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1.
Diabetes ; 70(9): 2120-2130, 2021 09.
Article in English | MEDLINE | ID: covidwho-1528788

ABSTRACT

Diabetes is a known risk factor for severe coronavirus disease 2019 (COVID-19), the disease caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there is a lack of knowledge about the mechanisms involved in the evolution of COVID-19 in individuals with diabetes. We aimed to evaluate whether the chronic low-grade inflammation of diabetes could play a role in the development of severe COVID-19. We collected clinical data and blood samples of patients with and without diabetes hospitalized for COVID-19. Plasma samples were used to measure inflammatory mediators and peripheral blood mononuclear cells, for gene expression analysis of the SARS-CoV-2 main receptor system (ACE2/TMPRSS2), and for the main molecule of the leukotriene B4 (LTB4) pathway (ALOX5). We found that diabetes activates the LTB4 pathway and that during COVID-19 it increases ACE2/TMPRSS2 as well as ALOX5 expression. Diabetes was also associated with COVID-19-related disorders, such as reduced oxygen saturation as measured by pulse oximetry/fraction of inspired oxygen (FiO2) and arterial partial pressure of oxygen/FiO2 levels, and increased disease duration. In addition, the expressions of ACE2 and ALOX5 are positively correlated, with increased expression in patients with diabetes and COVID-19 requiring intensive care assistance. We confirmed these molecular results at the protein level, where plasma LTB4 is significantly increased in individuals with diabetes. In addition, IL-6 serum levels are increased only in individuals with diabetes requiring intensive care assistance. Together, these results indicate that LTB4 and IL-6 systemic levels, as well as ACE2/ALOX5 blood expression, could be early markers of severe COVID-19 in individuals with diabetes.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Arachidonate 5-Lipoxygenase/metabolism , COVID-19/pathology , Diabetes Mellitus/pathology , Leukotriene B4/metabolism , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/genetics , Arachidonate 5-Lipoxygenase/genetics , COVID-19/metabolism , Gene Expression Regulation , Humans , Inflammation/metabolism , Leukotriene B4/genetics , Risk Factors , Signal Transduction
2.
Int J Biol Sci ; 17(1): 20-31, 2021.
Article in English | MEDLINE | ID: covidwho-1526974

ABSTRACT

The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global infection, and is seriously threatening human life, especially cancer patients. Thus, we sought to determine the clinical roles of ACE2 (the cell entry receptor of SARS-CoV-2) in ccRCC (clear cell renal cell carcinoma). TCGA, GEO and TIP datasets, and immunohistochemistry and western blot results were used to determine the prognostic and clinicopathological characteristics of ACE2. ACE2 expression was down-regulated in ccRCC tissues and cell lines. The multivariate Cox regression analysis results indicated that increased ACE2 expression was independent predictor of longer OS (HR: 0.8259, 95%CI: 0.7734-0.8819, P<0.0001) and RFS (HR: 0.8023, 95%CI: 0.7375-0.8729, P<0.0001) in ccRCC patients. Lower ACE2 expression was also associated with advanced tumor stage, higher histological grade and pathological stage, and metastasis. Besides, ACE2 expression was significantly positively and negatively correlated with CD4 Naïve infiltration and CD4 Memory infiltration, respectively. Moreover, higher CD4 Naïve and lower CD4 Memory infiltration levels were associated with better pathological features and longer OS and RFS. Furthermore, high ACE2 expression group in decreased CD4 Naïve, enriched CD4 Naïve and enriched CD4 memory cohort had favorable prognosis. These findings identified that AEC2 was significantly reduced in ccRCC, and decreased ACE2 was related to worse pathological features and poor prognosis. Low ACE2 expression in ccRCC may partially affect the prognosis due to altered immune cells infiltration levels.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Biomarkers, Tumor/metabolism , Carcinoma, Renal Cell/metabolism , Kidney Neoplasms/metabolism , CD4-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , Carcinoma, Renal Cell/immunology , Humans , Kidney Neoplasms/immunology , Prognosis , SARS-CoV-2/isolation & purification
3.
PLoS One ; 16(10): e0257892, 2021.
Article in English | MEDLINE | ID: covidwho-1526682

