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2.
J Psychiatr Res ; 129: 98-102, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32912598

RESUMO

This study aims to evaluate the impacts of COVID-19 on cognitive functions in recovered patients and its relationship with inflammatory profiles. Twenty-nine patients recovered from COVID-19 as confirmed by negative nucleic tests for two consecutive times were recruited. A total of 29 age-, gender- and education-matched healthy controls were also recruited. The cognitive functions of all subjects were evaluated by the iPad-based online neuropsychological tests, including the Trail Making Test (TMT), Sign Coding Test (SCT), Continuous Performance Test (CPT), and Digital Span Test (DST). Blood samples from all patients were collected for examining inflammatory profiles, including interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and C-reactive protein (CRP). The relationship between cognitive functions and inflammatory profiles were analyzed by Pearson correlation. In results, although no significant differences were found in TMT, SCT, and DST between the two groups, patients with COVID-19 scored lower in the correct number of the second and third parts of CPT, they also scored higher in the missing number of the third part of CPT (all P < 0.05). In patients with COVID-19, there was a trend of significant difference for lower reaction time in the first and second parts of CPT (P = 0.050, and 0.051, respectively), as well as the lower correct number of the second part of CPT (P = 0.050). Correlation analysis showed that the reaction time for the first and second parts of CPT was positively correlated with the CRP levels (r = 0.557 and 0.410, P < 0.05). In conclusion, our findings indicated that cognitive impairments exist even in patients recovered from COVID-19, and might be possibly linked to the underlying inflammatory processes.


Assuntos
Betacoronavirus , Disfunção Cognitiva/complicações , Infecções por Coronavirus/complicações , Inflamação/complicações , Pneumonia Viral/complicações , Sobreviventes/estatística & dados numéricos , Adulto , Disfunção Cognitiva/diagnóstico , Infecções por Coronavirus/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos/estatística & dados numéricos , Pandemias , Pneumonia Viral/psicologia
3.
J Psychiatr Res ; 129: 98-102, 2020 10.
Artigo em Inglês | MEDLINE | ID: covidwho-625731

RESUMO

This study aims to evaluate the impacts of COVID-19 on cognitive functions in recovered patients and its relationship with inflammatory profiles. Twenty-nine patients recovered from COVID-19 as confirmed by negative nucleic tests for two consecutive times were recruited. A total of 29 age-, gender- and education-matched healthy controls were also recruited. The cognitive functions of all subjects were evaluated by the iPad-based online neuropsychological tests, including the Trail Making Test (TMT), Sign Coding Test (SCT), Continuous Performance Test (CPT), and Digital Span Test (DST). Blood samples from all patients were collected for examining inflammatory profiles, including interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and C-reactive protein (CRP). The relationship between cognitive functions and inflammatory profiles were analyzed by Pearson correlation. In results, although no significant differences were found in TMT, SCT, and DST between the two groups, patients with COVID-19 scored lower in the correct number of the second and third parts of CPT, they also scored higher in the missing number of the third part of CPT (all P < 0.05). In patients with COVID-19, there was a trend of significant difference for lower reaction time in the first and second parts of CPT (P = 0.050, and 0.051, respectively), as well as the lower correct number of the second part of CPT (P = 0.050). Correlation analysis showed that the reaction time for the first and second parts of CPT was positively correlated with the CRP levels (r = 0.557 and 0.410, P < 0.05). In conclusion, our findings indicated that cognitive impairments exist even in patients recovered from COVID-19, and might be possibly linked to the underlying inflammatory processes.


Assuntos
Betacoronavirus , Disfunção Cognitiva/complicações , Infecções por Coronavirus/complicações , Inflamação/complicações , Pneumonia Viral/complicações , Sobreviventes/estatística & dados numéricos , Adulto , Disfunção Cognitiva/diagnóstico , Infecções por Coronavirus/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos/estatística & dados numéricos , Pandemias , Pneumonia Viral/psicologia
7.
Cell Signal ; 75: 109761, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32861744

