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1.
J Transl Med ; 20(1): 509, 2022 Nov 05.
Article in English | MEDLINE | ID: covidwho-2108801

ABSTRACT

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is a key enzyme of the renin-angiotensin system and a well-known functional receptor for the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells. The COVID-19 pandemic has brought ACE2 into the spotlight, and ACE2 expression in tumors and its relationship with SARS-COV-2 infection and prognosis of cancer patients have received extensive attention. However, the association between ACE2 expression and tumor therapy and prognosis, especially in breast cancer, remains ambiguous and requires further investigation. We have previously reported that ACE2 is elevated in drug-resistant breast cancer cells, but the exact function of ACE2 in drug resistance and progression of this malignant disease has not been explored. METHODS: The expression of ACE2 and HIF-1α in parental and drug-resistant breast cancer cells under normoxic and hypoxic conditions was analyzed by Western blot and qRT-PCR methods. The protein levels of ACE2 in plasma samples from breast cancer patients were examined by ELISA. The relationship between ACE2 expression and breast cancer treatment and prognosis was analyzed using clinical specimens and public databases. The reactive oxygen species (ROS) levels in breast cancer cells were measured by using a fluorescent probe. Small interfering RNAs (siRNAs) or lentivirus-mediated shRNA was used to silence ACE2 and HIF-1α expression in cellular models. The effect of ACE2 knockdown on drug resistance in breast cancer was determined by Cell Counting Kit 8 (CCK-8)-based assay, colony formation assay, apoptosis and EdU assay. RESULTS: ACE2 expression is relatively low in breast cancer cells, but increases rapidly and specifically after exposure to anticancer drugs, and remains high after resistance is acquired. Mechanistically, chemotherapeutic agents increase ACE2 expression in breast cancer cells by inducing intracellular ROS production, and increased ROS levels enhance AKT phosphorylation and subsequently increase HIF-1α expression, which in turn upregulates ACE2 expression. Although ACE2 levels in plasma and cancer tissues are lower in breast cancer patients compared with healthy controls, elevated ACE2 in patients after chemotherapy is a predictor of poor treatment response and an unfavorable prognostic factor for survival in breast cancer patients. CONCLUSION: ACE2 is a gene in breast cancer cells that responds rapidly to chemotherapeutic agents through the ROS-AKT-HIF-1α axis. Elevated ACE2 modulates the sensitivity of breast cancer cells to anticancer drugs by optimizing the balance of intracellular ROS. Moreover, increased ACE2 is not only a predictor of poor response to chemotherapy, but is also associated with a worse prognosis in breast cancer patients. Thus, our findings provide novel insights into the spatiotemporal differences in the function of ACE2 in the initiation and progression of breast cancer.


Subject(s)
Breast Neoplasms , COVID-19 , Humans , Female , Angiotensin-Converting Enzyme 2 , Proto-Oncogene Proteins c-akt/metabolism , Reactive Oxygen Species/metabolism , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , SARS-CoV-2 , Pandemics , Prognosis , Signal Transduction , RNA, Small Interfering , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
2.
Water Res ; 227: 119342, 2022 Dec 01.
Article in English | MEDLINE | ID: covidwho-2106149

ABSTRACT

Glutaraldehyde and didecyldimethylammonium bromide (GD) is a disinfectant widely used to prevent African swine fever (ASF) in livestock farms. However, the effect of residual GD on the activated sludge microbial ecology of receiving wastewater treatment plants (WWTPs) remains largely unknown. In this study, seven simulated systems were established to research the effects of GD on WWTPs and reveal the underlying mechanisms of microecological responses to GD at different concentrations. Both the nitrogen and carbon removal rates decreased with increasing GD concentrations, and nitrogen metabolism was inhibited more obviously, but the inhibition weakened with increasing stress duration. Microorganisms activated their SoxRS systems to promote ATP synthesis and electron transfer to support the hydrolysis and efflux of GD by producing a small number of ROS when exposed to GD at less than 1 mg/L. The overproduction of ROS led to a decrease of antioxidant and nitrogen removal enzyme activities, and upregulation of the porin gene increased the risk of GD entering the intracellular space upon exposure to GD at concentrations higher than 1 mg/L. Some denitrifiers survived via resistance and their basic capabilities of sugar metabolism and nitrogen assimilation. Notably, low concentrations of disinfectants could promote vertical and horizontal transfer of multiple resistance genes, especially aminoglycosides, among microorganisms, which might increase not only the adaptation capability of denitrifiers but also the risk to ecological systems. Therefore, the risks of disinfectants targeting ASF on ecology and health as well as the effects of disinfectant residuals from the COVID-19 epidemic should receive more attention.