ABSTRACT

BACKGROUND: Coronavirus Disease 2019 (COVID-19) is a respiratory viral illness causing pneumonia and systemic disease. Abnormalities in pulmonary function tests (PFT) after COVID-19 infection have been described. The determinants of these abnormalities are unclear. We hypothesized that inflammatory biomarkers and CT scan parameters at the time of infection would be associated with abnormal gas transfer at short term follow-up. METHODS: We retrospectively studied subjects who were hospitalized for COVID-19 pneumonia and discharged. Serum inflammatory biomarkers, CT scan and clinical characteristics were assessed. CT images were evaluated by Functional Respiratory Imaging with automated tissue segmentation algorithms of the lungs and pulmonary vasculature. Volumes of the pulmonary vessels that were ≤5mm (BV5), 5-10mm (BV5_10), and ≥10mm (BV10) in cross sectional area were analyzed. Also the amount of opacification on CT (ground glass opacities). PFT were performed 2-3 months after discharge. The diffusion capacity of carbon monoxide (DLCO) was obtained. We divided subjects into those with a DLCO <80% predicted (Low DLCO) and those with a DLCO ≥80% predicted (Normal DLCO). RESULTS: 38 subjects were included in our cohort. 31 out of 38 (81.6%) subjects had a DLCO<80% predicted. The groups were similar in terms of demographics, body mass index, comorbidities, and smoking status. Hemoglobin, inflammatory biomarkers, spirometry and lung volumes were similar between groups. CT opacification and BV5 were not different between groups, but both Low and Normal DLCO groups had lower BV5 measures compared to healthy controls. BV5_10 and BV10 measures were higher in the Low DLCO group compared to the normal DLCO group. Both BV5_10 and BV10 in the Low DLCO group were greater compared to healthy controls. BV5_10 was independently associated with DLCO<80% in multivariable logistic regression (OR 1.29, 95% CI 1.01, 1.64). BV10 negatively correlated with DLCO% predicted (r = -0.343, p = 0.035). CONCLUSIONS: Abnormalities in pulmonary vascular volumes at the time of hospitalization are independently associated with a low DLCO at follow-up. There was no relationship between inflammatory biomarkers during hospitalization and DLCO. Pulmonary vascular abnormalities during hospitalization for COVID-19 may serve as a biomarker for abnormal gas transfer after COVID-19 pneumonia.


Subject(s)
COVID-19/diagnostic imaging , Lung/blood supply , Lung/diagnostic imaging , SARS-CoV-2/metabolism , Tomography, X-Ray Computed , Adult , Aged , Biomarkers/metabolism , COVID-19/metabolism , COVID-19/therapy , Female , Follow-Up Studies , Hospitalization , Humans , Lung/metabolism , Lung/virology , Male , Middle Aged , Retrospective Studies
4.
Crit Care ; 25(1): 390, 2021 11 15.
Article in English | MEDLINE | ID: covidwho-1518286

ABSTRACT

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by lung inflammation and pulmonary edema. Coronavirus disease 2019 (COVID-19) is associated with ARDS in the more severe cases. This study aimed to compare the specificity of the metabolic alterations induced by COVID-19 or Influenza A pneumonia (IAP) in ARDS. METHODS: Eighteen patients with ARDS due to COVID-19 and twenty patients with ARDS due to IAP, admitted to the intensive care unit. ARDS was defined as in the American-European Consensus Conference. As compared with patients with COVID-19, patients with IAP were younger and received more often noradrenaline to maintain a mean arterial pressure > 65 mm Hg. Serum samples were analyzed by Nuclear Magnetic Resonance Spectroscopy. Multivariate Statistical Analyses were used to identify metabolic differences between groups. Metabolic pathway analysis was performed to identify the most relevant pathways involved in ARDS development. RESULTS: ARDS due to COVID-19 or to IAP induces a different regulation of amino acids metabolism, lipid metabolism, glycolysis, and anaplerotic metabolism. COVID-19 causes a significant energy supply deficit that induces supplementary energy-generating pathways. In contrast, IAP patients suffer more marked inflammatory and oxidative stress responses. The classificatory model discriminated against the cause of pneumonia with a success rate of 100%. CONCLUSIONS: Our findings support the concept that ARDS is associated with a characteristic metabolomic profile that may discriminate patients with ARDS of different etiologies, being a potential biomarker for the diagnosis, prognosis, and management of this condition.


