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1.
Cell Mol Biol Lett ; 27(1): 6, 2022 Jan 11.
Article in English | MEDLINE | ID: covidwho-1622208

ABSTRACT

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is associated with a high mortality rate. The majority of deaths in this disease are caused by ARDS (acute respiratory distress syndrome) followed by cytokine storm and coagulation complications. Although alterations in the level of the number of coagulation factors have been detected in samples from COVID-19 patients, the direct molecular mechanism which has been involved in this pathologic process has not been explored yet. The PI3K/AKT signaling pathway is an intracellular pathway which plays a central role in cell survival. Also, in recent years the association between this pathway and coagulopathies has been well clarified. Therefore, based on the evidence on over-activity of the PI3K/AKT signaling pathway in SARS-CoV-2 infection, in the current review, the probable role of this cellular pathway as a therapeutic target for the prevention of coagulation complications in patients with COVID-19 is discussed.


Subject(s)
Blood Coagulation Disorders/etiology , Blood Coagulation , COVID-19/complications , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Animals , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/metabolism , COVID-19/blood , COVID-19/metabolism , Humans , Inflammation/blood , Inflammation/etiology , Inflammation/metabolism , Molecular Targeted Therapy , SARS-CoV-2/physiology
2.
JAMA Netw Open ; 4(12): e2141328, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1592856

ABSTRACT

Importance: Hospitalized patients with COVID-19 pneumonia have high rates of morbidity and mortality. Objective: To assess the efficacy of colchicine in hospitalized patients with COVID-19 pneumonia. Design, Setting, and Participants: The Estudios Clínicos Latino América (ECLA) Population Health Research Institute (PHRI) COLCOVID trial was a multicenter, open-label, randomized clinical trial performed from April 17, 2020, to March 28, 2021, in adults with confirmed or suspected SARS-CoV-2 infection followed for up to 28 days. Participants received colchicine vs usual care if they were hospitalized with COVID-19 symptoms and had severe acute respiratory syndrome or oxygen desaturation. The main exclusion criteria were clear indications or contraindications for colchicine, chronic kidney disease, and negative results on a reverse transcription-polymerase chain reaction test for SARS-CoV-2 before randomization. Data were analyzed from June 20 to July 25, 2021. Interventions: Patients were assigned in a 1:1 ratio to usual care or usual care plus colchicine. Colchicine was administered orally in a loading dose of 1.5 mg immediately after randomization, followed by 0.5 mg orally within 2 hours of the initial dose and 0.5 mg orally twice a day for 14 days or discharge, whichever occurred first. Main Outcomes and Measures: The first coprimary outcome was the composite of a new requirement for mechanical ventilation or death evaluated at 28 days. The second coprimary outcome was death at 28 days. Results: A total of 1279 hospitalized patients (mean [SD] age, 61.8 [14.6] years; 449 [35.1%] women and 830 [64.9%] men) were randomized, including 639 patients in the usual care group and 640 patients in the colchicine group. Corticosteroids were used in 1171 patients (91.5%). The coprimary outcome of mechanical ventilation or 28-day death occurred in 160 patients (25.0%) in the colchicine group and 184 patients (28.8%) in the usual care group (hazard ratio [HR], 0.83; 95% CI, 0.67-1.02; P = .08). The second coprimary outcome, 28-day death, occurred in 131 patients (20.5%) in the colchicine group and 142 patients (22.2%) in the usual care group (HR, 0.88; 95% CI, 0.70-1.12). Diarrhea was the most frequent adverse effect of colchicine, reported in 68 patients (11.3%). Conclusions and Relevance: This randomized clinical trial found that compared with usual care, colchicine did not significantly reduce mechanical ventilation or 28-day mortality in patients hospitalized with COVID-19 pneumonia. Trial Registration: ClinicalTrials.gov Identifier: NCT04328480.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/therapy , Colchicine/therapeutic use , Hospitalization , Intubation, Intratracheal , Respiration, Artificial , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Anti-Inflammatory Agents/adverse effects , COVID-19/mortality , COVID-19/pathology , Colchicine/adverse effects , Female , Humans , Inflammation/drug therapy , Inflammation/etiology , Male , Middle Aged , SARS-CoV-2 , Standard of Care
3.
Lancet Respir Med ; 9(5): 533-544, 2021 05.
Article in English | MEDLINE | ID: covidwho-1537202

ABSTRACT

Cough is one of the most common presenting symptoms of COVID-19, along with fever and loss of taste and smell. Cough can persist for weeks or months after SARS-CoV-2 infection, often accompanied by chronic fatigue, cognitive impairment, dyspnoea, or pain-a collection of long-term effects referred to as the post-COVID syndrome or long COVID. We hypothesise that the pathways of neurotropism, neuroinflammation, and neuroimmunomodulation through the vagal sensory nerves, which are implicated in SARS-CoV-2 infection, lead to a cough hypersensitivity state. The post-COVID syndrome might also result from neuroinflammatory events in the brain. We highlight gaps in understanding of the mechanisms of acute and chronic COVID-19-associated cough and post-COVID syndrome, consider potential ways to reduce the effect of COVID-19 by controlling cough, and suggest future directions for research and clinical practice. Although neuromodulators such as gabapentin or opioids might be considered for acute and chronic COVID-19 cough, we discuss the possible mechanisms of COVID-19-associated cough and the promise of new anti-inflammatories or neuromodulators that might successfully target both the cough of COVID-19 and the post-COVID syndrome.


