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1.
Signal Transduct Target Ther ; 7(1): 29, 2022 01 28.
Article in English | MEDLINE | ID: covidwho-1655546

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted on mink farms between minks and humans in many countries. However, the systemic pathological features of SARS-CoV-2-infected minks are mostly unknown. Here, we demonstrated that minks were largely permissive to SARS-CoV-2, characterized by severe and diffuse alveolar damage, and lasted at least 14 days post inoculation (dpi). We first reported that infected minks displayed multiple organ-system lesions accompanied by an increased inflammatory response and widespread viral distribution in the cardiovascular, hepatobiliary, urinary, endocrine, digestive, and immune systems. The viral protein partially co-localized with activated Mac-2+ macrophages throughout the body. Moreover, we first found that the alterations in lipids and metabolites were correlated with the histological lesions in infected minks, especially at 6 dpi, and were similar to that of patients with severe and fatal COVID-19. Particularly, altered metabolic pathways, abnormal digestion, and absorption of vitamins, lipids, cholesterol, steroids, amino acids, and proteins, consistent with hepatic dysfunction, highlight metabolic and immune dysregulation. Enriched kynurenine in infected minks contributed to significant activation of the kynurenine pathway and was related to macrophage activation. Melatonin, which has significant anti-inflammatory and immunomodulating effects, was significantly downregulated at 6 dpi and displayed potential as a targeted medicine. Our data first illustrate systematic analyses of infected minks to recapitulate those observations in severe and fetal COVID-19 patients, delineating a useful animal model to mimic SARS-CoV-2-induced systematic and severe pathophysiological features and provide a reliable tool for the development of effective and targeted treatment strategies, vaccine research, and potential biomarkers.


Subject(s)
COVID-19/metabolism , Lung/metabolism , Macrophages, Alveolar/metabolism , Metabolome , Mink/virology , SARS-CoV-2/metabolism , Amino Acids/metabolism , Animals , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/genetics , COVID-19/pathology , Disease Models, Animal , Female , Humans , Lung/pathology , Lung/virology , Macrophages, Alveolar/pathology , Macrophages, Alveolar/virology , Melatonin/metabolism , Metabolic Networks and Pathways/genetics , Molecular Targeted Therapy/methods , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Sterols/metabolism , Virulence , Virus Replication/genetics
2.
Int J Mol Sci ; 22(6)2021 Mar 11.
Article in English | MEDLINE | ID: covidwho-1143517

ABSTRACT

The interactions at the atomic level between small molecules and the main components of cellular plasma membranes are crucial for elucidating the mechanisms allowing for the entrance of such small species inside the cell. We have performed molecular dynamics and metadynamics simulations of tryptophan, serotonin, and melatonin at the interface of zwitterionic phospholipid bilayers. In this work, we will review recent computer simulation developments and report microscopic properties, such as the area per lipid and thickness of the membranes, atomic radial distribution functions, angular orientations, and free energy landscapes of small molecule binding to the membrane. Cholesterol affects the behaviour of the small molecules, which are mainly buried in the interfacial regions. We have observed a competition between the binding of small molecules to phospholipids and cholesterol through lipidic hydrogen-bonds. Free energy barriers that are associated to translational and orientational changes of melatonin have been found to be between 10-20 kJ/mol for distances of 1 nm between melatonin and the center of the membrane. Corresponding barriers for tryptophan and serotonin that are obtained from reversible work methods are of the order of 10 kJ/mol and reveal strong hydrogen bonding between such species and specific phospholipid sites. The diffusion of tryptophan and melatonin is of the order of 10-7 cm2/s for the cholesterol-free and cholesterol-rich setups.


Subject(s)
1,2-Dipalmitoylphosphatidylcholine/chemistry , Cholesterol/chemistry , Dimyristoylphosphatidylcholine/chemistry , Melatonin/chemistry , Serotonin/chemistry , Tryptophan/chemistry , 1,2-Dipalmitoylphosphatidylcholine/metabolism , Cholesterol/metabolism , Dimyristoylphosphatidylcholine/metabolism , Hydrogen Bonding , Lipid Bilayers/chemistry , Lipid Bilayers/metabolism , Melatonin/metabolism , Molecular Dynamics Simulation , Serotonin/metabolism , Solutions , Static Electricity , Thermodynamics , Tryptophan/metabolism , Water/chemistry
3.
Molecules ; 25(19)2020 Sep 25.
Article in English | MEDLINE | ID: covidwho-1125084

