RESUMEN
A wide variety of inflammatory mediators, mainly cytokines and chemokines, are induced during SARS CoV-2 infection. Among these proinflammatory mediators, chemokines tend to play a pivotal role in virus-mediated immunopathology. The C-C chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1) is a potent proinflammatory cytokine and strong chemoattractant of monocytes, macrophages and CD4+ T cells bearing C-C chemokine receptor type-2 (CCR2). Besides controlling immune cell trafficking, CCL2 is also involved in multiple pathophysiological processes including systemic hyperinflammation associated cytokine release syndrome (CRS), organ fibrosis and blood coagulation. These pathological features are commonly manifested in severe and fatal cases of COVID-19. Given the crucial role of CCL2 in COVID-19 pathogenesis, the CCL2:CCR2 axis may constitute a potential therapeutic target to control virus-induced hyperinflammation and multi-organ dysfunction. Herein we describe recent advances on elucidating the role of CCL2 in COVID-19 pathogenesis, prognosis, and a potential target of anti-inflammatory interventions.
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COVID-19 , Quimiocina CCL2 , SARS-CoV-2 , Humanos , COVID-19/inmunología , COVID-19/virología , COVID-19/patología , Quimiocina CCL2/metabolismo , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Pronóstico , Receptores CCR2/metabolismo , Biomarcadores , Antiinflamatorios/uso terapéutico , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/virologíaRESUMEN
Epstein-Barr virus (EBV) is a ubiquitous and predominantly B cell tropic virus. One of the most common viruses to infect humans, EBV, is best known as the causative agent of infectious mononucleosis (IM). Although most people experience asymptomatic infection, EBV is a potent immune stimulus and as such it elicits robust proliferation and activation of the B-lymphocytes it infects as well as the immune cells that respond to infection. In certain individuals, such as those with inherited or acquired defects affecting the immune system, failure to properly control EBV leads to the accumulation of EBV-infected B cells and EBV-reactive immune cells, which together contribute to the development of often life-threatening cytokine storm syndromes (CSS). Here, we review the normal immune response to EBV and discuss several CSS associated with EBV, such as chronic active EBV infection, hemophagocytic lymphohistiocytosis, and post-transplant lymphoproliferative disorder. Given the critical role for cytokines in driving inflammation and contributing to disease pathogenesis, we also discuss how targeting specific cytokines provides a rational and potentially less toxic treatment for EBV-driven CSS.
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Síndrome de Liberación de Citoquinas , Citocinas , Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Humanos , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/virología , Herpesvirus Humano 4/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/complicaciones , Citocinas/inmunología , Citocinas/metabolismo , Linfohistiocitosis Hemofagocítica/inmunología , Linfohistiocitosis Hemofagocítica/virología , Linfocitos B/inmunología , Linfocitos B/virología , Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/virología , AnimalesRESUMEN
The herpesviruses are the most common infectious agents associated with both primary and secondary cytokine storm syndromes (CSS). While Epstein-Barr Virus (EBV) is most frequently reported in association with CSS, cytomegalovirus (CMV) and many other herpesviruses (e.g., herpes simplex virus, varicella zoster virus, and human herpesviruses 6 and 8) are clearly associated with CSS in children and adults. Immunocompromised hosts, whether due to primary immunodeficiency or secondary immune compromise (e.g., solid organ or stem cell transplantation), appear to be at particularly increased risk of herpesvirus-associated CSS. In this chapter, the association of the non-EBV herpesviruses with CSS will be discussed, including predisposing factors and treatment considerations.
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Síndrome de Liberación de Citoquinas , Infecciones por Herpesviridae , Herpesviridae , Humanos , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/virología , Infecciones por Herpesviridae/inmunología , Infecciones por Herpesviridae/virología , Infecciones por Herpesviridae/complicaciones , Herpesviridae/inmunología , Herpesviridae/patogenicidad , Herpesviridae/fisiología , Huésped InmunocomprometidoRESUMEN
IMPORTANCE: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has tragically claimed millions of lives through coronavirus disease 2019 (COVID-19), and there remains a critical gap in our understanding of the precise molecular mechanisms responsible for the associated fatality. One key viral factor of interest is the SARS-CoV-2 ORF3a protein, which has been identified as a potent inducer of host cellular proinflammatory responses capable of triggering the catastrophic cytokine storm, a primary contributor to COVID-19-related deaths. Moreover, ORF3a, much like the spike protein, exhibits a propensity for frequent mutations, with certain variants linked to the severity of COVID-19. Our previous research unveiled two distinct types of ORF3a mutant proteins, categorized by their subcellular localizations, setting the stage for a comparative investigation into the functional and mechanistic disparities between these two types of ORF3a variants. Given the clinical significance and functional implications of the natural ORF3a mutations, the findings of this study promise to provide invaluable insights into the potential roles undertaken by these mutant ORF3a proteins in the pathogenesis of COVID-19.
