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1.
Int J Mol Sci ; 22(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205487

RESUMO

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with excess mortality worldwide. The cardiovascular system is the second most common target of SARS-CoV-2, which leads to severe complications, including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism, as well as other major thrombotic events because of direct endothelial injury and an excessive systemic inflammatory response. This review focuses on the similarities and the differences of inflammatory pathways involved in COVID-19 and atherosclerosis. Anti-inflammatory agents and immunomodulators have recently been assessed, which may constitute rational treatments for the reduction of cardiovascular events in both COVID-19 and atherosclerotic heart disease.


Assuntos
Aterosclerose/patologia , COVID-19/patologia , Corticosteroides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Aterosclerose/complicações , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , COVID-19/complicações , COVID-19/tratamento farmacológico , COVID-19/virologia , Quimiocinas/metabolismo , Síndrome da Liberação de Citocina/etiologia , Citocinas/metabolismo , Humanos , Prognóstico , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/metabolismo
2.
Molecules ; 26(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203721

RESUMO

Interleukin-1 (IL1) is a proinflammatory cytokine and promotes cancer cell proliferation and invasiveness in a diversity of cancers, such as breast and colon cancer. Here, we focused on the pharmacological effect of Entelon® (ETL) on the tumorigenesis of triple-negative breast cancer (TNBC) cells by IL1-alpha (IL1A). IL1A enhanced the cell growth and invasiveness of TNBC cells. We observed that abnormal IL1A induction is related with the poor prognosis of TNBC patients. IL1A also increased a variety of chemokines such as CCL2 and IL8. Interestingly, IL1A expression was reduced by the ETL treatment. Here, we found that ETL significantly decreased the MEK/ERK signaling pathway in TNBC cells. IL1A expression was reduced by UO126. Lastly, we studied the effect of ETL on the metastatic potential of TNBC cells. Our results showed that ETL significantly reduced the lung metastasis of TNBC cells. Our results showed that IL1A expression was regulated by the MEK/ERK- and PI3K/AKT-dependent pathway. Taken together, ETL inhibited the MEK/ERK and PI3K/AKT signaling pathway and suppressing the lung metastasis of TNBC cells through downregulation of IL1A. Therefore, we propose the possibility of ETL as an effective adjuvant for treating TNBC.


Assuntos
Metástase Neoplásica/tratamento farmacológico , Extratos Vegetais/farmacologia , Vitis/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Quimiocinas/metabolismo , Humanos , Interleucina-1alfa/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais/metabolismo , Sementes/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
3.
Int J Mol Sci ; 22(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: covidwho-1282515

RESUMO

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with excess mortality worldwide. The cardiovascular system is the second most common target of SARS-CoV-2, which leads to severe complications, including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism, as well as other major thrombotic events because of direct endothelial injury and an excessive systemic inflammatory response. This review focuses on the similarities and the differences of inflammatory pathways involved in COVID-19 and atherosclerosis. Anti-inflammatory agents and immunomodulators have recently been assessed, which may constitute rational treatments for the reduction of cardiovascular events in both COVID-19 and atherosclerotic heart disease.


Assuntos
Aterosclerose/patologia , COVID-19/patologia , Corticosteroides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Aterosclerose/complicações , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , COVID-19/complicações , COVID-19/tratamento farmacológico , COVID-19/virologia , Quimiocinas/metabolismo , Síndrome da Liberação de Citocina/etiologia , Citocinas/metabolismo , Humanos , Prognóstico , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/metabolismo
4.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209845

RESUMO

The vulnerability of humankind to SARS-CoV-2 in the absence of a pre-existing immunity, the unpredictability of the infection outcome, and the high transmissibility, broad tissue tropism, and ability to exploit and subvert the immune response pose a major challenge and are likely perpetuating the COVID-19 pandemic. Nevertheless, this peculiar infectious scenario provides researchers with a unique opportunity for studying, with the latest immunological techniques and understandings, the immune response in SARS-CoV-2 naïve versus recovered subjects as well as in SARS-CoV-2 vaccinees. Interestingly, the current understanding of COVID-19 indicates that the combined action of innate immune cells, cytokines, and chemokines fine-tunes the outcome of SARS-CoV-2 infection and the related immunopathogenesis. Indeed, the emerging picture clearly shows that the excessive inflammatory response against this virus is among the main causes of disease severity in COVID-19 patients. In this review, the innate immune response to SARS-CoV-2 infection is described not only in light of its capacity to influence the adaptive immune response towards a protective phenotype but also with the intent to point out the multiple strategies exploited by SARS-CoV-2 to antagonize host antiviral response and, finally, to outline inborn errors predisposing individuals to COVID-19 disease severity.


