Inflammatory biomarkers: Breast cancer survival and possible role in COVID-19 associated comorbidity

It is known that inflammatory cytokines exacerbate the persistence and severity of various disease states. Breast cancer is the most frequently detected cancer among women worldwide and our recent studies suggest that the inflammatory state of breast (BrCa) cancer, a byproduct of elevated cytokine expression, induces epigenetic modifications leading to increased recurrence. Ongoing NCI clinical trial data (ClinicalTrials.gov, CCC19, NCT04354701) indicates that among patients with cancer and COVID-19, the mortality is high, and the most prevalent malignancies are of breast [21%] and prostate [16%] origin. Due to the risk of cytokine storm during SARS-CoV-2 infection, it is crucial to identify potential mechanisms of hyperinflammation in BrCa patients. In this study, we have evaluated the level of copy number alteration (CNA) of different inflammatory cytokines including IL-8, IL-1b, IL6, IL-8, GM-CSF, TNF-alpha and many others using cBioportal platform which includes over sixty-nine thousand tumor samples (n>69,000 from 213 different studies) from over 33 different cancers. We found that IL-8 has the highest level of amplification in different breast cancers subtypes. Besides, we also analyzed serum samples from BrCa patients, both recurrent and non-recurrent, by different proteomics methods to identify serum cytokines involved in prognosis and recurrence. Comparative data analysis between non-recurrent BrCa against recurrent BrCa patients identified several proteins with very high significance, mostly proteins associated with epigenetic pathways including HDAC9 (P = 0.0035), HDAC5 (P = 0.013), and HDAC7 (P = 0.020). Besides, we identified differential expression of several pro-inflammatory cytokines and immune regulators (IL-8, IL-4, IL-18, IL-12p70) that were present only in recurrent BrCa patient serum. Our data indicate that inflammatory processes contribute to epigenetic modifications that ultimately play a critical role in breast cancer recurrence. In terms of COVID-19 associated co-morbidity, the already dysregulated inflammatory state of BrCa patients may increase their susceptibility to cytokine-storm, leading to increased severity of COVID-related complications and increased mortality rate. Specifically, we hypothesize that the identified elevated level of IL-8 in BrCa patients may lead to a higher basal level of inflammation and contribute to the risk of attaining cytokine-storm during SARS-CoV-2 infection, making it a valuable target for future studies.

An epigenetic synopsis of parental substance use.

The rate of substance use is rising, especially among reproductive-age individuals. Emerging evidence suggests that paternal pre-conception and maternal prenatal substance use may alter offspring epigenetic regulation (changes to gene expression without modifying DNA) and outcomes later in life, including neurodevelopment and mental health. However, relatively little is known due to the complexities and limitations of existing studies, making causal interpretations challenging. This review examines the contributions and influence of parental substance use on the gametes and potential transmissibility to the offspring's epigenome as possible areas to target public health warnings and healthcare provider counseling of individuals or couples in the pre-conception and prenatal periods to ultimately mitigate short- and long-term offspring morbidity and mortality.

More people, especially those of reproductive age, are using substances, and there is growing evidence to suggest that parental substance use before and during pregnancy may adversely affect offspring and result in issues later in life, including mental health challenges. Such relationships have been demonstrated with nicotine, alcohol, cannabis, opioids and illegal drugs (e.g., heroin, cocaine, methamphetamines). Some of these adverse impacts on offspring can potentially be passed down in families even after parents have quit using the substance. Because more individuals are using drugs, especially during the COVID-19 pandemic, it is important that families learn more about the potential impact of substance use on their future offspring before they try to get pregnant.

Pregnancy, infection, and epigenetic regulation: A complex scenario.