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COVID-19 , Retículo Endoplásmico , SARS-CoV-2 , Proteínas Viroporinas , Humanos , COVID-19/virología , Síndrome de Liberación de Citoquinas/patología , Síndrome de Liberación de Citoquinas/virología , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/virología , Degradación Asociada con el Retículo Endoplásmico , Proteínas Mutantes , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Proteínas Viroporinas/genética , Proteínas Viroporinas/metabolismoRESUMEN
The spectrum of HHV-8-associated disorders includes Kaposi's sarcoma, primary effusion lymphoma, multicentric Castleman's disease, and the recently described KSHV inflammatory cytokine syndrome (KICS), a life-threatening disorder complicating HIV infection. There have been no reports in the literature concerning non-immunosuppressed individuals affected with KICS. We report here a KICS-like illness occurring in two elderly Greek men without HIV infection or other recognizable cause of immunosuppression.
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Herpesvirus Humano 8 , Humanos , Masculino , Anciano , Grecia , Infecciones por Herpesviridae/complicaciones , Infecciones por Herpesviridae/virología , Citocinas/sangre , Síndrome de Liberación de Citoquinas/virología , Sarcoma de Kaposi/virologíaRESUMEN
SARS-CoV-2 causes mostly mild cases. However, a considerable number of patients develop fatal acute respiratory distress syndrome due to the cytokine storm and imbalanced immune response. Several therapies depending on immunomodulation have been used, including glucocorticoids and IL-6 blockers. However, their efficacy is not perfect with all patients and patients with concomitant bacterial infections and sepsis. Accordingly, studies on different immunomodulators, including extracorporeal techniques, are crucial to save this category of patients. In this review, we overviewed the different immunomodulation techniques shortly, with a brief review of extracorporeal methods.
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Infecciones Bacterianas , COVID-19 , Síndrome de Liberación de Citoquinas , Hemofiltración , Humanos , Infecciones Bacterianas/complicaciones , COVID-19/complicaciones , COVID-19/terapia , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/virología , Citocinas , Inhibidores de la Interleucina-6/uso terapéutico , SARS-CoV-2RESUMEN
BACKGROUND: Acute lung injury (ALI) is a common complication of sepsis with poor effective interventions. Huashibaidu formula (HSBD) showed good therapeutic effects in treating coronavirus disease 2019 (COVID-19) patients. PURPOSE: This study was designed to investigate the therapeutic potential and precise mechanism of HSBD against sepsis-induced ALI based on network pharmacology and animal experiments. MATERIALS AND METHODS: Network pharmacology was used to predict the possible mechanism of HSBD against sepsis. Next, a sepsis-induced ALI rat model via intraperitoneal lipopolysaccharide (LPS) was constructed to evaluate the level of inflammatory cytokines and the degree of lung injury. The expression of inflammation-related signaling pathways, including TLR4/NF-κB and PI3K/Akt was determined by western blot. RESULTS: Network pharmacology analysis indicated that HSBD might have a therapeutic effect on sepsis mainly by affecting inflammatory and immune responses. Animal experiments demonstrated that HSBD protected the lung tissue from LPS-induced injury, and inhibited the levels of inflammatory cytokines such as interleukin (IL)-1ß, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ and tumor necrosis factor (TNF)-α in the serum and IL-1ß, IL-5, IL-6, IL-18, GM-CSF, IFN-γ and TNF-α in the lung tissue. Western blot results revealed that HSBD downregulated the expression of TLR4/NF-κB and upregulated the expression of PI3K/Akt. CONCLUSION: The therapeutic mechanism of HSBD against sepsis-induced ALI mainly involved suppressing cytokine storms and relieving inflammatory symptoms by regulating the expression of TLR4/NF-κB and PI3K/Akt. Our study provides a scientific basis for the mechanistic investigation and clinical application of HSBD in the treatment of sepsis and COVID-19.