Assuntos
COVID-19/patologia , Imunidade Inata , COVID-19/imunologia , COVID-19/virologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Monócitos/citologia , Monócitos/metabolismo , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença
5.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: covidwho-1288903

RESUMO

The vulnerability of humankind to SARS-CoV-2 in the absence of a pre-existing immunity, the unpredictability of the infection outcome, and the high transmissibility, broad tissue tropism, and ability to exploit and subvert the immune response pose a major challenge and are likely perpetuating the COVID-19 pandemic. Nevertheless, this peculiar infectious scenario provides researchers with a unique opportunity for studying, with the latest immunological techniques and understandings, the immune response in SARS-CoV-2 naïve versus recovered subjects as well as in SARS-CoV-2 vaccinees. Interestingly, the current understanding of COVID-19 indicates that the combined action of innate immune cells, cytokines, and chemokines fine-tunes the outcome of SARS-CoV-2 infection and the related immunopathogenesis. Indeed, the emerging picture clearly shows that the excessive inflammatory response against this virus is among the main causes of disease severity in COVID-19 patients. In this review, the innate immune response to SARS-CoV-2 infection is described not only in light of its capacity to influence the adaptive immune response towards a protective phenotype but also with the intent to point out the multiple strategies exploited by SARS-CoV-2 to antagonize host antiviral response and, finally, to outline inborn errors predisposing individuals to COVID-19 disease severity.


Assuntos
COVID-19/patologia , Imunidade Inata , COVID-19/imunologia , COVID-19/virologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Monócitos/citologia , Monócitos/metabolismo , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença
6.
Sci Rep ; 11(1): 13464, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34188167

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for coronavirus disease 2019 (COVID-19) that emerged in human populations recently. Severely ill COVID-19 patients exhibit the elevation of proinflammatory cytokines, and such an unbalanced production of proinflammatory cytokines is linked to acute respiratory distress syndrome with high mortality in COVID-19 patients. Our study provides evidence that the ORF3a, M, ORF7a, and N proteins of SARS-CoV-2 were NF-κB activators. The viral sequence from infected zoo lions belonged to clade V, and a single mutation of G251V is found for ORF3a gene compared to all other clades. No significant functional difference was found for clade V ORF3a, indicating the NF-κB activation is conserved among COVID-19 variants. Of the four viral proteins, the ORF7a protein induced the NF-κB dictated proinflammatory cytokines including IL-1α, IL-1ß, IL-6, IL-8, IL-10, TNF-α, and IFNß. The ORF7a protein also induced IL-3, IL-4, IL-7, IL-23. Of 15 different chemokines examined in the study, CCL11, CCL17, CCL19, CCL20, CCL21, CCL22, CCL25, CCL26, CCL27, and CXCL9 were significantly upregulated by ORF7. These cytokines and chemokines were frequently elevated in severely ill COVID-19 patients. Our data provide an insight into how SARS-CoV-2 modulates NF-κB signaling and inflammatory cytokine expressions. The ORF7a protein may be a desirable target for strategic developments to minimize uncontrolled inflammation in COVID-19 patients.


Assuntos
Citocinas/metabolismo , NF-kappa B/metabolismo , SARS-CoV-2/metabolismo , Proteínas Virais/metabolismo , Sequência de Aminoácidos , COVID-19/patologia , COVID-19/virologia , Quimiocinas/genética , Quimiocinas/metabolismo , Citocinas/genética , Células HeLa , Humanos , Mutação Puntual , SARS-CoV-2/isolamento & purificação , Alinhamento de Sequência , Índice de Gravidade de Doença , Regulação para Cima , Proteínas da Matriz Viral/genética , Proteínas Virais/genética , Proteínas Viroporinas/química , Proteínas Viroporinas/genética , Proteínas Viroporinas/metabolismo
7.
Sci Rep ; 11(1): 13464, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: covidwho-1287819