Subject(s)
African Swine Fever , COVID-19 , Disinfectants , Water Purification , Swine , Animals , Sewage , Disinfectants/pharmacology , Glutaral/pharmacology , Livestock , Reactive Oxygen Species , Nitrogen
3.
Emerg Microbes Infect ; 11(1): 2529-2543, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2107214

ABSTRACT

Autophagy, a cellular surveillance mechanism, plays an important role in combating invading pathogens. However, viruses have evolved various strategies to disrupt autophagy and even hijack it for replication and release. Here, we demonstrated that Middle East respiratory syndrome coronavirus (MERS-CoV) non-structural protein 1(nsp1) induces autophagy but inhibits autophagic activity. MERS-CoV nsp1 expression increased ROS and reduced ATP levels in cells, which activated AMPK and inhibited the mTOR signalling pathway, resulting in autophagy induction. Meanwhile, as an endonuclease, MERS-CoV nsp1 downregulated the mRNA of lysosome-related genes that were enriched in nsp1-located granules, which diminished lysosomal biogenesis and acidification, and inhibited autophagic flux. Importantly, MERS-CoV nsp1-induced autophagy can lead to cell death in vitro and in vivo. These findings clarify the mechanism by which MERS-CoV nsp1-mediated autophagy regulation, providing new insights for the prevention and treatment of the coronavirus.


Subject(s)
Middle East Respiratory Syndrome Coronavirus , Middle East Respiratory Syndrome Coronavirus/physiology , AMP-Activated Protein Kinases/metabolism , Reactive Oxygen Species/metabolism , RNA, Messenger/metabolism , Lysosomes/metabolism , Autophagy , Endonucleases/metabolism , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , Adenosine Triphosphate/metabolism
4.
Cells ; 11(20)2022 Oct 21.
Article in English | MEDLINE | ID: covidwho-2082060

ABSTRACT

The binding of SARS-CoV-2 spikes to the cell receptor angiotensin-converting enzyme 2 (ACE2) is a crucial target both in the prevention and in the therapy of COVID-19. We explored the involvement of oxidoreductive mechanisms by investigating the effects of oxidants and antioxidants on virus uptake by ACE2-expressing cells of human origin (ACE2-HEK293). The cell uptake of pseudoviruses carrying the envelope of either Delta or Omicron variants of SARS-CoV-2 was evaluated by means of a cytofluorimetric approach. The thiol N-acetyl-L-cysteine (NAC) inhibited the uptake of both variants in a reproducible and dose-dependent fashion. Ascorbic acid showed modest effects. In contrast, neither hydrogen peroxide (H2O2) nor a system-generating reactive oxygen species (ROS), which play an important role in the intracellular alterations produced by SARS-CoV-2, were able to affect the ability of either Delta or Omicron SARS-CoV-2 pseudoviruses to be internalized into ACE2-expressing cells. In addition, neither H2O2 nor the ROS generating system interfered with the ability of NAC to inhibit that mechanism. Moreover, based on previous studies, a preventive pharmacological approach with NAC would have the advantage of decreasing the risk of developing COVID-19, irrespective of its variants, and at the same time other respiratory viral infections and associated comorbidities.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Humans , SARS-CoV-2 , Acetylcysteine/pharmacology , COVID-19/drug therapy , Hydrogen Peroxide/pharmacology , Reactive Oxygen Species , Antioxidants/pharmacology , HEK293 Cells , Peptidyl-Dipeptidase A/metabolism , Ascorbic Acid/pharmacology , Oxidants/pharmacology , Sulfhydryl Compounds/pharmacology
5.
Int J Mol Sci ; 23(20)2022 Oct 15.
Article in English | MEDLINE | ID: covidwho-2071513

ABSTRACT

Platelet hyperreactivity and oxidative stress are the important causes of thrombotic disorders in patients with COVID-19. Oxidative stress, induced by the excessive generation of reactive oxygen species (ROS), could increase platelet function and the risk of thrombus formation. Coenzyme Q10 (CoQ10), exhibits strong antioxidative activity and anti-platelet effect. However, the effects and mechanisms of CoQ10 on attenuating platelet aggregation induced by spike protein have never been studied. This study aims to investigate whether the SARS-CoV-2 spike protein potentiates human platelet function via ROS signaling and the protective effect of CoQ10 in vitro. Using a series of platelet function assays, we found that spike protein potentiated platelet aggregation and oxidative stress, such as ROS level, mitochondrial membrane potential depolarization, and lipid damage level (MDA and 8-iso-PGF2α) in vitro. Furthermore, CoQ10 attenuated platelet aggregation induced by spike protein. As an anti-platelet mechanism, we showed that CoQ10 significantly decreased the excess production of ROS induced by spike protein. Our findings show that the protective effect of CoQ10 on spike protein-potentiated platelet aggregation is probably associated with its strong antioxidative ability.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Humans , Spike Glycoprotein, Coronavirus/metabolism , Reactive Oxygen Species/metabolism , Platelet Aggregation , COVID-19/drug therapy , SARS-CoV-2 , Ubiquinone/pharmacology , Ubiquinone/metabolism , Oxidative Stress , Antioxidants/pharmacology , Antioxidants/metabolism , Lipids/pharmacology
6.
Int J Mol Sci ; 23(19)2022 Oct 05.
Article in English | MEDLINE | ID: covidwho-2066137