RESUMO

A fine-tuned activation and deactivation of proteases and their inhibitors are involved in the execution of the inflammatory response. The zymogen/proenzyme plasminogen is converted to the serine protease plasmin, a key fibrinolytic factor by plasminogen activators including tissue-type plasminogen activator (tPA). Plasmin is part of an intricate protease network controlling proteins of initial hemostasis/coagulation, fibrinolytic and complement system. Activation of these protease cascades is required to mount a proper inflammatory response. Although best known for its ability to dissolve clots and cleave fibrin, recent studies point to the importance of fibrin-independent functions of plasmin during acute inflammation and inflammation resolution. In this review, we provide an up-to-date overview of the current knowledge of the enzymatic and cytokine-like effects of tPA and describe the role of tPA and plasminogen receptors in the regulation of the inflammatory response with emphasis on the cytokine storm syndrome such as observed during coronavirus disease 2019 or macrophage activation syndrome. We discuss tPA as a modulator of Toll like receptor signaling, plasmin as an activator of NFkB signaling, and summarize recent studies on the role of plasminogen receptors as controllers of the macrophage conversion into the M2 type and as mediators of efferocytosis during inflammation resolution.


Assuntos
Inflamação/imunologia , Plasminogênio/imunologia , Animais , Coagulação Sanguínea , Ativação do Complemento , Infecções por Coronavirus/sangue , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/imunologia , Citocinas/imunologia , Humanos , Sistema Imunitário/imunologia , Inflamação/sangue , Inflamação/complicações , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/imunologia , NF-kappa B/imunologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Ativador de Plasminogênio Tecidual/imunologia
8.
Cell Signal ; 75: 109761, 2020 11.
Artigo em Inglês | MEDLINE | ID: covidwho-733917

RESUMO

A fine-tuned activation and deactivation of proteases and their inhibitors are involved in the execution of the inflammatory response. The zymogen/proenzyme plasminogen is converted to the serine protease plasmin, a key fibrinolytic factor by plasminogen activators including tissue-type plasminogen activator (tPA). Plasmin is part of an intricate protease network controlling proteins of initial hemostasis/coagulation, fibrinolytic and complement system. Activation of these protease cascades is required to mount a proper inflammatory response. Although best known for its ability to dissolve clots and cleave fibrin, recent studies point to the importance of fibrin-independent functions of plasmin during acute inflammation and inflammation resolution. In this review, we provide an up-to-date overview of the current knowledge of the enzymatic and cytokine-like effects of tPA and describe the role of tPA and plasminogen receptors in the regulation of the inflammatory response with emphasis on the cytokine storm syndrome such as observed during coronavirus disease 2019 or macrophage activation syndrome. We discuss tPA as a modulator of Toll like receptor signaling, plasmin as an activator of NFkB signaling, and summarize recent studies on the role of plasminogen receptors as controllers of the macrophage conversion into the M2 type and as mediators of efferocytosis during inflammation resolution.


Assuntos
Inflamação/imunologia , Plasminogênio/imunologia , Animais , Coagulação Sanguínea , Ativação do Complemento , Infecções por Coronavirus/sangue , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/imunologia , Citocinas/imunologia , Humanos , Sistema Imunitário/imunologia , Inflamação/sangue , Inflamação/complicações , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/imunologia , NF-kappa B/imunologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Ativador de Plasminogênio Tecidual/imunologia
9.
Chin J Traumatol ; 23(4): 187-189, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32669221

RESUMO

The COVID-19 pandemic is still raging across the world. Everyday thousands of infected people lost their lives. What is worse, there is no specific medicine and we do not know when the end of the pandemic will come. The nearest global pandemic is the 1918 influenza, which caused about 50 million deaths and partly terminate the World War Ⅰ. We believe that no matter the virus H1N1 for the 1918 influenza or 2019-nCoV for COVID-19, they are essentially the same and the final cause of death is sepsis. The definition and diagnostic/management criteria of sepsis have been modified several times but the mortality rate has not been improved until date. Over decades, researchers focus either on the immunosuppression or on the excessive inflammatory response following trauma or body exposure to harmful stimuli. But the immune response is very complex with various regulating factors involved in, such as neurotransmitter, endocrine hormone, etc. Sepsis is not a kind of disease, instead a misbalance of the body following infection, trauma or other harmful stimulation. Therefore we should re-think sepsis comprehensively with the concept of systemic biology, i.e. inflammationomics.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/epidemiologia , Pneumonia Viral/epidemiologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Humanos , Tolerância Imunológica , Inflamação/complicações , Influenza Humana/complicações , Influenza Humana/imunologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Sepse/etiologia
10.
PLoS One ; 15(7): e0232741, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32649699