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Lesión Pulmonar Aguda , Síndrome de Liberación de Citoquinas , Sepsis , Animales , Ratas , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/etiología , COVID-19 , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/virología , Citocinas/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Hyperinflammation characterized by elevated proinflammatory cytokines known as 'cytokine storms' is the major cause of high severity and mortality seen in COVID-19 patients. The pathology behind the cytokine storms is currently unknown. Increased HMGB1 levels in serum/plasma of COVID-19 patients were reported by many studies, which positively correlated with the level of proinflammatory cytokines. Dead cells following SARS-CoV-2 infection might release a large amount of HMGB1 and RNA of SARS-CoV-2 into extracellular space. HMGB1 is a well-known inflammatory mediator. Additionally, extracellular HMGB1 might interact with SARS-CoV-2 RNA because of its high capability to bind with a wide variety of molecules including nucleic acids and could trigger massive proinflammatory immune responses. This review aimed to critically explore the many possible pathways by which HMGB1-SARS-CoV-2 RNA complexes mediate proinflammatory responses in COVID-19. The contribution of these pathways to impair host immune responses against SARS-CoV-2 infection leading to a cytokine storm was also evaluated. Moreover, since blocking the HMGB1-SARS-CoV-2 RNA interaction might have therapeutic value, some of the HMGB1 antagonists have been reviewed. The HMGB1- SARS-CoV-2 RNA complexes might trigger endocytosis via RAGE which is linked to lysosomal rupture, PRRs activation, and pyroptotic death. High levels of the proinflammatory cytokines produced might suppress many immune cells leading to uncontrolled viral infection and cell damage with more HMGB1 released. Altogether these mechanisms might initiate a proinflammatory cycle leading to a cytokine storm. HMGB1 antagonists could be considered to give benefit in alleviating cytokine storms and serve as a potential candidate for COVID-19 therapy.
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Antivirales , Tratamiento Farmacológico de COVID-19 , COVID-19 , Síndrome de Liberación de Citoquinas , Proteína HMGB1 , Terapia Molecular Dirigida , ARN Viral , SARS-CoV-2 , Humanos , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/virología , COVID-19/complicaciones , COVID-19/inmunología , Proteína HMGB1/antagonistas & inhibidores , Proteína HMGB1/metabolismo , ARN Viral/metabolismo , Interacciones Microbiota-Huesped/inmunología , SARS-CoV-2/metabolismo , Antivirales/farmacología , Antivirales/uso terapéuticoRESUMEN
Background: In 2019, the coronavirus pandemic emerged, resulting in the highest mortality and morbidity rate globally. It has a prevailing transmission rate and continues to be a global burden. There is a paucity of data regarding the role of long non-coding RNAs (lncRNAs) in COVID-19. Therefore, the current study aimed to investigate lncRNAs, particularly NEAT1 and TUG1, and their association with IL-6, CCL2, and TNF-α in COVID-19 patients with moderate and severe disease. Methods: The study was conducted on 80 COVID-19 patients (35 with severe and 45 with moderate infection) and 40 control subjects. Complete blood count (CBC), D-dimer assay, serum ferritin, and CRP were assayed. qRT-PCR was used to measure RNAs and lncRNAs. Results: NEAT1 and TUG1 expression levels were higher in COVID-19 patients compared with controls (P<0.001). Furthermore, CCL2, IL-6, and TNF-α expressions were higher in COVID-19 patients compared to controls (P<0.001). CCL2 and IL-6 expression levels were significantly higher in patients with severe compared to those with moderate COVID-19 infection (P<0.001). IL-6 had the highest accuracy in distinguishing COVID-19 patients (AUC=1, P<0.001 at a cutoff of 0.359), followed by TUG1 (AUC=0.999, P<0.001 at a cutoff of 2.28). NEAT1 and TUG1 had significant correlations with the measured cytokines, and based on the multivariate regression analysis, NEAT1 is the independent predictor for survival in COVID-19 patients (P=0.02). Conclusion: In COVID-19 patients, significant overexpression of NEAT1 and TUG1 was observed, consistent with cytokine storm. TUG1 could be an efficient diagnostic biomarker, whereas NEAT1 was an independent predictor for overall survival.