ABSTRACT

As a result of SARS-CoV-2 infection, inflammation develops, which promotes oxidative stress, leading to modification of phospholipid metabolism. Therefore, the aim of this study is to compare the effects of COVID-19 on the levels of phospholipid and free polyunsaturated fatty acids (PUFAs) and their metabolites produced in response to reactions with reactive oxygen species (ROS) and enzymes (cyclooxygenases-(COXs) and lipoxygenase-(LOX)) in the plasma of patients who either recovered or passed away within a week of hospitalization. In the plasma of COVID-19 patients, especially of the survivors, the actions of ROS and phospholipase A2 (PLA2) cause a decrease in phospholipid fatty acids level and an increase in free fatty acids (especially arachidonic acid) despite increased COXs and LOX activity. This is accompanied by an increased level in lipid peroxidation products (malondialdehyde and 8-isoprostaglandin F2α) and lipid mediators generated by enzymes. There is also an increase in eicosanoids, both pro-inflammatory as follows: thromboxane B2 and prostaglandin E2, and anti-inflammatory as follows: 15-deoxy-Δ-12,14-prostaglandin J2 and 12-hydroxyeicosatetraenoic acid, as well as endocannabinoids (anandamide-(AEA) and 2-arachidonylglycerol-(2-AG)) observed in the plasma of patients who recovered. Moreover, the expression of tumor necrosis factor α and interleukins (IL-6 and IL-10) is increased in patients who recovered. However, in the group of patients who died, elevated levels of N-oleoylethanolamine and N-palmitoylethanolamine are found. Since lipid mediators may have different functions depending on the onset of pathophysiological processes, a stronger pro-inflammatory response in patients who have recovered may be the result of the defensive response to SARS-CoV-2 in survivors associated with specific changes in the phospholipid metabolism, which could also be considered a prognostic factor.


Subject(s)
COVID-19 , Endocannabinoids , Arachidonic Acids/metabolism , Dinoprostone/metabolism , Eicosanoids/metabolism , Endocannabinoids/metabolism , Fatty Acids, Nonesterified , Hospitalization , Hospitals , Humans , Hydroxyeicosatetraenoic Acids , Interleukin-10/metabolism , Interleukin-6/metabolism , Lipid Peroxidation , Lipoxygenase/metabolism , Malondialdehyde , Phospholipases A2/metabolism , Phospholipids/metabolism , Prostaglandin-Endoperoxide Synthases/metabolism , Reactive Oxygen Species/metabolism , SARS-CoV-2 , Survivors , Thromboxane B2 , Tumor Necrosis Factor-alpha/metabolism
7.
Bull Exp Biol Med ; 173(5): 606-610, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-2059913

ABSTRACT

The indicators of spermatogenesis and the state of LPO and antioxidant protection in men with pathozoospermia after COVID-19 were assessed before and after treatment an antioxidant complex. Blood plasma served as the material for biochemical studies. In the examined patients, the parameters of spermatogenesis, as well as blood concentration of LPO components (diene conjugates and TBA-reactive substances) were analyzed. The total antioxidant activity of the blood was determined as an indicator characterizing the total activity of LPO inhibitors and determining its buffer capacity. In patients recovered from COVID-19, an increase in spermatogenesis disorders and shifts towards the predominance of prooxidant factors were observed. After a course (1 month) of antioxidant complex, patients showed increased sperm motility, decreased leukocyte count in the ejaculate, and restored balance in the prooxidant-antioxidant system towards antioxidant components. The effectiveness of correction of post-COVID disorders largely depends on the degree of damage to the structure and function of cell membranes caused by oxidative stress. The use of the antioxidant complex is a promising option, because it reduces the level of LPO, enhances antioxidant protection of the body, and also normalizes some parameters of spermatogenesis.


Subject(s)
Antioxidants , COVID-19 , Antioxidants/metabolism , Antioxidants/therapeutic use , COVID-19/drug therapy , Humans , Lipid Peroxidation/physiology , Male , Oxidative Stress/physiology , Reactive Oxygen Species , Sperm Motility , Spermatogenesis
8.
Mol Med Rep ; 26(5)2022 Nov.
Article in English | MEDLINE | ID: covidwho-2055488

ABSTRACT

COVID­19 patients with severe infection have been observed to have elevated auto­antibodies (AAs) against angiotensin II receptor type 1 (AT1R) and endothelin (ET) 1 receptor type A (ETAR), compared with healthy controls and patients with favorable (mild) infection. AT1R and ETAR are G protein­coupled receptors, located on vascular smooth muscle cells, fibroblasts, immune and endothelial cells, and are activated by angiotensin II (Ang II) and ET1 respectively. AAs that are specific for these receptors have a functional role similar to the natural ligands, but with a more prolonged vasoconstrictive effect. They also induce the production of fibroblast collagen, the release of reactive oxygen species and the secretion of proinflammatory cytokines (including IL­6, IL­8 and TNF­α) by immune cells. Despite the presence of AAs in severe COVID­19 infected patients, their contribution and implication in the severity of the disease is still not well understood and further studies are warranted. The present review described the major vascular homeostasis systems [ET and renin­angiotensin­aldosterone system (RAAS)], the vital regulative role of nitric oxide, the AAs, and finally the administration of angiotensin II receptor blockers (ARBs), so as to provide more insight into the interplay that exists among these components and their contribution to the severity, prognosis and possible treatment of COVID­19.


