-induced obesity in mice models, as reviewed in detail by Mimura and Itoh [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

The Role of NRF2 in Obesity-Associated Cardiovascular Risk Factors

et al. 2022

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The raising prevalence of obesity is associated with an increased risk for cardiovascular diseases (CVDs), particularly coronary artery disease (CAD), and heart failure, including atrial fibrillation, ventricular arrhythmias and sudden death. Obesity contributes directly to incident cardiovascular risk factors, including hyperglycemia or diabetes, dyslipidemia, and hypertension, which are involved in atherosclerosis, including structural and functional cardiac alterations, which lead to cardiac dysfunction. CVDs are the main cause of morbidity and mortality worldwide. In obesity, visceral and epicardial adipose tissue generate inflammatory cytokines and reactive oxygen species (ROS), which induce oxidative stress and contribute to the pathogenesis of CVDs. Nuclear factor erythroid 2-related factor 2 (NRF2; encoded by Nfe2l2 gene) protects against oxidative stress and electrophilic stress. NRF2 participates in the regulation of cell inflammatory responses and lipid metabolism, including the expression of over 1000 genes in the cell under normal and stressed environments. NRF2 is downregulated in diabetes, hypertension, and inflammation. Nfe2l2 knockout mice develop structural and functional cardiac alterations, and NRF2 deficiency in macrophages increases atherosclerosis. Given the endothelial and cardiac protective effects of NRF2 in experimental models, its activation using pharmacological or natural products is a promising therapeutic approach for obesity and CVDs. This review provides a comprehensive summary of the current knowledge on the role of NRF2 in obesity-associated cardiovascular risk factors.

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Keap1/Nrf2 Signaling Pathway

Cited by 15 publications

References 38 publications

Lactoferrin Alleviates Acute Alcoholic Liver Injury by Improving Redox-Stress Response Capacity in Female C57BL/6J Mice

Lactoferrin Alleviates Acute Alcoholic Liver Injury by Improving Redox-Stress Response Capacity in Female C57BL/6J Mice

Lactoferrin Prevents Chronic Alcoholic Injury by Regulating Redox Balance and Lipid Metabolism in Female C57BL/6J Mice

The Role of NRF2 in Obesity-Associated Cardiovascular Risk Factors

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