RESUMO

INTRODUCTION: Inflammation plays a major role in the development of atherosclerosis and cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. Toll-like receptor-4 (TLR4) is a major receptor for lipopolysaccharides (endotoxin) and other ligands involved in the pathogenesis of inflammation. We determined whether endotoxin levels and the presence of TLR4 polymorphisms are associated with markers of inflammation and atherosclerosis among South African CKD patients. MATERIALS AND METHODS: Endotoxin, lipopolysaccharide binding protein (LBP), serum CD14 (sCD14), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and carotid intima media thickness (CIMT) were measured in 160 participants (120 CKD patients and 40 controls). Associations between endotoxins and CIMT in the presence of sCD14, IL-8 and MCP-1, were assessed using odds ratios. Participants were screened for the presence of Asp299Gly and Thr399Ile TLR4 polymorphisms, and CIMT and inflammatory markers were compared between subjects with and without TLR4 polymorphisms. RESULTS: Endotoxin levels correlated with sCD14 (r = 0.441, p<0.001) and MCP-1 (r = 0.388, p<0.001) levels while increased CIMT was associated with MCP-1 (r = 0.448, p<0.001), sCD14 levels (r = 0.476, p<0.001), LBP (r = 0.340, p<0.001), and IL-8 (r = 0.395, p<0.001). Atherosclerosis was associated with endotoxin levels (odds ratio: 4.95; 95% confidence interval: 2.52-9.73; p<0.001), and was predicted by higher serum levels of inflammatory markers. Analysis of patients with TLR4 polymorphisms showed reduced serum levels of inflammatory markers and CIMT values compared with the patients carrying the wild type TLR4 alleles. CONCLUSION: The study demonstrated associations between circulating endotoxaemia, systemic inflammation and accelerated atherosclerosis among South African CKD patients, and showed that the atherogenic predictive power of endotoxaemia was significantly increased by the presence of elevated levels of inflammatory markers. Additional findings, which must be confirmed, suggest that TLR4 polymorphisms are associated with low levels of inflammatory markers and CIMT values.


Assuntos
Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Aterosclerose/complicações , Grupos Populacionais/estatística & dados numéricos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/epidemiologia , Adulto , Espessura Intima-Media Carotídea , Estudos de Coortes , Suscetibilidade a Doenças , Feminino , Genótipo , Humanos , Inflamação/complicações , Masculino , Polimorfismo Genético , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Risco , Receptor 4 Toll-Like/genética
11.
Nat Commun ; 11(1): 3755, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709874

RESUMO

Obesity is associated with low-grade chronic inflammation promoting insulin-resistance and diabetes. Gut microbiota dysbiosis is a consequence as well as a driver of obesity and diabetes. Mucosal-associated invariant T cells (MAIT) are innate-like T cells expressing a semi-invariant T cell receptor restricted to the non-classical MHC class I molecule MR1 presenting bacterial ligands. Here we show that during obesity MAIT cells promote inflammation in both adipose tissue and ileum, leading to insulin resistance and impaired glucose and lipid metabolism. MAIT cells act in adipose tissue by inducing M1 macrophage polarization in an MR1-dependent manner and in the gut by inducing microbiota dysbiosis and loss of gut integrity. Both MAIT cell-induced tissue alterations contribute to metabolic dysfunction. Treatment with MAIT cell inhibitory ligand demonstrates its potential as a strategy against inflammation, dysbiosis and metabolic disorders.


Assuntos
Disbiose/imunologia , Inflamação/patologia , Intestinos/patologia , Células T Invariáveis Associadas à Mucosa/patologia , Obesidade/metabolismo , Tecido Adiposo/patologia , Animais , Citocinas/genética , Citocinas/metabolismo , Dieta Hiperlipídica , Disbiose/complicações , Microbioma Gastrointestinal , Teste de Tolerância a Glucose , Íleo/patologia , Inflamação/complicações , Mucosa Intestinal/patologia , Intestinos/diagnóstico por imagem , Ligantes , Contagem de Linfócitos , Macrófagos/metabolismo , Imagem por Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/complicações , Obesidade/diagnóstico por imagem , Fenótipo , Pterinas/farmacologia , Receptores de Antígenos de Linfócitos T/metabolismo
12.
Cell Metab ; 32(3): 437-446.e5, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32697943