Subject(s)
COVID-19 , Vascular Diseases , Angiotensin II , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors , Collagen , Endothelial Cells , Endothelins , Humans , Interleukin-6 , Interleukin-8 , Nitric Oxide , Reactive Oxygen Species , Receptor, Angiotensin, Type 1 , Receptor, Endothelin A , Receptors, Angiotensin , Tumor Necrosis Factor-alpha
9.
BMC Mol Cell Biol ; 23(1): 42, 2022 Sep 29.
Article in English | MEDLINE | ID: covidwho-2053858

ABSTRACT

BACKGROUND: COVID-19 is a disease caused by SARS-CoV-2, which can cause mild to serious infections in humans. We aimed to explore the effect of growth hormone (GH)/estrogen/androgen in normal human lung epithelial BEAS-2B cells on COVID-19-type proinflammatory responses. METHODS: A BEAS-2B COVID-19-like proinflammatory cell model was constructed. After that, the cells were treated with GH, 17ß-estradiol (E2), and testosterone (Tes) for 24 h. CCK-8 assays were utilized to evaluate cell viability. The mRNA expression of ACE2, AGTR1, TMRRSS2, and ISG15 and the protein expression of ACE2, AGTR1, TMRRSS2, and ISG15 were measured by qRT‒PCR and Western blotting, respectively. ELISAs were performed to determine IL-6, MCP-1, MDA and SOD expression. Flow cytometry was used to measure ROS levels. Finally, MAPK/NF-κB pathway-related factor expression was evaluated. RESULTS: The COVID-19-type proinflammatory model was successfully constructed, and 1000 ng/mL RBD treatment for 24 h was selected as the condition for the model group for subsequent experiments. After RBD treatment, cell viability decreased, the mRNA expression of ACE2, AGTR1, TMRRSS2, and ISG15 and the protein expression of ACE2, AGTR1, TMRRSS2, and ISG15 increased, IL-6, MCP-1, MDA and ROS levels increased, and MDA levels decreased. The mRNA levels of MAPK14 and RELA increased, but the protein levels did not change significantly. In addition, phospho-MAPK14 and phospho-RELA protein levels were also increased. Among the tested molecules, E2 had the most pronounced effect, followed by GH, while Tes showed the opposite effect. CONCLUSION: GH/E2 alleviated inflammation in a COVID-19-type proinflammatory model, but Tes showed the opposite effect.


Subject(s)
COVID-19 , Mitogen-Activated Protein Kinase 14 , Androgens , Angiotensin-Converting Enzyme 2 , COVID-19/drug therapy , Estradiol/pharmacology , Estrogens , Growth Hormone , Humans , Interleukin-6 , Lung , NF-kappa B , Reactive Oxygen Species , SARS-CoV-2 , Sincalide , Superoxide Dismutase , Testosterone
10.
Commun Biol ; 5(1): 1039, 2022 09 30.
Article in English | MEDLINE | ID: covidwho-2050558

ABSTRACT

SARS-CoV-2 infection causes COVID-19, a severe acute respiratory disease associated with cardiovascular complications including long-term outcomes. The presence of virus in cardiac tissue of patients with COVID-19 suggests this is a direct, rather than secondary, effect of infection. Here, by expressing individual SARS-CoV-2 proteins in the Drosophila heart, we demonstrate interaction of virus Nsp6 with host proteins of the MGA/MAX complex (MGA, PCGF6 and TFDP1). Complementing transcriptomic data from the fly heart reveal that this interaction blocks the antagonistic MGA/MAX complex, which shifts the balance towards MYC/MAX and activates glycolysis-with similar findings in mouse cardiomyocytes. Further, the Nsp6-induced glycolysis disrupts cardiac mitochondrial function, known to increase reactive oxygen species (ROS) in heart failure; this could explain COVID-19-associated cardiac pathology. Inhibiting the glycolysis pathway by 2-deoxy-D-glucose (2DG) treatment attenuates the Nsp6-induced cardiac phenotype in flies and mice. These findings point to glycolysis as a potential pharmacological target for treating COVID-19-associated heart failure.