Subject(s)
COVID-19/metabolism , Influenza A Virus, H1N1 Subtype , Influenza, Human/metabolism , Respiratory Distress Syndrome/metabolism , Adult , Aged , COVID-19/complications , Female , Humans , Influenza, Human/complications , Male , Middle Aged , Respiratory Distress Syndrome/virology
5.
Biomed Pharmacother ; 144: 112230, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1517059

ABSTRACT

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has become a serious challenge for medicine and science. Analysis of the molecular mechanisms associated with the clinical manifestations and severity of COVID-19 has identified several key points of immune dysregulation observed in SARS-CoV-2 infection. For diabetic patients, factors including higher binding affinity and virus penetration, decreased virus clearance and decreased T cell function, increased susceptibility to hyperinflammation, and cytokine storm may make these patients susceptible to a more severe course of COVID-19 disease. Metabolic changes induced by diabetes, especially hyperglycemia, can directly affect the immunometabolism of lymphocytes in part by affecting the activity of the mTOR protein kinase signaling pathway. High mTOR activity can enhance the progression of diabetes due to the activation of effector proinflammatory subpopulations of lymphocytes and, conversely, low activity promotes the differentiation of T-regulatory cells. Interestingly, metformin, an extensively used antidiabetic drug, inhibits mTOR by affecting the activity of AMPK. Therefore, activation of AMPK and/or inhibition of the mTOR-mediated signaling pathway may be an important new target for drug therapy in COVID-19 cases mostly by reducing the level of pro-inflammatory signaling and cytokine storm. These suggestions have been partially confirmed by several retrospective analyzes of patients with diabetes mellitus hospitalized for severe COVID-19.


Subject(s)
COVID-19/drug therapy , Diabetes Mellitus/drug therapy , Hypoglycemic Agents/therapeutic use , Immunity, Cellular/drug effects , Metformin/therapeutic use , Severity of Illness Index , COVID-19/epidemiology , COVID-19/immunology , COVID-19/metabolism , Diabetes Mellitus/epidemiology , Diabetes Mellitus/immunology , Diabetes Mellitus/metabolism , Humans , Hypoglycemic Agents/pharmacology , Immunity, Cellular/physiology , Lymphocytes/drug effects , Lymphocytes/immunology , Lymphocytes/metabolism , Metformin/pharmacology , Mortality/trends , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/immunology , TOR Serine-Threonine Kinases/metabolism
6.
JAMA Netw Open ; 4(11): e2133090, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1516696

ABSTRACT

Importance: Antidepressant use may be associated with reduced levels of several proinflammatory cytokines suggested to be involved with the development of severe COVID-19. An association between the use of selective serotonin reuptake inhibitors (SSRIs)-specifically fluoxetine hydrochloride and fluvoxamine maleate-with decreased mortality among patients with COVID-19 has been reported in recent studies; however, these studies had limited power due to their small size. Objective: To investigate the association of SSRIs with outcomes in patients with COVID-19 by analyzing electronic health records (EHRs). Design, Setting, and Participants: This retrospective cohort study used propensity score matching by demographic characteristics, comorbidities, and medication indication to compare SSRI-treated patients with matched control patients not treated with SSRIs within a large EHR database representing a diverse population of 83 584 patients diagnosed with COVID-19 from January to September 2020 and with a duration of follow-up of as long as 8 months in 87 health care centers across the US. Exposures: Selective serotonin reuptake inhibitors and specifically (1) fluoxetine, (2) fluoxetine or fluvoxamine, and (3) other SSRIs (ie, not fluoxetine or fluvoxamine). Main Outcomes and Measures: Death. Results: A total of 3401 adult patients with COVID-19 prescribed SSRIs (2033 women [59.8%]; mean [SD] age, 63.8 [18.1] years) were identified, with 470 receiving fluoxetine only (280 women [59.6%]; mean [SD] age, 58.5 [18.1] years), 481 receiving fluoxetine or fluvoxamine (285 women [59.3%]; mean [SD] age, 58.7 [18.0] years), and 2898 receiving other SSRIs (1733 women [59.8%]; mean [SD] age, 64.7 [18.0] years) within a defined time frame. When compared with matched untreated control patients, relative risk (RR) of mortality was reduced among patients prescribed any SSRI (497 of 3401 [14.6%] vs 1130 of 6802 [16.6%]; RR, 0.92 [95% CI, 0.85-0.99]; adjusted P = .03); fluoxetine (46 of 470 [9.8%] vs 937 of 7050 [13.3%]; RR, 0.72 [95% CI, 0.54-0.97]; adjusted P = .03); and fluoxetine or fluvoxamine (48 of 481 [10.0%] vs 956 of 7215 [13.3%]; RR, 0.74 [95% CI, 0.55-0.99]; adjusted P = .04). The association between receiving any SSRI that is not fluoxetine or fluvoxamine and risk of death was not statistically significant (447 of 2898 [15.4%] vs 1474 of 8694 [17.0%]; RR, 0.92 [95% CI, 0.84-1.00]; adjusted P = .06). Conclusions and Relevance: These results support evidence that SSRIs may be associated with reduced severity of COVID-19 reflected in the reduced RR of mortality. Further research and randomized clinical trials are needed to elucidate the effect of SSRIs generally, or more specifically of fluoxetine and fluvoxamine, on the severity of COVID-19 outcomes.


