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Signalling Pathways in The Regulation of Cellular Responses to Exercise
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Anders Gudiksen, Stine Ringholm, Henriette Pilegaard
Most antioxidant enzymes have antioxidant response elements (ARE) in the promoter for interaction with redox-sensitive transcription factors (3). The transcription factor nuclear factor erythroid-derived 2-like 2 (NFE2L2 or Nrf2) has been reported to be regulated by ROS and to induce the transcription of antioxidant enzymes. Thus, Nrf2 is kept in the cytosol bound to Kelch-like ECH associated protein (Keap)1, but increases in ROS lead to dissociation of Keap1 and Nrf2 with concomitant translocation of Nrf2 to the nucleus (67). A single 6-hour exercise bout has been shown to increase Nrf2 localization in the nucleus as well as Nrf2 binding to ARE with an associated increase in the mRNA content of SOD1 and 2, as well as catalase in mouse SkM (71). Moreover, Nrf2 was required for exercise-induced mRNA responses of antioxidant proteins in mouse SkM (79). Together these findings support that Nrf2 mediates transcriptional regulation of antioxidant enzymes in SkM in response to exercise-induced ROS signalling (Figure 8.2).
Lung Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Squamous cell carcinoma (SCC) now accounts for up to 30% of patients diagnosed with NSCLC in Western countries, occurring usually in men and typically related to smoking. Historically, these tumors were stereotypically found proximally in the major bronchi, but increasing numbers are now found more peripherally. Macroscopically, these tumors appear as firm lesions with a pale-grey, gritty surface and can be cavitating. Microscopically, the hallmarks of squamous differentiation are apparent, with prominent intercellular bridges and keratinization. Immunohistochemical staining with antibodies against cytokeratin 5, 6, p40, and p63 increases confidence in the diagnosis. Molecularly, SCC has been shown to demonstrate recurrent mutations in 11 genes, including mutation of TP53 in almost all sampled cases. Significantly altered pathways included NFE2L2 and KEAP1 in 34%, squamous differentiation genes in 44%, phosphatidylinositol-3-OH kinase pathway genes in 47%, and CDKN2A and RB1 in 72% of tumors.6 None of these commonest mutations in SCC are currently targetable.
Mitochondrial Redox Regulation in Adaptation to Exercise
Published in James N. Cobley, Gareth W. Davison, Oxidative Eustress in Exercise Physiology, 2022
Christopher P. Hedges, Troy L. Merry
Activation of classical cytosolic intracellular stress signalling pathways, such as AMPK, p38 MAPK and ERK, can be attenuated by antioxidant supplementation prior to exercise, and result in impaired responses in what is seen as a master regulator of exercise and mitochondrial adaptation, PGC-1α. However, the primary redox-sensitive pathways targets of exercise are not well defined (Merry and Ristow, 2016b), and further insights are expected as redox-proteomics develops as a field. However, antioxidant supplementation and gene knockout models have provided evidence that the transcription factors NF-κB and NFE2L2 (also known as Nrf2) are both exercise and redox sensitive, and potentially contribute to coordinating exercise-induced ROS-driven gene transcription (Gomez-Cabrera et al., 2008a; Gomez-Cabrera et al., 2005; Merry and Ristow, 2016c). While the production site of the exercise-induced ROS that target these transcription factors are difficult to discern from studies using non-site-specific antioxidants, the ability of allopurinol to suppress exercise-induced activation of mitochondrial biogenesis pathways suggests xanthine oxidase is a key redox enzyme regulating exercise adaptations (Wadley et al., 2013; Gomez-Cabrera et al., 2008b). Similarly, recent evidence that ablation of the NADPH oxidase enzyme NOX2 (Henriquez-Olguin et al., 2019b) impairs high-intensity exercise training responses in mice – in terms of both exercise performance and molecular-level adaptation of mitochondrial biogenesis and antioxidant gene expression – suggests cytosolic or extracellular ROS source(s) are required for optimal exercise adaptations.
Lycopene mitigates arsenic-induced nephrotoxicity with activation of the Nrf2 pathway in mice
Published in Toxin Reviews, 2022
Shimaa S. Ramadan, Rafa Almeer, Gadah Albasher, Ahmed E. Abdel Moneim
Renal expression of Nfe2l2 was determined in our study to explore the mechanism that caused changes in the renal antioxidant ability. Nfe2l2 (also known as Nrf2) is a major transcription factor and it controls the transcription of antioxidants (Al Olayan et al.2020). Moreover, Nfe2l2 activation can relieve several types of nephropathy such as those caused by type 2 diabetes mellitus, acute kidney injury in addition to chronic kidney diseases (Cui et al.2017, Nezu and Suzuki 2020). Lyc can enhance the renal antioxidant ability by activating Nrf2 expression (Yu et al.2018). In the current study, we found that Lyc administration enhanced the expression of Nfe2l2. These results indicate that the beneficial influence of Lyc may be related to its ability to activate Nrf2, probably by activating other factors, such as AKT and ERK (Huang et al.2019).
Identification of genes and miRNAs in paclitaxel treatment for breast cancer
Published in Gynecological Endocrinology, 2021
Jie Wu, Yijian Zhang, Maolan Li
Another upregulated gene, PTGS2, also caught our attention. PTGS2, also known as cyclooxygenase-2 (COX-2), is the key enzyme in prostaglandin biosynthesis, and acts both as a dioxygenase and as a peroxidase [29]. Ghosh et al. revealed that madhuca indica and paclitaxel inhibited breast cancer cell proliferation by modulating COX-2 expression [30]. Furthermore, GO analysis showed PTGS2 was enriched in the inflammatory response. Accumulating evidence demonstrated that local immune response and systemic inflammation had a role in progression of tumors and survival of patients with cancer, thus targeting these inflammatory responses could improve patients’ outcomes [31]. Therefore, PTGS2 served role in breast cancer treatment by affecting the immune response. Additionally, the regulatory network showed that has-miR-508-3p targeted PTGS2. Zhai et al. claimed that miR-508-3p could inhibit renal cancer cell proliferation and migration, and promotes apoptosis [32]. Huang et al. also observed that miR-508-3p acted a tumor suppressor in gastric cancer [33]. From the above, we predicted that miR-508-3p might target PTGS2 to play certain therapeutic effect in breast cancer. However, the relationship between miR-4782-3p and PTGS2 had not been reported, more clinical samples were needed for validation in further studies. Another key TF, NFE2L2, has been found to regulate PTGS2 in the posttreatment breast cancer. The recent research reported that NFE2L2 which participated in Nrf2 pathway had anticancer effect [34, 35]. Hence, the PTGS2, NFE2L2, as well as miR-508-3p might play significantly regulatory roles in paclitaxel treatment, and these genes could be considered as therapeutic targets for the breast cancer.
Therapeutic potential of PGC-1α in age-related macular degeneration (AMD) – the involvement of mitochondrial quality control, autophagy, and antioxidant response
Published in Expert Opinion on Therapeutic Targets, 2021
Juha Hyttinen, Janusz Blasiak, Pasi Tavi, Kai Kaarniranta
NFE2L2 is a primary component in the cellular antioxidant response as it interacts with Kelch-like ECH-associated protein 1 (KEAP), which senses the oxidative and electrophilic stress in the cell. Once electrophilic ligands associate with KEAP1, NFE2L2 becomes detached from the complex. Next, it is transferred to the nucleus, where it launches the expression of antioxidant genes by binding to their antioxidant response elements (AREs) [22].