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for coronavirus disease 2019 (COVID-19) that emerged in human populations recently. Severely ill COVID-19 patients exhibit the elevation of proinflammatory cytokines, and such an unbalanced production of proinflammatory cytokines is linked to acute respiratory distress syndrome with high mortality in COVID-19 patients. Our study provides evidence that the ORF3a, M, ORF7a, and N proteins of SARS-CoV-2 were NF-κB activators. The viral sequence from infected zoo lions belonged to clade V, and a single mutation of G251V is found for ORF3a gene compared to all other clades. No significant functional difference was found for clade V ORF3a, indicating the NF-κB activation is conserved among COVID-19 variants. Of the four viral proteins, the ORF7a protein induced the NF-κB dictated proinflammatory cytokines including IL-1α, IL-1ß, IL-6, IL-8, IL-10, TNF-α, and IFNß. The ORF7a protein also induced IL-3, IL-4, IL-7, IL-23. Of 15 different chemokines examined in the study, CCL11, CCL17, CCL19, CCL20, CCL21, CCL22, CCL25, CCL26, CCL27, and CXCL9 were significantly upregulated by ORF7. These cytokines and chemokines were frequently elevated in severely ill COVID-19 patients. Our data provide an insight into how SARS-CoV-2 modulates NF-κB signaling and inflammatory cytokine expressions. The ORF7a protein may be a desirable target for strategic developments to minimize uncontrolled inflammation in COVID-19 patients.


Assuntos
Citocinas/metabolismo , NF-kappa B/metabolismo , SARS-CoV-2/metabolismo , Proteínas Virais/metabolismo , Sequência de Aminoácidos , COVID-19/patologia , COVID-19/virologia , Quimiocinas/genética , Quimiocinas/metabolismo , Citocinas/genética , Células HeLa , Humanos , Mutação Puntual , SARS-CoV-2/isolamento & purificação , Alinhamento de Sequência , Índice de Gravidade de Doença , Regulação para Cima , Proteínas da Matriz Viral/genética , Proteínas Virais/genética , Proteínas Viroporinas/química , Proteínas Viroporinas/genética , Proteínas Viroporinas/metabolismo
8.
Molecules ; 26(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070943

RESUMO

The medicinal plant noni (Morinda citrifolia) is widely dispersed throughout Southeast Asia, the Caribbean, and Australia. We previously reported that fermented Noni could alleviate atopic dermatitis (AD) by recovering Th1/Th2 immune balance and enhancing skin barrier function induced by 2,4-dinitrochlorobenzene. Noni has a high deacetylasperulosidic acid (DAA) content, whose concentration further increased in fermented noni as an iridoid constituent. This study aimed to determine the anti-AD effects and mechanisms of DAA on HaCaT, HMC-1, and EOL-1 cells. DAA inhibited the gene expression and secretion of AD-related cytokines and chemokines including interleukin (IL)-1ß, IL-4, IL-6, IL-8, IL-25, IL-33, thymic stromal lymphopoietin, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, thymus and activation-regulated chemokine, macrophage-derived chemokine, and regulated upon activation, normal T cell expressed and secreted, in all cells, and inhibited histamine release in HMC-1 cells. DAA controlled mitogen-activated protein kinase phosphorylation levels and the translocation of nuclear factor-kappa light chain enhancer of activated B cells into the nucleus by inhibiting IκBα decomposition in all the cells. Furthermore, DAA increased the expression of proteins involved in skin barrier functions such as filaggrin and involucrin in HaCaT cells. These results confirmed that DAA could relieve AD by controlling immune balance and recovering skin barrier function.


Assuntos
Dermatite Atópica/tratamento farmacológico , Glicosídeos/farmacologia , Linhagem Celular , Quimiocinas/imunologia , Quimiocinas/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Dermatite Atópica/patologia , Eczema/tratamento farmacológico , Eczema/patologia , Glicosídeos/metabolismo , Humanos , Queratinócitos/efeitos dos fármacos , Morinda/metabolismo , Extratos Vegetais/farmacologia , Pele/metabolismo , Equilíbrio Th1-Th2/efeitos dos fármacos
9.
Nat Commun ; 12(1): 3523, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112769

RESUMO

There is currently no approved treatment for primary Sjögren's syndrome, a disease that primarily affects adult women. The difficulty in developing effective therapies is -in part- because of the heterogeneity in the clinical manifestation and pathophysiology of the disease. Finding common molecular signatures among patient subgroups could improve our understanding of disease etiology, and facilitate the development of targeted therapeutics. Here, we report, in a cross-sectional cohort, a molecular classification scheme for Sjögren's syndrome patients based on the multi-omic profiling of whole blood samples from a European cohort of over 300 patients, and a similar number of age and gender-matched healthy volunteers. Using transcriptomic, genomic, epigenetic, cytokine expression and flow cytometry data, combined with clinical parameters, we identify four groups of patients with distinct patterns of immune dysregulation. The biomarkers we identify can be used by machine learning classifiers to sort future patients into subgroups, allowing the re-evaluation of response to treatments in clinical trials.