Subject(s)
Antidepressive Agents , COVID-19/mortality , Fluoxetine , Fluvoxamine , Serotonin Uptake Inhibitors , Severity of Illness Index , Adult , Aged , Antidepressive Agents/pharmacology , COVID-19/metabolism , Citalopram/pharmacology , Cytokines/metabolism , Female , Fluoxetine/pharmacology , Fluvoxamine/pharmacology , Humans , Male , Middle Aged , Prescription Drugs , Retrospective Studies , Risk , SARS-CoV-2 , Serotonin Uptake Inhibitors/pharmacology , Sertraline , United States
7.
Sci Rep ; 11(1): 22042, 2021 11 11.
Article in English | MEDLINE | ID: covidwho-1510622

ABSTRACT

The mutation of SARS-CoV-2 influences viral function as residue replacements affect both physiochemical properties and folding conformations. Although a large amount of data on SARS-CoV-2 is available, the investigation of how viral functions change in response to mutations is hampered by a lack of effective structural analysis. Here, we exploit the advances of protein structure fingerprint technology to study the folding conformational changes induced by mutations. With integration of both protein sequences and folding conformations, the structures are aligned for SARS-CoV to SARS-CoV-2, including Alpha variant (lineage B.1.1.7) and Delta variant (lineage B.1.617.2). The results showed that the virus evolution with change in mutational positions and physicochemical properties increased the affinity between spike protein and ACE2, which plays a critical role in coronavirus entry into human cells. Additionally, these structural variations impact vaccine effectiveness and drug function over the course of SARS-CoV-2 evolution. The analysis of structural variations revealed how the coronavirus has gradually evolved in both structure and function and how the SARS-CoV-2 variants have contributed to more severe acute disease worldwide.


Subject(s)
COVID-19/virology , Evolution, Molecular , Mutation , SARS-CoV-2/genetics , Amino Acid Sequence , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Humans , Models, Molecular , Protein Conformation , Protein Folding , Protein Interaction Maps , Protein Multimerization , SARS Virus/chemistry , SARS Virus/genetics , SARS Virus/metabolism , SARS-CoV-2/chemistry , SARS-CoV-2/metabolism , Sequence Alignment , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
8.
Molecules ; 26(21)2021 Nov 08.
Article in English | MEDLINE | ID: covidwho-1512511

ABSTRACT

This work describes an untargeted analytical approach for the screening, identification, and characterization of the trans-epithelial transport of green tea (Camellia sinensis) catechin extracts with in vitro inhibitory effect against the SARS-CoV-2 papain-like protease (PLpro) activity. After specific catechin extraction, a chromatographic separation obtained six fractions were carried out. The fractions were assessed in vitro against the PLpro target. Fraction 5 showed the highest inhibitory activity against the SARS-CoV-2 PLpro (IC50 of 0.125 µg mL-1). The untargeted characterization revealed that (-)-epicatechin-3-gallate (ECG) was the most abundant compound in the fraction and the primary molecule absorbed by differentiated Caco-2 cells. Results indicated that fraction 5 was approximately 10 times more active than ECG (IC50 value equal to 11.62 ± 0.47 µg mL-1) to inhibit the PLpro target. Overall, our findings highlight the synergistic effects of the various components of the crude extract compared to isolated ECG.