ABSTRACT

Fighting infectious diseases, particularly viral infections, is a demanding task for human health. Targeting the pathogens or targeting the host are different strategies, but with an identical purpose, i.e., to curb the pathogen's spreading and cure the illness. It appears that targeting a host to increase tolerance against pathogens can be of substantial advantage and is a strategy used in evolution. Practically, it has a broader protective spectrum than that of only targeting the specific pathogens, which differ in terms of susceptibility. Methods for host targeting applied in one pandemic can even be effective for upcoming pandemics with different pathogens. This is even more urgent if we consider the possible concomitance of two respiratory diseases with potential multi-organ afflictions such as Coronavirus disease 2019 (COVID-19) and seasonal flu. Melatonin is a molecule that can enhance the host's tolerance against pathogen invasions. Due to its antioxidant, anti-inflammatory, and immunoregulatory activities, melatonin has the capacity to reduce the severity and mortality of deadly virus infections including COVID-19. Melatonin is synthesized and functions in mitochondria, which play a critical role in viral infections. Not surprisingly, melatonin synthesis can become a target of viral strategies that manipulate the mitochondrial status. For example, a viral infection can switch energy metabolism from respiration to widely anaerobic glycolysis even if plenty of oxygen is available (the Warburg effect) when the host cell cannot generate acetyl-coenzyme A, a metabolite required for melatonin biosynthesis. Under some conditions, including aging, gender, predisposed health conditions, already compromised mitochondria, when exposed to further viral challenges, lose their capacity for producing sufficient amounts of melatonin. This leads to a reduced support of mitochondrial functions and makes these individuals more vulnerable to infectious diseases. Thus, the maintenance of mitochondrial function by melatonin supplementation can be expected to generate beneficial effects on the outcome of viral infectious diseases, particularly COVID-19.


Subject(s)
Coronavirus Infections/drug therapy , Melatonin/therapeutic use , Mitochondria/drug effects , Pneumonia, Viral/drug therapy , Virus Diseases/drug therapy , Virus Diseases/immunology , COVID-19 , Coronavirus Infections/metabolism , Drug Delivery Systems , Humans , Melatonin/metabolism , Mitochondria/metabolism , Pandemics , Pneumonia, Viral/metabolism , Virus Diseases/metabolism
4.
Int J Mol Sci ; 22(1)2020 Dec 25.
Article in English | MEDLINE | ID: covidwho-1004733

ABSTRACT

This article reviews the dynamic interactions of the tumour microenvironment, highlighting the roles of acetyl-CoA and melatonergic pathway regulation in determining the interactions between oxidative phosphorylation (OXPHOS) and glycolysis across the array of cells forming the tumour microenvironment. Many of the factors associated with tumour progression and immune resistance, such as yin yang (YY)1 and glycogen synthase kinase (GSK)3ß, regulate acetyl-CoA and the melatonergic pathway, thereby having significant impacts on the dynamic interactions of the different types of cells present in the tumour microenvironment. The association of the aryl hydrocarbon receptor (AhR) with immune suppression in the tumour microenvironment may be mediated by the AhR-induced cytochrome P450 (CYP)1b1-driven 'backward' conversion of melatonin to its immediate precursor N-acetylserotonin (NAS). NAS within tumours and released from tumour microenvironment cells activates the brain-derived neurotrophic factor (BDNF) receptor, TrkB, thereby increasing the survival and proliferation of cancer stem-like cells. Acetyl-CoA is a crucial co-substrate for initiation of the melatonergic pathway, as well as co-ordinating the interactions of OXPHOS and glycolysis in all cells of the tumour microenvironment. This provides a model of the tumour microenvironment that emphasises the roles of acetyl-CoA and the melatonergic pathway in shaping the dynamic intercellular metabolic interactions of the various cells within the tumour microenvironment. The potentiation of YY1 and GSK3ß by O-GlcNAcylation will drive changes in metabolism in tumours and tumour microenvironment cells in association with their regulation of the melatonergic pathway. The emphasis on metabolic interactions across cell types in the tumour microenvironment provides novel future research and treatment directions.