A unique immunological condition, pregnancy ensures fetus from maternal rejection, allows adequate fetal development, and protects against microorganisms. Infections during pregnancy may lead to devastating consequences for pregnant women and fetuses, resulting in the mother's death, miscarriage, premature childbirth, or neonate with congenital infection and severe diseases and defects. Epigenetic (heritable changes in gene expression) mechanisms like DNA methylation, chromatin modification, and gene expression modulation during gestation are linked with the number of defects in the fetus and adolescents. The feto-maternal crosstalk for fetal survival during the entire gestational stages are tightly regulated by various cellular pathways, including epigenetic mechanisms that respond to both internal as well outer environmental factors, which can influence the fetal development across the gestational stages. Due to the intense physiological, endocrinological, and immunological changes, pregnant women are more susceptible to bacterial, viral, parasitic, and fungal infections than the general population. Microbial infections with viruses (LCMV, SARS-CoV, MERS-CoV, and SARS-CoV-2) and bacteria (Clostridium perfringens, Coxiella burnetii, Listeria monocytogenes, Salmonella enteritidis) further increase the risk to maternal and fetal life and developmental outcome. If the infections remain untreated, the possibility of maternal and fetal death exists. This article focused on the severity and susceptibility to infections caused by Salmonella, Listeria, LCMV, and SARS-CoV-2 during pregnancy and their impact on maternal health and the fetus. How epigenetic regulation during pregnancy plays a vital role in deciding the fetus's developmental outcome under various conditions, including infection and other stress. A better understanding of the host-pathogen interaction, the characterization of the maternal immune system, and the epigenetic regulations during pregnancy may help protect the mother and fetus from infection-mediated outcomes.

Inflammasome but Not Ifn-I/Iii Response Is Altered in Children with Long Covid

Background: Severe COVID-19 is less common in children than in adults. Increasing evidence show that distinct immune-pathological changes can persist weeks or months after SARS-CoV2 infection, leading to Long COVID (LC). We investigated the systemic type I/III interferon (IFN-I/III) and inflammation response in peripheral blood mononuclear cells (PBMCs) of children with and without LC symptoms. Method(s): Blood samples were collected from children attending Umberto I hospital of Rome, within 3-6 months after a SARS-CoV-2 positive test and from control children. RNA was extracted from PBMCs for determining the levels of IFN-I (IFN-Alpha2, -Beta, -Epsilon and -Omega), IFN-III (IFN-Lambda1-3), NLRP3 and IL-1beta genes, and miR-141 expression by quantitative RealTime-PCR assays, normalized to housekeeping GUS gene and RNU6B, respectively. Result(s): 28 participants (M 12.5y SD 3.0) with LC symptoms, 28 participants (M 11.8y SD 3.0) without LC symptoms and 18 children who've never had SARS-CoV- 2 infection (M 10.5y SD 3.1) were enrolled. Comparing the three study groups, we found reduced levels of IFN-Lambda1, IFN-Lambda2 and IFN-Lambda3 (p=0.006, p< 0.001, p=0.012, respectively;Kruskal-Wallis (KW) test) mRNA in patients who have had SARS-CoV-2 infection as opposed to control group, whereas transcript levels of IFN-Epsilon (p= 0.019;KW test) were increased in the former with respect to the latter group;as well, remaining IFN-I genes analyzed showed a tendency to be up-regulated. As far as NLRP3 and IL-1beta levels was concerned, these genes were increased in LC patients (p< 0.001 for both genes;KW test). Additionally, miR-141, which has been reported to regulate inflammasome response, was overexpressed in LC patients (p< 0.001;Mann-Whitney test). Conclusion(s): These results showed a decreased levels of IFN-III mRNAs and an overexpression of IFN-Epsilon in children after 3-6 months of SARS-CoV-2 infection regardless of development of LC symptoms, suggesting that SARSCoV- 2 could have caused dysregulation of IFN response through unknown mechanisms (e.g. epigenetic modifications). Also, we found an overexpression of miR-141, NLRP3 and IL-1beta mRNAs in LC patients, indicating that a prolonged activation of inflammasome pathways could be associated with the development of LC symptoms.

The role of air pollution in fetal origins of childhood allergy: Challenges and opportunities

Allergic disease is still a serious global public health problem, affecting 30-40% of world population. The rapid increase in prevalence indicates gene-by-environment interaction, in which epigenetics may be the underlying mechanism. We reviewed recent epidemiological studies about the association between prenatal exposure to air pollution and childhood allergies. On the other hand, we reviewed the evidence that maternal exposure to air pollution caused epigenetic alterations that changed the gene expression or transcription in offspring. We further discussed the challenges of the global warming and COVID-19 to the childhood allergies especially in developing countries, and suggested the opportunities to prevention or control by early intervention, immunotherapy, and epigenetic therapy.