Assuntos
Citocinas/sangue , Metilação de DNA , Interferons/sangue , Proteoma/metabolismo , Síndrome de Sjogren/imunologia , Transcriptoma/genética , Adulto , Autoanticorpos/sangue , Biomarcadores/sangue , Quimiocinas/análise , Quimiocinas/genética , Quimiocinas/metabolismo , Estudos de Coortes , Biologia Computacional , Simulação por Computador , Estudos Transversais , Citocinas/análise , Citocinas/genética , Metilação de DNA/genética , Bases de Dados Genéticas , Bases de Dados de Proteínas , Feminino , Citometria de Fluxo , Estudo de Associação Genômica Ampla , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Interferons/genética , Masculino , Pessoa de Meia-Idade , Família Multigênica , Polimorfismo de Nucleotídeo Único , Proteoma/genética , RNA-Seq , Síndrome de Sjogren/sangue , Síndrome de Sjogren/genética , Síndrome de Sjogren/fisiopatologia
10.
PLoS One ; 16(5): e0252026, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1243847

RESUMO

To investigate the mechanisms underlying the SARS-CoV-2 infection severity observed in patients with obesity, we performed a prospective study of 51 patients evaluating the impact of multiple immune parameters during 2 weeks after admission, on vital organs' functions according to body mass index (BMI) categories. High-dimensional flow cytometric characterization of immune cell subsets was performed at admission, 30 systemic cytokines/chemokines levels were sequentially measured, thirteen endothelial markers were determined at admission and at the zenith of the cytokines. Computed tomography scans on admission were quantified for lung damage and hepatic steatosis (n = 23). Abnormal BMI (> 25) observed in 72.6% of patients, was associated with a higher rate of intensive care unit hospitalization (p = 0.044). SARS-CoV-2 RNAaemia, peripheral immune cell subsets and cytokines/chemokines were similar among BMI groups. A significant association between inflammatory cytokines and liver, renal, and endothelial dysfunctions was observed only in patients with obesity (BMI > 30). In contrast, early signs of lung damage (ground-glass opacity) correlated with Th1/M1/inflammatory cytokines only in normal weight patients. Later lesions of pulmonary consolidation correlated with BMI but were independent of cytokine levels. Our study reveals distinct physiopathological mechanisms associated with SARS-CoV-2 infection in patients with obesity that may have important clinical implications.


Assuntos
COVID-19/patologia , Citocinas/metabolismo , Fígado/fisiopatologia , Pulmão/fisiopatologia , Obesidade/patologia , Idoso , Biomarcadores/metabolismo , Índice de Massa Corporal , COVID-19/complicações , COVID-19/virologia , Quimiocinas/sangue , Quimiocinas/metabolismo , Citocinas/sangue , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Unidades de Terapia Intensiva , Fígado/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Estudos Prospectivos , RNA Viral/sangue , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença
11.
Front Immunol ; 12: 666223, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1247864

RESUMO

Background: SARS, MERS, and COVID-19 share similar characteristics. For instance, the genetic homology of SARS-CoV-2 compared to SARS-CoV and MERS-CoV is 80% and 50%, respectively, which may cause similar clinical features. Moreover, uncontrolled release of proinflammatory mediators (also called a cytokine storm) by activated immune cells in SARS, MERS, and COVID-19 patients leads to severe phenotype development. Aim: This systematic review and meta-analysis aimed to evaluate the inflammatory cytokine profile associated with three strains of severe human coronavirus diseases (MERS-CoV, SARS-CoV, and SARS-CoV-2). Method: The PubMed, Embase, and Cochrane Library databases were searched for studies published until July 2020. Randomized and observational studies reporting the inflammatory cytokines associated with severe and non-severe human coronavirus diseases, including MERS-CoV, SARS-CoV, and SARS-CoV-2, were included. Two reviewers independently screened articles, extracted data, and assessed the quality of the included studies. Meta-analysis was performed using a random-effects model with a 95% confidence interval to estimate the pooled mean of inflammatory biomarkers. Results: A high level of circulating IL-6 could be associated with the severity of infection of the three coronavirus strains. TNF, IL-10, and IL-8 are associated with the severity of COVID-19. Increased circulating levels of CXCL10/IP10 and CCL2/MCP-1 might also be related to the severity of MERS. Conclusion: This study suggests that the immune response and immunopathology in the three severe human coronavirus strains are somewhat similar. The findings highlight that nearly all studies reporting severe cases of SARS, MERS, and COVID-19 have been associated with elevated levels of IL-6. This could be used as a potential therapeutic target to improve patients' outcomes in severe cases. Systematic Review Registration: PROSPERO registration 94 number: CRD42020209931.


