From Prometheus to the present day oxidative stress: a window onto the entrail of COVID-19

Having stolen fire from the gods and given it to men, Prometheus received a hideous punishment: Zeus, the father of the gods, ordered that he be chained to a rock, and that an eagle should come every day to devour the hero’s liver, only for it to grow back overnight. Prometheus was condemned to endless suffering.

In December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) broke out in Wuhan, China. The serious respiratory disease that this virus causes in human beings (COVID-19) has been declared a pandemic by the World Health Organization (Zhang and Ma, 2020). Several months ago, the Mexican government declared a public health emergency as a result of the SARS CoV-2 epidemic. My heart took a leap when I learned the news. The Ministry of External Affairs made a call to the scientific community to join in the work of research and analysis required to confront the pandemic. The situation is developing rapidly: as many as 20% of COVID-19 cases have been described as serious illnesses, with fever and pneumonia, leading to acute respiratory distress syndrome (ARDS) (Moore and June, 2020). There are no clear clinical or paraclinical parameters yet to indicate the course of its evolution. I have spent ten years of my life in the fascinating world of hepatocytes, oxidative stress, quality of life, and the effects of all these things on social cognition, as well as how metabolic comorbidities are associated with diseases of the severity of COVID-19. I have formulated a hypothesis here that I hope will interconnect all these matters.

Chronic hepatitis is one of the leading causes of death all over the world. It can be caused by different mechanisms, including chronic viral infections, alcohol abuse, and metabolic alterations. It is known that, in the early stages, the liver can repair the damage caused to it, but that, if the ailment continues, the accumulation of molecules produces fibrosis, which eventually progresses towards cirrhosis and, finally, hepatocellular carcinoma (M. Masarone et al., 2018).

The metabolic alterations that produce a significant accumulation of fat in more than 5% of hepatocytes and which are not the result of the consumption of a “dangerous” amount of alcohol or of any other cause of hepatic disorders constitute a potentially pathological condition known as nonalcoholic fatty liver disease (NAFLD).

Over the last two decades, NAFLD has become an increasingly widespread condition all over the world, taking the place of the hepatic damage traditionally caused by viral infections, the incidence of which has been reduced. This is due, perhaps, to an increase in the prevalence of obesity, diabetes, and dyslipidemias, among other causes, owing to the adoption of habits commonly gathered under the umbrella designation of a “Western lifestyle” (M. Masarone et al., 2018).

It has been estimated that the prevalence of NAFLD among the general population ranges anywhere from 17% to as high as 33%. Mexico is one of the countries whose population shows several risk factors for the disease, where its incidence could surpass 50% (R. Bernal-Reyes et al., 2019). It is as high as 75% among persons with obesity and even higher among patients with type 2 diabetes mellitus (DM2). DM2 and hepatic damage both constitute risk factors for the development of cardiovascular diseases, and central obesity is an acknowledged risk factor for the development of NAFLD. Prevalence differs on the basis of gender, race, and ethnicity, with genetic and epigenetic factors playing a role in the pathogenesis of the disease. Resistance to insulin is the principal factor in the physiopathology of NAFLD, along with metabolic syndrome, a cluster of conditions which include central obesity, high blood pressure, glucose intolerance, and dyslipidemia (Zhang and Ma, 2020).

Lack of exercise, overweightness, and poor nutrition can all provoke an increase in reactive oxygen species (ROS), which lead to a state of chronic oxidative stress (Moore and June, 2020). In a model of multiple parallel impact ― the presence of a significant accumulation of fat in the hepatocytes, resistance to insulin, liberation of inflammatory substances (cytokines) through the adipose tissue, an increase of free fatty acids coming from adipocytes and diet―, an imbalance in the liver is produced that leads to accelerated oxidation of fatty acids (mitochondrial beta-oxidation) and the production of reactive oxygen species. ROS are a group of small reactive molecules that perform critical roles in the regulation of various cellular functions and biological processes. The principal evidence for the strict physio-pathological link between the mechanisms of oxidative stress, the presence of NAFLD, and its progression, are mitochondrial dysfunction, reticular stress, iron metabolism and brain-gut-axis disorders, fatty liver disease, and endothelial dysfunction (R. Bernal-Reyes et al., 2019).

