Physiological Modulation

Oxidative Stress (OS) is a condition due to unbalanced RedOx state of the organism, and several high impact factor journals (Nature Review, Science and Science Translational Medicine) reported comprehensive reviews about the pathophysiological role of RedOx signalling in central homeostatic mechanisms at the molecular, cellular, tissue and apparatus levels.1–8

OS can be counteracted through supplementation of natural substances. Indeed, a large portion of antioxidants is taken through the diet but an inappropriate supplementation can result in inefficacy or even damage. In this context, physiological modulators can be used to restore the homeostatic RedOx status. “Physiological modulators” are natural substances (“physiological”) able to act on a specific body function (“modulator”). In order to reach the desired effects the physiological modulation has to be achieved by supplementing substances commonly present in diet, but administered with appropriate formulation and dosages and OS status has to be considered in that specific compartment/organ/apparatus (locally), addressing the specific need of that compartment/organ/apparatus.

We believe in three key concepts for a correct physiological modulation:

  • the right dosage

physiological modulators can have an RDA (Recommended Daily Allowance, Figure 1) and the use of such substances in inappropriate dosages can lead to inefficacy risk (I Risk) when the modulators are supplemented at too low dosage or to excess risk (E risk) when they are at too high dosage, leading to the exacerbation of OS.

Figure 1. Cartoon representation for the adequate intake scheme of natural substances characterized by RDA. EAR = Estimated Average Requirements; RDA = Recommended Daily Allowance; UL = tolerable Upper intake Levels; AI = Adequate Intake. Highlighted with a green dashed lines the theoretical region of AI for a general substance with an RDA.

Figure 1
  • the right combination

physiological modulators have to be supplemented in the right combination enabling the re-generation of the main antioxidant species, sustaining the antioxidant network of the organism (Figure 2).9,10 In Figure 2 it is shown how Vit. E is the main antioxidant species, which acts as antioxidant on oxidized human biomolecules (RO* and ROO*), which are reduced to their natural form (ROH and ROOH). At this point the oxidized form of Vit. E (T-O*) is re-generated by the presence of Vit. C,11 the oxidized Vit. C (AScO–) is in turn re-generated by the action of GSH (glutathione), which is oxidized to GSSG. Finally, GSSH is reduced to GSH, thanks to the action of glutathione peroxidase enzymes, which require Selenium as co-factor and L-Cys as substrate. Providing the right proportion of all these substances allow the use of small amount of vit. E, which is re-generated on demand, thus supporting the antioxidant defence system of our body.

Figure 2. Cartoon representation of the ROS-scavenging network involving Vit. E, C and glutathione (GSH).

Figure 2
  • for the right place

in our body each tissue/organ (compartment) is endowed with its own specific antioxidant defensive system, depending on the feature and the function of that compartment (CNS, Cardiovascular, Oral Cavity, Immune Defense, etc..). Therefore, OS status has to be considered in that specific compartment or locally and the physiological modulation must address that specific compartment/organ/apparatus (Figure 3).

Figure 3. Each tissue/organ is endowed with its own specific antioxidant defence system.

Figure 3

Our products are rationally developed taking into account all these key aspects and natural substances are combined to produce new food supplements according to our pillars:

  • Tissue-specificity: because each tissue requires a specific combination of antioxidant substances, the modulators in our food supplements are chosen to address the specific metabolic and RedOx demands of the compartment considered.
  • Power and activity: our food supplements contain several co-factors (e.g. Selenium (Se), vitamins of the B group, etc..) that are required from endogenous enzymatic antioxidants, which are the most powerful defenses against OS. There are also relevant direct and indirect antioxidants such as vitamins C, E and L-cysteine able to sustain the antioxidant network.
  • Harmonization: the type and quantity of antioxidants are chosen to exploit synergistic effects, allowing the re-balancing of the antioxidant network. Each ingredient is administered in the right amount, avoiding issues related to inappropriate supplementation and exploiting their synergistic action to maximum extent.

References

The TOC of this article is the original artwork of Leon Zernitsky. All Rights Reserved. 

1.          Sies, H. & Jones, D. P. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol 21, 363–383 (2020).

2.         Laforge, M. et al. Tissue damage from neutrophil-induced oxidative stress in COVID-19. Nature Reviews Immunology 20, 515–516 (2020).

3.         Azzimato, V. et al. Liver macrophages inhibit the endogenous antioxidant response in obesity-associated insulin resistance. Sci Transl Med 12, (2020).

4.        Hamanaka, R. B. & Chandel, N. S. Warburg Effect and Redox Balance. Science 334, 1219–1220 (2011).

5.        Krengel, U. & Tornroth-Horsefield, S. Coping with oxidative stress. Science 347, 125–126 (2015).

6.        Kujoth, G. C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481–484 (2005).

7.         Pierre, P. Integrating stress responses and immunity. Science 365, 28–29 (2019).

8.        Storz, P. Reactive Oxygen Species-Mediated Mitochondria-to-Nucleus Signaling: A Key to Aging and Radical-Caused Diseases. Science Signaling 2006, re3–re3 (2006).

9.        Packer, L., Weber, S. U. & Rimbach, G. Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling. J Nutr 131, 369S–73S (2001).

10.       Szarka, A., Tomasskovics, B. & Bánhegyi, G. The ascorbate-glutathione-α-tocopherol triad in abiotic stress response. Int J Mol Sci 13, 4458–4483 (2012).

11.         Scientific Opinion on the substantiation of health claims related to vitamin C and reduction of tiredness and fatigue (ID 139, 2622), contribution to normal psychological functions (ID 140), regeneration of the reduced form of vitamin E (ID 202), contribution to normal energy-yielding metabolism…. https://www.efsa.europa.eu/en/efsajournal/pub/1815.