Subject(s)
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , COVID-19 , Drosophila Proteins/metabolism , Heart Failure , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Deoxyglucose/metabolism , Drosophila/metabolism , Glycolysis , Heart Failure/metabolism , Mice , Myocytes, Cardiac/metabolism , Polycomb Repressive Complex 1/metabolism , Reactive Oxygen Species/metabolism , SARS-CoV-2
11.
Cells ; 11(18)2022 09 16.
Article in English | MEDLINE | ID: covidwho-2043594

ABSTRACT

Rationale: Infection with the SARS-CoV2 virus is associated with elevated neutrophil counts. Evidence of neutrophil dysfunction in COVID-19 is based on transcriptomics or single functional assays. Cell functions are interwoven pathways, and understanding the effect across the spectrum of neutrophil function may identify therapeutic targets. Objectives: Examine neutrophil phenotype and function in 41 hospitalised, non-ICU COVID-19 patients versus 23 age-matched controls (AMC) and 26 community acquired pneumonia patients (CAP). Methods: Isolated neutrophils underwent ex vivo analyses for migration, bacterial phagocytosis, ROS generation, NETosis and receptor expression. Circulating DNAse 1 activity, levels of cfDNA, MPO, VEGF, IL-6 and sTNFRI were measured and correlated to clinical outcome. Serial sampling on day three to five post hospitalization were also measured. The effect of ex vivo PI3K inhibition was measured in a further cohort of 18 COVID-19 patients. Results: Compared to AMC and CAP, COVID-19 neutrophils demonstrated elevated transmigration (p = 0.0397) and NETosis (p = 0.0332), and impaired phagocytosis (p = 0.0036) associated with impaired ROS generation (p < 0.0001). The percentage of CD54+ neutrophils (p < 0.001) was significantly increased, while surface expression of CD11b (p = 0.0014) and PD-L1 (p = 0.006) were significantly decreased in COVID-19. COVID-19 and CAP patients showed increased systemic markers of NETosis including increased cfDNA (p = 0.0396) and impaired DNAse activity (p < 0.0001). The ex vivo inhibition of PI3K γ and δ reduced NET release by COVID-19 neutrophils (p = 0.0129). Conclusions: COVID-19 is associated with neutrophil dysfunction across all main effector functions, with altered phenotype, elevated migration and NETosis, and impaired antimicrobial responses. These changes highlight that targeting neutrophil function may help modulate COVID-19 severity.


Subject(s)
COVID-19 , Neutrophils , B7-H1 Antigen , COVID-19/immunology , Cell-Free Nucleic Acids , Deoxyribonucleases , Humans , Interleukin-6/pharmacology , Neutrophils/cytology , Phenotype , Phosphatidylinositol 3-Kinases , Reactive Oxygen Species/metabolism , SARS-CoV-2
12.
Int J Mol Sci ; 23(18)2022 Sep 10.
Article in English | MEDLINE | ID: covidwho-2039867

ABSTRACT

Acute hepatopancreatic necrosis disease (AHPND), caused by a unique strain of Vibrio parahaemolyticus (Vp (AHPND)), has become the world's most severe debilitating disease in cultured shrimp. Thus far, the pathogenesis of AHPND remains largely unknow. Herein, in Litopenaeus vannamei, we found that a Vp (AHPND) infection significantly increased the expression of lipid droplets (LDs) protein LvPerilipin, as well as promoted the formation of LDs. In addition, the knockdown of LvPerilipin increased the shrimp survival rate in response to the Vp (AHPND) infection, and inhibited the proliferation of Vp (AHPND). Furthermore, we demonstrated that LvPerilipin depletion could increase the production of reactive oxygen species (ROS), which may be responsible for the decreased Vp (AHPND) proliferation. Taken together, our current data for the first time reveal that the shrimp lipid droplets protein Perilipin is involved in the pathogenesis of Vp (AHPND) via promoting LDs accumulation and decreasing ROS production.


Subject(s)
Penaeidae , Vibrio parahaemolyticus , Animals , Lipid Droplets , Perilipin-1 , Reactive Oxygen Species , Vibrio parahaemolyticus/physiology
13.
PLoS One ; 17(9): e0274910, 2022.
Article in English | MEDLINE | ID: covidwho-2039433