Subject(s)
COVID-19/complications , COVID-19/physiopathology , Cough/etiology , Inflammation/etiology , Nervous System Diseases/etiology , Neuroimmunomodulation , Cough/physiopathology , Humans , Inflammation/physiopathology , Nervous System Diseases/physiopathology , SARS-CoV-2 , Syndrome
4.
J Clin Immunol ; 41(8): 1723-1732, 2021 11.
Article in English | MEDLINE | ID: covidwho-1525557

ABSTRACT

BACKGROUND: SARS-CoV-2 infection leads to high viral loads in the upper respiratory tract that may be determinant in virus dissemination. The extent of intranasal antiviral response in relation to symptoms is unknown. Understanding how local innate responses control virus is key in the development of therapeutic approaches. METHODS: SARS-CoV-2-infected patients were enrolled in an observational study conducted at the Geneva University Hospitals, Switzerland, investigating virological and immunological characteristics. Nasal wash and serum specimens from a subset of patients were collected to measure viral load, IgA specific for the S1 domain of the spike protein, and a cytokine panel at different time points after infection; cytokine levels were analyzed in relation to symptoms. RESULTS: Samples from 13 SARS-CoV-2-infected patients and six controls were analyzed. We found an increase in CXCL10 and IL-6, whose levels remained elevated for up to 3 weeks after symptom onset. SARS-CoV-2 infection also induced CCL2 and GM-CSF, suggesting local recruitment and activation of myeloid cells. Local cytokine levels correlated with viral load but not with serum cytokine levels, nor with specific symptoms, including anosmia. Some patients had S1-specific IgA in the nasal cavity while almost none had IgG. CONCLUSION: The nasal epithelium is an active site of cytokine response against SARS-CoV-2 that can last more than 2 weeks; in this mild COVID-19 cohort, anosmia was not associated with increases in any locally produced cytokines.


Subject(s)
COVID-19/immunology , Cytokines/biosynthesis , Inflammation/etiology , Nasal Mucosa/immunology , SARS-CoV-2 , Viral Load , Adult , Aged , Antibodies, Viral , COVID-19/virology , Female , Humans , Longitudinal Studies , Male , Middle Aged , Prospective Studies , SARS-CoV-2/immunology
5.
Eur Rev Med Pharmacol Sci ; 25(19): 5889-5903, 2021 10.
Article in English | MEDLINE | ID: covidwho-1478931

ABSTRACT

OBJECTIVE: Evidence supports a sex disparity in clinical outcomes of COVID-19 patients, with men exhibiting higher mortality rates compared to women. We aimed to test the correlation between serum levels of sex hormones [total testosterone, estradiol (E2), estradiol to testosterone (E2/T) ratio, progesterone), prolactin and 25-hydroxyvitamin D [25(OH)D] and markers of inflammation, coagulation and sepsis at admission in hospitalized men with COVID-19. PATIENTS AND METHODS: We conducted an exploratory retrospective study including symptomatic men with confirmed SARS-CoV-2 infection who were consecutively admitted to our Institution between April 1 and May 31, 2020. RESULTS: Patients were divided into survivors (n=20) and non-survivors (n=39). As compared to survivors, non-survivors showed significantly higher median neutrophil-to-lymphocyte ratio (NLR) values, D-dimer and procalcitonin (PCT) levels, along with significantly lower median 25(OH)D levels and total testosterone levels. Non-survivors exhibited significantly higher median values of E2/T ratio (a marker of aromatase activity). Spearman's correlation analysis revealed that total testosterone levels were significantly and inversely correlated with NLR, high-sensitivity C-reactive protein (hsCRP), interleukin-6, D-dimer and PCT. Conversely, E2/T ratio values were significantly and positively correlated with the aforementioned markers and with white blood cell (WBC) count. In a multivariate analysis performed by a logistic regression model after adjusting for major confounders (age, body mass index, hypertension and cardiovascular disease, diabetes mellitus and malignancy), total testosterone levels were significantly and inversely associated with risk of COVID-19-related in-hospital mortality. CONCLUSIONS: Low total testosterone levels and elevated E2/T ratio values at admission are associated with hyperinflammatory state in hospitalized men with COVID-19. Low total testosterone levels at admission represent an independent risk factor for in-hospital mortality in such patients. Therefore, total testosterone and E2/T ratio may serve as prognostic markers of disease severity in this population.


