Abstract:Kahweol is a diterpene found in coffee beans and unfiltered coffee drinks. Several studies have demonstrated that kahweol induces the nuclear factor erythroid-2 related factor 2/ hemeoxygenase-1 (Nrf2/HO-1) pathway; however, the mechanisms involved are currently unknown. Kelch-like ECH-associated protein 1 (Keap1) is a major regulator of Nrf2 expression and is degraded mostly by autophagy. The p62 protein enhances binding to Keap1 and contributes to the activation of Nrf2. Here, we examined the role of Keap1 r… Show more
“…3 ): modification of Kelch-like ECH-associated protein 1 (KEAP1; regulates proteasomal degradation of NRF2), which is inactivated when its sensor cysteines form adducts with electrophiles or when they are oxidized to disulfides; disruption of the interaction between β-transducin repeat-containing protein (βTrCP; ubiquitylates NRF2 for degradation) and NRF2, via oxidative inhibition of the axis of glycogen synthase kinase 3β (GSK3β)–NRF2 phosphorylation at the Neh6 domain–βTrCP; KEAP1 sequestration by p62; de novo synthesis of NRF2 that escapes degradation by inactivated KEAP1 (ref. 181 ); and BACH1 inhibitors that reduce NRF2 suppression by BACH1, including agents that inhibit BACH1 translation 182 and promote BACH1 degradation 183 . Fig.…”
Oxidative stress is a component of many diseases, including atherosclerosis, chronic obstructive pulmonary disease, Alzheimer disease and cancer. Although numerous small molecules evaluated as antioxidants have exhibited therapeutic potential in preclinical studies, clinical trial results have been disappointing. A greater understanding of the mechanisms through which antioxidants act and where and when they are effective may provide a rational approach that leads to greater pharmacological success. Here, we review the relationships between oxidative stress, redox signalling and disease, the mechanisms through which oxidative stress can contribute to pathology, how antioxidant defences work, what limits their effectiveness and how antioxidant defences can be increased through physiological signalling, dietary components and potential pharmaceutical intervention.
“…3 ): modification of Kelch-like ECH-associated protein 1 (KEAP1; regulates proteasomal degradation of NRF2), which is inactivated when its sensor cysteines form adducts with electrophiles or when they are oxidized to disulfides; disruption of the interaction between β-transducin repeat-containing protein (βTrCP; ubiquitylates NRF2 for degradation) and NRF2, via oxidative inhibition of the axis of glycogen synthase kinase 3β (GSK3β)–NRF2 phosphorylation at the Neh6 domain–βTrCP; KEAP1 sequestration by p62; de novo synthesis of NRF2 that escapes degradation by inactivated KEAP1 (ref. 181 ); and BACH1 inhibitors that reduce NRF2 suppression by BACH1, including agents that inhibit BACH1 translation 182 and promote BACH1 degradation 183 . Fig.…”
Oxidative stress is a component of many diseases, including atherosclerosis, chronic obstructive pulmonary disease, Alzheimer disease and cancer. Although numerous small molecules evaluated as antioxidants have exhibited therapeutic potential in preclinical studies, clinical trial results have been disappointing. A greater understanding of the mechanisms through which antioxidants act and where and when they are effective may provide a rational approach that leads to greater pharmacological success. Here, we review the relationships between oxidative stress, redox signalling and disease, the mechanisms through which oxidative stress can contribute to pathology, how antioxidant defences work, what limits their effectiveness and how antioxidant defences can be increased through physiological signalling, dietary components and potential pharmaceutical intervention.
“…Studies suggest that CF and KW may condition health-promoting effects via Nrf2, but unlike caffeine, without exerting influence on cAMP levels. There is no known cAMP modulation by CF or KW [51][52][53].…”
Alzheimer disease (AD) is an emerging medical problem worldwide without any cure yet. By 2050, more than 152 million people will be affected. AD is characterized by mitochondrial dys-function (MD) and increased amyloid beta (Aβ) levels. Coffee is one of the most commonly consumed beverages. It has many bioactive and neuroprotective ingredients of which caffeine (Cof), kahweohl (KW) and cafestol (CF) shows a variety of pharmacological properties such as anti-inflammatory and neuroprotective effects. Effects of Cof, KW, and CF were tested in a cel-lular model of AD on MD and Aβ. SH-SY5Y-APP695 cells were incubated with 50μM Cof, 1μM CF and 1μM KW for 24h. The energetic metabolite ATP was determined using a luciferase-catalyzed bioluminescence assay. The activity of mitochondrial respiration chain complexes was assessed by high-resolution respirometry using a Clarke electrode. Expression levels genes were deter-mined using quantitative real-time polymerase chain reaction (qRT-PCR). The levels of amyloid β-protein (Aβ1-40) were measured using homogeneous time-resolved fluorescence (HTRF). ROS levels, cAMP levels, and peroxidase activity were determined using a fluorescence assay. The combination of Cof, KW and CF significantly increased ATP levels. The combination had neither a significant effect on MMP, on activity of respiration chain complexes, nor on A β1-40 levels. cAMP levels were slightly increased after incubation with the combination, but not the peroxi-dase activity. Pyruvate levels and the lactate-pyruvate-ration but not lactate levels were signifi-cantly enhanced. No effect was seen on the expression level of lactate dehydrogenase and py-ruvate dehydrogenase kinase. In some experiments we have tested the single substances. They showed significant results especially in ATP, lactate and pyruvate values compared to the con-trol. The combinations have a lesser effect on mitochondrial dysfunction in cells and none on Aβ production. Whereas ATP levels and pyruvate levels were significantly increased. This suggests a change in glycolysis in neuronal cells harbouring human genes relevant for AD.
“…Furthermore, animal studies have revealed that cobalt protoporphyrin-induced HO-1 or its upstream regulatory gene Nrf2 is effective against hepatitis C and B viruses, dengue virus, Zika virus, Ebola virus, human immunodeficiency virus, and human respiratory syncytial virus (Hooper 2020 ; Wu et al 2019a ). HO-1 expression is essentially regulated by the Keap1/Nrf2 system at the transcriptional level (Seo et al 2020 ).…”
Section: Nrf2’s Anti-viral Roles In Covid-19mentioning
The coronavirus disease 2019 (COVID-19) is caused by a novel severe acute respiratory syndrome (SARS)–like coronavirus (SARS-CoV-2). Critically ill patients with SARS-COV-2 infection frequently exhibit signs of high oxidative stress and systemic inflammation, which accounts for most of the mortality. Antiviral strategies to inhibit the pathogenic consequences of COVID-19 are urgently required. The nuclear factor erythroid 2–related transcription factor (Nrf2) is a transcription factor that is involved in antioxidant and anti-inflammatory defense in several tissues and cells. This review tries to present an overview of the role of Nrf2 in the treatment of COVID-19.
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