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Trostchansky, A.; Souza, J.; Da Silva, R.; Scheffer, D.; Penteado, R.; , .; Budde, H.; Latini, A. Antioxidant Effects on the Brain and Skeletal Muscle. Encyclopedia. Available online: https://encyclopedia.pub/entry/22713 (accessed on 20 June 2024).
Trostchansky A, Souza J, Da Silva R, Scheffer D, Penteado R,  , et al. Antioxidant Effects on the Brain and Skeletal Muscle. Encyclopedia. Available at: https://encyclopedia.pub/entry/22713. Accessed June 20, 2024.
Trostchansky, Andrés, Jennyffer Souza, Rodrigo Da Silva, Debora Scheffer, Rafael Penteado,  , Henning Budde, Alexandra Latini. "Antioxidant Effects on the Brain and Skeletal Muscle" Encyclopedia, https://encyclopedia.pub/entry/22713 (accessed June 20, 2024).
Trostchansky, A., Souza, J., Da Silva, R., Scheffer, D., Penteado, R., , ., Budde, H., & Latini, A. (2022, May 09). Antioxidant Effects on the Brain and Skeletal Muscle. In Encyclopedia. https://encyclopedia.pub/entry/22713
Trostchansky, Andrés, et al. "Antioxidant Effects on the Brain and Skeletal Muscle." Encyclopedia. Web. 09 May, 2022.
Antioxidant Effects on the Brain and Skeletal Muscle
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Erythroid-related nuclear factor 2 (NRF2) and the antioxidant-responsive-elements (ARE) signaling pathway are the master regulators of cell antioxidant defenses, playing a key role in maintaining cellular homeostasis, a scenario in which proper mitochondrial function is essential. Increasing evidence indicates that the regular practice of physical exercise increases cellular antioxidant defenses by activating NRF2 signaling.

NRF2 oxidative stress exercise brain tetrahydrobiopterin neopterin epigenetics

1. Role of BH4 on NRF2/ARE Pathway Activated by Physical Exercise

BH4 is a pteridine that acts as a mandatory cofactor for the activity of phenylalanine, tyrosine, and tryptophan hydroxylases, for alkylglycerol monooxygenase, and all isoforms of nitric-oxide synthases (NOS) [1]. Therefore, BH4 is essential for the biosynthesis of the neurotransmitters, dopamine and serotonin, for the catabolism of phenylalanine and ether lipids, and for the formation of nitric oxide.
Three biosynthetic pathways are responsible for tuning the intracellular concentrations of BH4: the de novo, the salvage, and the recycling pathways. The de novo pathway synthesizes BH4 from guanosine triphosphate through the sequential action of guanosine triphosphate cyclohydrolase I (GTPCH), 6-pyruvoyl tetrahydropterin synthase (PTPS), and sepiapterin reductase (SPR) [1]. GTPCH is the rate-limiting enzyme of the de novo pathway and is transcriptionally regulated by inflammatory mediators, including interferon-γ (IFN-γ), lipopolysaccharide (LPS), interleukin-1β (IL-1β), and hydrogen peroxide [2]. Thus, under inflammatory conditions, the expression of GCH1, the gene that encodes for GTPCH, is up-regulated several times; however, since the other enzymes in the pathway are not inducible by inflammation, a metabolic pseudo-blockage is generated, resulting in the production of neopterin [3]. Indeed, neopterin has been used as a sensitive marker of immune-system activation for several decades [4]. The salvage pathway synthesizes BH4 by utilizing intermediates from the de novo pathway to form sepiapterin, which is later converted to BH4 by the action of the enzymes SPR and dihydrofolate reductase (DHFR) [2]. The recycling pathway is a mechanism that maintains adequate intracellular concentrations of BH4 without the need for energy expenditure in tissues with a high demand for this pteridine, i.e., in the liver for the proper metabolism of phenylalanine. After BH4 is used as an essential cofactor, the molecule is oxidized to quinonoid dihydrobiopterin (qBH2) and recycled back to BH4 by the action of dihydropteridin reductase (DHPR) [1].
BH4 is traditionally known due to its activity as an enzyme cofactor [1]. However, the researchers' group and others have shown that the BH4 pathway is essential for maintaining the activity of mitochondria and the antioxidant system, and for inducing an anti-inflammatory scenario [5][6][7]. This has positioned BH4 metabolism as a potential new target to prevent or attenuate the cytotoxicity linked to chronic inflammatory diseases. In this context, the researchers' lab has shown that a single intracerebroventricular administration of neopterin (a dose that will slightly increase the levels of the compound in the cerebrospinal fluid) to naïve mice provoked the increase of the antioxidant response by augmenting glutathione levels and the activity of GPx, which are downstream components of the erythroid-related nuclear factor 2(NRF2)/ antioxidant-responsive element (ARE)-pathway activation, in the brain [8]. In addition, the treatment also prevented the brain’s massive increase of pro-inflammatory cytokines after an intraperitoneal LPS challenge, suggesting that neopterin also maintains the balance between NRF2 and the master regulator of inflammation, nuclear factor-κB (NF-kB) [9].
To try to dissect the mechanisms involved in the antioxidant effect of neopterin, the researchers' group also exposed nerve cells obtained from mammals, humans, and rodents to neopterin. The researchers observed that the pre-conditioning with neopterin prevented the activation of the inflammasome, which is a macromolecular protein complex that mediates the synthesis of IL1-β through the activation of pro-inflammatory caspase [10], and also the production of reactive oxygen species (ROS) induced by LPS and IFN-γ [9]. The treatment with neopterin to naïve cells provoked the rapid nuclear translocation of NRF2, the production of HO-1, and increased mitochondrial activity [4][9]. The latter was evidenced by increased activity of complexes I and IV and by increased basal respiration. The enhanced mitochondrial activity was accompanied by reduced lactate formation, indicating that neopterin increased mitochondrial oxidative metabolism and reduced anaerobic glycolysis. Furthermore, the researchers' group also observed that neopterin exposure provoked the formation of very low concentrations of superoxide radicals, which can be responsible for an electrophilic attack and consequent activation of the NRF2/ARE pathway [9].
The antioxidant, anti-inflammatory, and mitochondrial-activator properties shown by neopterin might also be responsible for the mnemonic effects of the molecule. The researchers' group demonstrated that neopterin enhances aversive memory acquisition by reducing the threshold to generate hippocampal long-term potentiation, which is an essential mechanism for memory formation [11].
It is widely described that all the above-mentioned cytoprotective mechanisms are induced by the regular practice of moderate-intensity physical exercise. These effects have been described in the blood, muscle, liver, and brain of animals and also in the blood and urine of humans [12][13]. Recently, the researchers have shown that moderate running exercise increases urinary neopterin levels under basal conditions and prevents exacerbated immune-system activation under an inflammatory scenario [14].
Since the researchers have characterized the cytoprotective effects of the BH4 metabolic pathway on the brain of experimental systems and cultured cells, it is feasible that part of the effects induced by exercise might be mediated by the activation of BH4 metabolism. The relationship between BH4 metabolism and NRF2 activation remains unclear, but in vitro studies using Gch1-deficient macrophages indicated the existence of a NRF2/GCH1/BH4 axis, which has the function of protecting against oxidative stress, with GCH1 being one effector switch [5][15]. Furthermore, the researchers' group demonstrated that neopterin can activate the expression, content, and activity of NRF2 in vitro [9], and increase the content of the downstream proteins of the pathway [9]. Independently, it has been also shown in an in vitro study with macrophages that NRF2 requires BH4 for its activation [15]. The correlation between neopterin and the beneficial effects of physical exercise has led sport and exercise medicine to use it as an indicator of immune-system activation. Its use as a biomarker is also growing when compared with other traditional inflammatory markers [16][17].
Regarding plasma levels of BH4 increase, it has been shown that the levels can increase rapidly and can be sustained for up to 2 h after the practice of strong physical exercise in young and middle-aged individuals, pointing to a temporal response of this metabolic pathway with exercise intensity [18][19].
During physical exercise, there is an inherent consumption of energy, generation of ROS, and consequent activation of the immune system [20]. Increased plasma levels of neopterin have been demonstrated after running [21], ergometer [22][23], and even after ultra-endurance competition [24]. This increase has also been reported in urine after running [25], rugby [26], bodybuilding competition [27], triathlon [28] and ultra-marathon [29]. The rapid and transient increase in BH4 and neopterin after exhausting exercises can be also interpreted as the result of an oxidative burst followed by the activation of monocytes and macrophages, reflecting the immune activation stimulated in this context [22]. The presented scenario indicates that BH4 metabolism can behave as a biomarker of inflammation induced by high-intensity physical exercise, but also as a cytoprotective and neurological mediator of the beneficial effect generated by physical exercise on the antioxidant system, including the activation of NRF2 [30].