Subject(s)
COVID-19/blood , COVID-19/mortality , Estradiol/blood , Inflammation/blood , Inflammation/etiology , Testosterone/blood , Vitamin D/analogs & derivatives , Adult , Aged , Aged, 80 and over , Fibrin Fibrinogen Degradation Products/analysis , Hospital Mortality , Hospitalization , Humans , Leukocyte Count , Lymphocyte Count , Male , Middle Aged , Procalcitonin/blood , Retrospective Studies , Risk Factors , Severity of Illness Index , Survival Analysis , Vitamin D/blood
6.
Int J Mol Sci ; 22(19)2021 Oct 01.
Article in English | MEDLINE | ID: covidwho-1463708

ABSTRACT

Social behavioral changes, including social isolation or loneliness, increase the risk for stress-related disorders, such as major depressive disorder, posttraumatic stress disorder (PTSD), and suicide, which share a strong neuroinflammatory etiopathogenetic component. The peroxisome-proliferator activated receptor (PPAR)-α, a newly discovered target involved in emotional behavior regulation, is a ligand-activated nuclear receptor and a transcription factor that, following stimulation by endogenous or synthetic ligands, may induce neuroprotective effects by modulating neuroinflammation, and improve anxiety and depression-like behaviors by enhancing neurosteroid biosynthesis. How stress affects epigenetic mechanisms with downstream effects on inflammation and emotional behavior remains poorly understood. We studied the effects of 4-week social isolation, using a mouse model of PTSD/suicide-like behavior, on hippocampal PPAR-α epigenetic modification. Decreased PPAR-α expression in the hippocampus of socially isolated mice was associated with increased levels of methylated cytosines of PPAR-α gene CpG-rich fragments and deficient neurosteroid biosynthesis. This effect was associated with increased histone deacetylases (HDAC)1, methyl-cytosine binding protein (MeCP)2 and decreased ten-eleven translocator (TET)2 expression, which favor hypermethylation. These alterations were associated with increased TLR-4 and pro-inflammatory markers (e.g., TNF-α,), mediated by NF-κB signaling in the hippocampus of aggressive mice. This study contributes the first evidence of stress-induced brain PPAR-α epigenetic regulation. Social isolation stress may constitute a risk factor for inflammatory-based psychiatric disorders associated with neurosteroid deficits, and targeting epigenetic marks linked to PPAR-α downregulation may offer a valid therapeutic approach.


Subject(s)
Aggression , Hippocampus/metabolism , Inflammation/etiology , PPAR alpha/genetics , Social Isolation , Stress, Psychological , Aggression/psychology , Animals , Behavior, Animal , Chromatin Assembly and Disassembly , CpG Islands , Disease Models, Animal , Disease Susceptibility , Epigenesis, Genetic , Gene Expression , Inflammation/metabolism , Inflammation Mediators/metabolism , Male , Methylation , Mice , PPAR alpha/metabolism , Promoter Regions, Genetic , Signal Transduction
7.
Cochrane Database Syst Rev ; 10: CD013101, 2020 10 12.
Article in English | MEDLINE | ID: covidwho-1453526