Assuntos
Infecções por Coronavirus/imunologia , Coronavirus/fisiologia , Síndrome da Liberação de Citocina/imunologia , Inflamação/imunologia , Animais , Circulação Sanguínea , Quimiocinas/metabolismo , Citocinas/metabolismo , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
Phytomedicine ; 87: 153583, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: covidwho-1213465

RESUMO

BACKGROUND: A key clinical feature of COVID-19 is a deep inflammatory state known as "cytokine storm" and characterized by high expression of several cytokines, chemokines and growth factors, including IL-6 and IL-8. A direct consequence of this inflammatory state in the lungs is the Acute Respiratory Distress Syndrome (ARDS), frequently observed in severe COVID-19 patients. The "cytokine storm" is associated with severe forms of COVID-19 and poor prognosis for COVID-19 patients. Sulforaphane (SFN), one of the main components of Brassica oleraceae L. (Brassicaceae or Cruciferae), is known to possess anti-inflammatory effects in tissues from several organs, among which joints, kidneys and lungs. PURPOSE: The objective of the present study was to determine whether SFN is able to inhibit IL-6 and IL-8, two key molecules involved in the COVID-19 "cytokine storm". METHODS: The effects of SFN were studied in vitro on bronchial epithelial IB3-1 cells exposed to the SARS-CoV-2 Spike protein (S-protein). The anti-inflammatory activity of SFN on IL-6 and IL-8 expression has been evaluated by RT-qPCR and Bio-Plex analysis. RESULTS: In our study SFN inhibits, in cultured IB3-1 bronchial cells, the gene expression of IL-6 and IL-8 induced by the S-protein of SARS-CoV-2. This represents the proof-of-principle that SFN may modulate the release of some key proteins of the COVID-19 "cytokine storm". CONCLUSION: The control of the cytokine storm is one of the major issues in the management of COVID-19 patients. Our study suggests that SFN can be employed in protocols useful to control hyperinflammatory state associated with SARS-CoV-2 infection.


Assuntos
Brônquios/virologia , Interleucina-6/genética , Interleucina-8/genética , Isotiocianatos/farmacologia , Glicoproteína da Espícula de Coronavírus/toxicidade , Sulfóxidos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Brônquios/citologia , Brônquios/efeitos dos fármacos , COVID-19/fisiopatologia , Linhagem Celular , Quimiocinas/genética , Quimiocinas/metabolismo , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , SARS-CoV-2/patogenicidade , Regulação para Cima/efeitos dos fármacos
13.
Front Immunol ; 12: 638446, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1211811

RESUMO

Interleukin-1 receptor-associated kinase 4 (IRAK4) and interferon regulatory factor 5 (IRF5) lie sequentially on a signaling pathway activated by ligands of the IL-1 receptor and/or multiple TLRs located either on plasma or endosomal membranes. Activated IRF5, in conjunction with other synergistic transcription factors, notably NF-κB, is crucially required for the production of proinflammatory cytokines in the innate immune response to microbial infection. The IRAK4-IRF5 axis could therefore have a major role in the induction of the signature cytokines and chemokines of the hyperinflammatory state associated with severe morbidity and mortality in COVID-19. Here a case is made for considering IRAK4 or IRF5 inhibitors as potential therapies for the "cytokine storm" of COVID-19.


