All living organisms on Earth live under an oxidant atmosphere, characterized by a percentage of molecular oxygen of about 20%. We all know the fate of a piece of iron left outside: in a short time, it becomes completely oxidized (rusted). Why does the same not happen to us?
The reason is simple: biological lifeforms, during evolution on Earth, developed various mechanisms for sensing and counteracting the deleterious effects of free radicals or reactive oxygen species (ROS), the highly reactive by-products of oxygen metabolism. Several systems have evolved in prokaryotic and eukaryotic cells to regulate ROS, and today almost all organisms control free-radical levels by maintaining a fine equilibrium, the reductive-oxidative (RedOx) balance.[2,3]
In physiological conditions, ROS are largely produced by metabolic reactions and this happens at every moment in every single cell of our body. Thus, production of oxidizing species and free radicals is a physiological process. The deleterious effects of ROS are neutralised by an ensemble of enzyme and molecules endowed with antioxidant capacity. However, when ROS production exceeds the neutralising ability of antioxidant defences, a state of oxidative stress occurs, causing cell damage and death, and eventually organ dysfunction (Figure 1).
Therefore, Oxidative stress is a disturbance of the physiological RedOx balance that is not balanced by adequate adaptive responses from the body.
Figure 1. RedOx homeostasis. The RedOX balance is preserved thanks to the existing equilibrium between ROS production rate and antioxidant defence system. Highlighted in red possible sources of ROS, while in green the antioxidant defences. Oxidative stress (OS) is a condition where there is an overproduction of ROS or a reduced ability of the antioxidant defences to counteract the production of ROS. OS can induce cellular and tissue injury through different mechanisms.
Nature is often drastic in its behaviour, and one has to keep in mind that living organisms are evolved to preserve genomic integrity. Individual cells can be easily sacrificed if endogenous check-point mechanisms suspect genomic damage. When this happens, we perceive it as a tissue lesion, as a weakness, as aging and wellness unbalance.
The main causes of oxidative stress are pollution, inflammation, the immune response, and incorrect management of ROS produced in the mitochondria, as well as various metabolic reactions (Figure 1).
Consider the case of atmospheric pollution: aromatic hydrocarbon particles constantly challenge our body. These particles have a high potential to harm the cell’s DNA and thus detoxifying mechanisms based on oxidation of these aromatic hydrocarbons are constantly activated. The free radicals formed in these processes easily react with any molecule in their vicinity (lipids, proteins, nucleic acids), damaging it, often impairing its function, and propagating oxidative damage. Indeed, strong and massive oxidation produces a huge amount of ROS, which severely harm cells leading to premature aging and decline.
In the last years the signalling and damaging properties of ROS have received particular attention being implicated in central homeostatic mechanisms at the molecular, cellular, tissue and apparatus levels. Recently high impact factor journals (Nature Review, Science and Science Translational Medicine) reported comprehensive reviews about the pathophysiological role of RedOx signalling.[2,4–10] Oxidative Stress (OS) has been linked to several human diseases, including: ADHD, cancer, Parkinson’s disease (PD), Alzheimer’s disease (AD),[14,14,15] heart failure and myocardial infarction.[16–18]
Human brain and central nervous system are characterized by distinctive features that make it highly sensitive to OS. Indeed, they are one of the organ and apparatus with the highest O2 utilisation, they have the highest content of docosahexaenoic acid, which is a polyunsaturated fatty acid extremely sensitive to lipoperoxidation processes, and in the brain, there is also a high content of RedOx-active metals (Fe, Cu). Therefore, it is not surprising that most of the neurodegenerative disorders are characterized by an OS component, also considering that OS increases with the age. Several experimental evidences suggest that ROS play crucial role in neurodegenerative disorders since increased OS levels have been observed in tissue samples of patients with AD or PD and protein modifications induced directly or indirectly by ROS and lipid peroxidation processes have also been observed.
In evaluating cerebral OS four key elements have to be considered:
In light of the previous observations the protection of brain and central nervous system from oxidative stress requires specific, synergic and harmonic supplementation of ingredients able to concurrently address the main aspects of cerebral OS.
The challenge for researchers and producers is to catch this complexity and translate it into new supplements with robust validation. The challenge for consumers is to expect robust validation and trust evidence-based results. At Cor.Con. International our innovative food supplements are patented, tested in clinical studies. The use of specific ingredients promotes the normal function of the nervous system, protects the cells from oxidative stress, promotes the normal psychological function, the normal cysteine synthesis, and the normal homocysteine metabolism.
1. Margulis, L.; Sagan, D. Microcosmos: Four Billion Years of Evolution from Our Microbial Ancestors; University of California Press: Berkeley, 1997; ISBN 978-0-520-21064-6.