ABSTRACT

BACKGROUND: Corticosteroids are routinely given to children undergoing cardiac surgery with cardiopulmonary bypass (CPB) in an attempt to ameliorate the inflammatory response. Their use is still controversial and the decision to administer the intervention can vary by centre and/or by individual doctors within that centre. OBJECTIVES: This review is designed to assess the benefits and harms of prophylactic corticosteroids in children between birth and 18 years of age undergoing cardiac surgery with CPB. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and Conference Proceedings Citation Index-Science in June 2020. We also searched four clinical trials registers and conducted backward and forward citation searching of relevant articles. SELECTION CRITERIA: We included studies of prophylactic administration of corticosteroids, including single and multiple doses, and all types of corticosteroids administered via any route and at any time-point in the perioperative period. We excluded studies if steroids were administered therapeutically. We included individually randomised controlled trials (RCTs), with two or more groups (e.g. multi-drug or dose comparisons with a control group) but not 'head-to-head' trials without a placebo or a group that did not receive corticosteroids. We included studies in children, from birth up to 18 years of age, including preterm infants, undergoing cardiac surgery with the use of CPB. We also excluded studies in patients undergoing heart or lung transplantation, or both; studies in patients already receiving corticosteroids; in patients with abnormalities of the hypothalamic-pituitary-adrenal axis; and in patients given steroids at the time of cardiac surgery for indications other than cardiac surgery. DATA COLLECTION AND ANALYSIS: We used the Covidence systematic review manager to extract and manage data for the review. Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We resolved disagreements by consensus or by consultation with a third review author. We assessed the certainty of evidence with GRADE. MAIN RESULTS: We found 3748 studies, of which 888 were duplicate records. Two studies had the same clinical trial registration number, but reported different populations and interventions. We therefore included them as separate studies. We screened titles and abstracts of 2868 records and reviewed full text reports for 84 studies to determine eligibility. We extracted data for 13 studies. Pooled analyses are based on eight studies. We reported the remaining five studies narratively due to zero events for both intervention and placebo in the outcomes of interest. Therefore, the final meta-analysis included eight studies with a combined population of 478 participants. There was a low or unclear risk of bias across the domains. There was moderate certainty of evidence that corticosteroids do not change the risk of in-hospital mortality (five RCTs; 313 participants; risk ratio (RR) 0.83, 95% confidence interval (CI) 0.33 to 2.07) for children undergoing cardiac surgery with CPB. There was high certainty of evidence that corticosteroids reduce the duration of mechanical ventilation (six RCTs; 421 participants; mean difference (MD) 11.37 hours lower, 95% CI -20.29 to -2.45) after the surgery. There was high-certainty evidence that the intervention probably made little to no difference to the length of postoperative intensive care unit (ICU) stay (six RCTs; 421 participants; MD 0.28 days lower, 95% CI -0.79 to 0.24) and moderate-certainty evidence that the intervention probably made little to no difference to the length of the postoperative hospital stay (one RCT; 176 participants; mean length of stay 22 days; MD -0.70 days, 95% CI -2.62 to 1.22). There was moderate certainty of evidence for no effect of the intervention on all-cause mortality at the longest follow-up (five RCTs; 313 participants; RR 0.83, 95% CI 0.33 to 2.07) or cardiovascular mortality at the longest follow-up (three RCTs; 109 participants; RR 0.40, 95% CI 0.07 to 2.46). There was low certainty of evidence that corticosteroids probably make little to no difference to children separating from CPB (one RCT; 40 participants; RR 0.20, 95% CI 0.01 to 3.92). We were unable to report information regarding adverse events of the intervention due to the heterogeneity of reporting of outcomes. We downgraded the certainty of evidence for several reasons, including imprecision due to small sample sizes, a single study providing data for an individual outcome, the inclusion of both appreciable benefit and harm in the confidence interval, and publication bias. AUTHORS' CONCLUSIONS: Corticosteroids  probably do not change the risk of mortality for children having heart surgery using CPB at any time point. They probably reduce the duration of postoperative ventilation in this context, but have little or no effect on the total length of postoperative ICU stay or total postoperative hospital stay. There was inconsistency in the adverse event outcomes reported which, consequently, could not be pooled. It is therefore impossible to provide any implications and policy-makers will be unable to make any recommendations for practice without evidence about adverse effects. The review highlighted the need for well-conducted RCTs powered for clinical outcomes to confirm or refute the effect of corticosteroids versus placebo in children having cardiac surgery with CPB. A core outcome set for adverse event reporting in the paediatric major surgery and intensive care setting is required.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , Cardiac Surgical Procedures/methods , Cardiopulmonary Bypass/adverse effects , Inflammation/prevention & control , Adolescent , Adrenal Cortex Hormones/adverse effects , Bias , Cardiac Surgical Procedures/mortality , Cardiopulmonary Bypass/mortality , Cause of Death , Child , Child, Preschool , Dexamethasone/therapeutic use , Heart-Lung Machine/adverse effects , Hospital Mortality , Humans , Hydrocortisone/therapeutic use , Infant , Infant, Newborn , Inflammation/etiology , Intensive Care Units, Pediatric/statistics & numerical data , Length of Stay , Methylprednisolone/therapeutic use , Randomized Controlled Trials as Topic , Respiration, Artificial/statistics & numerical data
8.
Dis Markers ; 2021: 4129993, 2021.
Article in English | MEDLINE | ID: covidwho-1440848

ABSTRACT

Hyperinflammation is related to the development of COVID-19. Resveratrol is considered an anti-inflammatory and antiviral agent. Herein, we used a network pharmacological approach and bioinformatic gene analysis to explore the pharmacological mechanism of Resveratrol in COVID-19 therapy. Potential targets of Resveratrol were obtained from public databases. SARS-CoV-2 differentially expressed genes (DEGs) were screened out via bioinformatic analysis Gene Expression Omnibus (GEO) datasets GSE147507, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis; then, protein-protein interaction network was constructed. The common targets, GO terms, and KEGG pathways of Resveratrol targets and SARS-CoV-2 DEGs were confirmed. KEGG Mapper queried the location of common targets in the key pathways. A notable overlap of the GO terms and KEGG pathways between Resveratrol targets and SARS-CoV-2 DEGs was revealed. The shared targets between Resveratrol targets and SARS-CoV-2 mainly involved the IL-17 signaling pathway, NF-kappa B signaling pathway, and TNF signaling pathway. Our study uncovered that Resveratrol is a promising therapeutic candidate for COVID-19 and we also revealed the probable key targets and pathways involved. Ultimately, we bring forward new insights and encourage more studies on Resveratol to benefit COVID-19 patients.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/complications , Inflammation/drug therapy , Resveratrol/therapeutic use , COVID-19/virology , Gene Ontology , Genes, Viral , Humans , Inflammation/etiology , Molecular Docking Simulation , Protein Interaction Maps , Resveratrol/chemistry , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification
10.
Int J Mol Sci ; 22(19)2021 Sep 26.
Article in English | MEDLINE | ID: covidwho-1438630