RESUMO

COVID-19 can result in severe lung injury. It remained to be determined why diabetic individuals with uncontrolled glucose levels are more prone to develop the severe form of COVID-19. The molecular mechanism underlying SARS-CoV-2 infection and what determines the onset of the cytokine storm found in severe COVID-19 patients are unknown. Monocytes and macrophages are the most enriched immune cell types in the lungs of COVID-19 patients and appear to have a central role in the pathogenicity of the disease. These cells adapt their metabolism upon infection and become highly glycolytic, which facilitates SARS-CoV-2 replication. The infection triggers mitochondrial ROS production, which induces stabilization of hypoxia-inducible factor-1α (HIF-1α) and consequently promotes glycolysis. HIF-1α-induced changes in monocyte metabolism by SARS-CoV-2 infection directly inhibit T cell response and reduce epithelial cell survival. Targeting HIF-1ɑ may have great therapeutic potential for the development of novel drugs to treat COVID-19.


Assuntos
Betacoronavirus/fisiologia , Glicemia/metabolismo , Infecções por Coronavirus/complicações , Complicações do Diabetes/complicações , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Monócitos/metabolismo , Pneumonia Viral/complicações , Adulto , Linhagem Celular , Infecções por Coronavirus/metabolismo , Complicações do Diabetes/metabolismo , Diabetes Mellitus/metabolismo , Feminino , Glicólise , Humanos , Inflamação/complicações , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/virologia , Pandemias , Pneumonia Viral/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
13.
J Infect Public Health ; 13(10): 1397-1404, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: covidwho-643374

RESUMO

Secondary bacterial infections are commonly associated with prior or concomitant respiratory viral infections. Viral infections damage respiratory airways and simultaneously defects both innate and acquired immune response that provides a favorable environment for bacterial growth, adherence, and facilitates invasion into healthy sites of the respiratory tract. Understanding the molecular mechanism of viral-induced secondary bacterial infections will provide us a chance to develop novel and effective therapeutic approaches for disease prevention. The present study describes details about the secondary bacterial infection during viral infections and their immunological changes.The outcome of discussion avails an opportunity to understand possible secondary bacterial infections associated with novel SARS-CoV-2, presently causing pandemic outbreak COVID-19.


Assuntos
Infecções Bacterianas/imunologia , Infecções Bacterianas/virologia , Infecções por Coronavirus/imunologia , Influenza Humana/imunologia , Pneumonia Viral/imunologia , Imunidade Adaptativa , Bactérias/crescimento & desenvolvimento , Aderência Bacteriana , Betacoronavirus , Infecções por Coronavirus/complicações , Humanos , Tolerância Imunológica , Imunidade Inata , Inflamação/complicações , Influenza Humana/complicações , Interações Microbianas , Pandemias , Gravidade do Paciente , Pneumonia Viral/complicações
14.
J Infect Public Health ; 13(10): 1397-1404, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32712106

RESUMO

Secondary bacterial infections are commonly associated with prior or concomitant respiratory viral infections. Viral infections damage respiratory airways and simultaneously defects both innate and acquired immune response that provides a favorable environment for bacterial growth, adherence, and facilitates invasion into healthy sites of the respiratory tract. Understanding the molecular mechanism of viral-induced secondary bacterial infections will provide us a chance to develop novel and effective therapeutic approaches for disease prevention. The present study describes details about the secondary bacterial infection during viral infections and their immunological changes.The outcome of discussion avails an opportunity to understand possible secondary bacterial infections associated with novel SARS-CoV-2, presently causing pandemic outbreak COVID-19.