Assuntos
COVID-19/imunologia , Síndrome da Liberação de Citocina/metabolismo , Fatores Reguladores de Interferon/antagonistas & inibidores , Fatores Reguladores de Interferon/metabolismo , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Quinases Associadas a Receptores de Interleucina-1/metabolismo , COVID-19/tratamento farmacológico , COVID-19/metabolismo , COVID-19/fisiopatologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Humanos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Viroses/metabolismo
14.
Front Immunol ; 12: 638446, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936053

RESUMO

Interleukin-1 receptor-associated kinase 4 (IRAK4) and interferon regulatory factor 5 (IRF5) lie sequentially on a signaling pathway activated by ligands of the IL-1 receptor and/or multiple TLRs located either on plasma or endosomal membranes. Activated IRF5, in conjunction with other synergistic transcription factors, notably NF-κB, is crucially required for the production of proinflammatory cytokines in the innate immune response to microbial infection. The IRAK4-IRF5 axis could therefore have a major role in the induction of the signature cytokines and chemokines of the hyperinflammatory state associated with severe morbidity and mortality in COVID-19. Here a case is made for considering IRAK4 or IRF5 inhibitors as potential therapies for the "cytokine storm" of COVID-19.


Assuntos
COVID-19/imunologia , Síndrome da Liberação de Citocina/metabolismo , Fatores Reguladores de Interferon/antagonistas & inibidores , Fatores Reguladores de Interferon/metabolismo , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Quinases Associadas a Receptores de Interleucina-1/metabolismo , COVID-19/tratamento farmacológico , COVID-19/metabolismo , COVID-19/fisiopatologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Humanos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Viroses/metabolismo
15.
Front Immunol ; 12: 666223, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34046036

RESUMO

Background: SARS, MERS, and COVID-19 share similar characteristics. For instance, the genetic homology of SARS-CoV-2 compared to SARS-CoV and MERS-CoV is 80% and 50%, respectively, which may cause similar clinical features. Moreover, uncontrolled release of proinflammatory mediators (also called a cytokine storm) by activated immune cells in SARS, MERS, and COVID-19 patients leads to severe phenotype development. Aim: This systematic review and meta-analysis aimed to evaluate the inflammatory cytokine profile associated with three strains of severe human coronavirus diseases (MERS-CoV, SARS-CoV, and SARS-CoV-2). Method: The PubMed, Embase, and Cochrane Library databases were searched for studies published until July 2020. Randomized and observational studies reporting the inflammatory cytokines associated with severe and non-severe human coronavirus diseases, including MERS-CoV, SARS-CoV, and SARS-CoV-2, were included. Two reviewers independently screened articles, extracted data, and assessed the quality of the included studies. Meta-analysis was performed using a random-effects model with a 95% confidence interval to estimate the pooled mean of inflammatory biomarkers. Results: A high level of circulating IL-6 could be associated with the severity of infection of the three coronavirus strains. TNF, IL-10, and IL-8 are associated with the severity of COVID-19. Increased circulating levels of CXCL10/IP10 and CCL2/MCP-1 might also be related to the severity of MERS. Conclusion: This study suggests that the immune response and immunopathology in the three severe human coronavirus strains are somewhat similar. The findings highlight that nearly all studies reporting severe cases of SARS, MERS, and COVID-19 have been associated with elevated levels of IL-6. This could be used as a potential therapeutic target to improve patients' outcomes in severe cases. Systematic Review Registration: PROSPERO registration 94 number: CRD42020209931.


Assuntos
Infecções por Coronavirus/imunologia , Coronavirus/fisiologia , Síndrome da Liberação de Citocina/imunologia , Inflamação/imunologia , Animais , Circulação Sanguínea , Quimiocinas/metabolismo , Citocinas/metabolismo , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
16.
PLoS One ; 16(5): e0252026, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34038475

RESUMO

To investigate the mechanisms underlying the SARS-CoV-2 infection severity observed in patients with obesity, we performed a prospective study of 51 patients evaluating the impact of multiple immune parameters during 2 weeks after admission, on vital organs' functions according to body mass index (BMI) categories. High-dimensional flow cytometric characterization of immune cell subsets was performed at admission, 30 systemic cytokines/chemokines levels were sequentially measured, thirteen endothelial markers were determined at admission and at the zenith of the cytokines. Computed tomography scans on admission were quantified for lung damage and hepatic steatosis (n = 23). Abnormal BMI (> 25) observed in 72.6% of patients, was associated with a higher rate of intensive care unit hospitalization (p = 0.044). SARS-CoV-2 RNAaemia, peripheral immune cell subsets and cytokines/chemokines were similar among BMI groups. A significant association between inflammatory cytokines and liver, renal, and endothelial dysfunctions was observed only in patients with obesity (BMI > 30). In contrast, early signs of lung damage (ground-glass opacity) correlated with Th1/M1/inflammatory cytokines only in normal weight patients. Later lesions of pulmonary consolidation correlated with BMI but were independent of cytokine levels. Our study reveals distinct physiopathological mechanisms associated with SARS-CoV-2 infection in patients with obesity that may have important clinical implications.