Subject(s)
Catechin/pharmacology , Coronavirus Papain-Like Proteases/metabolism , Tea/metabolism , Antiviral Agents/chemistry , COVID-19/drug therapy , COVID-19/metabolism , Caco-2 Cells , Camellia sinensis/metabolism , Catechin/analogs & derivatives , Catechin/chemistry , Catechin/metabolism , Coronavirus Papain-Like Proteases/drug effects , Epithelium/drug effects , Epithelium/metabolism , Humans , Mass Spectrometry/methods , Plant Extracts/chemistry , Plant Extracts/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Tea/chemistry , Tea/physiology
9.
PLoS One ; 16(11): e0257549, 2021.
Article in English | MEDLINE | ID: covidwho-1511814

ABSTRACT

Particulate generation occurs during exercise-induced exhalation, and research on this topic is scarce. Moreover, infection-control measures are inadequately implemented to avoid particulate generation. A laminar airflow ventilation system (LFVS) was developed to remove respiratory droplets released during treadmill exercise. This study aimed to investigate the relationship between the number of aerosols during training on a treadmill and exercise intensity and to elucidate the effect of the LFVS on aerosol removal during anaerobic exercise. In this single-center observational study, the exercise tests were performed on a treadmill at Running Science Lab in Japan on 20 healthy subjects (age: 29±12 years, men: 80%). The subjects had a broad spectrum of aerobic capacities and fitness levels, including athletes, and had no comorbidities. All of them received no medication. The exercise intensity was increased by 1-km/h increments until the heart rate reached 85% of the expected maximum rate and then maintained for 10 min. The first 10 subjects were analyzed to examine whether exercise increased the concentration of airborne particulates in the exhaled air. For the remaining 10 subjects, the LFVS was activated during constant-load exercise to compare the number of respiratory droplets before and after LFVS use. During exercise, a steady amount of particulates before the lactate threshold (LT) was followed by a significant and gradual increase in respiratory droplets after the LT, particularly during anaerobic exercise. Furthermore, respiratory droplets ≥0.3 µm significantly decreased after using LFVS (2120800±759700 vs. 560 ± 170, p<0.001). The amount of respiratory droplets significantly increased after LT. The LFVS enabled a significant decrease in respiratory droplets during anaerobic exercise in healthy subjects. This study's findings will aid in exercising safely during this pandemic.


Subject(s)
Air Conditioning/methods , COVID-19/prevention & control , Exercise/physiology , Particulate Matter/chemistry , Adult , Aerosols/chemistry , Air Filters , Anaerobic Threshold/physiology , COVID-19/metabolism , Exercise Test/methods , Exhalation/physiology , Female , Heart Rate/physiology , Humans , Japan , Lactic Acid/metabolism , Male , Oxygen Consumption/physiology , Respiration , Respiratory System/physiopathology , Running/physiology , SARS-CoV-2/pathogenicity , Ventilation/methods
10.
Clin Appl Thromb Hemost ; 27: 10760296211051764, 2021.
Article in English | MEDLINE | ID: covidwho-1511654

ABSTRACT

The precise mechanisms of pathology in severe COVID-19 remains elusive. Current evidence suggests that inflammatory mediators are responsible for the manifestation of clinical symptoms that precedes a fatal response to infection. This review examines the nature of platelet activating factor and emphasizes the similarities between the physiological effects of platelet activating factor and the clinical complications of severe COVID-19.


Subject(s)
COVID-19/metabolism , Platelet Activating Factor/metabolism , Animals , COVID-19/complications , COVID-19/mortality , COVID-19/pathology , Humans , Inflammation/complications , Inflammation/metabolism , Inflammation/mortality , Inflammation/pathology , Multiple Organ Failure/complications , Multiple Organ Failure/metabolism , Multiple Organ Failure/mortality , Multiple Organ Failure/pathology , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/mortality , Respiratory Distress Syndrome/pathology , SARS-CoV-2/physiology , Severity of Illness Index , Thrombosis/complications , Thrombosis/metabolism , Thrombosis/mortality , Thrombosis/pathology
11.
JCI Insight ; 6(21)2021 11 08.
Article in English | MEDLINE | ID: covidwho-1506181

ABSTRACT

COVID-19 is caused by SARS-CoV-2 (SC2) and is more prevalent and severe in elderly and patients with comorbid diseases (CM). Because chitinase 3-like-1 (CHI3L1) is induced during aging and CM, the relationships between CHI3L1 and SC2 were investigated. Here, we demonstrate that CHI3L1 is a potent stimulator of the SC2 receptor angiotensin converting enzyme 2 (ACE2) and viral spike protein priming proteases (SPP), that ACE2 and SPP are induced during aging, and that anti-CHI3L1, kasugamycin, and inhibitors of phosphorylation abrogate these ACE2- and SPP-inductive events. Human studies also demonstrate that the levels of circulating CHI3L1 are increased in the elderly and patients with CM, where they correlate with COVID-19 severity. These studies demonstrate that CHI3L1 is a potent stimulator of ACE2 and SPP, that this induction is a major mechanism contributing to the effects of aging during SC2 infection, and that CHI3L1 co-opts the CHI3L1 axis to augment SC2 infection. CHI3L1 plays a critical role in the pathogenesis of and is an attractive therapeutic target in COVID-19.