2. Epigenetics as a Key Player in NRF2 Upregulation Induced by Physical Exercise

The term epigenetics was conceived by Conrad Waddington in 1940 to describe the possible causal processes acting on genes that regulate phenotype [31]. Over the years, the definition and concept of epigenetics have gradually evolved to mean the existence of a process that alters gene activity without changing the nucleotide sequences [32]. Epigenetic profiles are controlled by several biochemical processes, including DNA methylation, histone modification, and non-coding-RNA-modulated expression. These mechanisms mainly control gene expression at the transcriptional level through chromatin compaction and/or relaxation, thereby blocking/allowing the accessibility of transcription factors to the promoter region [33]. Epigenetic processes can also prevent protein translation by inactivating or degrading messenger RNA (mRNA) through the action of interfering microRNAs (miRNA) [34][35].

2.1. DNA Methylation

DNA methylation is the most characterized epigenetic alteration and consists of the covalent addition of a methyl group catalyzed by DNA methyltransferases (DNMTs). DNMTs transfer a methyl group from S-adenosylmethionine (SAM) to the 5′ carbon of a cytosine that usually precedes guanine (CpG dinucleotide), forming 5-methyl cytosine (5-meC). DNA methylation of CpG regions, called CpG islands, is usually associated with the inhibition of gene expression [36]. DNA methylation can be also modified by a family of 2-oxoglutarate- and Fe (II)-dependent dioxygenase enzymes named TET translocation proteins (TET-eleven-translocation). These proteins, TET1–3, can oxidize 5-meC into 5-hydroxymethylcytosine (5-hmC) and 5-carboxycytosine (5-caC). The decarboxylation of 5caC will provoke the demethylation of the DNA [37]. Studies have suggested a direct action of CpG-island hypermethylation in the regulation of NRF2 transcriptional activity [38]. The downregulation of NRF2 by DNA methylation has been described in a cellular model of Alzheimer’s disease [39], diabetic cardiomyopathy [40], and especially in different types of cancers [38]. Furthermore, DNA methylation has been associated with the protective effect of physical exercise [41]. Although exercise-induced redox disturbances can act as downstream modulators of the epigenetic machinery, data demonstrating a direct exercise-induced epigenetic modulation of NRF2 gene expression are scarce [42]. The increased activation of NRF2 has been attributed to the hypermethylation of KEAP1, favoring NRF2translocation to the cell nucleus [43][44]. In agreement, it has been shown that running exercise can reverse NRF2 promoter hypermethylation in a pre-clinical osteoporosis model, thereby attenuating the suppression of antioxidant enzymes [45]. In addition, it is well established that physical exercise increases ROS production, and recent studies indicate that ROS can activate TET DNA demethylases and cause hypomethylation of the NFE2L2 promoter, resulting in NRF2 activation [46][47].