In physiological conditions there is a state of equilibrium between the functional interaction of oxidant agents derived from the incomplete reduction of oxygen, the ROS, and the enzymatic antioxidant agents. Oxidative stress occurs when the redox balance is lost owing to a greater generation of oxidant agents than of antioxidant agents. Chronic oxidative stress is harmful to the cells, as it provokes oxidation of macromolecules and causes changes in cell-signaling pathways, altering their function and even causing cell death (C. Poblete-Aro et al., 2018).

The biochemical integrity of the brain is vital to the normal function of the central nervous system (S. Salim, 2017). Owing to its high consumption of oxygen and rich lipid content, the brain is also highly susceptible to oxidative stress. As a result, the damage caused to the brain by oxidative stress has a high potential for negatively impacting the normal functions of the central nervous system. Although oxidative stress has generally played a role in neurodegenerative disorders, such as Alzheimer’s, Huntington’s, and Parkinson’s diseases, it has also been related to other diagnoses in the field of mental health. We also find it in many neuropsychiatric disorders, such as depression, anxiety, and schizophrenia, as well as along the autism spectrum, where it significantly affects behavior and cognitive functions and has a negative impact on quality of life (Zhang and Ma, 2020). The biochemical integrity of the brain is vital to the normal functioning of the central nervous system (S. Salim, 2017).

Another tissue that is frequently damaged is the vascular endothelium. Oxidative stress induced by the excessive generation of reactive oxygen species has become a common mechanism in arterial sclerosis. Although ROS are essential to vascular homeostasis, their uncontrolled production is a factor in strokes.

The evaluation of the redox state in the human organism is complex, owing to a large variety of biomarkers, both for oxidant and antioxidant agents. The most commonly employed strategies to evaluate oxidative stress are: 1) measuring the abundance and activity of antioxidant proteins; 2) quantifying products derived from oxidation; and 3) analyzing the oxidant/antioxidant balance (S. MuñizHernández, 2012).

Many of these biomarkers can be detected in blood samples (red blood cells, plasma, or urine). A correlation has been observed between the levels of oxidative stress biomarkers in the blood and central organs, such as the liver, skeletal muscle, heart, and kidneys. These findings suggest that the analysis of oxidative stress biomarkers obtained from blood samples may offer a broader vision of the organism’s redox state (M. Masarone et al., 2018). The field of metabolomics has become a powerful discipline for identifying new biomarkers in an non-invasive way and may guide us to earlier diagnoses and more effective treatments. Metabolomics is the scientific study of the chemical processes that involve metabolites.

Specifically, metabolomics is the “systematic study of the unique traces left by specific cellular processes as they occur”: in other words, the study of the profile of metabolites (small molecules) of a biological sample. The metabolome is the complete set of metabolites in a cell, tissue, organ, or organism that are the result of cellular processes. The metabolic profile provides an instant window onto the physiology of the cell. The endogenous molecules modified by the chemical interactions, with high levels of reactive oxygen and nitrogen species in the cellular microenvironment, can be considered biomarkers of oxidative stress and, together with any alteration of the metabolic composition, would constitute specific early predictors of many diseases.

It is necessary to look for early markers that allow doctors to react in a timely fashion to any such non-specific and rapidly evolving clinical picture. Advanced age, cardiac complications, disorders of the central nervous system, and pneumonia are elements enough to draw up a metabolic and nitro-oxidative profile to study the cellular process of the natural course of this disease.

Nitro-oxidative stress plays a role in the inflammation, cell damage, and process of tissue repair of the respiratory tract (Y. Kyogoku et al., 2019), and the modulation of redox imbalance and its causes can be useful in diagnosing and evaluating the severity of COVID-19. Understanding oxidative stress and its biological processes as a common factor in chronic-degenerative diseases, which have such great impact on public health, requires us to implement structural public policies in the near future, with its new normal: evidence-based interventions that favor a positive antioxidant state for the general population.

We have the opportunity to create an historic link and to lay the groundwork for a new development in human wellbeing and quality of life. An innovative way of buffering the severe blow suffered by humanity as a result of the COVID-19 crisis. In short, a way of redeeming Prometheus from his eternal torment.

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Dra. Ana Villaseñor-Todd PhD candidate (Technical committee: Rosa del Carmen López- Sánchez, PhD, and José A Hernández-Hernández, PhD)

Mexican scientist noted for her research studies in minimal encephalopathy, oxidative stress, quality of life and social cognition. He complemented his graduate studies at Texas A&M University. Candidate to receive the degree of doctor of medicine by the UANL. Founder and CEO of AVE strategic consulting.