Subject(s)
Aging , COVID-19/metabolism , Chitinase-3-Like Protein 1/metabolism , Aging/drug effects , Aminoglycosides/pharmacology , Aminoglycosides/therapeutic use , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , Cell Line, Tumor , Chitinase-3-Like Protein 1/antagonists & inhibitors , HEK293 Cells , Humans , SARS-CoV-2/physiology
12.
Cell Metab ; 31(6): 1037-1040, 2020 06 02.
Article in English | MEDLINE | ID: covidwho-1505489

ABSTRACT

In the era of a pandemic, networking opportunities have evaporated, and researchers are reinventing ways to connect with the community. It is our pleasure to build some of those connections, especially for young authors, by introducing you to eleven scientists whose work is featured in this issue. Here, they share their diverse and splendid journeys-from early concepts to the fruition of published work.


Subject(s)
COVID-19/metabolism , Humans
13.
Cell Metab ; 31(6): 1035-1036, 2020 06 02.
Article in English | MEDLINE | ID: covidwho-1505488

ABSTRACT

We are excited to announce that the Cell Metabolism Advisory Board has grown to better represent the metabolism community. We are honored to present these leaders as they share their perspectives. From taking unexpected journeys to pushing for a stronger future, they emphasize the indisputable value of curiosity, teamwork, diversity, and support.


Subject(s)
COVID-19/metabolism , COVID-19/genetics , Humans
14.
Front Immunol ; 12: 732913, 2021.
Article in English | MEDLINE | ID: covidwho-1504188

ABSTRACT

Obesity prevails worldwide to an increasing effect. For example, up to 42% of American adults are considered obese. Obese individuals are prone to a variety of complications of metabolic disorders including diabetes mellitus, hypertension, cardiovascular disease, and chronic kidney disease. Recent meta-analyses of clinical studies in patient cohorts in the ongoing coronavirus-disease 2019 (COVID-19) pandemic indicate that the presence of obesity and relevant disorders is linked to a more severe prognosis of COVID-19. Given the significance of obesity in COVID-19 progression, we provide a review of host metabolic and immune responses in the immunometabolic dysregulation exaggerated by obesity and the viral infection that develops into a severe course of COVID-19. Moreover, sequela studies of individuals 6 months after having COVID-19 show a higher risk of metabolic comorbidities including obesity, diabetes, and kidney disease. These collectively implicate an inter-systemic dimension to understanding the association between obesity and COVID-19 and suggest an interdisciplinary intervention for relief of obesity-COVID-19 complications beyond the phase of acute infection.


Subject(s)
COVID-19/immunology , COVID-19/metabolism , Obesity/immunology , Obesity/metabolism , COVID-19/complications , Disease Progression , Host-Pathogen Interactions/immunology , Humans , Immunity , Metabolic Diseases/immunology , Metabolic Diseases/metabolism , Obesity/complications , Prognosis , SARS-CoV-2/pathogenicity , Severity of Illness Index
15.
Sci Rep ; 11(1): 21633, 2021 11 04.
Article in English | MEDLINE | ID: covidwho-1503836

ABSTRACT

Although the serum lipidome is markedly affected by COVID-19, two unresolved issues remain: how the severity of the disease affects the level and the composition of serum lipids and whether serum lipidome analysis may identify specific lipids impairment linked to the patients' outcome. Sera from 49 COVID-19 patients were analyzed by untargeted lipidomics. Patients were clustered according to: inflammation (C-reactive protein), hypoxia (Horowitz Index), coagulation state (D-dimer), kidney function (creatinine) and age. COVID-19 patients exhibited remarkable and distinctive dyslipidemia for each prognostic factor associated with reduced defense against oxidative stress. When patients were clustered by outcome (7 days), a peculiar lipidome signature was detected with an overall increase of 29 lipid species, including-among others-four ceramide and three sulfatide species, univocally related to this analysis. Considering the lipids that were affected by all the prognostic factors, we found one sphingomyelin related to inflammation and viral infection of the respiratory tract and two sphingomyelins, that are independently related to patients' age, and they appear as candidate biomarkers to monitor disease progression and severity. Although preliminary and needing validation, this report pioneers the translation of lipidome signatures to link the effects of five critical clinical prognostic factors with the patients' outcomes.


