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Terpenoids in Treatment of Liver Disease
Published in Dijendra Nath Roy, Terpenoids Against Human Diseases, 2019
Sujan Chatterjee, Debajyoti Patra, Pujita Ghosh, Akash Prasad, Kaustav Dutta Chowdhury
Terpenoids such as OA and UA may provide some hepatoprotection against liver damage induced by acetaminophen, a drug that is well known for its hepatotoxicity. Generally, Nrf2 binds to Keap1 in the cytoplasm, and the remaining Keap1 molecules are inactivated and easily degraded. Under oxidative stress, terpenoids activate Nrf2 by dissociating it from Keap1 via Keap1 modification or Nrf2 phosphorylation. Activated Nrf2 then translocates into the nucleus and interacts with anti-oxidant response element (ARE), promoting the expression of cytoprotective target genes including anti-oxidant enzymes and phase II detoxifying enzymes to protect the liver (Zhang et al. 2013b).
Protective effects of natural compounds against paraquat-induced pulmonary toxicity: the role of the Nrf2/ARE signaling pathway
Published in International Journal of Environmental Health Research, 2023
Hasan Badibostan, Nastaran Eizadi-Mood, A. Wallace Hayes, Gholamreza Karimi
Since the Nrf2 signaling pathway is the most important endogenous antioxidant system, the modulatory effect of natural compounds on this pathway has been investigated (He et al. 2012; Jeon et al. 2016). Nrf2 activators should be more precisely named “KEAP1 inhibitors” as their main target is KEAP1. Most Nrf2 activators are electrophilic compounds that covalently modify cysteine residues in the thiol-rich KEAP1 protein. One mechanism of KEAP1 inhibition is its sequestration in complexes with Nrf2 that cannot be ubiquitinated. Modification of cysteines in KEAP1 produces a closed form with both Neh2 motifs (DLG and ETGE) of Nrf2 interacting with the KEAP1 dimer but not leading to ubiquitination. As a result, free KEAP1 is not regenerated at an adequate rate, and recently synthesized Nrf2 has been shown to escape KEAP1-mediated ubiquitination. Curcumin, sulforaphane, and resveratrol are examples of NCs which affect KEAP1, owing to their electrophilic characteristic (Turpaev 2013; Robledinos-Antón et al. 2019).
Cadmium induces cytotoxicity in normal mouse renal MM55.K cells
Published in International Journal of Environmental Health Research, 2022
Ho Jeong Lee, Ju Hong Lee, Seon Min Lee, Na Hyun Kim, Yeon Gyu Moon, Tae Kil Tak, Moonjung Hyun, Jeong Doo Heo
ROS and ER stress mediate apoptotic processes through the mitochondria (Gobe and Crane 2010). It has been reported that HO-1 is associated with the synthesis of ROS in many studies on chemical toxic (Hu et al. 2015; Zhou et al. 2017). Even the Nrf2(Nuclear factor(erythroid-derived 2) factor 2 has been reported an emerging regulator of cellular resistance to oxidants (Kovac et al. 2015). Keap1(Kelch-like ECH associated protein 1)-Nrf2 signaling has been shown to play important role in protecting cells from oxidative stress (Wei et al. 2019). In our study, the expression of HO-1 protein levels was increased and Nrf2 protein levels of nuclear fraction was decreased significantly in CdCl2-treated MM55.K cells. Moreover, Cd induces ER stress and then activates IRE1, PERK, and ATF6 through GRP78 and CHOP, leading to the induction of apoptosis (Malhotra and Kaufman 2007; Rasheva and Domingos 2009). GRP78 is a central regulator of ER stress and the IRE1 pathway induced apoptosis involves caspase-3 (Szegezdi et al. 2006; Kim et al. 2008). The present study, CdCl2 significantly upregulated GRP78 and CHOP in MM55.K cells. It confirmed that Cd may cause ROS generation owing to HO-1 and Nrf2 and ER stress regulated through GRP78 and CHOP.
Pequi enriched diets protect Drosophila melanogaster against paraquat-induced locomotor deficits and oxidative stress
Published in Journal of Toxicology and Environmental Health, Part A, 2019
Sandra Mara Duavy, Assis Ecker, Gerson Torres Salazar, Julia Loreto, José Galberto Martins Da Costa, Nilda Vargas Barbosa
This pathway is constituted by the transcription factor CncC – cap’n’collar (Nrf2 ortholog) and by the repressor Keap1. Under oxidative stress, the interaction between Keap1 and CncC is disrupted, inducing translocation of CncC to the nucleus. In the nucleus, CncC forms a heterodimer with Maf-s proteins (Musculo-Aponeurotic Fibrosarcoma), which also binds to ARE (Misra et al. 2011; Misra, Lam, and Thummel 2013). Our data demonstrated that the PQ enhanced production of RS and lipid peroxidation in flies exposed to PQ which was accompanied by increasing activities of CAT and GST enzymes as well as elevated expression of Keap1 and antioxidant genes CAT, SOD and TrxR-1. Taken together, these findings suggest that the CncC/Nrf2 from D. melanogaster was activated as a compensatory response to oxidative events induced by PQ. Although the activity of all proteins expressed by mRNA of these genes was not examined, the increased activity of CAT and GST enzymes provides evidence to confirm this hypothesis (Ayala, Muñoz, and Argüelles 2014; Oakley 2011).