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Reactive oxygen species (ROS) are the initiators in foods and in the stomach of oxidized dietary lipids, proteins, and lipid-oxidation end-products (ALEs), inducing in humans the development of several chronic diseases and cancer. Epidemiological, human clinical and animal studies supported the role of dietary polyphenols and derivatives in prevention of development of such chronic diseases. There is much evidence that polyphenols/derivatives at the right timing and concentration, which is critical, acts mostly in the aerobic stomach and generally in the gastrointestinal tract as reducing agents, scavengers of free radicals, trappers of reactive carbonyls, modulators of enzyme activity, generators of beneficial gut microbiota and effectors of cellular signaling. In the blood system, at low concentration, they act as generators of electrophiles and low concentration of H2O2, acting mostly as cellular signaling, activating the PI3K/Akt-mediated Nrf2/eNOS pathways and inhibiting the inflammatory transcription factor NF-κB, inducing the cells, organs and organism for eustress, adaptation and surviving.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease that can develop into an aggressive form called nonalcoholic steatohepatitis (NASH), which ultimately progresses to cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver failure. Currently, the deterioration of NAFLD is attributed to specific lipid toxicity which could be due to lipotoxicity and/or ferroptosis. In the current study, we evaluated the involvement of the nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf-2), which is a main activator of phase II metabolism in the two types of lipid-induced toxicity in hepatocytes, lipotoxicity by saturated fatty acids, and in ferroptosis, and the effect of NO donor treatment. AML12 cells were exposed to 600 μM palmitic acid to induce lipotoxicity or treated with 20 μM erastin or 5 μM RSL3 for ferroptosis. In SFA-lipotoxicity, pretreatment with the Nrf2 activator dimethyl fumarate (DMF) managed to ameliorate the cells and the oxidative stress level while aggravating ferroptosis due to emptying the thiol pool. On the other hand, the nitric oxide (NO)-donor, S-nitroso-N-acetylcysteine (NAC-SNO) proved to be effective in the prevention of hepatocytes ferroptosis.

Human health benefits from different polyphenols molecules consumption in the diet, derived mainly by their common activities in the gastrointestinal tract and at the level of blood micro-capillary. In the stomach, intestine and colon, polyphenols act as reducing agents preventing lipid peroxidation, generation and absorption of AGEs/ALEs (advanced glycation end products/advanced lipid oxidation end products) and postprandial oxidative stress. The low absorption of polyphenols in blood does not support their activity as antioxidants and their mechanism of activity is not fully understood. The results are from in vitro, animal and human studies, detected by relevant oxidative stress markers. The review carries evidences that polyphenols, by generating H2O2 at nM concentration, exogenous to cells and organs, act as activators of signaling factors increasing cell Eustress. When polyphenols attain high concentration in the blood system, they generate H2O2 at µM concentration, acting as cytotoxic agents and Distress. Pre-treatment of cells or organisms with polyphenols, by generating H2O2 at low levels, inhibits cellular PTPs (protein tyrosine phosphatases), inducing cell signaling through transcription of the Nrf2 (nuclear factor erythroid 2-related factor 2) axis of adaptation and protection to oxidation stress. Polyphenols ingestion at the right amount and time during the meal acts synergistically at the level of the gastrointestinal tract (GIT) and blood system, for keeping the redox homeostasis in our organism and better balancing human health.