ABSTRACT

It is well known that the presence of comorbidities and age-related health issues may hide biochemical and metabolic features triggered by SARS-CoV-2 infection and other diseases associated to hypoxia, as they are by themselves chronic inflammatory conditions that may potentially disturb metabolic homeostasis and thereby negatively impact on COVID-19 progression. To unveil the metabolic abnormalities inherent to hypoxemia caused by COVID-19, we here applied gas chromatography coupled to mass spectrometry to analyze the main metabolic changes exhibited by a population of male patients less than 50 years of age with mild/moderate and severe COVID-19 without pre-existing comorbidities known to predispose to life-threatening complications from this infection. Several differences in serum levels of particular metabolites between normal controls and patients with COVID-19 as well as between mild/moderate and severe COVID-19 were identified. These included increased glutamic acid and reduced glutamine, cystine, threonic acid, and proline levels. In particular, using the entire metabolomic fingerprint obtained, we observed that glutamine/glutamate metabolism was associated with disease severity as patients in the severe COVID-19 group presented the lowest and higher serum levels of these amino acids, respectively. These data highlight the hypoxia-derived metabolic alterations provoked by SARS-CoV-2 infection in the absence of pre-existing co-morbidities as well as the value of amino acid metabolism in determining reactive oxygen species recycling pathways, which when impaired may lead to increased oxidation of proteins and cell damage. They also provide insights on new supportive therapies for COVID-19 and other disorders that involve altered redox homeostasis and lower oxygen levels that may lead to better outcomes of disease severity.


Subject(s)
COVID-19 , Glutamic Acid , Amino Acids/metabolism , Cystine/metabolism , Gas Chromatography-Mass Spectrometry , Glutamic Acid/metabolism , Glutamine/metabolism , Homeostasis , Humans , Hypoxia , Male , Oxidation-Reduction , Oxygen , Proline/metabolism , Reactive Oxygen Species , SARS-CoV-2
14.
Oxid Med Cell Longev ; 2022: 4032704, 2022.
Article in English | MEDLINE | ID: covidwho-2038371

ABSTRACT

The hallmark of the coronavirus disease 2019 (COVID-19) pathophysiology was reported to be an inappropriate and uncontrolled immune response, evidenced by activated macrophages, and a robust surge of proinflammatory cytokines, followed by the release of reactive oxygen species, that synergistically result in acute respiratory distress syndrome, fibroproliferative lung response, and possibly even death. For these reasons, all identified risk factors and pathophysiological processes of COVID-19, which are feasible for the prevention and treatment, should be addressed in a timely manner. Accordingly, the evolving anti-inflammatory and antifibrotic therapy for severe COVID-19 and hindering post-COVID-19 fibrosis development should be comprehensively investigated. Experimental evidence indicates that renalase, a novel amino-oxidase, derived from the kidneys, exhibits remarkable organ protection, robustly addressing the most powerful pathways of cell trauma: inflammation and oxidative stress, necrosis, and apoptosis. As demonstrated, systemic renalase administration also significantly alleviates experimentally induced organ fibrosis and prevents adverse remodeling. The recognition that renalase exerts cytoprotection via sirtuins activation, by raising their NAD+ levels, provides a "proof of principle" for renalase being a biologically impressive molecule that favors cell protection and survival and maybe involved in the pathogenesis of COVID-19. This premise supports the rationale that renalase's timely supplementation may prove valuable for pathologic conditions, such as cytokine storm and related acute respiratory distress syndrome. Therefore, the aim for this review is to acknowledge the scientific rationale for renalase employment in the experimental model of COVID-19, targeting the acute phase mechanisms and halting fibrosis progression, based on its proposed molecular pathways. Novel therapies for COVID-19 seek to exploit renalase's multiple and distinctive cytoprotective mechanisms; therefore, this review should be acknowledged as the thorough groundwork for subsequent research of renalase's employment in the experimental models of COVID-19.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Sirtuins , Cytokines/metabolism , Fibrosis , Humans , Monoamine Oxidase/metabolism , NAD/metabolism , Oxidative Stress , Reactive Oxygen Species , Sirtuins/metabolism
15.
J Med Chem ; 65(19): 12562-12593, 2022 10 13.
Article in English | MEDLINE | ID: covidwho-2036741

ABSTRACT

Viral pathologies encompass activation of pro-oxidative pathways and inflammatory burst. Alleviating overproduction of reactive oxygen species and cytokine storm in COVID-19 is essential to counteract the immunogenic damage in endothelium and alveolar membranes. Antioxidants alleviate oxidative stress, cytokine storm, hyperinflammation, and diminish the risk of organ failure. Direct antiviral roles imply: impact on viral spike protein, interference with the ACE2 receptor, inhibition of dipeptidyl peptidase 4, transmembrane protease serine 2 or furin, and impact on of helicase, papain-like protease, 3-chyomotrypsin like protease, and RNA-dependent RNA polymerase. Prooxidative environment favors conformational changes in the receptor binding domain, promoting the affinity of the spike protein for the host receptor. Viral pathologies imply a vicious cycle, oxidative stress promoting inflammatory responses, and vice versa. The same was noticed with respect to the relationship antioxidant impairment-viral replication. Timing, dosage, pro-oxidative activities, mutual influences, and interference with other antioxidants should be carefully regarded. Deficiency is linked to illness severity.