2.2. Histone Modifications

Histone modification is another key mechanism in the regulation of gene expression. An octamer of histone proteins makes up the main repeating element of chromatin, the nucleosome. Histones have N-terminal tails that are prone to a variety of post-translational changes, with histones H3 and H4 being the most studied concerning gene-expression regulation [33][48][49]. These modifications are controlled by four groups of enzymes: histone acetyltransferases (HATs), histone methyltransferases (HMTs), histone deacetylases (HDACs), and histone demethylases [50][51]. In this scenario, it has been demonstrated that increased histone acetylation occurred in the hippocampus of rats that were subjected to physical exercise. This epigenetic modification was associated with improved neurocognition and aversive-memory performance [52][53].
The HDACs family is composed of sirtuins (Sirts), which due to their NAD+-dependence on the deacetylase activity, can regulate redox reactions by modulating transcription factors that control the expression of antioxidant enzymes [54]. NRF2 has been suggested to be a downstream regulator of Sirt1 in a cardiac-ischemia model [55]. On the other hand, Sirt2 has been associated with the deacetylation of NRF2 and consequent reduction of its total cellular and nuclear levels, leading to a decrease in its transcriptional activity [56]. NRF2 levels can also be modulated by Sirt2 through Akt phosphorylation, leading to the regulation of glutathione concentrations, suggesting a role in the NRF2/ARE system [57]. Although studies demonstrating the association between physical exercise, Sirts and NRF2 are scarce, the available evidence that exercise modulates sirtuins [58][59][60] and that they can act in the regulation of NRF2 [55][56][57] reveal an area to be studied and a possible mechanism generated by the practice of physical exercise.

2.3. Post-Transcriptional Regulation

Recently, non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs), have been implicated as important epigenetic modulators due to the ability to neutralize miRNAs by their sponge activity. LncRNAs are also capable of directing DNA methylation and histone modifications, thereby modulating gene expression [61]. NcRNAs can act as competitive endogenous RNAs to absorb and suppress the activity of bound miRNAs, effectively derepressing other targets of these miRNAs [62]. The regulation of gene expression by lncRNAs at the epigenetic, transcriptional and post-transcriptional levels have been widely studied, and there are strong indications that the expression of certain lncRNAs can modulate the effects of physical exercise (Table 1).
Table 1. Effects of exercise-induced lncRNA modulation.
Physical Exercise LncRNA Reported Effect References
Swimming CPhar Prevention of myocardial ischemia-reperfusion injury and cardiac dysfunction [63]
Swimming Mhrt779 Heart antihypertrophic effect [64]
Treadmill MSTRG.2625
MSTRG.1557
MSTRG.691
MSTRG.7497
Promotion of osteogenic differentiation [65]
Treadmill CYTOR Regulation of fast-twitch myogenesis in aging [66]
Aerobic exercise (single jump rope, double jump rope, round-trip running, and gymnastics) MALAT1 Improvement of endothelial dysfunction [67]
Swimming LOC102633466
LOC102637865
LOC102638670
Improved motor performance [68]
Treadmill TUG1 Reduction of hippocampal neuronal apoptosis [69]
Treadmill Neat1
Meg3
Malat1
Kcnq1ot1
Possible involvement in insulin resistance and glucose homeostasis pathways [70]
Running wheels SNHG14 Improvement of cognitive disorder and inflammation [71]

LncRNA studies provide new insights into the regulation of beneficial exercise-induced effects, but despite NRF2 having a central role in these effects, studies demonstrating the involvement of lncRNA in the regulation of exercise-induced NRF2 expression are scarce. Following aerobic exercise, miR-340-5p has been shown to play a role in the post-transcriptional regulation of NRF2 expression in mouse skeletal muscles [72].