Subject(s)
COVID-19/metabolism , Lipids/blood , Serum/chemistry , Adult , Aged , Biomarkers/blood , COVID-19/blood , Dyslipidemias/metabolism , Female , Humans , Italy , Lipidomics/methods , Lipids/analysis , Male , Middle Aged , Oxidative Stress/physiology , Prognosis , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Sphingomyelins/blood
16.
Semin Hematol ; 58(3): 182-187, 2021 07.
Article in English | MEDLINE | ID: covidwho-1500774

ABSTRACT

Iron is a micronutrient essential for a wide range of metabolic processes in virtually all living organisms. During infections, a battle for iron takes place between the human host and the invading pathogens. The liver peptide hepcidin, which is phylogenetically and structurally linked to defensins (antimicrobial peptides of the innate immunity), plays a pivotal role by subtracting iron to pathogens through its sequestration into host cells, mainly macrophages. While this phenomenon is well studied in certain bacterial infections, much less is known regarding viral infections. Iron metabolism also has implications on the functionality of cells of the immune system. Once primed by the contact with antigen presenting cells, lymphocytes need iron to sustain the metabolic burst required for mounting an effective cellular and humoral response. The COVID-19 pandemic has boosted an amount of clinical and translational research over the possible influences of nutrients on SARS-CoV-2 infection, in terms of either susceptibility or clinical course. Here we review the intersections between iron metabolism and COVID-19, belonging to the wider domain of the so-called "nutritional immunity". A better understanding of such connections has potential broad implications, either from a mechanistic standpoint, or for the development of more effective strategies for managing COVID-19 and possible future pandemics.


Subject(s)
COVID-19 , Iron/metabolism , COVID-19/immunology , COVID-19/metabolism , Humans , Immunity, Innate , Lymphocytes , Pandemics
17.
Sci Rep ; 11(1): 21514, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1500512

ABSTRACT

Coronavirus disease 2019 (COVID-19) is associated with systemic inflammation. A wide range of adipokines activities suggests they influence pathogenesis and infection course. The aim was to assess concentrations of chemerin, omentin, and vaspin among COVID-19 patients with an emphasis on adipokines relationship with COVID-19 severity, concomitant metabolic abnormalities and liver dysfunction. Serum chemerin, omentin and vaspin concentrations were measured in serum collected from 70 COVID-19 patients at the moment of admission to hospital, before any treatment was applied and 20 healthy controls. Serum chemerin and omentin concentrations were significantly decreased in COVID-19 patients compared to healthy volunteers (271.0 vs. 373.0 ng/ml; p < 0.001 and 482.1 vs. 814.3 ng/ml; p = 0.01, respectively). There were no correlations of analyzed adipokines with COVID-19 severity based on the presence of pneumonia, dyspnea, or necessity of Intensive Care Unit hospitalization (ICU). Liver test abnormalities did not influence adipokines levels. Elevated GGT activity was associated with ICU admission, presence of pneumonia and elevated concentrations of CRP, ferritin and interleukin 6. Chemerin and omentin depletion in COVID-19 patients suggests that this adipokines deficiency play influential role in disease pathogenesis. However, there was no relationship between lower adipokines level and frequency of COVID-19 symptoms as well as disease severity. The only predictive factor which could predispose to a more severe COVID-19 course, including the presence of pneumonia and ICU hospitalization, was GGT activity.


Subject(s)
Adipokines/blood , Chemokines/blood , Cytokines/blood , Lectins/blood , Serpins/blood , Aged , Body Mass Index , C-Reactive Protein/analysis , COVID-19/complications , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Case-Control Studies , Female , GPI-Linked Proteins/blood , Hospitalization , Humans , Liver/metabolism , Male , Metabolic Syndrome/complications , Middle Aged , SARS-CoV-2/isolation & purification , gamma-Glutamyltransferase/metabolism
18.
Mitochondrion ; 61: 147-158, 2021 11.
Article in English | MEDLINE | ID: covidwho-1500157