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COVID-19 , Síndrome de Liberación de Citoquinas , ARN Largo no Codificante , COVID-19/complicaciones , Síndrome de Liberación de Citoquinas/genética , Síndrome de Liberación de Citoquinas/virología , Humanos , Incidencia , Interleucina-6 , ARN Largo no Codificante/genética , Factor de Necrosis Tumoral alfaRESUMEN
BACKGROUND: Coronavirus disease 2019 (COVID-19) can cause cytokine release syndrome (CRS), which leads to high mortality rates. Tocilizumab suppresses CRS by blocking the signal transduction of interleukin-6 (IL-6). OBJECTIVE: To evaluate the clinical and laboratory parameters associated with mortality among patients receiving tocilizumab treatment. DESIGN AND SETTING: Retrospective observational study conducted in the chest disease departments of two different training and research hospitals in the center of Ankara, Turkey. METHODS: Patients who were hospitalized and treated with tocilizumab in September 2020 were retrospectively analyzed. Their laboratory parameters and clinical characteristics were obtained from the hospital information system database. Comparative analyses were performed between the patients who died and the ones who survived. RESULTS: A total of 58 patients who received tocilizumab treatment were included in this study, among whom 35 (60.3%) died. There was no difference between the mortality and survival groups in terms of white blood cell (WBC), neutrophil, lymphocyte, ferritin or C-reactive protein (CRP) levels detected on admission. WBC, lymphocyte, neutrophil and CRP levels measured on the third and fifth days after tocilizumab administration were found to be significantly lower in the survival group (P < 0.05). In multiple logistic regression analysis, age and oxygen saturation were determined to be independent risk factors for mortality. CONCLUSION: Persistently high WBC, CRP and neutrophil levels and low lymphocyte levels could be considered to be valuable indicators of mortality among COVID-19 patients treated with tocilizumab. Age and low oxygen saturation are independent risk factors for mortality among patients receiving tocilizumab treatment.
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Anticuerpos Monoclonales Humanizados , Tratamiento Farmacológico de COVID-19 , COVID-19 , Anticuerpos Monoclonales Humanizados/uso terapéutico , Proteína C-Reactiva/análisis , COVID-19/sangre , COVID-19/complicaciones , Síndrome de Liberación de Citoquinas/prevención & control , Síndrome de Liberación de Citoquinas/virología , Ferritinas/sangre , Humanos , Interleucina-6/sangre , Recuento de Leucocitos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Acute cardiac injuries occur in 20%-25% of hospitalized COVID-19 patients. Herein, we demonstrate that human cardiac organoids (hCOs) are a viable platform to model the cardiac injuries caused by COVID-19 hyperinflammation. As IL-1ß is an upstream cytokine and a core COVID-19 signature cytokine, it was used to stimulate hCOs to induce the release of a milieu of proinflammatory cytokines that mirror the profile of COVID-19 cytokine storm. The IL-1ß treated hCOs recapitulated transcriptomic, structural, and functional signatures of COVID-19 hearts. The comparison of IL-1ß treated hCOs with cardiac tissue from COVID-19 autopsies illustrated the critical roles of hyper-inflammation in COVID-19 cardiac insults and indicated the cardioprotective effects of endothelium. The IL-1ß treated hCOs thus provide a defined and robust model to assess the efficacy and potential side effects of immunomodulatory drugs, as well as the reversibility of COVID-19 cardiac injuries at baseline and simulated exercise conditions.