3. Effects of BH4 on Epigenetic Modulation Induced by Physical Exercise

Folate and BH4 are chemically defined as pterins due to the presence of the heterocycle ring pteridine. Different from BH4, folate is an essential vitamin that needs to be included in the diet in order to modulate metabolism as a micronutrient. Dietary folate requires the activity of DHFR to be converted first into dihydrofolate and then into tetrahydrofolate (THF), a universal one-carbon unit acceptor. DHFR is also an active enzyme in the BH4 salvage pathway, where it catalyzes the reduction of BH2 into BH4 [2]. THF accepts one-carbon units derived from the amino acids, serine and glycine, and the resulting methylated-THF exists in several interchangeable forms with varying chemical structures. These include formyl-THF, methyl-THF, and methylene-THF, which, respectively, donate their one-carbon units to purine synthesis, the methionine recycling pathway (via homocysteine methylation), and thymidylate synthesis [73].
Several studies have associated folate metabolism with increased DNA methylation in blood cells [74], liver [75], kidney [76], and gut [77], as well as, with increased concentrations of SAM in erythrocytes [78], a key metabolite involved in DNA methylation. On the other hand, it has been shown that the reduction of DHFR activity diminishes the cellular THF pool, altering the folate-dependent enzyme activity, and therefore, epigenetic profiles [79]. Folate deficits have been extensively associated with an increased risk of cardiovascular diseases, multiple cancers, and neural-tube defects due to deficient DNA methylation [80][81][82][83]. In addition, BH4 non-hereditable or genetic deficiencies have also been related to conditions where folate metabolism was reported to be compromised, including brain-maturation defects [84] and cardiovascular diseases [85]. Moreover, DHFR inhibition is essential to the action of antifolate medications used to treat cancer and some inflammatory diseases, and it is well described that methotrexate reduces BH4 levels [86], denoting the intricate association between these two metabolic pathways in regulating DNA methylation.
The practice of physical exercise is known to modulate DNA methylation, favoring the hypermethylation of some DNA regions and the hypomethylation of others. The outcome is the permissive gene expression of genes beneficial for cell health, i.e., anti-inflammatory and antioxidant genes. In this scenario, it has been shown that acute resistance exercise used to stimulate hypertrophy can induce different epigenetic modifications in human skeletal muscle, including the hypermethylation of GPAM and SREBF2 genes [87]. GPAM and SREBF2 encode for enzymes involved in the biosynthesis of lipids, a metabolism that has been proposed to be dependent on appropriate intracellular levels of BH4 [88].
The practice of light-intensity physical activity by a general cohort of a healthy middle-aged population generated hypermethylation of the gene speck-like protein containing a caspase recruitment domain (ASC) in peripheral blood mononuclear cells, resulting in a decrease in expression [89]. ASC encodes an adapter protein that is necessary for inflammasome formation and the consequent activation of pro-caspase 1 and IL1-β synthesis [90]. ASC hypermethylation was correlated with a decrease in the pro-inflammatory cytokines IL-6, IL-8, IL-15, and TNF-a, resulting in a decrease in systemic inflammation in middle-aged individuals [89]. Furthermore, hypermethylation of NFκB in peripheral blood cells has also been demonstrated after low-intensity walking exercise by elderly individuals, also demonstrating a decrease in exercise-induced systemic inflammation mediated by epigenetic mechanism [91]. This scenario suggests a possible relationship between BH4 metabolism and the effects induced by exercise on DNA methylation, favoring the antioxidant response (Figure 1); however, studies in this area have not been performed to date.
Figure 1. Regulation of the erythroid-related-nuclear-factor-2 (NRF2) pathway mediated by physical exercise. (A) Under basal conditions, cytosolic NRF2 is maintained at low levels by ubiquitin-mediated proteasomal degradation. (B) Electrophilic stress and NRF2 phosphorylation can induce NRF2 nuclear translocation and further interaction of the transcription factor with the antioxidant-responsive element (ARE). The interaction with ARE mediates the transcriptional activation of many genes encoding phase II drug-metabolizing and antioxidant enzymes, or proteins that will enhance mitochondrial activity and number, and promote an anti-inflammatory status. (C) Signaling pathways activated by physical exercise. The regular practice of physical exercise positively regulates NRF2 nuclear translocation, the synthesis of tetrahydrobiopterin (BH4) and epigenetic modifications, including DNA methylation. DNA methylation could be the result of an interplay among methionine, folate and BH4 pathways. Folate is transformed into tetrahydrofolate (THF) by the enzyme dihydrofolate reductase (DHFR), the same enzyme that catalyzes the reduction of dihydrobiopterin (BH2) into BH4 in the BH4 biosynthetic pathway. THF is transformed to 5-methyltetrahydrofolate (5-MTF) by MTHFR and converted back to THF by methionine synthase (MS), allowing the methylation of homocysteine to methionine. The latter is then transformed into S-adenoslymethionine (SAM), which can donate a methyl group for DNA methylation, leading to the formation of S-adenosylhomocysteine (SAH) and methylated DNA. The enzymes involved in DNA methylation are DNA methyltransferases (DNMTs), which transfer the methyl group from SAM to DNA, leading to methylation of the promoter region of KEAP1 gene, decreasing its expression and favoring NRF2 translocation. In addition, the hypermethylation of the promoter region of the ASC gene and NFkB, which encode proteins involved in promoting an anti-inflammatory status, will promote an anti-inflammatory environment.

4. Conclusions

A vast number of studies have demonstrated the beneficial role of physical exercise in potentiating the NRF2/ARE pathway. Although the mechanisms induced by physical exercise to modulate the antioxidant system are not fully elucidated, increasing evidence indicates the involvement of the BH4 pathway and epigenetic events in the process. A better understanding of which mechanistic mediators are involved in this effect will potentially allow the development of non-pharmacological strategies, or co-adjuvant therapies, that seek the prevention of chronic or neurodegenerative diseases where oxidative stress, inflammation, and mitochondrial dysfunction are involved in physiopathology.