Subject(s)
Neoplasms/pathology , Tumor Microenvironment , Acetyl Coenzyme A/metabolism , Age Factors , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Computational Biology , Humans , Immunomodulation , Melatonin/metabolism , Metabolic Networks and Pathways , Mitochondria/metabolism , Models, Biological , Neoplasms/etiology , Neoplasms/metabolism , Organ Specificity/genetics , Organ Specificity/immunology , Receptors, Aryl Hydrocarbon/genetics , Receptors, Aryl Hydrocarbon/metabolism , Sirtuins/metabolism , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology
6.
Turk J Med Sci ; 50(6): 1504-1512, 2020 10 22.
Article in English | MEDLINE | ID: covidwho-709719

ABSTRACT

The aim of this review is to summarize current studies on the relationship between melatonin and aging. Nowadays, age-related diseases come into prominence, and identifying age-related changes and developing proper therapeutic approaches are counted as some of the major issues regarding community health. Melatonin is the main hormone of the pineal gland. Melatonin is known to influence many biological processes in the body, including circadian rhythms, the immune system, and neuroendocrine and cardiovascular functions.Melatoninrhythms also reflect the biological process of aging. Aging is an extremely complex and multifactorial process. Melatonin levels decline considerably with aging and its decline is associated with several age-related diseases. Aging is closely associated with oxidative damage and mitochondrial dysfunction. Free radical reactions initiated by the mitochondria constitute the inherent aging process. Melatonin plays a pivotal role in preventing age-related oxidative stress. Coronavirus disease 2019 (COVID-19) fatality rates increase with chronic diseases and age, where melatonin levels decrease. For this reason, melatonin supplementation in elderly could be beneficial in COVID-19 treatment. Therefore, studies on the usage of melatonin in COVID-19 treatment are needed.


Subject(s)
Aging , Antioxidants/therapeutic use , Coronavirus Infections/drug therapy , Melatonin/therapeutic use , Oxidative Stress/drug effects , Pneumonia, Viral/drug therapy , Aged , Aging/metabolism , Animals , Antioxidants/metabolism , Antioxidants/pharmacology , Betacoronavirus , COVID-19 , Coronavirus Infections/virology , Dietary Supplements , Humans , Melatonin/metabolism , Melatonin/pharmacology , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2
7.
Med Hypotheses ; 144: 110147, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-680479

ABSTRACT

Recent data has revealed an association between coronavirus disease-19 (COVID-19) incidence and seasonally regulated androgen sensitivity. This potential relationship between SARS-CoV-2 infection and clock genes, coupled with previously reported effects of night shift work on health, leads us to hypothesize that night shift workers may be at an increased physiological risk of coronavirus disease-19 (COVID-19). Shift work, especially night shift work, has long been associated with several chronic health conditions. The mechanisms that drive these associations are not well understood; however, current literature suggests that the disruption of circadian rhythms may cause downstream hormonal and immune effects that render night shift workers more susceptible to disease. First, circadian rhythms may play a role in the mechanism of viral infection, as viral vaccines administered in the morning elicit greater immune responses than those administered in the afternoon. Next, increased exposure to light at night may inhibit the production of melatonin, which has been observed to enhance DNA repair and shown to upregulate expression of Bmal1, an established inhibitor of herpes simplex virus and influenza. Finally, abnormal immune cell and cytokine levels have been observed following night-shift work. These data suggest that further research is warranted and that high-risk occupations should be taken into consideration as public health policies are introduced and evolve.


Subject(s)
COVID-19/epidemiology , Circadian Rhythm , Disease Susceptibility , Work Schedule Tolerance , ARNTL Transcription Factors/metabolism , COVID-19/diagnosis , Cytokines/metabolism , DNA Repair , Humans , Melatonin/metabolism , Public Health , Risk , SARS-CoV-2 , Sleep/physiology
8.
Allergol Immunopathol (Madr) ; 48(5): 500-506, 2020.
Article in English | MEDLINE | ID: covidwho-627878