Epigenetic regulation of the COVID-19 pathogenesis: its impact on the host immune response and disease progression

Coronavirus disease 2019 (COVID-19) is highly infectious and may induce epigenetic alteration of the host immune system. Understanding the role of epigenetic mechanisms in COVID-19 infection is a clinical need to minimize critical illness and widespread transmission. The susceptibility to infection and progression of COVID-19 varies from person to person;pathophysiology substantially depends on epigenetic changes in the immune system and preexisting health conditions. Recent experimental and epidemiological studies have revealed the method of transmission and clinical presentation related to COVID-19 pathogenesis, however, the underlying pathology of variation in the severity of infection remains questionable. Epigenetic changes may also be responsible factors for multisystem association and deadly systemic complications of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infected patients. Commonly, epigenetic changes are evoked by alteration of the host's immune response, stress, preexisting condition, oxidative stress response, external behavioral or environmental factors, and age. In addition, the viral infection itself might manipulate the host immune responses associated with inflammation by reprogramming epigenetic processes which are the susceptible factor for disease severity and death. As a result, epigenetic events such as histone modification and DNA methylation are implicated in regulating pro-inflammatory cytokines production by remodeling macrophage and T-cell activity towards inflammation, consequently, may also affect tissue repair and injury resolution process. This review aims to discuss the comprehensive understanding of the epigenetic landscape of COVID-19 disease progression that varies from person to person with supporting interdisciplinary prognosis protocol to overcome systemic impairment.

Trained innate immunity and diseases: Bane with the boon

Emerging research shows that innate immunity can also keep the memory of prior experiences, challenging the long-held notion that immunological memory is only the domain of the adaptive immune cells. However, the absence of immunological memory in innate immune responses has recently been brought into question. Now it is known that after a few transient activations, innate immune cells may acquire immunological memory phenotype, resulting in a stronger response to a subsequent secondary challenge. When exposed to particular microbial and/or inflammatory stimuli, trained innate immunity is characterized by the enhanced non-specific response, which is regulated by substantial metabolic alterations and epigenetic reprogramming. Trained immunity is acquired by two main reprogramming, namely, epigenetic reprogramming and metabolic adaptation/reprogramming. Epigenetic reprogramming causes changes in gene expression and cell physiology, resulting in internal cell signaling and/or accelerated and amplified cytokine release. Metabolic changes due to trained immunity induce accelerated glycolysis and glutaminolysis. As a result, trained immunity can have unfavorable outcomes, such as hyper inflammation and the development of cardiovascular diseases, autoinflammatory diseases, and neuroinflammation. In this review, the current scenario in the area of trained innate immunity, its mechanisms, and its involvement in immunological disorders are briefly outlined.Copyright © 2022

Translational research strategies

Advances in basic research have generated a better understanding of the mechanisms in human diseases;however, only a small part of the scientific discoveries have generated new treatments, changes in clinical practice and new diagnostic methods. Trying to find faster implementation solutions, the Translational technique "from bench to bedside” offers the advantage of establishing a continuous and two-way communication path to transmit and make known data acquired from the laboratory, in basic molecular and genetic research, through animal experiments, to the clinical aspects of acceptance and treatment in humans. It is key that basic research provides knowledge that responds to the needs of clinical practice. An example is the rapid development of treatments in the COVID-19 pandemic. In this chapter of the book, we make reference to specific areas in which translational research is being used and should be encouraged to develop newer and more effective therapies for substance use disorder. Multiple tools from basic research are already opening up in the modern medicine of addictive disorders. With the development of neurobiology and a better understanding of the brain, we now know that addiction is a disease that affects both the brain and behavior. Basic and clinical research on addictive disorders focuses on understanding the molecular bases of addiction, on the genetic and epigenetic variations involved in the long-term persistence of addiction, and on the study of new pharmacological targets with therapeutic potential. A future line of work is the complete analysis of the individual's genome, which would make it possible to detect small DNA variations called single nucleotide polymorphisms. Finally, in this chapter we wanted to know the current lines of research that can make health service providers better equipped to provide patients with the most appropriate treatments and dosages of medications for addiction. © 2023 Elsevier Inc. All rights reserved.

Biological age is increased by stress and restored upon recovery.