References

  1. Thony, B.; Auerbach, G.; Blau, N.; Thöny, B.; Auerbach, G.; Blau, N.; Thöny, B.; Auerbach, G.; Blau, N. Tetrahydrobiopterin biosynthesis, regeneration and functions. Biochem. J. 2000, 347 Pt 1, 1–16.
  2. Werner, E.R.E.R.; Blau, N.; Thöny, B. Tetrahydrobiopterin: Biochemistry and pathophysiology. Biochem. J. 2011, 438, 397–414.
  3. Werner, E.R.; Werner-Felmayer, G.; Fuchs, D.; Hausen, A.; Reibnegger, G.; Yim, J.J.; Pfleiderer, W.; Wachter, H. Tetrahydrobiopterin biosynthetic activities in human macrophages, fibroblasts, THP-1, and T 24 cells. GTP-cyclohydrolase I is stimulated by interferon-gamma, and 6-pyruvoyl tetrahydropterin synthase and sepiapterin reductase are constitutively present. J. Biol. Chem. 1990, 265, 3189–3192.
  4. Ghisoni, K.; de Paula Martins, R.; Barbeito, L.; Latini, A. Neopterin as a potential cytoprotective brain molecule. J. Psychiatr. Res. 2015, 71, 134–139.
  5. Cronin, S.J.F.; Seehus, C.; Weidinger, A.; Talbot, S.; Reissig, S.; Seifert, M.; Pierson, Y.; McNeill, E.; Longhi, M.S.; Turnes, B.L.; et al. The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. Nature 2018, 563, 564–568.
  6. Choi, H.J.; Lee, S.Y.; Cho, Y.; No, H.; Kim, S.W.; Hwang, O. Tetrahydrobiopterin causes mitochondrial dysfunction in dopaminergic cells: Implications for Parkinson’s disease. Neurochem. Int. 2006, 48, 255–262.
  7. Bailey, J.; Shaw, A.; Fischer, R.; Ryan, B.J.; Kessler, B.M.; McCullagh, J.; Wade-Martins, R.; Channon, K.M.; Crabtree, M.J. A novel role for endothelial tetrahydrobiopterin in mitochondrial redox balance. Free Radic. Biol. Med. 2017, 104, 214–225.
  8. Ghisoni, K.; Latini, A. Kuehne LK, Reiber H, Bechter K, Hagberg L, Fuchs D., Cerebrospinal fluid neopterin is brain-derived and not associated with blood-CSF barrier dysfunction in non-inflammatory affective and schizophrenic spectrum disorders. Letter to the Editor. J. Psychiatr. Res. 2015, 63, 141–142.
  9. Martins, R.D.P.; Ghisoni, K.; Lim, C.K.; Aguiar, A.S.; Guillemin, G.J.; Latini, A. Neopterin preconditioning prevents inflammasome activation in mammalian astrocytes. Free Radic. Biol. Med. 2018, 115, 371–382.
  10. Martinon, F.; Burns, K.; Tschopp, J. The Inflammasome: A Molecular Platform Triggering Activation of Inflammatory Caspases and Processing of proIL-β. Mol. Cell 2002, 10, 417–426.
  11. Ghisoni, K.; Aguiar, A.S.; de Oliveira, P.A.; Matheus, F.C.; Gabach, L.; Perez, M.; Carlini, V.P.; Barbeito, L.; Mongeau, R.; Lanfumey, L.; et al. Neopterin acts as an endogenous cognitive enhancer. Brain. Behav. Immun. 2016, 56, 156–164.
  12. Tutakhail, A.; Nazary, Q.A.; Lebsir, D.; Kerdine-Romer, S.; Coudore, F. Induction of brain Nrf2-HO-1 pathway and antinociception after different physical training paradigms in mice. Life Sci. 2018, 209, 149–156.
  13. Aguiar, A.S.; Duzzioni, M.; Remor, A.P.; Tristão, F.S.M.; Matheus, F.C.; Raisman-Vozari, R.; Latini, A.; Prediger, R.D. Moderate-intensity physical exercise protects against experimental 6-hydroxydopamine-induced hemiparkinsonism through Nrf2-antioxidant response element pathway. Neurochem. Res. 2016, 41, 64–72.
  14. da Luz Scheffer, D.; Ghisoni, K.; Aguiar, A.S.; Latini, A. Moderate running exercise prevents excessive immune system activation. Physiol. Behav. 2019, 204, 248–255.
  15. McNeill, E.; Crabtree, M.J.; Sahgal, N.; Patel, J.; Chuaiphichai, S.; Iqbal, A.J.; Hale, A.B.; Greaves, D.R.; Channon, K.M. Regulation of iNOS function and cellular redox state by macrophage Gch1 reveals specific requirements for tetrahydrobiopterin in NRF2 activation. Free Radic. Biol. Med. 2015, 79, 206–216.
  16. Lindsay, A.; Costello, J.T. Realising the Potential of Urine and Saliva as Diagnostic Tools in Sport and Exercise Medicine. Sport. Med. 2017, 47, 11–31.
  17. Gieseg, S.; Baxter-Parker, G.; Lindsay, A. Neopterin, Inflammation, and Oxidative Stress: What Could We Be Missing? Antioxidants 2018, 7, 80.
  18. HASHIMOTO, R.; NAGATSU, T.; OHTA, T.; MIZUTANI, M.; OMURA, I. Changes in the Concentrations of Tetrahydrobiopterin, the Cofactor of Tyrosine Hydroxylase, in Blood under Physical Stress and in Depression. Ann. N. Y. Acad. Sci. 2004, 1018, 378–386.
  19. Mizutani, M.; Hashimoto, R.; Ohta, T.; Nakazawa, K.; Nagatsu, T. The Effect of Exercise on Plasma Biopterin Levels. Neuropsychobiology 1994, 29, 53–56.
  20. Finsterer, J. Biomarkers of peripheral muscle fatigue during exercise. BMC Musculoskelet. Disord. 2012, 13, 218.
  21. Sprenger, H.; Jacobs, C.; Nain, M.; Gressner, A.M.; Prinz, H.; Wesemann, W.; Gemsa, D. Enhanced release of cytokines, interleukin-2 receptors, and neopterin after long-distance running. Clin. Immunol. Immunopathol. 1992, 63, 188–195.
  22. Baxter-Parker, G.; Chu, A.; Petocz, P.; Samman, S.; Gieseg, S.P. Simultaneous analysis of neopterin, kynurenine and tryptophan by amine-HPLC shows minor oxidative stress from short-term exhaustion exercise. Pteridines 2019, 30, 21–32.