ABSTRACT

The COVID-19 pandemic prompted the FDA to authorize a new nucleoside analogue, remdesivir, for emergency use in affected individuals. We examined the effects of its active metabolite, remdesivir triphosphate (RTP), on the activity of the replicative mitochondrial DNA polymerase, Pol γ. We found that while RTP is not incorporated by Pol γ into a nascent DNA strand, it remains associated with the enzyme impeding its synthetic activity and stimulating exonucleolysis. In spite of that, we found no evidence for deleterious effects of remdesivir treatment on the integrity of the mitochondrial genome in human cells in culture.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , COVID-19/drug therapy , DNA Polymerase gamma/metabolism , DNA Replication/drug effects , DNA, Mitochondrial/biosynthesis , Fibroblasts/metabolism , SARS-CoV-2 , Adenosine Monophosphate/pharmacology , Alanine/pharmacology , COVID-19/metabolism , Cells, Cultured , Humans
19.
Front Biosci (Landmark Ed) ; 26(10): 740-751, 2021 10 30.
Article in English | MEDLINE | ID: covidwho-1498507

ABSTRACT

Objectives: To quantify the integrated levels of ACE2 and TMPRSS2, the two well-recognized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry-related genes, and to further identify key factors contributing to SARS-CoV-2 susceptibility in head and neck squamous cell carcinoma (HNSC). Methods: We developed a metric of the potential for tissue infected with SARS-CoV-2 ("TPSI") based on ACE2 and TMPRSS2 transcript levels and compared TPSI levels between tumor and matched normal tissues across 11 tumor types. For further analysis of HNSC, weighted gene co-expression network analysis (WGCNA), functional analysis, and single sample gene set enrichment analysis (ssGSEA) were conducted to investigate TPSI-relevant biological processes and their relationship with the immune landscape. TPSI-related factors were identified from clinical and mutational domains, followed by lasso regression to determine their relative effects on TPSI levels. Results: TPSI levels in tumors were generally lower than in the normal tissues. In HNSC, the genes highly associated with TPSI were enriched in viral entry-related processes, and TPSI levels were positively correlated with both eosinophils and T helper 17 (Th17) cell infiltration. Furthermore, the site of onset, human papillomaviruses (HPV) status, and nuclear receptor binding SET domain protein 1 (NSD1) mutations were identified as the most important factors shaping TPSI levels. Conclusions: This study identified the infection risk of SARS-CoV-2 between tumor and normal tissues, and provided evidence for the risk stratification of HNSC.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Carcinoma, Squamous Cell/genetics , Head and Neck Neoplasms/genetics , Serine Endopeptidases/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , COVID-19/virology , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/virology , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks , Head and Neck Neoplasms/metabolism , Head and Neck Neoplasms/virology , Humans , Reverse Transcriptase Polymerase Chain Reaction/methods , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Virus Internalization
20.
PLoS One ; 16(10): e0259179, 2021.
Article in English | MEDLINE | ID: covidwho-1496531

ABSTRACT

This paper focuses on the application of deep learning (DL) in the diagnosis of coronavirus disease (COVID-19). The novelty of this work is in the introduction of optimized InceptionResNetV2 for COVID-19 (CO-IRv2) method. A part of the CO-IRv2 scheme is derived from the concepts of InceptionNet and ResNet with hyperparameter tuning, while the remaining part is a new architecture consisting of a global average pooling layer, batch normalization, dense layers, and dropout layers. The proposed CO-IRv2 is applied to a new dataset of 2481 computed tomography (CT) images formed by collecting two independent datasets. Data resizing and normalization are performed, and the evaluation is run up to 25 epochs. Various performance metrics, including precision, recall, accuracy, F1-score, area under the receiver operating characteristics (AUC) curve are used as performance metrics. The effectiveness of three optimizers known as Adam, Nadam and RMSProp are evaluated in classifying suspected COVID-19 patients and normal people. Results show that for CO-IRv2 and for CT images, the obtained accuracies of Adam, Nadam and RMSProp optimizers are 94.97%, 96.18% and 96.18%, respectively. Furthermore, it is shown here that for the case of CT images, CO-IRv2 with Nadam optimizer has better performance than existing DL algorithms in the diagnosis of COVID-19 patients. Finally, CO-IRv2 is applied to an X-ray dataset of 1662 images resulting in a classification accuracy of 99.40%.


Subject(s)
COVID-19/classification , COVID-19/diagnostic imaging , Image Processing, Computer-Assisted/methods , Algorithms , COVID-19/metabolism , Data Accuracy , Deep Learning , Humans , Neural Networks, Computer , ROC Curve , Radiography/methods , SARS-CoV-2/pathogenicity , Sensitivity and Specificity , Tomography, X-Ray Computed/methods
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