Aging is classically conceptualized as an ever-increasing trajectory of damage accumulation and loss of function, leading to increases in morbidity and mortality. However, recent in vitro studies have raised the possibility of age reversal. Here, we report that biological age is fluid and exhibits rapid changes in both directions. At epigenetic, transcriptomic, and metabolomic levels, we find that the biological age of young mice is increased by heterochronic parabiosis and restored following surgical detachment. We also identify transient changes in biological age during major surgery, pregnancy, and severe COVID-19 in humans and/or mice. Together, these data show that biological age undergoes a rapid increase in response to diverse forms of stress, which is reversed following recovery from stress. Our study uncovers a new layer of aging dynamics that should be considered in future studies. The elevation of biological age by stress may be a quantifiable and actionable target for future interventions.

The association among circadian rhythm, circadian genes and chrononutrition, its effect on obesity: a review of current evidence

Circadian rhythms, also known as circadian clocks, are cyclic endogenous biological patterns of an approximately 24-hour cycle which regulate the timing of physiology, metabolism, and behavior. Recent research in the field of circadian science has suggested that the timing of food intake may also play a role in markers of health, in addition to food choice and food quantity. There is emerging evidence suggesting that the timing of dietary intake, so-called chrono-nutrition, may be influenced by an individual<apos;>s chronotype. For example, the evening type has been linked to unhealthy diet, which could indicate a higher possibility of obesity. On the other hand, the continuum of chronotype diversity is largely mediated by genes. The presence of single nucleotide polymorphisms (SNP) of clock genes have been associated with obesity, chronotype, metabolic disturbances, and dietary habits (e.g., breakfast skipping, meal timing, energy/macronutrient intake). In this review, we outline the current knowledge of the interactions between clock genes, chronotype, dietary intake and chrono-nutrition.Additionally, it is emphasized that the COVID-19 pandemichas had a significant impact on the circadian system, dietary choices and meal timing. For this reason, the current review aims to focus on how chronotype/sleep and chrono-nutrition are affected during the COVID-19 pandemic.Copyright © 2022 Informa UK Limited, trading as Taylor & Francis Group.

COVID-19 Epigenetics and Implications for Public Health

Background: COVID-19 debilitated communities globally in varying complexities and capacities in recent months. Objective(s): The epigenetic changes in the COVID-19 patients were discussed in this article to explore various processes contributing to disease severity and elevation of risk due to infection. Method(s): Percentages of hospitalization, with and without intensive care, in the presence of diseases with increased ACE2 expression, were compared, based on the best available data. Further analysis compared two different age groups, 19-64 and >=65 years of age. Result & Conclusion(s): The COVID-19 disease is observed to be the most severe in the 65 and-higher-age group with pre-existing chronic conditions. This observational study is a nonexperimental empirical investigation of the outcomes of COVID-19 in different patient groups. Results are promising for conducting clinical trials with intervention groups. To ultimately succeed in disease prevention, researchers and clinicians must integrate epigenetic mechanisms to generate valid prescriptions for global well-being.Copyright © 2021 Bentham Science Publishers.

Integrative Analysis of DNA Methylation and Gene Expression Data Identifies Potential Biomarkers and Functional Epigenetic Modules for SARS-CoV-2.

To integrate gene expression and DNA methylation data and find the potential role of DNA methylation in the invasion and replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We first conducted differential expression and methylation analysis between the coronavirus disease of 2019 (COVID-19) and healthy controls. FEM was employed to identify functional epigenetic modules, from which a diagnostic model for COVID-19 was built. SKA1 and WSB1 modules were identified, with SKA1 module enriched in COVID-19 replication and transcription, and WSB1 module related to ubiquitin-protein activity. The differentially expressed or differentially methylated genes in these two modules could be used to distinguish COVID-19 from healthy controls, with AUC reaching 1 and 0.98 for SKA1 and WSB1 modules, respectively. Two epigenetically activated genes (CENPM and KNL1) from the SKA1 module were upregulated in HPV- or HBV-positive tumor samples and were found to be significantly associated with the survival of tumor patients. In conclusion, the identified FEM modules and potential signatures play an essential role in the replication and transcription of coronavirus.

Epigenetic immune monitoring for COVID-19 disease course prognosis.