ABSTRACT

A high incidence of thromboembolic events associated with high mortality has been reported in severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections with respiratory failure. The present study characterized post-transcriptional gene regulation by global microRNA (miRNA) expression in relation to activated coagulation and inflammation in 21 critically ill SARS-CoV-2 patients. The cohort consisted of patients with moderate respiratory failure (n = 11) and severe respiratory failure (n = 10) at an acute stage (day 0-3) and in the later course of the disease (>7 days). All patients needed supplemental oxygen and severe patients were defined by the requirement of positive pressure ventilation (intubation). Levels of D-dimers, activated partial thromboplastin time (aPTT), C-reactive protein (CRP), and interleukin (IL)-6 were significantly higher in patients with severe compared with moderate respiratory failure. Concurrently, next generation sequencing (NGS) analysis demonstrated increased dysregulation of miRNA expression with progression of disease severity connected to extreme downregulation of miR-320a, miR-320b and miR-320c. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed involvement in the Hippo signaling pathway, the transforming growth factor (TGF)-ß signaling pathway and in the regulation of adherens junctions. The expression of all miR-320 family members was significantly correlated with CRP, IL-6, and D-dimer levels. In conclusion, our analysis underlines the importance of thromboembolic processes in patients with respiratory failure and emphasizes miRNA-320s as potential biomarkers for severe progressive SARS-CoV-2 infection.


Subject(s)
COVID-19/complications , COVID-19/genetics , MicroRNAs/genetics , Respiratory Insufficiency/etiology , Respiratory Insufficiency/genetics , Aged , Aged, 80 and over , Blood Coagulation , COVID-19/blood , Disease Progression , Down-Regulation , Female , Humans , Inflammation/blood , Inflammation/etiology , Inflammation/genetics , Male , MicroRNAs/blood , Middle Aged , Respiratory Insufficiency/blood , SARS-CoV-2/isolation & purification , Severity of Illness Index
11.
Int Immunopharmacol ; 100: 108137, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1428075

ABSTRACT

A growing body of evidence indicates that neutrophil elastase (NE) is involved in the pathogenesis of respiratory infectious diseases, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study aimed to analyze the dynamic changes in serum levels of NE associated with inflammation, disease activity, and mortality rate in patients with COVID-19. We measured the serum concentrations of NE, C-Reactive protein (CRP), interleukin (IL)- 4, IL-6, IL-8, IL-10, and vitamin D levels in 83 ICU and 69 non-ICU patients compared with 82 healthy subjects (HS) in three-time points (T1-T3). Serum levels of NE, IL-6, IL-8, and CRP in ICU and non-ICU patients were significantly higher than HS (P < 0.001) in three-time points. Also, serum levels of NE, IL-6, IL-8, and CRP in ICU patients were significantly higher than in non-ICU patients (P < 0.05). On the day of admission (T1), the levels of NE, CRP, IL-6, IL-8 were gradually decreased from T1 to T3. At the same time, IL-4 and IL-10 were gradually increased from T1 to T2 and then reduced to T3. Further analyses demonstrated that the levels of NE, IL-6, and IL-8 in deceased patients were significantly higher than in recovered patients (P < 0.05). The ROC curve analysis demonstrated that markers, including NE, IL-6, and IL-8, were valuable indicators in evaluating the activity of COVID-19. Overall, our results signify the critical role of NE in the pathogenesis of COVID-19, and also, further support that NE has a potential therapeutic target for the attenuation of COVID-19 severity.


Subject(s)
COVID-19/etiology , Inflammation/etiology , Leukocyte Elastase/physiology , SARS-CoV-2 , Adult , Aged , C-Reactive Protein/analysis , COVID-19/mortality , Case-Control Studies , Cytokines/blood , Female , Humans , Intensive Care Units , Leukocyte Elastase/blood , Male , Middle Aged
12.
Int Immunopharmacol ; 100: 108150, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1401545