2. Sies, H.; Jones, D.P. Reactive Oxygen Species (ROS) as Pleiotropic Physiological Signalling Agents. Nat Rev Mol Cell Biol 2020, 21, 363–383, doi:10.1038/s41580-020-0230-3.
3. Ursini, F.; Maiorino, M.; Forman, H.J. Redox Homeostasis: The Golden Mean of Healthy Living. Redox Biol 2016, 8, 205–215, doi:10.1016/j.redox.2016.01.010.
4. Laforge, M.; Elbim, C.; Frère, C.; Hémadi, M.; Massaad, C.; Nuss, P.; Benoliel, J.-J.; Becker, C. Tissue Damage from Neutrophil-Induced Oxidative Stress in COVID-19. Nature Reviews Immunology 2020, 20, 515–516, doi:10.1038/s41577-020-0407-1.
5. Azzimato, V.; Jager, J.; Chen, P.; Morgantini, C.; Levi, L.; Barreby, E.; Sulen, A.; Oses, C.; Willerbrords, J.; Xu, C.; et al. Liver Macrophages Inhibit the Endogenous Antioxidant Response in Obesity-Associated Insulin Resistance. Sci Transl Med 2020, 12, doi:10.1126/scitranslmed.aaw9709.
6. Hamanaka, R.B.; Chandel, N.S. Warburg Effect and Redox Balance. Science 2011, 334, 1219–1220, doi:10.1126/science.1215637.
7. Krengel, U.; Tornroth-Horsefield, S. Coping with Oxidative Stress. Science 2015, 347, 125–126, doi:10.1126/science.aaa3602.
8. Kujoth, G.C.; Hiona, A.; Pugh, T.D.; Someya, S.; Panzer, K.; Wohlgemuth, S.E.; Hofer, T.; Seo, A.Y.; Sullivan, R.; Jobling, W.A.; et al. Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in Mammalian Aging. Science 2005, 309, 481–484, doi:10.1126/science.1112125.
9. Pierre, P. Integrating Stress Responses and Immunity. Science 2019, 365, 28–29, doi:10.1126/science.aay0987.
10. Storz, P. Reactive Oxygen Species-Mediated Mitochondria-to-Nucleus Signaling: A Key to Aging and Radical-Caused Diseases. Science Signaling 2006, 2006, re3–re3, doi:10.1126/stke.3322006re3.
11. Joseph, N.; Zhang-James, Y.; Perl, A.; Faraone, S.V. Oxidative Stress and ADHD: A Meta-Analysis. J Atten Disord 2015, 19, 915–924, doi:10.1177/1087054713510354.
12. Poprac, P.; Jomova, K.; Simunkova, M.; Kollar, V.; Rhodes, C.J.; Valko, M. Targeting Free Radicals in Oxidative Stress-Related Human Diseases. Trends in Pharmacological Sciences 2017, 38, 592–607, doi:10.1016/j.tips.2017.04.005.
13. Hwang, O. Role of Oxidative Stress in Parkinson’s Disease. Exp Neurobiol 2013, 22, 11–17, doi:10.5607/en.2013.22.1.11.
14. Valko, M.; Leibfritz, D.; Moncol, J.; Cronin, M.T.D.; Mazur, M.; Telser, J. Free Radicals and Antioxidants in Normal Physiological Functions and Human Disease. The International Journal of Biochemistry & Cell Biology 2007, 39, 44–84, doi:10.1016/j.biocel.2006.07.001.
15. Liu, Z.; Zhou, T.; Ziegler, A.C.; Dimitrion, P.; Zuo, L. Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications Available online: https://www.hindawi.com/journals/omcl/2017/2525967/ (accessed on 12 June 2020).
16. Ramond, A.; Godin-Ribuot, D.; Ribuot, C.; Totoson, P.; Koritchneva, I.; Cachot, S.; Levy, P.; Joyeux-Faure, M. Oxidative Stress Mediates Cardiac Infarction Aggravation Induced by Intermittent Hypoxia: Oxidative Stress Mediates IH-Induced Infarction Aggravation. Fundamental & Clinical Pharmacology 2013, 27, 252–261, doi:10.1111/j.1472-8206.2011.01015.x.
17. van der Pol, A.; van Gilst, W.H.; Voors, A.A.; van der Meer, P. Treating Oxidative Stress in Heart Failure: Past, Present and Future. Eur J Heart Fail 2019, 21, 425–435, doi:10.1002/ejhf.1320.