  23. Strasser, B.; Geiger, D.; Schauer, M.; Gatterer, H.; Burtscher, M.; Fuchs, D. Effects of Exhaustive Aerobic Exercise on Tryptophan-Kynurenine Metabolism in Trained Athletes. PLoS ONE 2016, 11, e0153617.
  24. Dantas de Lucas, R.; Caputo, F.; Mendes de Souza, K.; Sigwalt, A.R.; Ghisoni, K.; Lock Silveira, P.C.; Remor, A.P.; da Luz Scheffer, D.; Antonacci Guglielmo, L.G.; Latini, A. Increased platelet oxidative metabolism, blood oxidative stress and neopterin levels after ultra-endurance exercise. J. Sports Sci. 2014, 32, 22–30.
  25. Moser, B.; Schroecksnadel, K.; Hörtnagl, H.; Rieder, J.; Fuchs, D.; Gottardis, M. Influence of Extreme Long Endurance Sports Activity on Neopterin Excretion. Pteridines 2008, 19, 114–119.
  26. Lindsay, A.; Lewis, J.; Scarrott, C.; Draper, N.; Gieseg, S.P. Changes in acute biochemical markers of inflammatory and structural stress in rugby union. J. Sports Sci. 2015, 33, 882–891.
  27. Lindsay, A.; Janmale, T.; Draper, N.; Gieseg, S.P. Measurement of changes in urinary neopterin and total neopterin in body builders using SCX HPLC. Pteridines 2014, 25, 53–63.
  28. Mrakic-Sposta, S.; Gussoni, M.; Vezzoli, A.; Dellanoce, C.; Comassi, M.; Giardini, G.; Bruno, R.M.; Montorsi, M.; Corciu, A.; Greco, F.; et al. Acute Effects of Triathlon Race on Oxidative Stress Biomarkers. Oxid. Med. Cell. Longev. 2020, 2020, 1–14.
  29. Mrakic-Sposta, S.; Gussoni, M.; Moretti, S.; Pratali, L.; Giardini, G.; Tacchini, P.; Dellanoce, C.; Tonacci, A.; Mastorci, F.; Borghini, A.; et al. Effects of Mountain Ultra-Marathon Running on ROS Production and Oxidative Damage by Micro-Invasive Analytic Techniques. PLoS ONE 2015, 10, e0141780.
  30. da Luz Scheffer, D.; Latini, A. Exercise-induced immune system response: Anti-inflammatory status on peripheral and central organs. Biochim. Biophys. Acta - Mol. Basis Dis. 2020, 1866, 165823.
  31. Waddington, C.H. The epigenotype. 1942. Int. J. Epidemiol. 2012, 41, 10–13.
  32. Bird, A. Perceptions of epigenetics. Nature 2007, 447, 396–398.
  33. Tost, J. DNA methylation: An introduction to the biology and the disease-associated changes of a promising biomarker. Mol. Biotechnol. 2010, 44, 71–81.
  34. Hamilton, A.J.; Baulcombe, D.C. A species of small antisense RNA in posttranscriptional gene silencing in plants. Science (80-. ). 1999, 286, 950–952.
  35. Gibney, E.R.; Nolan, C.M. Epigenetics and gene expression. Heredity (Edinb). 2010, 105, 4–13.
  36. Sawan, C.; Vaissiere, T.; Murr, R.; Herceg, Z. Epigenetic drivers and genetic passengers on the road to cancer. Mutat. Res. 2008, 642, 1–13.
  37. Loenarz, C.; Schofield, C.J. Oxygenase catalyzed 5-methylcytosine hydroxylation. Chem. Biol. 2009, 16, 580–583.
  38. Guo, Y.; Yu, S.; Zhang, C.; Kong, A.N.T. Epigenetic regulation of Keap1-Nrf2 signaling. Free Radic. Biol. Med. 2015, 88, 337–349.
  39. Zhao, F.; Zhang, J.; Chang, N. Epigenetic modification of Nrf2 by sulforaphane increases the antioxidative and anti-inflammatory capacity in a cellular model of Alzheimer’s disease. Eur. J. Pharmacol. 2018, 824, 1–10.
  40. Liu, Z.-Z.; Zhao, X.-Z.; Zhang, X.-S.; Zhang, M. Promoter DNA demethylation of Keap1 gene in diabetic cardiomyopathy. Int. J. Clin. Exp. Pathol. 2014, 7, 8756–8762.
  41. Ferrari, L.; Vicenzi, M.; Tarantini, L.; Barretta, F.; Sironi, S.; Baccarelli, A.A.; Guazzi, M.; Bollati, V. Effects of Physical Exercise on Endothelial Function and DNA Methylation. Int. J. Environ. Res. Public Health 2019, 16, 2530.
  42. Dimauro, I.; Paronetto, M.P.; Caporossi, D. Exercise, redox homeostasis and the epigenetic landscape. Redox Biol. 2020, 35, 101477.
  43. Wang, D.; Ma, Y.; Yang, X.; Xu, X.; Zhao, Y.; Zhu, Z.; Wang, X.; Deng, H.; Li, C.; Gao, F.; et al. Hypermethylation of the Keap1 gene inactivates its function, promotes Nrf2 nuclear accumulation, and is involved in arsenite-induced human keratinocyte transformation. Free Radic. Biol. Med. 2015, 89, 209–219.
  44. Wang, R.; An, J.; Ji, F.; Jiao, H.; Sun, H.; Zhou, D. Hypermethylation of the Keap1 gene in human lung cancer cell lines and lung cancer tissues. Biochem. Biophys. Res. Commun. 2008, 373, 151–154.
  45. Chen, X.; Zhu, X.; Wei, A.; Chen, F.; Gao, Q.; Lu, K.; Jiang, Q.; Cao, W. Nrf2 epigenetic derepression induced by running exercise protects against osteoporosis. Bone Res. 2021, 9, 15.
  46. Kang, K.A.; Piao, M.J.; Kim, K.C.; Kang, H.K.; Chang, W.Y.; Park, I.C.; Keum, Y.S.; Surh, Y.J.; Hyun, J.W. Epigenetic modification of Nrf2 in 5-fluorouracil-resistant colon cancer cells: Involvement of TET-dependent DNA demethylation. Cell Death Dis. 2014, 5, e1183.
  47. Kang, K.A.; Piao, M.J.; Ryu, Y.S.; Kang, H.K.; Chang, W.Y.; Keum, Y.S.; Hyun, J.W. Interaction of DNA demethylase and histone methyltransferase upregulates Nrf2 in 5-fluorouracil-resistant colon cancer cells. Oncotarget 2016, 7, 40594–40620.