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COVID-19 , Síndrome de Liberación de Citoquinas , Cardiopatías , COVID-19/complicaciones , Síndrome de Liberación de Citoquinas/virología , Citocinas/metabolismo , Cardiopatías/virología , Humanos , Modelos Biológicos , OrganoidesRESUMEN
In this study, we assessed the potential synergistic effect of the Erns RNase activity and the poly-U insertion in the 3' untranslated region (UTR) of the low-virulence classical swine fever virus (CSFV) isolate Pinar de Rio (PdR) in innate and adaptive immunity regulation and its relationship with classical swine fever (CSF) pathogenesis in pigs. We knocked out the Erns RNase activity of PdR and replaced the long polyuridine sequence of the 3' UTR with 5 uridines found typically at this position, resulting in a double mutant, vPdR-H30K-5U. This mutant induced severe CSF in 5-day-old piglets and 3-week-old pigs, with higher lethality in the newborn (89.5%) than in the older (33.3%) pigs. However, the viremia and viral excretion were surprisingly low, while the virus load was high in the tonsils. Only alpha interferon (IFN-α) and interleukin 12 (IL-12) were highly and consistently elevated in the two groups. Additionally, high IL-8 levels were found in the newborn but not in the older pigs. This points toward a role of these cytokines in the CSF outcome, with age-related differences. The disproportional activation of innate immunity might limit systemic viral spread from the tonsils and increase virus clearance, inducing strong cytokine-mediated symptoms. Infection with vPdR-H30K-5U resulted in poor neutralizing antibody responses compared with results obtained previously with the parent and RNase knockout PdR. This study shows for the first time the synergistic effect of the 3' UTR and the Erns RNase function in regulating innate immunity against CSFV, favoring virus replication in target tissue and thus contributing to disease severity. IMPORTANCE CSF is one of the most relevant viral epizootic diseases of swine, with high economic and sanitary impact. Systematic stamping out of infected herds with and without vaccination has permitted regional virus eradication. However, the causative agent, CSFV, persists in certain areas of the world, leading to disease reemergence. Nowadays, low- and moderate-virulence strains that could induce unapparent CSF forms are prevalent, posing a challenge for disease eradication. Here, we show for the first time the synergistic role of lacking the Erns RNase activity and the 3' UTR polyuridine insertion from a low-virulence CSFV isolate in innate immunity disproportional activation. This might limit systemic viral spread to the tonsils and increase virus clearance, inducing strong cytokine-mediated symptoms, thus contributing to disease severity. These results highlight the role played by the Erns RNase activity and the 3' UTR in CSFV pathogenesis, providing new perspectives for novel diagnostic tools and vaccine strategies.
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Virus de la Fiebre Porcina Clásica , Peste Porcina Clásica , Síndrome de Liberación de Citoquinas , Regiones no Traducidas 3'/genética , Inmunidad Adaptativa/genética , Animales , Peste Porcina Clásica/inmunología , Peste Porcina Clásica/patología , Peste Porcina Clásica/virología , Virus de la Fiebre Porcina Clásica/enzimología , Virus de la Fiebre Porcina Clásica/genética , Virus de la Fiebre Porcina Clásica/inmunología , Virus de la Fiebre Porcina Clásica/patogenicidad , Síndrome de Liberación de Citoquinas/genética , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/virología , Citocinas , Inmunidad Innata/genética , Interferón-alfa/inmunología , Interleucina-12/inmunología , Ribonucleasas/genética , Ribonucleasas/metabolismo , Porcinos , Vacunas Virales , Virulencia/genéticaRESUMEN
BACKGROUND: Interleukin-11 is a pleiotropic cytokine that is known to play an important role in the progression of various forms of cancer by modulating the survival and proliferation of tumour cells. IL11 also demonstrates a structural homology to IL6, the predominant cytokine involved in COVID-19. This makes IL11 a potential therapeutic target in both diseases. OBJECTIVE: This study aimed to evaluate the impact of the two-point mutations, R135E and R190E, on the stability of IL11 and their effect on the binding affinity of IL11 with its receptor IL11Rα. It is a molecular level analysis based on the existing experimental validation. METHODS: Computer-aided drug designing techniques, such as molecular modelling, molecular docking, and molecular dynamics simulations, were employed to determine the consequential effects of the two-point mutations. RESULTS: Our analysis revealed that the two mutations led to a decrease in the overall stability of IL11. This was evident by the increased atomic fluctuations in the mutated regions as well as the corresponding elevation in the deviations seen through RMSD and Rg values. It was also accompanied by a loss in the secondary structural organisation in the mutated proteins. Moreover, mutation R135E led to an increase in the binding affinity of IL11 with IL11Rα and the formation of a more stable complex in comparison to the wild-type protein with its receptor. CONCLUSION: Mutation R190E led to the formation of a less stable complex than the wild-type, which suggests a decrease in the binding affinity between IL11 and IL11Rα.
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COVID-19 , Síndrome de Liberación de Citoquinas , Interleucina-11 , Neoplasias , COVID-19/genética , Síndrome de Liberación de Citoquinas/genética , Síndrome de Liberación de Citoquinas/virología , Citocinas , Humanos , Interleucina-11/genética , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Neoplasias/genéticaRESUMEN
We read the recent review article by Marta Kopanska et al. [...].