18. Pigazzani, F.; Gorni, D.; Dyar, K.A.; Pedrelli, M.; Kennedy, G.; Costantino, G.; Bruno, A.; Mackenzie, I.; MacDonald, T.M.; Tietge, U.J.F.; et al. The Prognostic Value of Derivatives-Reactive Oxygen Metabolites (d-ROMs) for Cardiovascular Disease Events and Mortality: A Review. Antioxidants 2022, 11, 1541, doi:10.3390/antiox11081541.
19. Babiloni, C.; Bosco, P.; Ghidoni, R.; Del Percio, C.; Squitti, R.; Binetti, G.; Benussi, L.; Ferri, R.; Frisoni, G.; Lanuzza, B.; et al. Homocysteine and Electroencephalographic Rhythms in Alzheimer Disease: A Multicentric Study. Neuroscience 2007, 145, 942–954, doi:10.1016/j.neuroscience.2006.12.065.
20. Seshadri, S.; Beiser, A.; Selhub, J.; Jacques, P.F.; Rosenberg, I.H.; D’Agostino, R.B.; Wilson, P.W.F.; Wolf, P.A. Plasma Homocysteine as a Risk Factor for Dementia and Alzheimer’s Disease. N Engl J Med 2002, 346, 476–483, doi:10.1056/NEJMoa011613.
21. Lai, W.K.C.; Kan, M.Y. Homocysteine-Induced Endothelial Dysfunction. Ann Nutr Metab 2015, 67, 1–12, doi:10.1159/000437098.
22. Cheng, Z.-J.; Yang, X.; Wang, H. Hyperhomocysteinemia and Endothelial Dysfunction. CHYR 2009, 5, 158–165, doi:10.2174/157340209788166940.
23. Austin, R.C.; Lentz, S.R.; Werstuck, G.H. Role of Hyperhomocysteinemia in Endothelial Dysfunction and Atherothrombotic Disease. Cell Death Differ 2004, 11, S56–S64, doi:10.1038/sj.cdd.4401451.
24. Walsh, D.; Selkoe, D. Oligomers on the Brain: The Emerging Role of Soluble Protein Aggregates in Neurodegeneration. PPL 2004, 11, 213–228, doi:10.2174/0929866043407174.
25. Guiotto, A.; Calderan, A.; Ruzza, P.; Borin, G. Carnosine and Carnosine-Related Antioxidants: A Review. CMC 2005, 12, 2293–2315, doi:10.2174/0929867054864796.
26. McKenna, M.C.; Dienel, G.A.; Sonnewald, U.; Waagepetersen, H.S.; Schousboe, A. Energy Metabolism of the Brain. In Basic Neurochemistry; Elsevier, 2012; pp. 200–231 ISBN 978-0-12-374947-5.
27. Lin, M.T.; Beal, M.F. Mitochondrial Dysfunction and Oxidative Stress in Neurodegenerative Diseases. Nature 2006, 443, 787–795, doi:10.1038/nature05292.
28. Sas, K.; Robotka, H.; Toldi, J.; Vécsei, L. Mitochondria, Metabolic Disturbances, Oxidative Stress and the Kynurenine System, with Focus on Neurodegenerative Disorders. Journal of the Neurological Sciences 2007, 257, 221–239, doi:10.1016/j.jns.2007.01.033.
29. Mohanty, J.G.; Eckley, D.M.; Williamson, J.D.; Launer, L.J.; Rifkind, J.M. Do Red Blood Cell-β-Amyloid Interactions Alter Oxygen Delivery in Alzheimer’s Disease? In Oxygen Transport to Tissue XXIX; Kang, K.A., Harrison, D.K., Bruley, D.F., Eds.; Advances In Experimental Medicine And Biology; Springer US: Boston, MA, 2008; Vol. 614, pp. 29–35 ISBN 978-0-387-74910-5.
30. Singer, S.J.; Dewji, N.N. Evidence That Perutz’s Double-Beta-Stranded Subunit Structure for Beta-Amyloids Also Applies to Their Channel-Forming Structures in Membranes. Proceedings of the National Academy of Sciences 2006, 103, 1546–1550, doi:10.1073/pnas.0509892103.
31. Chmielewska, K.; Dzierzbicka, K.; Inkielewicz-Stępniak, I.; Przybyłowska, M. Therapeutic Potential of Carnosine and Its Derivatives in the Treatment of Human Diseases. Chem. Res. Toxicol. 2020, acs.chemrestox.0c00010, doi:10.1021/acs.chemrestox.0c00010.
32. Cornelli, U. Treatment of Alzheimer’s Disease with a Cholinesterase Inhibitor Combined with Antioxidants. Neurodegenerative Dis 2010, 7, 193–202, doi:10.1159/000295663.