Subject(s)
COVID-19 , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , Anti-Inflammatory Agents , Antioxidants/pharmacology , Antioxidants/therapeutic use , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome , Dipeptidyl Peptidase 4 , Furin , Humans , Papain , RNA-Dependent RNA Polymerase , Reactive Oxygen Species , Serine , Spike Glycoprotein, Coronavirus/metabolism
16.
Free Radic Biol Med ; 190: 247-263, 2022 09.
Article in English | MEDLINE | ID: covidwho-2036015

ABSTRACT

Clinical studies have shown a significant positive correlation between age and the likelihood of being infected with SARS-CoV-2. This increased susceptibility is positively correlated with chronic inflammation and compromised neurocognitive functions. Postmortem analyses suggest that acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), with systemic and lung hyperinflammation, can cause significant morbidity and mortality in COVID-19 patients. Supraphysiological supplemental oxygen, also known as hyperoxia, is commonly used to treat decreased blood oxygen saturation in COVID-19 patients. However, prolonged exposure to hyperoxia alone can cause oxygen toxicity, due to an excessive increase in the levels of reactive oxygen species (ROS), which can overwhelm the cellular antioxidant capacity. Subsequently, this causes oxidative cellular damage and increased levels of aging biomarkers, such as telomere shortening and inflammaging. The oxidative stress in the lungs and brain can compromise innate immunity, resulting in an increased susceptibility to secondary lung infections, impaired neurocognitive functions, and dysregulated hyperinflammation, which can lead to ALI/ARDS, and even death. Studies indicate that lung inflammation is regulated by the central nervous system, notably, the cholinergic anti-inflammatory pathway (CAIP), which is innervated by the vagus nerve and α7 nicotinic acetylcholine receptors (α7nAChRs) on lung cells, particularly lung macrophages. The activation of α7nAChRs attenuates oxygen toxicity in the lungs and improves clinical outcomes by restoring hyperoxia-compromised innate immunity. Mechanistically, α7nAChR agonist (e.g., GAT 107 and GTS-21) can regulate redox signaling by 1) activating Nrf2, a master regulator of the antioxidant response and a cytoprotective defense system, which can decrease cellular damage caused by ROS and 2) inhibiting the activation of the NF-κB-mediated inflammatory response. Notably, GTS-21 has been shown to be safe and it improves neurocognitive functions in humans. Therefore, targeting the α7nAChR may represent a viable therapeutic approach for attenuating dysregulated hyperinflammation-mediated ARDS and sepsis in COVID-19 patients receiving prolonged oxygen therapy.


Subject(s)
Acute Lung Injury , COVID-19 , Hyperoxia , Pneumonia , Respiratory Distress Syndrome , Acute Lung Injury/metabolism , Aging , Antioxidants/metabolism , COVID-19/therapy , Humans , Hyperoxia/complications , Hyperoxia/metabolism , Lung/metabolism , Oxygen/metabolism , Pneumonia/metabolism , Reactive Oxygen Species/metabolism , SARS-CoV-2 , alpha7 Nicotinic Acetylcholine Receptor/metabolism
17.
Environ Pollut ; 313: 120166, 2022 Nov 15.
Article in English | MEDLINE | ID: covidwho-2031270

ABSTRACT

The rapid growth of plastic wastes exceeds efforts to eliminate plastic pollution owing to the outbreak of COVID-19 in 2020 and then aggravates inherent environmental threats to the ecosystem. The paper provided a short introduction relating to the hazards of plastic wastes on environment and a detailed statement about plastic toxicity on human. The article stated on plastic how to enter the body and cause harm for us step by step. Given the toxicity and harm of plastic wastes on human, the degradation of plastic wastes via the physical, chemical and biotic methodologies is looked back. The advanced physical techniques are introduced briefly at firstly. Additionally, evaluate on chemical method for plastic decomposition and review on biotic degradation of plastic. The reactive oxygen species and the enzymes play a crucial role in chemical and biotic degradation processes, respectively. The reactive oxygen species are derived from the activated state of oxides, and the enzymes that aid the microorganism to ingest plastic through its metabolic mechanism are secreted by the microorganism. Subsequently, the potential possibility of upcycling plastic is analyzed from two aspects of the technology and application. The innovative technology utilizes sunlight as driver-power of plastic upcycling. And the carbon capture, utilization and sequestration and the growth substrate provided the novel guided directions for plastic recycle. Lastly, the three suggestions on plastic waste management are expected to establish an economy and efficient plastic sorting system, and two engineering solutions on plastic recycle are to make a contribution for sustainable upcycling of plastic.