Assuntos
Infecções Bacterianas/imunologia , Infecções Bacterianas/virologia , Infecções por Coronavirus/imunologia , Influenza Humana/imunologia , Pneumonia Viral/imunologia , Imunidade Adaptativa , Bactérias/crescimento & desenvolvimento , Aderência Bacteriana , Betacoronavirus , Infecções por Coronavirus/complicações , Humanos , Tolerância Imunológica , Imunidade Inata , Inflamação/complicações , Influenza Humana/complicações , Interações Microbianas , Pandemias , Gravidade do Paciente , Pneumonia Viral/complicações
15.
Hautarzt ; 71(10): 805-808, 2020 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-32696202

RESUMO

Tattoos, including permanent makeup, may entail diverse complications like viral or bacterial infections and allergic and inflammatory reactions. In the latter case, besides exogenous pigment, histology shows an either lymphocytic or histiocytic-granulomatous infiltrate, depending on the predominant reaction pattern. We report successful treatment with intralesional triamcinolone acetonide injections in two individuals who developed granulomatous inflammation after tattooing.


Assuntos
Granuloma/induzido quimicamente , Hipersensibilidade/etiologia , Inflamação/induzido quimicamente , Tatuagem/efeitos adversos , Granuloma/complicações , Humanos , Inflamação/complicações , Injeções Intralesionais
16.
Chin J Traumatol ; 23(4): 187-189, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: covidwho-614262

RESUMO

The COVID-19 pandemic is still raging across the world. Everyday thousands of infected people lost their lives. What is worse, there is no specific medicine and we do not know when the end of the pandemic will come. The nearest global pandemic is the 1918 influenza, which caused about 50 million deaths and partly terminate the World War Ⅰ. We believe that no matter the virus H1N1 for the 1918 influenza or 2019-nCoV for COVID-19, they are essentially the same and the final cause of death is sepsis. The definition and diagnostic/management criteria of sepsis have been modified several times but the mortality rate has not been improved until date. Over decades, researchers focus either on the immunosuppression or on the excessive inflammatory response following trauma or body exposure to harmful stimuli. But the immune response is very complex with various regulating factors involved in, such as neurotransmitter, endocrine hormone, etc. Sepsis is not a kind of disease, instead a misbalance of the body following infection, trauma or other harmful stimulation. Therefore we should re-think sepsis comprehensively with the concept of systemic biology, i.e. inflammationomics.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/epidemiologia , Pneumonia Viral/epidemiologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Humanos , Tolerância Imunológica , Inflamação/complicações , Influenza Humana/complicações , Influenza Humana/imunologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Sepse/etiologia
17.
Cell Metab ; 32(3): 437-446.e5, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: covidwho-670096

RESUMO

COVID-19 can result in severe lung injury. It remained to be determined why diabetic individuals with uncontrolled glucose levels are more prone to develop the severe form of COVID-19. The molecular mechanism underlying SARS-CoV-2 infection and what determines the onset of the cytokine storm found in severe COVID-19 patients are unknown. Monocytes and macrophages are the most enriched immune cell types in the lungs of COVID-19 patients and appear to have a central role in the pathogenicity of the disease. These cells adapt their metabolism upon infection and become highly glycolytic, which facilitates SARS-CoV-2 replication. The infection triggers mitochondrial ROS production, which induces stabilization of hypoxia-inducible factor-1α (HIF-1α) and consequently promotes glycolysis. HIF-1α-induced changes in monocyte metabolism by SARS-CoV-2 infection directly inhibit T cell response and reduce epithelial cell survival. Targeting HIF-1ɑ may have great therapeutic potential for the development of novel drugs to treat COVID-19.


Assuntos
Betacoronavirus/fisiologia , Glicemia/metabolismo , Infecções por Coronavirus/complicações , Complicações do Diabetes/complicações , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Monócitos/metabolismo , Pneumonia Viral/complicações , Adulto , Linhagem Celular , Infecções por Coronavirus/metabolismo , Complicações do Diabetes/metabolismo , Diabetes Mellitus/metabolismo , Feminino , Glicólise , Humanos , Inflamação/complicações , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/virologia , Pandemias , Pneumonia Viral/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
18.
J Infect ; 81(2): 205-212, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32579986

RESUMO

A subgroup of COVID-19 patients develop very severe disease with requirement for ICU treatment, ventilation, and ECMO therapy. Laboratory tests indicate that the immune and clotting system show marked alterations with hyper-activation, hyper-inflammation, cytokine storm development. Furthermore, organ-specific biomarkers demonstrate the involvement of cardiac muscle, kidney, and liver dysfunction in many patients. In this article the use of laboratory biomarkers is discussed with regard to their use for diagnosis, disease progression, and risk assessment.