ABSTRACT

The etiological agent of coronavirus disease (COVID-19) is the new member of the Coronaviridae family, a severe acute respiratory syndrome coronavirus 2 virus (SARS-CoV-2), responsible for the pandemic that is plaguing the world. The single-stranded RNA virus is capable of infecting the respiratory tract, by binding the spike (S) protein on its viral surface to receptors for the angiotensin II-converting enzyme (ACE2), highly expressed in the pulmonary tissue, enabling the interaction of the virus with alveolar epithelial cells promoting endocytosis and replication of viral material. The infection triggers the activation of the immune system, increased purinergic signaling, and the release of cytokines as a defense mechanism, but the response can become exaggerated and prompt the so-called "cytokine storm", developing cases such as severe acute respiratory syndrome (SARS). This is characterized by fever, cough, and difficulty breathing, which can progress to pneumonia, failure of different organs and death. Thus, the present review aims to compile and correlate the mechanisms involved between the immune and purinergic systems with COVID-19, since the modulation of purinergic receptors, such as A2A, A2B, and P2X7 expressed by immune cells, seems to be effective as a promising therapy, to reduce the severity of the disease, as well as aid in the treatment of acute lung diseases and other cases of generalized inflammation.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/drug therapy , Receptors, Purinergic/drug effects , SARS-CoV-2 , Adenosine Triphosphate/physiology , Humans , Inflammation/etiology , Receptors, Purinergic/physiology , Severity of Illness Index , Signal Transduction/physiology
13.
Int Immunopharmacol ; 100: 108125, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1401542

ABSTRACT

Mucosal barrier alterations may play a role in the pathogenesis of several diseases, including COVID-19. In this study we evaluate the association between bacterial translocation markers and systemic inflammation at the earliest time-point after hospitalization and at the last 72 h of hospitalization in survivors and non-survivors COVID-19 patients. Sixty-six SARS-CoV-2 RT-PCR positive patients and nine non-COVID-19 pneumonia controls were admitted in this study. Blood samples were collected at hospital admission (T1) (Controls and COVID-19 patients) and 0-72 h before hospital discharge (T2, alive or dead) to analyze systemic cytokines and chemokines, lipopolysaccharide (LPS) concentrations and soluble CD14 (sCD14) levels. THP-1 human monocytic cell line was incubated with plasma from survivors and non-survivors COVID-19 patients and their phenotype, activation status, TLR4, and chemokine receptors were analyzed by flow cytometry. COVID-19 patients presented higher IL-6, IFN-γ, TNF-α, TGF-ß1, CCL2/MCP-1, CCL4/MIP-1ß, and CCL5/RANTES levels than controls. Moreover, LPS and sCD14 were higher at hospital admission in SARS-CoV-2-infected patients. Non-survivors COVID-19 patients had increased LPS levels concomitant with higher IL-6, TNF-α, CCL2/MCP-1, and CCL5/RANTES levels at T2. Increased expression of CD16 and CCR5 were identified in THP-1 cells incubated with the plasma of survivor patients obtained at T2. The incubation of THP-1 with T2 plasma of non-survivors COVID-19 leads to higher TLR4, CCR2, CCR5, CCR7, and CD69 expression. In conclusion, the coexistence of increased microbial translocation and hyperinflammation in patients with severe COVID-19 may lead to higher monocyte activation, which may be associated with worsening outcomes, such as death.


Subject(s)
COVID-19/immunology , Inflammation/etiology , Lipopolysaccharides/blood , Monocytes/physiology , SARS-CoV-2 , Aged , Aged, 80 and over , Bacterial Translocation , COVID-19/mortality , Female , Hospitalization , Humans , Inflammation Mediators/blood , Male , Middle Aged , Severity of Illness Index , THP-1 Cells
14.
Clin Immunol ; 232: 108852, 2021 11.
Article in English | MEDLINE | ID: covidwho-1401324

ABSTRACT

BACKGROUND: The majority of the coronavirus disease 2019 (COVID-19) non-survivors meet the criteria for disseminated intravascular coagulation (DIC). Although timely monitoring of clotting hemorrhagic development during the natural course of COVID-19 is critical for understanding pathogenesis, diagnosis, and treatment of the disease, however, limited data are available on the dynamic processes of inflammation/coagulopathy/fibrinolysis (ICF). METHODS: We monitored the dynamic progression of ICF in patients with moderate COVID-19. Out of 694 COVID-19 inpatients from 10 hospitals in Wenzhou, China, we selected 293 adult patients without comorbidities. These patients were divided into different daily cohorts according to the COVID-19 onset-time. Furthermore, data of 223 COVID-19 patients with comorbidities and 22 critical cases were analyzed. Retrospective data were extracted from electronic medical records. RESULTS: The virus-induced damages to pre-hospitalization patients triggered two ICF fluctuations during the 14-day course of the disease. C-reactive protein (CRP), fibrinogen, and D-dimer levels increased and peaked at day 5 (D) 5 and D9 during the 1st and 2nd fluctuations, respectively. The ICF activities were higher during the 2nd fluctuation. Although 12-day medication returned high CRP concentrations to normal and blocked fibrinogen increase, the D-dimer levels remained high on days 17 ±â€¯2 and 23 ±â€¯2 days of the COVID-19 course. Notably, although the oxygenation index, prothrombin time and activated partial thromboplastin time were within the normal range in critical COVID-19 patients at administration, 86% of these patients had a D-dimer level > 500 µg/L. CONCLUSION: COVID-19 is linked with chronic DIC, which could be responsible for the progression of the disease. Understanding and monitoring ICF progression during COVID-19 can help clinicians in identifying the stage of the disease quickly and accurately and administering suitable treatment.