  48. Garcea, R.L.; Alberts, B.M. Comparative Studies of Histone Acetylation in Nucleosomes, Nuclei, and Intact Cells. Biol. Chem. 1980, 255, 11454–11463.
  49. Fowler, E.; Farb, R.; El-Saidy, S. Distribution of the core histones H2A H2B, H3 and H4 during cell replication. Nucleic Acids Res. 1982, 10, 735–748.
  50. Yang, X.-J.; Seto, E. HATs and HDACs: From structure, function and regulation to novel strategies for therapy and prevention. Oncogene 2007, 26, 5310–5318.
  51. Jiang, Y.; Jakovcevski, M.; Bharadwaj, R.; Connor, C.; Schroeder, F.A.; Lin, C.L.; Straubhaar, J.; Martin, G.; Akbarian, S. Setdb1 histone methyltransferase regulates mood-related behaviors and expression of the NMDA receptor subunit NR2B. J. Neurosci. 2010, 30, 7152–7167.
  52. Zhong, T.; Ren, F.; Huang, C.S.; Zou, W.Y.; Yang, Y.; Pan, Y.D.; Sun, B.; Wang, E.; Guo, Q.L. Swimming exercise ameliorates neurocognitive impairment induced by neonatal exposure to isoflurane and enhances hippocampal histone acetylation in mice. Neuroscience 2016, 316, 378–388.
  53. de Meireles, L.C.F.; Bertoldi, K.; Cechinel, L.R.; Schallenberger, B.L.; da Silva, V.K.; Schröder, N.; Siqueira, I.R. Treadmill exercise induces selective changes in hippocampal histone acetylation during the aging process in rats. Neurosci. Lett. 2016, 634, 19–24.
  54. Singh, C.K.; Chhabra, G.; Ndiaye, M.A.; Garcia-Peterson, L.M.; Mack, N.J.; Ahmad, N. The Role of Sirtuins in Antioxidant and Redox Signaling. Antioxid. Redox Signal. 2018, 28, 643–661.
  55. Xue, F.; Huang, J.; Ding, P.; Zang, H.; Kou, Z.; Li, T.; Fan, J.; Peng, Z.; Yan, W. Nrf2/antioxidant defense pathway is involved in the neuroprotective effects of Sirt1 against focal cerebral ischemia in rats after hyperbaric oxygen preconditioning. Behav. Brain Res. 2016, 309, 1–8.
  56. Yang, X.; Park, S.-H.; Chang, H.-C.; Shapiro, J.S.; Vassilopoulos, A.; Sawicki, K.T.; Chen, C.; Shang, M.; Burridge, P.W.; Epting, C.L.; et al. Sirtuin 2 regulates cellular iron homeostasis via deacetylation of transcription factor NRF2. J. Clin. Invest. 2017, 127, 1505–1516.
  57. Cao, W.; Hong, Y.; Chen, H.; Wu, F.; Wei, X.; Ying, W. SIRT2 mediates NADH-induced increases in Nrf2, GCL, and glutathione by modulating Akt phosphorylation in PC12 cells. FEBS Lett. 2016, 590, 2241–2255.
  58. Chen, W.-K.; Tsai, Y.-L.; Shibu, M.A.; Shen, C.-Y.; Chang-Lee, S.N.; Chen, R.-J.; Yao, C.-H.; Ban, B.; Kuo, W.-W.; Huang, C.-Y. Exercise training augments Sirt1-signaling and attenuates cardiac inflammation in D-galactose induced-aging rats. Aging (Albany. NY). 2018, 10, 4166–4174.
  59. Tunca, U.; Saygin, M.; Ozmen, O.; Aslankoc, R.; Yalcin, A. The impact of moderate-intensity swimming exercise on learning and memory in aged rats: The role of Sirtuin-1. Iran. J. Basic Med. Sci. 2021, 24, 1413–1420.
  60. Vargas-Ortiz, K.; Pérez-Vázquez, V.; Macías-Cervantes, M.H. Exercise and Sirtuins: A Way to Mitochondrial Health in Skeletal Muscle. Int. J. Mol. Sci. 2019, 20, 2717.
  61. Kopp, F.; Mendell, J.T. Functional Classification and Experimental Dissection of Long Noncoding RNAs. Cell 2018, 172, 393–407.
  62. Thomson, D.W.; Dinger, M.E. Endogenous microRNA sponges: Evidence and controversy. Nat. Rev. Genet. 2016, 17, 272–283.
  63. Gao, R.; Wang, L.; Bei, Y.; Wu, X.; Wang, J.; Zhou, Q.; Tao, L.; Das, S.; Li, X.; Xiao, J. Long Noncoding RNA Cardiac Physiological Hypertrophy–Associated Regulator Induces Cardiac Physiological Hypertrophy and Promotes Functional Recovery After Myocardial Ischemia-Reperfusion Injury. Circulation 2021, 144, 303–317.
  64. Lin, H.; Zhu, Y.; Zheng, C.; Hu, D.; Ma, S.; Chen, L.; Wang, Q.; Chen, Z.; Xie, J.; Yan, Y.; et al. Antihypertrophic Memory After Regression of Exercise-Induced Physiological Myocardial Hypertrophy Is Mediated by the Long Noncoding RNA Mhrt779. Circulation 2021, 143, 2277–2292.
  65. Qiu, Y.; Zhu, G.; Zeng, C.; Yuan, S.; Qian, Y.; Ye, Z.; Zhao, S.; Li, R. Next-generation sequencing of miRNAs and lncRNAs from rat femur and tibia under mechanical stress. Mol. Med. Rep. 2021, 24, 561.
  66. Wohlwend, M.; Laurila, P.-P.; Williams, K.; Romani, M.; Lima, T.; Pattawaran, P.; Benegiamo, G.; Salonen, M.; Schneider, B.L.; Lahti, J.; et al. The exercise-induced long noncoding RNA CYTOR promotes fast-twitch myogenesis in aging. Sci. Transl. Med. 2021, 13.
  67. Zhao, W.; Yin, Y.; Cao, H.; Wang, Y. Exercise Improves Endothelial Function via the lncRNA MALAT1/miR-320a Axis in Obese Children and Adolescents. Cardiol. Res. Pract. 2021, 2021, 1–8.
  68. Zhang, X.; Wang, Y.; Zhao, Z.; Chen, X.; Li, W.; Li, X. Transcriptome sequencing reveals aerobic exercise training-associated lncRNAs for improving Parkinson’s disease. 3 Biotech 2020, 10, 498.
  69. Wang, J.; Niu, Y.; Tao, H.; Xue, M.; Wan, C. Knockdown of lncRNA TUG1 inhibits hippocampal neuronal apoptosis and participates in aerobic exercise-alleviated vascular cognitive impairment. Biol. Res. 2020, 53, 53.