Assuntos
Infecções por Coronavirus/diagnóstico , Inflamação/virologia , Pneumonia Viral/diagnóstico , Betacoronavirus , Biomarcadores/análise , Infecções por Coronavirus/complicações , Infecções por Coronavirus/fisiopatologia , Citocinas/análise , Progressão da Doença , Humanos , Inflamação/complicações , Pulmão/virologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/fisiopatologia , Medição de Risco
19.
Proc Natl Acad Sci U S A ; 117(26): 15281-15292, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32546520

RESUMO

Whether G protein-coupled receptors signal from endosomes to control important pathophysiological processes and are therapeutic targets is uncertain. We report that opioids from the inflamed colon activate δ-opioid receptors (DOPr) in endosomes of nociceptors. Biopsy samples of inflamed colonic mucosa from patients and mice with colitis released opioids that activated DOPr on nociceptors to cause a sustained decrease in excitability. DOPr agonists inhibited mechanically sensitive colonic nociceptors. DOPr endocytosis and endosomal signaling by protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) pathways mediated the sustained inhibitory actions of endogenous opioids and DOPr agonists. DOPr agonists stimulated the recruitment of Gαi/o and ß-arrestin1/2 to endosomes. Analysis of compartmentalized signaling revealed a requirement of DOPr endocytosis for activation of PKC at the plasma membrane and in the cytosol and ERK in the nucleus. We explored a nanoparticle delivery strategy to evaluate whether endosomal DOPr might be a therapeutic target for pain. The DOPr agonist DADLE was coupled to a liposome shell for targeting DOPr-positive nociceptors and incorporated into a mesoporous silica core for release in the acidic and reducing endosomal environment. Nanoparticles activated DOPr at the plasma membrane, were preferentially endocytosed by DOPr-expressing cells, and were delivered to DOPr-positive early endosomes. Nanoparticles caused a long-lasting activation of DOPr in endosomes, which provided sustained inhibition of nociceptor excitability and relief from inflammatory pain. Conversely, nanoparticles containing a DOPr antagonist abolished the sustained inhibitory effects of DADLE. Thus, DOPr in endosomes is an endogenous mechanism and a therapeutic target for relief from chronic inflammatory pain.


Assuntos
Leucina Encefalina-2-Alanina/farmacologia , Inflamação/complicações , Dor/tratamento farmacológico , Dor/metabolismo , Receptores Opioides delta/agonistas , Animais , Colo/inervação , Leucina Encefalina-2-Alanina/administração & dosagem , Células HEK293 , Humanos , Camundongos , Nanopartículas/administração & dosagem , Neurônios , Nociceptores/metabolismo , Receptores Opioides delta/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
20.
Clin Sci (Lond) ; 134(12): 1403-1432, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32556180

RESUMO

Flavonoids are polyphenolic compounds naturally occurring in fruits and vegetables, in addition to beverages such as tea and coffee. Flavonoids are emerging as potent therapeutic agents for cardiovascular as well as metabolic diseases. Several studies corroborated an inverse relationship between flavonoid consumption and cardiovascular disease (CVD) or adipose tissue inflammation (ATI). Flavonoids exert their anti-atherogenic effects by increasing nitric oxide (NO), reducing reactive oxygen species (ROS), and decreasing pro-inflammatory cytokines. In addition, flavonoids alleviate ATI by decreasing triglyceride and cholesterol levels, as well as by attenuating inflammatory mediators. Furthermore, flavonoids inhibit synthesis of fatty acids and promote their oxidation. In this review, we discuss the effect of the main classes of flavonoids, namely flavones, flavonols, flavanols, flavanones, anthocyanins, and isoflavones, on atherosclerosis and ATI. In addition, we dissect the underlying molecular and cellular mechanisms of action for these flavonoids. We conclude by supporting the potential benefit for flavonoids in the management or treatment of CVD; yet, we call for more robust clinical studies for safety and pharmacokinetic values.


Assuntos
Tecido Adiposo/patologia , Aterosclerose/tratamento farmacológico , Flavonoides/uso terapêutico , Inflamação/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Aterosclerose/complicações , Flavonoides/química , Flavonoides/farmacologia , Humanos , Inflamação/complicações , Modelos Biológicos
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