Background: The course of COVID-19 is associated with severe dysbalance of the immune system, causing both leukocytosis and lymphopenia. Immune cell monitoring may be a powerful tool to prognosticate disease outcome. However, SARS-CoV-2 positive subjects are isolated upon initial diagnosis, thus barring standard immune monitoring using fresh blood. This dilemma may be solved by epigenetic immune cell counting. Methods: In this study, we used epigenetic immune cell counting by qPCR as an alternative way of quantitative immune monitoring for venous blood, capillary blood dried on filter paper (dried blood spots, DBS) and nasopharyngeal swabs, potentially allowing a home-based monitoring approach. Results: Epigenetic immune cell counting in venous blood showed equivalence with dried blood spots and with flow cytometrically determined cell counts of venous blood in healthy subjects. In venous blood, we detected relative lymphopenia, neutrophilia, and a decreased lymphocyte-to-neutrophil ratio for COVID-19 patients (n =103) when compared with healthy donors (n = 113). Along with reported sex-related differences in survival we observed dramatically lower regulatory T cell counts in male patients. In nasopharyngeal swabs, T and B cell counts were significantly lower in patients compared to healthy subjects, mirroring the lymphopenia in blood. Naïve B cell frequency was lower in severely ill patients than in patients with milder stages. Conclusions: Overall, the analysis of immune cell counts is a strong predictor of clinical disease course and the use of epigenetic immune cell counting by qPCR may provide a tool that can be used even for home-isolated patients.

Emerging Roles of SIRT5 in Metabolism, Cancer, and SARS-CoV-2 Infection.

Sirtuin 5 (SIRT5) is a predominantly mitochondrial enzyme catalyzing the removal of glutaryl, succinyl, malonyl, and acetyl groups from lysine residues through a NAD+-dependent deacylase mechanism. SIRT5 is an important regulator of cellular homeostasis and modulates the activity of proteins involved in different metabolic pathways such as glycolysis, tricarboxylic acid (TCA) cycle, fatty acid oxidation, electron transport chain, generation of ketone bodies, nitrogenous waste management, and reactive oxygen species (ROS) detoxification. SIRT5 controls a wide range of aspects of myocardial energy metabolism and plays critical roles in heart physiology and stress responses. Moreover, SIRT5 has a protective function in the context of neurodegenerative diseases, while it acts as a context-dependent tumor promoter or suppressor. In addition, current research has demonstrated that SIRT5 is implicated in the SARS-CoV-2 infection, although opposing conclusions have been drawn in different studies. Here, we review the current knowledge on SIRT5 molecular actions under both healthy and diseased settings, as well as its functional effects on metabolic targets. Finally, we revise the potential of SIRT5 as a therapeutic target and provide an overview of the currently reported SIRT5 modulators, which include both activators and inhibitors.

BCG-induced trained immunity: history, mechanisms and potential applications.

The Bacillus Calmette-Guérin (BCG) vaccine was discovered a century ago and has since been clinically applicable. BCG can not only be used for the prevention of tuberculosis, but also has a non-specific protective effect on the human body called trained immunity that is mediated by innate immune cells such as monocytes, macrophages, and natural killer cells. Mechanisms of trained immunity include epigenetic reprogramming, metabolic reprogramming, and long-term protection mediated by hematopoietic stem cells. Trained immunity has so far shown beneficial effects on cancer, viral-infections, autoimmune diseases, and a variety of other diseases, especially bladder cancer, respiratory viruses, and type 1 diabetes. The modulation of the immune response by BCG has led to the development of a variety of recombinant vaccines. Although the specific mechanism of BCG prevention on diseases has not been fully clarified, the potential role of BCG deserves further exploration, which is of great significance for prevention and treatment of diseases.

Influence of Immune System Abnormalities Caused by Maternal Immune Activation in the Postnatal Period.

The developmental origins of health and disease (DOHaD) indicate that fetal tissues and organs in critical and sensitive periods of development are susceptible to structural and functional changes due to the adverse environment in utero. Maternal immune activation (MIA) is one of the phenomena in DOHaD. Exposure to maternal immune activation is a risk factor for neurodevelopmental disorders, psychosis, cardiovascular diseases, metabolic diseases, and human immune disorders. It has been associated with increased levels of proinflammatory cytokines transferred from mother to fetus in the prenatal period. Abnormal immunity induced by MIA includes immune overreaction or immune response failure in offspring. Immune overreaction is a hypersensitivity response of the immune system to pathogens or allergic factor. Immune response failure could not properly fight off various pathogens. The clinical features in offspring depend on the gestation period, inflammatory magnitude, inflammatory type of MIA in the prenatal period, and exposure to prenatal inflammatory stimulation, which might induce epigenetic modifications in the immune system. An analysis of epigenetic modifications caused by adverse intrauterine environments might allow clinicians to predict the onset of diseases and disorders before or after birth.