Assuntos
COVID-19/patologia , Citocinas/metabolismo , Fígado/fisiopatologia , Pulmão/fisiopatologia , Obesidade/patologia , Idoso , Biomarcadores/metabolismo , Índice de Massa Corporal , COVID-19/complicações , COVID-19/virologia , Quimiocinas/sangue , Quimiocinas/metabolismo , Citocinas/sangue , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Unidades de Terapia Intensiva , Fígado/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Estudos Prospectivos , RNA Viral/sangue , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença
17.
Phytomedicine ; 87: 153583, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34033999

RESUMO

BACKGROUND: A key clinical feature of COVID-19 is a deep inflammatory state known as "cytokine storm" and characterized by high expression of several cytokines, chemokines and growth factors, including IL-6 and IL-8. A direct consequence of this inflammatory state in the lungs is the Acute Respiratory Distress Syndrome (ARDS), frequently observed in severe COVID-19 patients. The "cytokine storm" is associated with severe forms of COVID-19 and poor prognosis for COVID-19 patients. Sulforaphane (SFN), one of the main components of Brassica oleraceae L. (Brassicaceae or Cruciferae), is known to possess anti-inflammatory effects in tissues from several organs, among which joints, kidneys and lungs. PURPOSE: The objective of the present study was to determine whether SFN is able to inhibit IL-6 and IL-8, two key molecules involved in the COVID-19 "cytokine storm". METHODS: The effects of SFN were studied in vitro on bronchial epithelial IB3-1 cells exposed to the SARS-CoV-2 Spike protein (S-protein). The anti-inflammatory activity of SFN on IL-6 and IL-8 expression has been evaluated by RT-qPCR and Bio-Plex analysis. RESULTS: In our study SFN inhibits, in cultured IB3-1 bronchial cells, the gene expression of IL-6 and IL-8 induced by the S-protein of SARS-CoV-2. This represents the proof-of-principle that SFN may modulate the release of some key proteins of the COVID-19 "cytokine storm". CONCLUSION: The control of the cytokine storm is one of the major issues in the management of COVID-19 patients. Our study suggests that SFN can be employed in protocols useful to control hyperinflammatory state associated with SARS-CoV-2 infection.


Assuntos
Brônquios/virologia , Interleucina-6/genética , Interleucina-8/genética , Isotiocianatos/farmacologia , Glicoproteína da Espícula de Coronavírus/toxicidade , Sulfóxidos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Brônquios/citologia , Brônquios/efeitos dos fármacos , COVID-19/fisiopatologia , Linhagem Celular , Quimiocinas/genética , Quimiocinas/metabolismo , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , SARS-CoV-2/patogenicidade , Regulação para Cima/efeitos dos fármacos
18.
Int J Mol Sci ; 22(7)2021 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-33800554

RESUMO

CXCL16 is a chemotactic cytokine belonging to the α-chemokine subfamily. It plays a significant role in the progression of cancer, as well as the course of atherosclerosis, renal fibrosis, and non-alcoholic fatty liver disease (NAFLD). Since there has been no review paper discussing the importance of this chemokine in various diseases, we have collected all available knowledge about CXCL16 in this review. In the first part of the paper, we discuss background information about CXCL16 and its receptor, CXCR6. Next, we focus on the importance of CXCL16 in a variety of diseases, with an emphasis on cancer. We discuss the role of CXCL16 in tumor cell proliferation, migration, invasion, and metastasis. Next, we describe the role of CXCL16 in the tumor microenvironment, including involvement in angiogenesis, and its significance in tumor-associated cells (cancer associated fibroblasts (CAF), microglia, tumor-associated macrophages (TAM), tumor-associated neutrophils (TAN), mesenchymal stem cells (MSC), myeloid suppressor cells (MDSC), and regulatory T cells (Treg)). Finally, we focus on the antitumor properties of CXCL16, which are mainly caused by natural killer T (NKT) cells. At the end of the article, we summarize the importance of CXCL16 in cancer therapy.