Subject(s)
COVID-19 , Plastics , Carbon , Ecosystem , Humans , Oxides , Plastics/toxicity , Reactive Oxygen Species , Technology
18.
Viruses ; 14(8)2022 08 15.
Article in English | MEDLINE | ID: covidwho-2024290

ABSTRACT

DNA damage response (DDR) is an evolutionarily conserved mechanism by which eukaryotic cells sense DNA lesions caused by intrinsic and extrinsic stimuli, including virus infection. Although interactions between DNA viruses and DDR have been extensively studied, how RNA viruses, especially coronaviruses, regulate DDR remains unknown. A previous study showed that the porcine epidemic diarrhea virus (PEDV), a member of the genus Alphacoronavirus in the Coronaviridae family, induces DDR in infected cells. However, the underlying mechanism was unclear. This study showed that PEDV activates the ATM-Chk2 signaling, while inhibition of ATM or Chk2 dampens the early stage of PEDV infection. Additionally, we found that PEDV-activated ATM signaling correlates with intracellular ROS production. Interestingly, we showed that, unlike the typical γH2AX foci, PEDV infection leads to a unique γH2AX staining pattern, including phase I (nuclear ring staining), II (pan-nuclear staining), and III (co-staining with apoptotic bodies), which highly resembles the apoptosis process. Furthermore, we demonstrated that PEDV-induced H2AX phosphorylation depends on the activation of caspase-7 and caspase-activated DNAse (CAD), but not ATM-Chk2. Finally, we showed that the knockdown of H2AX attenuates PEDV replication. Taken together, we conclude that PEDV induces DDR through the ROS-ATM and caspase7-CAD-γH2AX signaling pathways to foster its early replication.


Subject(s)
Coronavirus Infections , Porcine epidemic diarrhea virus , Animals , Coronavirus Infections/veterinary , Deoxyribonucleases , Phosphorylation , Porcine epidemic diarrhea virus/genetics , Reactive Oxygen Species , Signal Transduction , Swine
19.
Viruses ; 14(8)2022 08 04.
Article in English | MEDLINE | ID: covidwho-2024283

ABSTRACT

Enterovirus (EV) 71 caused episodes of outbreaks in China and Southeast Asia during the last few decades. We have previously reported that EV71 induces reactive oxygen species (ROS). However, the underlying mechanism remains elusive. Co-immunoprecipitation-proteomic analysis revealed that enteroviral 2B protein interacted with mitochondrial voltage-dependent anion channel 3 (VDAC3). Knockdown (KD) of VDAC3 expression specifically inhibited enteroviral replication. Single-round viral replication was also inhibited in KD cells, suggesting that VDAC3 plays an essential role in replication. Consistent with this, VDAC3 gene KD significantly reduced the EV71-induced mitochondrial ROS generation. Exogenous 2B expression could induce the mitochondrial ROS generation that was significantly reduced in VDAC3-KD cells or in the Mito-TEMPO-treated cells. Moreover, VDAC3 appears to be necessary for regulation of antioxidant metabolism. VDAC3 gene KD led to the enhancement of such pathways as hypotaurine/taurine synthesis in the infected cells. Taken together, these findings suggest that 2B and VDAC3 interact to enhance mitochondrial ROS generation, which promotes viral replication.


Subject(s)
Enterovirus A, Human , Picornaviridae , Enterovirus A, Human/metabolism , Mitochondria/metabolism , Picornaviridae/metabolism , Proteomics , Reactive Oxygen Species/metabolism , Virus Replication , Voltage-Dependent Anion Channels/genetics , Voltage-Dependent Anion Channels/metabolism
20.
Cells ; 11(16)2022 08 22.
Article in English | MEDLINE | ID: covidwho-2023200

ABSTRACT

Obesity is of concern to the population because it is known to cause inflammation and oxidative stress throughout the body, leading to patient predisposition for health conditions such as diabetes, hypertension, and some cancers. However, some proteins that are activated in times of oxidative stress may provide cytoprotective properties. In this study, we aim to gain further understanding of the interconnection between Nrf2 and Sesn2 during obesity-related stress and how this relationship can play a role in cardio-protection. Cardiomyocyte-specific Sesn2 knockout (cSesn2-/-) and Sesn2 overexpressed (tTa-tet-Sesn2) mice and their wildtype littermates (Sesn2flox/flox and tet-Sesn2, respectively) were assigned to either a normal chow (NC) or a high-fat (HF) diet to induce obesity. After 16 weeks of dietary intervention, heart function was evaluated via echocardiography and cardiac tissue was collected for analysis. Immunoblotting, histology, and ROS staining were completed. Human heart samples were obtained via the LifeLink Foundation and were also subjected to analysis. Overall, these results indicated that the overexpression of Sesn2 appears to have cardio-protective effects on the obese heart through the reduction of ROS and fibrosis present in the tissues and in cardiac function. These results were consistent for both mouse and human heart samples. In human samples, there was an increase in Sesn2 and Nrf2 expression in the obese patients' LV tissue. However, there was no observable pattern of Sesn2/Nrf2 expression in mouse LV tissue samples. Further investigation into the link between the Sesn2/Nrf2 pathway and obesity-related oxidative stress is needed.


Subject(s)
Heart Diseases , NF-E2-Related Factor 2 , Animals , Diet, High-Fat , GA-Binding Protein Transcription Factor , Humans , Mice , NF-E2-Related Factor 2/metabolism , Nuclear Proteins/metabolism , Obesity , Reactive Oxygen Species/metabolism , Sestrins
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