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Acetilcolinesterasa/metabolismo , COVID-19/metabolismo , Síndrome de Liberación de Citoquinas/metabolismo , Receptores Nicotínicos/metabolismo , SARS-CoV-2/metabolismo , Acetilcolina/metabolismo , Antivirales/uso terapéutico , COVID-19/prevención & control , COVID-19/virología , Cafeína/uso terapéutico , Síndrome de Liberación de Citoquinas/virología , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/virología , Miastenia Gravis/metabolismo , Miastenia Gravis/virología , Nicotina/uso terapéutico , Unión Proteica , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/fisiología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Nervio Vago/metabolismo , Nervio Vago/virologíaRESUMEN
We have carefully read the Letter to the Editor by Concetta Cafiero, Alessandra Micera, Agnese Re, Beniamino Schiavone, Giulio Benincasa, and Raffaele Palmirotta related to our paper entitled "Disorders of the Cholinergic System in COVID-19 Era-A Review of the Latest Research" [...].
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Acetilcolinesterasa/metabolismo , COVID-19/metabolismo , Síndrome de Liberación de Citoquinas/metabolismo , Receptores Nicotínicos/metabolismo , SARS-CoV-2/metabolismo , Adulto , Enzima Convertidora de Angiotensina 2/metabolismo , Basigina/metabolismo , COVID-19/virología , Neuronas Colinérgicas/metabolismo , Neuronas Colinérgicas/virología , Síndrome de Liberación de Citoquinas/virología , Humanos , Miastenia Gravis/metabolismo , Miastenia Gravis/virología , Unión Proteica , Receptores Virales/metabolismo , SARS-CoV-2/fisiología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Nervio Vago/metabolismo , Nervio Vago/virologíaRESUMEN
Growth differentiation factor 15 (GDF-15) is a transforming growth factor (TGF)-ß superfamily cytokine that plays a central role in metabolism regulation. Produced in response to mitochondrial stress, tissue damage or hypoxia, this cytokine has emerged as one of the strongest predictors of disease severity during inflammatory conditions, cancers and infections. Reports suggest that GDF-15 plays a tissue protective role via sympathetic and metabolic adaptation in the context of mitochondrial damage, although the exact mechanisms involved remain uncertain. In this review, we discuss the emergence of GDF-15 as a distinctive marker of viral infection severity, especially in the context of COVID-19. We will critically review the role of GDF-15 as an inflammation-induced mediator of disease tolerance, through metabolic and immune reprogramming. Finally, we discuss potential mechanisms of GDF-15 elevation during COVID-19 cytokine storm and its limitations. Altogether, this cytokine seems to be involved in disease tolerance to viral infections including SARS-CoV-2, paving the way for novel therapeutic interventions.
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Adaptación Psicológica/fisiología , Biomarcadores/metabolismo , COVID-19/metabolismo , Factor 15 de Diferenciación de Crecimiento/metabolismo , Animales , COVID-19/virología , Síndrome de Liberación de Citoquinas/metabolismo , Síndrome de Liberación de Citoquinas/virología , Citocinas/metabolismo , HumanosAsunto(s)
Antivirales/farmacología , Tratamiento Farmacológico de COVID-19 , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Expresión Génica/efectos de los fármacos , Progesterona/farmacología , SARS-CoV-2/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , COVID-19/genética , COVID-19/inmunología , COVID-19/virología , Cricetulus , Síndrome de Liberación de Citoquinas/genética , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/virología , Modelos Animales de Enfermedad , Humanos , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-10/genética , Interleucina-10/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/virología , Masculino , SARS-CoV-2/crecimiento & desarrollo , SARS-CoV-2/inmunología , Índice de Severidad de la Enfermedad , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Preventing the cytokine storm observed in COVID-19 is a crucial goal for reducing the occurrence of severe acute respiratory failure and improving outcomes. Here, we identify Aldo-Keto Reductase 1B10 (AKR1B10) as a key enzyme involved in the expression of pro-inflammatory cytokines. The analysis of transcriptomic data from lung samples of patients who died from COVID-19 demonstrates an increased expression of the gene encoding AKR1B10. Measurements of the AKR1B10 protein in sera from hospitalised COVID-19 patients suggests a significant link between AKR1B10 levels and the severity of the disease. In macrophages and lung cells, the over-expression of AKR1B10 induces the expression of the pro-inflammatory cytokines Interleukin-6 (IL-6), Interleukin-1ß (IL-1ß) and Tumor Necrosis Factor a (TNFα), supporting the biological plausibility of an AKR1B10 involvement in the COVID-19-related cytokine storm. When macrophages were stressed by lipopolysaccharides (LPS) exposure and treated by Zopolrestat, an AKR1B10 inhibitor, the LPS-induced production of IL-6, IL-1ß, and TNFα is significantly reduced, reinforcing the hypothesis that the pro-inflammatory expression of cytokines is AKR1B10-dependant. Finally, we also show that AKR1B10 can be secreted and transferred via extracellular vesicles between different cell types, suggesting that this protein may also contribute to the multi-organ systemic impact of COVID-19. These experiments highlight a relationship between AKR1B10 production and severe forms of COVID-19. Our data indicate that AKR1B10 participates in the activation of cytokines production and suggest that modulation of AKR1B10 activity might be an actionable pharmacological target in COVID-19 management.