  70. Kazeminasab, F.; Marandi, S.M.; Baharlooie, M.; Safaeinejad, Z.; Nasr-Esfahani, M.H.; Ghaedi, K. Aerobic exercise modulates noncoding RNA network upstream of FNDC5 in the Gastrocnemius muscle of high-fat-diet-induced obese mice. J. Physiol. Biochem. 2021, 77, 589–600.
  71. He, Y.; Qiang, Y. Mechanism of Autonomic Exercise Improving Cognitive Function of Alzheimer’s Disease by Regulating lncRNA SNHG14. Am. J. Alzheimer’s Dis. Other Dement. 2021, 36, 36.
  72. Mei, T.; Liu, Y.; Wang, J.; Zhang, Y. miR-340-5p: A potential direct regulator of Nrf2 expression in the post-exercise skeletal muscle of mice. Mol. Med. Rep. 2018, 19, 1340–1348.
  73. Tibbetts, A.S.; Appling, D.R. Compartmentalization of Mammalian Folate-Mediated One-Carbon Metabolism. Annu. Rev. Nutr. 2010, 30, 57–81.
  74. Vineis, P.; Chuang, S.-C.; Vaissière, T.; Cuenin, C.; Ricceri, F.; Collaborators, G.; Johansson, M.; Ueland, P.; Brennan, P.; Herceg, Z. DNA methylation changes associated with cancer risk factors and blood levels of vitamin metabolites in a prospective study. Epigenetics 2011, 6, 195–201.
  75. Wakefield, L.; Boukouvala, S.; Sim, E. Characterisation of CpG methylation in the upstream control region of mouse Nat2: Evidence for a gene–environment interaction in a polymorphic gene implicated in folate metabolism. Gene 2010, 452, 16–21.
  76. McKay, J.A.; Xie, L.; Harris, S.; Wong, Y.K.; Ford, D.; Mathers, J.C. Blood as a surrogate marker for tissue-specific DNA methylation and changes due to folate depletion in post-partum female mice. Mol. Nutr. Food Res. 2011, 55, 1026–1035.
  77. McKay, J.A.; Wong, Y.K.; Relton, C.L.; Ford, D.; Mathers, J.C. Maternal folate supply and sex influence gene-specific DNA methylation in the fetal gut. Mol. Nutr. Food Res. 2011, 55, 1717–1723.
  78. Hirsch, S.; Ronco, A.M.; Guerrero-Bosagna, C.; de la Maza, M.P.; Leiva, L.; Barrera, G.; Llanos, M.; Alliende, M.A.; Silva, F.; Bunout, D. Methylation status in healthy subjects with normal and high serum folate concentration. Nutrition 2008, 24, 1103–1109.
  79. Chen, M.J.; Shimada, T.; Moulton, A.D.; Cline, A.; Humphries, R.K.; Maizel, J.; Nienhuis, A.W. The functional human dihydrofolate reductase gene. J. Biol. Chem. 1984, 259, 3933–3943.
  80. Holmquist, C.; Larsson, S.; Wolk, A.; de Faire, U. Multivitamin Supplements Are Inversely Associated with Risk of Myocardial Infarction in Men and Women—Stockholm Heart Epidemiology Program (SHEEP). J. Nutr. 2003, 133, 2650–2654.
  81. Lamprecht, S.A.; Lipkin, M. Chemoprevention of colon cancer by calcium, vitamin D and folate: Molecular mechanisms. Nat. Rev. Cancer 2003, 3, 601–614.
  82. Smithells, R.W.; Sheppard, S.; Schorah, C.J. Vitamin dificiencies and neural tube defects. Arch. Dis. Child. 1976, 51, 944–950.
  83. Laurence, K.M.; James, N.; Miller, M.H.; Tennant, G.B.; Campbell, H. Double-blind randomised controlled trial of folate treatment before conception to prevent recurrence of neural-tube defects. BMJ 1981, 282, 1509–1511.
  84. Yoshida, Y.-I.; Eda, S.; Masada, M. Alterations of tetrahydrobiopterin biosynthesis and pteridine levels in mouse tissues during growth and aging. Brain Dev. 2000, 22, 45–49.
  85. Bendall, J.K.; Douglas, G.; McNeill, E.; Channon, K.M.; Crabtree, M.J. Tetrahydrobiopterin in Cardiovascular Health and Disease. Antioxid. Redox Signal. 2014, 20, 3040–3077.
  86. Crabtree, M.J.; Tatham, A.L.; Hale, A.B.; Alp, N.J.; Channon, K.M. Critical Role for Tetrahydrobiopterin Recycling by Dihydrofolate Reductase in Regulation of Endothelial Nitric-oxide Synthase Coupling. J. Biol. Chem. 2009, 284, 28128–28136.
  87. Bagley, J.R.; Burghardt, K.J.; McManus, R.; Howlett, B.; Costa, P.B.; Coburn, J.W.; Arevalo, J.A.; Malek, M.H.; Galpin, A.J. Epigenetic Responses to Acute Resistance Exercise in Trained vs. Sedentary Men. J. Strength Cond. Res. 2020, 34, 1574–1580.
  88. Thöny, B. Tetrahydrobiopterin and its functions. In PKU and BH4: Advances in Phenylketonuria and Tetrahydrobiopterin Research; SPS Publications: Heilbronn, Germany, 2006; pp. 503–504.
  89. Nishida, Y.; Hara, M.; Higaki, Y.; Taguchi, N.; Nakamura, K.; Nanri, H.; Horita, M.; Shimanoe, C.; Yasukata, J.; Miyoshi, N.; et al. Habitual Light-intensity Physical Activity and ASC Methylation in a Middle-aged Population. Int. J. Sports Med. 2019, 40, 670–677.
  90. Mariathasan, S.; Newton, K.; Monack, D.M.; Vucic, D.; French, D.M.; Lee, W.P.; Roose-Girma, M.; Erickson, S.; Dixit, V.M. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 2004, 430, 213–218.
  91. Zhang, Y.; Hashimoto, S.; Fujii, C.; Hida, S.; Ito, K.; Matsumura, T.; Sakaizawa, T.; Morikawa, M.; Masuki, S.; Nose, H.; et al. NFκB2 Gene as a Novel Candidate that Epigenetically Responds to Interval Walking Training. Int. J. Sports Med. 2015, 36, 769–775.
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