Role of epigenetics in the clinical evolution of COVID-19 disease. Epigenome-wide association study identifies markers of severe outcome.

BACKGROUND: COVID-19 has a wide spectrum of clinical manifestations and given its impact on morbidity and mortality, there is an unmet medical need to discover endogenous cellular and molecular biomarkers that predict the expected clinical course of the disease. Recently, epigenetics and especially DNA methylation have been pointed out as a promising tool for outcome prediction in several diseases. METHODS AND RESULTS: Using the Illumina Infinium Methylation EPIC BeadChip850K, we investigated genome-wide differences in DNA methylation in an Italian Cohort of patients with comorbidities and compared severe (n = 64) and mild (123) prognosis. Results showed that the epigenetic signature, already present at the time of Hospital admission, can significantly predict risk of severe outcomes. Further analyses provided evidence of an association between age acceleration and a severe prognosis after COVID-19 infection. The burden of Stochastic Epigenetic Mutation (SEMs) has been significantly increased in patients with poor prognosis. Results have been replicated in silico considering COVID-19 negative subjects and available previously published datasets. CONCLUSIONS: Using original methylation data and taking advantage of already published datasets, we confirmed in the blood that epigenetics is actively involved in immune response after COVID-19 infection, allowing the identification of a specific signature able to discriminate the disease evolution. Furthermore, the study showed that epigenetic drift and age acceleration are associated with severe prognosis. All these findings prove that host epigenetics undergoes notable and specific rearrangements to respond to COVID-19 infection which can be used for a personalized, timely, and targeted management of COVID-19 patients during the first stages of hospitalization.

Developmental Programming in Animal Models: Critical Evidence of Current Environmental Negative Changes.

The Developmental Origins of Health and Disease (DOHaD) approach answers questions surrounding the early events suffered by the mother during reproductive stages that can either partially or permanently influence the developmental programming of children, predisposing them to be either healthy or exhibit negative health outcomes in adulthood. Globally, vulnerable populations tend to present high obesity rates, including among school-age children and women of reproductive age. In addition, adults suffer from high rates of diabetes, hypertension, cardiovascular, and other metabolic diseases. The increase in metabolic outcomes has been associated with the combination of maternal womb conditions and adult lifestyle-related factors such as malnutrition and obesity, smoking habits, and alcoholism. However, to date, "new environmental changes" have recently been considered negative factors of development, such as maternal sedentary lifestyle, lack of maternal attachment during lactation, overcrowding, smog, overurbanization, industrialization, noise pollution, and psychosocial stress experienced during the current SARS-CoV-2 pandemic. Therefore, it is important to recognize how all these factors impact offspring development during pregnancy and lactation, a period in which the subject cannot protect itself from these mechanisms. This review aims to introduce the importance of studying DOHaD, discuss classical programming studies, and address the importance of studying new emerging programming mechanisms, known as actual lifestyle factors, during pregnancy and lactation.

Vitamin B12 attenuates leukocyte inflammatory signature in COVID-19 via methyl-dependent changes in epigenetic markings.

COVID-19 induces chromatin remodeling in host immune cells, and it had previously been shown that vitamin B12 downregulates some inflammatory genes via methyl-dependent epigenetic mechanisms. In this work, whole blood cultures from moderate or severe COVID-19 patients were used to assess the potential of B12 as adjuvant drug. The vitamin normalized the expression of a panel of inflammatory genes still dysregulated in the leukocytes despite glucocorticoid therapy during hospitalization. B12 also increased the flux of the sulfur amino acid pathway, that regulates the bioavailability of methyl. Accordingly, B12-induced downregulation of CCL3 strongly and negatively correlated with the hypermethylation of CpGs in its regulatory regions. Transcriptome analysis revealed that B12 attenuates the effects of COVID-19 on most inflammation-related pathways affected by the disease. As far as we are aware, this is the first study to demonstrate that pharmacological modulation of epigenetic markings in leukocytes favorably regulates central components of COVID-19 physiopathology.