Subject(s)
Blood Coagulation/physiology , COVID-19/complications , Fibrinolysis/physiology , Inflammation/etiology , Inflammation/virology , Adult , Anticoagulants/pharmacology , Blood Coagulation/drug effects , Blood Coagulation Disorders/etiology , Blood Coagulation Disorders/metabolism , Blood Coagulation Disorders/pathology , Blood Coagulation Disorders/virology , COVID-19/metabolism , COVID-19/pathology , China , Disease Progression , Disseminated Intravascular Coagulation/etiology , Disseminated Intravascular Coagulation/metabolism , Disseminated Intravascular Coagulation/pathology , Disseminated Intravascular Coagulation/virology , Female , Fibrin Fibrinogen Degradation Products/metabolism , Fibrinogen/metabolism , Hemorrhage/etiology , Hemorrhage/pathology , Hemorrhage/virology , Humans , Inflammation/pathology , Male , Middle Aged , Prothrombin Time , SARS-CoV-2/pathogenicity
15.
Med Hypotheses ; 146: 110396, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1386308

ABSTRACT

We have reviewed a considerable amount of recent scientific papers relating inflammation caused by air pollution with chronic and severe medical conditions. Furthermore, there are evidences relating organ inflammation caused by not only outdoor long-term but also short-term inhaled radioisotopes contained in high polluted air or in household natural radioactive background aerosols, in addition to SARS-COV-2 attached to bioaerosols, which are related with a worst evolution of severe acute respiratory syndrome patients. Reactive oxygen species (ROS) production induced by the interaction with environmental ionizing radiation contained in pollution is pointed out as a critical mechanism that predispose mainly to elder population, but not excluding young subjects, presenting previous chronic conditions of lung inflammation or neuroinflammation, which can lead to the most serious consequences.


Subject(s)
Air Pollution, Radioactive/adverse effects , COVID-19/etiology , Climate Change , Inflammation/etiology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , SARS-CoV-2/pathogenicity , Aerosols , Air Microbiology , COVID-19/mortality , Causality , Humans , Inflammasomes/metabolism , Inflammasomes/radiation effects , Models, Biological , Nervous System Diseases/etiology , Pandemics , Particle Size , Particulate Matter/adverse effects , Pneumonia/etiology
17.
Oxid Med Cell Longev ; 2021: 8671713, 2021.
Article in English | MEDLINE | ID: covidwho-1378091

ABSTRACT

The outbreak of the COVID-19 pandemic represents an ongoing healthcare emergency responsible for more than 3.4 million deaths worldwide. COVID-19 is the disease caused by SARS-CoV-2, a virus that targets not only the lungs but also the cardiovascular system. COVID-19 can manifest with a wide range of clinical manifestations, from mild symptoms to severe forms of the disease, characterized by respiratory failure due to severe alveolar damage. Several studies investigated the underlying mechanisms of the severe lung damage associated with SARS-CoV-2 infection and revealed that the respiratory failure associated with COVID-19 is the consequence not only of acute respiratory distress syndrome but also of macro- and microvascular involvement. New observations show that COVID-19 is an endothelial disease, and the consequent endotheliopathy is responsible for inflammation, cytokine storm, oxidative stress, and coagulopathy. In this review, we show the central role of endothelial dysfunction, inflammation, and oxidative stress in the COVID-19 pathogenesis and present the therapeutic targets deriving from this endotheliopathy.


Subject(s)
COVID-19/complications , Cytokine Release Syndrome/pathology , Endothelium, Vascular/pathology , Inflammation/pathology , Oxidative Stress , SARS-CoV-2/isolation & purification , Vascular Diseases/pathology , COVID-19/virology , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/therapy , Endothelium, Vascular/virology , Humans , Inflammation/etiology , Inflammation/therapy , Vascular Diseases/etiology , Vascular Diseases/therapy
18.
Neuropharmacology ; 198: 108766, 2021 10 15.
Article in English | MEDLINE | ID: covidwho-1376075

ABSTRACT

The coronavirus disease 2019 (Covid-19) pandemic intensified the already catastrophic drug overdose and substance use disorder (SUD) epidemic, signaling a syndemic as social isolation, economic and mental health distress, and disrupted treatment services disproportionally impacted this vulnerable population. Along with these social and societal factors, biological factors triggered by intense stress intertwined with incumbent overactivity of the immune system and the resulting inflammatory outcomes may impact the functional status of the central nervous system (CNS). We review the literature concerning SARS-CoV2 infiltration and infection in the CNS and the prospects of synergy between stress, inflammation, and kynurenine pathway function during illness and recovery from Covid-19. Taken together, inflammation and neuroimmune signaling, a consequence of Covid-19 infection, may dysregulate critical pathways and underlie maladaptive changes in the CNS, to exacerbate the development of neuropsychiatric symptoms and in the vulnerability to develop SUD. This article is part of the special Issue on 'Vulnerabilities to Substance Abuse'.


