Oxidative Stress, Reductive Stress and Antioxidants in Vascular Pathogenesis and Aging

Abstract

This review is focused on the mechanisms that regulate health, disease and aging redox status, the signal pathways that counteract oxidative and reductive stress, the role of food components and additives with antioxidant properties (curcumin, polyphenols, vitamins, carotenoids, flavonoids, etc.), and the role of the hormones irisin and melatonin in the redox homeostasis of animal and human cells. The correlations between the deviation from optimal redox conditions and inflammation, allergic, aging and autoimmune responses are discussed. Special attention is given to the vascular system, kidney, liver and brain oxidative stress processes. The role of hydrogen peroxide as an intracellular and paracrine signal molecule is also reviewed. The cyanotoxins β-N-methylamino-l-alanine (BMAA), cylindrospermopsin, microcystins and nodularins are introduced as potentially dangerous food and environment pro-oxidants.

Keywords: NADPH oxidase; ROS signaling; aging; anti-inflammatory; antiallergic; curcumin; cyanotoxins; irisin; melatonin; mitochondria.

Figure 1

Nrf2 and SIRT1 signaling pathways regulation by antioxidants. (A) At optimal conditions, Nrf2 forms a KEAP1-ubiquitin complex, which downregulates Nrf2 via proteasomal degradation. Nrf2 activity is also inhibited by PTEN. This phosphatase decreases 3-phosphoinositides (PIP3) by conversion into PIP2, and the downstream Akt-GSK3β are not activated. The small amount of Nrf2 cannot be phosphorylated and translocated into the nucleus. Another mechanism of antioxidants involves SIRT1/FOXOa3 and the PGC1α pathway by expression of the antioxidant defense genes and mitochondrial biogenesis. (B) With physiological doses of antioxidants, KEAP1 is oxidized and the Nrf2 complex is destroyed, which results in an increased amount of Nrf2. PTEN is also suppressed and, thus, activates the previously described pathway with the following translocation of Nrf2 into the nucleus. Phosphorylated Nrf2 binds to the electrophile response element (EpRE) that starts the expression of the phase II antioxidant enzymes. Metabolic stress activates the Nrf2 pathway in the same manner. Moderate physical exercise stimulates both Nrf2 and SIRT1 signaling. Melatonin exerts its antioxidant effects through receptor-mediated transcriptional activity and after diffusion in the cytosol via several different pathways.

Figure 2

Chemical structures of curcumin related compounds. Abbreviations: glu: glucose; gal: galactose; *: tetraacetate or octaacetate.

Figure 3

Effects of THC on Th2 differentiation. Allergic inflammation and asthma are characterized by pathological Th2 cell activation. THC treatment reduced the expression of IL-4Rα and GATA3, and the phosphorylation of Jak1 and STAT6 in Th2. The inhibitory effect of THC was additionally supported by the downregulation of Jagged1/Jagged2 and NICD1/NICD2 signaling.

Figure 4

Mechanism of antioxidative stress after supplementation with polyphenolic overdoses. Many antioxidants lead to the overexpression of antioxidant enzymes, which dramatically decreases the ROS signaling pathway. As a result, the induction of an inflammatory response, carcinogenesis and instability in the cell redox balance are observed, all of which are collectively determined as antioxidative stress.