ABSTRACT

The reasons for the relative resistance of children to certain infections such as that caused by coronavirus SARS-CoV2 are not yet fully clear. Deciphering these differences can provide important information about the pathogenesis of the disease. Regarding the SARS-CoV2 virus, children are at the same risk of infection as the general population of all ages, with the most serious cases being found in infants. However, it has been reported that the disease is much less frequent than in adults and that most cases are benign or moderate (even with high viral loads), provided there are no other risk factors or underlying diseases. It is not clear why they have lower morbidity and virtually no mortality. A series of findings, relationships and behavioral patterns between the infectious agent and the child host may account for the lower incidence and a greatly attenuated clinical presentation of the disease in children.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/epidemiology , Coronavirus Infections/pathology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/pathology , Adult , Age Factors , Angiotensin-Converting Enzyme 2 , COVID-19 , Carrier State/transmission , Carrier State/virology , Child , Coinfection/epidemiology , Coinfection/immunology , Coinfection/pathology , Coronavirus Infections/immunology , Coronavirus Infections/transmission , Humans , Immune System , Life Style , Melatonin/immunology , Melatonin/metabolism , Pandemics , Peptidyl-Dipeptidase A/immunology , Peptidyl-Dipeptidase A/metabolism , Pneumococcal Vaccines/immunology , Pneumonia, Viral/immunology , Pneumonia, Viral/transmission , Respiratory Tract Infections/epidemiology , Respiratory Tract Infections/immunology , Respiratory Tract Infections/pathology , SARS-CoV-2
9.
Chronobiol Int ; 37(7): 961-973, 2020 07.
Article in English | MEDLINE | ID: covidwho-592274

ABSTRACT

Maternal circadian rhythms provide highly important input into the entrainment and programming of fetal and newborn circadian rhythms. The light-dark cycle is an important regulator of the internal biological clock. Even though pregnant women spend a greater part of the day at home during the latter stages of pregnancy, natural light exposure is crucial for the fetus. The current recommended COVID-19 lockdown might dramatically alter normal environmental lighting conditions of pregnant women, resulting in exposure to extremely low levels of natural daylight and high-intensity artificial light sources during both day and night. This article summarizes the potential effects on pregnant woman and their fetuses due to prolonged exposure to altered photoperiod and as consequence altered circadian system, known as chronodisruption, that may result from the COVID-19 lockdown.


Subject(s)
Betacoronavirus/pathogenicity , Circadian Rhythm/physiology , Coronavirus Infections/virology , Pneumonia, Viral/virology , Pregnancy Complications, Infectious/virology , COVID-19 , Circadian Clocks/physiology , Female , Fetus/virology , Humans , Melatonin/metabolism , Melatonin/pharmacology , Pandemics , Pregnancy , SARS-CoV-2
10.
Rev Med Virol ; 30(3): e2109, 2020 05.
Article in English | MEDLINE | ID: covidwho-95194

ABSTRACT

There is a growing appreciation that the regulation of the melatonergic pathways, both pineal and systemic, may be an important aspect in how viruses drive the cellular changes that underpin their control of cellular function. We review the melatonergic pathway role in viral infections, emphasizing influenza and covid-19 infections. Viral, or preexistent, suppression of pineal melatonin disinhibits neutrophil attraction, thereby contributing to an initial "cytokine storm", as well as the regulation of other immune cells. Melatonin induces the circadian gene, Bmal1, which disinhibits the pyruvate dehydrogenase complex (PDC), countering viral inhibition of Bmal1/PDC. PDC drives mitochondrial conversion of pyruvate to acetyl-coenzyme A (acetyl-CoA), thereby increasing the tricarboxylic acid cycle, oxidative phosphorylation, and ATP production. Pineal melatonin suppression attenuates this, preventing the circadian "resetting" of mitochondrial metabolism. This is especially relevant in immune cells, where shifting metabolism from glycolytic to oxidative phosphorylation, switches cells from reactive to quiescent phenotypes. Acetyl-CoA is a necessary cosubstrate for arylalkylamine N-acetyltransferase, providing an acetyl group to serotonin, and thereby initiating the melatonergic pathway. Consequently, pineal melatonin regulates mitochondrial melatonin and immune cell phenotype. Virus- and cytokine-storm-driven control of the pineal and mitochondrial melatonergic pathway therefore regulates immune responses. Virus-and cytokine storm-driven changes also increase gut permeability and dysbiosis, thereby suppressing levels of the short-chain fatty acid, butyrate, and increasing circulating lipopolysaccharide (LPS). The alterations in butyrate and LPS can promote viral replication and host symptom severity via impacts on the melatonergic pathway. Focussing on immune regulators has treatment implications for covid-19 and other viral infections.


Subject(s)
Coronavirus Infections/physiopathology , Influenza, Human/metabolism , Melatonin/metabolism , Pneumonia, Viral/physiopathology , Animals , Betacoronavirus/physiology , Biosynthetic Pathways , COVID-19 , Circadian Rhythm , Circadian Rhythm Signaling Peptides and Proteins/genetics , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cytokines/immunology , Humans , Influenza, Human/immunology , Melatonin/immunology , Mitochondria/metabolism , Orthomyxoviridae/physiology , Pandemics , Pineal Gland/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2 , Viruses/classification
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