Assuntos
Quimiocina CXCL16/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias/metabolismo , Neoplasias/patologia , Microambiente Tumoral , Proteína ADAM10/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Movimento Celular , Proliferação de Células , Quimiocina CXCL16/fisiologia , Quimiocinas/metabolismo , Células Endoteliais/metabolismo , Humanos , Inflamação , Linfócitos do Interstício Tumoral/metabolismo , Proteínas de Membrana/metabolismo , Células-Tronco Mesenquimais/citologia , Camundongos , Invasividade Neoplásica , Metástase Neoplásica , Receptores CXCR6/metabolismo
19.
Phytother Res ; 35(6): 3181-3193, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33893660

RESUMO

Anaphylactoid reactions are potentially fatal allergic diseases caused by mast cells (MCs), which release histamine and lipid mediators under certain stimuli. Therefore, there is an urgent need to develop new drug candidates to treat anaphylactoid reactions. The MrgX2 receptor mediates anaphylactoid reactions that cause inflammatory diseases. Cortex dictamni is a Chinese herb used for treating allergy-related diseases; however, its active compound is still unknown and its mechanism of action has not yet been reported. The aim of this study was to screen the anti-anaphylactoid compound from C. dictamni extracts. An MrgX2/CMC-HPLC method was established for screening MrgX2-specific compounds retained from the alcohol extract of C. dictamni. A mouse model of hindpaw extravasation was used to evaluate the anti-anaphylactoid effect of this ingredient. Intracellular Ca2+ mobilization was assessed using a calcium imaging assay. Enzyme immunoassays were performed to measure cytokine and chemokine release levels. The molecular signaling pathways were explored by western blotting. As a result, dictamnine was identified as an effective compound using the MrgX2/CMC method, which remarkably suppressed MC intracellular Ca2+ mobilization and the release of de novo degranulated substances, and inhibited PKC-PLCγ-IP3R-associated protein signaling molecules. Hence, dictamnine is a novel therapeutic candidate for anaphylactoid reactions via MrgX2.


Assuntos
Anafilaxia/tratamento farmacológico , Mastócitos/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Quinolinas/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Animais , Cálcio/metabolismo , Degranulação Celular/efeitos dos fármacos , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Histamina/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais
20.
Cells ; 10(3)2021 03 10.
Artigo em Inglês | MEDLINE | ID: covidwho-1125934

RESUMO

We herein characterize the immunopathological features of two Italian COVID-19 patients who underwent bilateral lung transplantation (bLTx). Removed lungs underwent histopathological evaluation. Gene expression profiling (GEP) for immune-related signatures was performed on lung specimens and SARS-CoV-2-stimulated peripheral blood mononuclear cells (PBMCs). Cytokine levels were measured on lungs, bronchoalveolar lavage fluids and in culture supernatants. Pathological assessment showed extensive lung damage with the pattern of proliferative to fibrotic phases, with diffuse alveolar damage mimicking usual interstitial pneumonia (UIP). Lungs' GEP revealed overexpression of pathogen recognition receptors, effector cytokines and chemokines, immune activation receptors and of the inflammasome components. Multiplex cytokine analysis confirmed a proinflammatory state, with high levels of monocyte/macrophage chemotactic and activating factors and of IL-6 and TNF-α. A similar profile was observed in SARS-CoV-2-stimulated PBMCs collected 7 days after transplant. The pattern of tissue damage observed in the lungs suggests that this may represent the output of protracted disease, resembling a diffuse UIP-like picture. The molecular immune profiling supports the paradigm of a persistent proinflammatory state and sustained humoral immunity, conditions that are maintained despite the iatrogenic immunosuppression.


Assuntos
COVID-19/cirurgia , Quimiocinas/metabolismo , Citocinas/metabolismo , Leucócitos Mononucleares/metabolismo , Transplante de Pulmão , Pulmão/patologia , Síndrome do Desconforto Respiratório/cirurgia , Adolescente , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/virologia , COVID-19/sangue , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/imunologia , Genótipo , Humanos , Inflamassomos/metabolismo , Interleucina-6/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/virologia , Linfonodos/patologia , Linfonodos/virologia , Masculino , Pessoa de Meia-Idade , Plasma/virologia , Polimorfismo de Nucleotídeo Único , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/patologia , Síndrome do Desconforto Respiratório/virologia , Fator de Necrose Tumoral alfa/metabolismo
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