Asunto(s)
Aldo-Ceto Reductasas/fisiología , COVID-19/genética , Síndrome de Liberación de Citoquinas/genética , Síndrome de Dificultad Respiratoria/genética , Aldo-Ceto Reductasas/antagonistas & inhibidores , Aldo-Ceto Reductasas/genética , Animales , COVID-19/complicaciones , COVID-19/metabolismo , COVID-19/patología , Estudios de Casos y Controles , Células Cultivadas , Síndrome de Liberación de Citoquinas/metabolismo , Síndrome de Liberación de Citoquinas/patología , Síndrome de Liberación de Citoquinas/virología , Citocinas/metabolismo , Inhibidores Enzimáticos/farmacología , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Gravedad del Paciente , Células RAW 264.7 , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/patología , Síndrome de Dificultad Respiratoria/virología , SARS-CoV-2/fisiología , TranscriptomaRESUMEN
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as COVID-19, is currently developing into a rapidly disseminating and an overwhelming worldwide pandemic. In severe COVID-19 cases, hypercoagulability and inflammation are two crucial complications responsible for poor prognosis and mortality. In addition, coagulation system activation and inflammation overlap and produce life-threatening complications, including coagulopathy and cytokine storm, which are associated with overproduction of cytokines and activation of the immune system; they might be a lead cause of organ damage. However, patients with severe COVID-19 who received anticoagulant therapy had lower mortality, especially with elevated D-dimer or fibrin degradation products (FDP). In this regard, the discovery of natural products with anticoagulant potential may help mitigate the numerous side effects of the available synthetic drugs. This review sheds light on blood coagulation and its impact on the complication associated with COVID-19. Furthermore, the sources of natural anticoagulants, the role of nanoparticle formulation in this outbreak, and the prevalence of thrombosis with thrombocytopenia syndrome (TTS) after COVID-19 vaccines are also reviewed. These combined data provide many research ideas related to the possibility of using these anticoagulant agents as a treatment to relieve acute symptoms of COVID-19 infection.
Asunto(s)
Anticoagulantes/uso terapéutico , Trastornos de la Coagulación Sanguínea/etiología , Vacunas contra la COVID-19/química , COVID-19/complicaciones , COVID-19/prevención & control , Nanopartículas/uso terapéutico , Anticoagulantes/administración & dosificación , Anticoagulantes/aislamiento & purificación , Coagulación Sanguínea , Trastornos de la Coagulación Sanguínea/clasificación , Trastornos de la Coagulación Sanguínea/prevención & control , Trastornos de la Coagulación Sanguínea/virología , Vacunas contra la COVID-19/administración & dosificación , Síndrome de Liberación de Citoquinas/prevención & control , Síndrome de Liberación de Citoquinas/virología , Humanos , Inflamación/etiología , Inflamación/prevención & control , Nanopartículas/química , SARS-CoV-2/patogenicidad , Trombofilia/etiologíaRESUMEN
The coronavirus disease 2019 (COVID-19) is a highly transmissible disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that poses a major threat to global public health. Although COVID-19 primarily affects the respiratory system, causing severe pneumonia and acute respiratory distress syndrome in severe cases, it can also result in multiple extrapulmonary complications. The pathogenesis of extrapulmonary damage in patients with COVID-19 is probably multifactorial, involving both the direct effects of SARS-CoV-2 and the indirect mechanisms associated with the host inflammatory response. Recognition of features and pathogenesis of extrapulmonary complications has clinical implications for identifying disease progression and designing therapeutic strategies. This review provides an overview of the extrapulmonary complications of COVID-19 from immunological and pathophysiologic perspectives and focuses on the pathogenesis and potential therapeutic targets for the management of COVID-19.