Subject(s)
COVID-19/epidemiology , Drug Misuse/statistics & numerical data , SARS-CoV-2 , Substance-Related Disorders/epidemiology , Adaptation, Psychological , Angiotensin-Converting Enzyme 2/physiology , Animals , Axons/virology , COVID-19/immunology , COVID-19/physiopathology , COVID-19/psychology , Comorbidity , Disease Susceptibility , Endothelial Cells/virology , Humans , Immunity, Innate , Inflammation/etiology , Kynurenine/metabolism , Neurons/virology , Neurotransmitter Agents/metabolism , Olfactory Mucosa/virology , Pandemics , SARS-CoV-2/physiology , Social Isolation , Stress, Psychological , Substance-Related Disorders/etiology , Substance-Related Disorders/physiopathology , Tryptophan/metabolism , Viral Tropism
19.
J Leukoc Biol ; 110(3): 425-431, 2021 09.
Article in English | MEDLINE | ID: covidwho-1375609

ABSTRACT

The immune response plays a critical role in the pathophysiology of SARS-CoV-2 infection ranging from protection to tissue damage and all occur in the development of acute respiratory distress syndrome (ARDS). ARDS patients display elevated levels of inflammatory cytokines and innate immune cells, and T and B cell lymphocytes have been implicated in this dysregulated immune response. Mast cells are abundant resident cells of the respiratory tract and are able to release different inflammatory mediators rapidly following stimulation. Recently, mast cells have been associated with tissue damage during viral infections, but their role in SARS-CoV-2 infection remains unclear. In this study, we examined the profile of mast cell activation markers in the serum of COVID-19 patients. We noticed that SARS-CoV-2-infected patients showed increased carboxypeptidase A3 (CPA3) and decreased serotonin levels in their serum when compared with symptomatic SARS-CoV-2-negative patients. CPA3 levels correlated with C-reactive protein, the number of circulating neutrophils, and quick SOFA. CPA3 in serum was a good biomarker for identifying severe COVID-19 patients, whereas serotonin was a good predictor of SARS-CoV-2 infection. In summary, our results show that serum CPA3 and serotonin levels are relevant biomarkers during SARS-CoV-2 infection. This suggests that mast cells and basophils are relevant players in the inflammatory response in COVID-19 and may represent targets for therapeutic intervention.


Subject(s)
COVID-19/diagnosis , Carboxypeptidases A/metabolism , Inflammation Mediators/metabolism , Inflammation/diagnosis , Mast Cells/immunology , SARS-CoV-2/isolation & purification , Serotonin/metabolism , Biomarkers/analysis , COVID-19/complications , COVID-19/metabolism , COVID-19/virology , Humans , Inflammation/etiology , Inflammation/metabolism , Inflammation/pathology , Mast Cells/pathology , Severity of Illness Index
20.
Int Immunopharmacol ; 100: 108071, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1364131

ABSTRACT

COVID-19 is the cause of a pandemic associated with substantial morbidity and mortality. As yet, there is no available approved drug to eradicate the virus. In this review article, we present an alternative study area that may contribute to the development of therapeutic targets for COVID-19. Growing evidence is revealing further pathophysiological mechanisms of COVID-19 related to the disregulation of inflammation pathways that seem to play a critical role toward COVID-19 complications. The NF-kB and JAK/STAT signaling pathways are highly activated in acute inflammation, and the excessive activity of these pathways in COVID-19 patients likely exacerbates the inflammatory responses of the host. A group of non-coding RNAs (miRNAs) manage certain features of the inflammatory process. In this study, we discuss recent advances in our understanding of miRNAs and their connection to inflammatory responses. Additionally, we consider the link between perturbations in miRNA levels and the onset of COVID-19 disease. Furthermore, previous studies published in the online databases, namely web of science, MEDLINE (PubMed), and Scopus, were reviewed for the potential role of miRNAs in the inflammatory manifestations of COVID-19. Moreover, we disclosed the interactions of inflammatory genes using STRING DB and designed interactions between miRNAs and target genes using Cityscape software. Several miRNAs, particularly miR-9, miR-98, miR-223, and miR-214, play crucial roles in the regulation of NF-kB and JAK-STAT signaling pathways as inflammatory regulators. Therefore, this group of miRNAs that mitigate inflammatory pathways can be further regarded as potential targets for far-reaching-therapeutic strategies in COVID-19 diseases.


Subject(s)
COVID-19/etiology , Inflammation/etiology , Janus Kinases/physiology , MicroRNAs/physiology , NF-kappa B/physiology , SARS-CoV-2 , STAT Transcription Factors/physiology , Humans , Signal Transduction/physiology
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