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1.
Front Immunol ; 11: 1942, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983123

RESUMO

Severe cases of COVID-19 present with serious lung inflammation, acute respiratory distress syndrome and multiorgan damage. SARS-CoV-2 infection is associated with high cytokine levels, including interleukin-6 and certain subsets of immune cells, in particular, NK, distinguished according to the cell surface density of CD56. Cytokine levels are inversely correlated with lymphocyte count, therefore cytokine release syndrome may be an impediment to the adaptive immune response against SARS-CoV-2 infection. Canakinumab, a monoclonal antibody targeting IL-1ß is under investigation for the treatment of severe SAR-CoV-2 infection. An 85 year old male presenting in our hospital with COVID-19, whose condition was complicated by acute respiratory distress syndrome and cardiac and renal failure (with oliguria) after 25 days of hospitalization, was intubated and received canakinumab for compassionate use. On the next day, diuresis recovered and conditions improved: high IL-6 levels and NK cells expressing CD56 bright (associated with cytokine relase) were significantly reduced giving rise to NK CD56 dim . Patient died on day 58 with pulmonary bacterial superinfection and persistent SARS-CoV-2 positivity. In conclusion, canakinumab rescued a high risk, very elderly patient, from multiorgan damage complicating COVID-19. It may represent an useful treatment in severe cases.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacologia , Antígeno CD56/metabolismo , Infecções por Coronavirus/virologia , Evolução Fatal , Humanos , Interleucina-1beta/antagonistas & inibidores , Interleucina-6/sangue , Células Matadoras Naturais/imunologia , Masculino , Pandemias , Pneumonia Viral/virologia , Síndrome do Desconforto Respiratório do Adulto/virologia , Índice de Gravidade de Doença
2.
Am Heart J ; 228: 81-90, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32866928

RESUMO

Recurrent pericarditis (RP) occurs in 15% to 30% of patients following a first episode, despite standard treatment with nonsteroidal anti-inflammatory drugs, colchicine, and corticosteroids; many patients become dependent on corticosteroids. Rilonacept (KPL-914), an interleukin-1α and ß inhibitor, is in development for the treatment of RP. RHAPSODY, a double-blind, placebo-controlled, randomized-withdrawal (RW) pivotal Phase 3 trial (NCT03737110), enrolls patients 12 years or older presenting with at least a third pericarditis episode, pericarditis pain score ≥4 (11-point numeric rating scale [NRS]), and C-reactive protein ≥1 mg/dL at screening. After a subcutaneous loading dose (adults, 320 mg; children, 4.4 mg/kg), all patients receive blinded weekly subcutaneous rilonacept (adults, 160 mg; children, 2.2 mg/kg) during the run-in period. Patients must taper and discontinue concomitant pericarditis medications during the blinded run-in period and achieve clinical response (C-reactive protein ≤0.5 mg/dL and weekly average NRS ≤2.0 during the 7 days prior to and including the day of randomization) by end of the run-in (while on rilonacept monotherapy) to be randomized to either continued rilonacept or placebo in the RW period. Primary efficacy end point was time to adjudicated pericarditis recurrence during the RW period; secondary efficacy end points were proportion of patients maintaining clinical response, percentage of days with NRS ≤2, and percentage of patients with no-to-minimal pericarditis symptoms at week 16 of the RW period. Safety evaluations include adverse event monitoring, physical examinations, and laboratory tests. The RHAPSODY trial will evaluate the efficacy and safety of rilonacept in the treatment of RP to improve outcomes and patient health-related quality of life.


Assuntos
Monitoramento de Medicamentos/métodos , Pericardite , Qualidade de Vida , Proteínas Recombinantes de Fusão , Prevenção Secundária/métodos , Adolescente , Adulto , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Interleucina-1alfa/antagonistas & inibidores , Interleucina-1beta/antagonistas & inibidores , Masculino , Pericardite/diagnóstico , Pericardite/tratamento farmacológico , Pericardite/fisiopatologia , Pericardite/psicologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos
3.
Front Immunol ; 11: 1518, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32655582

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the genus Betacoronavirus within the family Coronaviridae. It is an enveloped single-stranded positive-sense RNA virus. Since December of 2019, a global expansion of the infection has occurred with widespread dissemination of coronavirus disease 2019 (COVID-19). COVID-19 often manifests as only mild cold-like symptomatology, but severe disease with complications occurs in 15% of cases. Respiratory failure occurs in severe disease that can be accompanied by a systemic inflammatory reaction characterized by inflammatory cytokine release. In severe cases, fatality is caused by the rapid development of severe lung injury characteristic of acute respiratory distress syndrome (ARDS). Although ARDS is a complication of SARS-CoV-2 infection, it is not viral replication or infection that causes tissue injury; rather, it is the result of dysregulated hyperinflammation in response to viral infection. This pathology is characterized by intense, rapid stimulation of the innate immune response that triggers activation of the Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome pathway and release of its products including the proinflammatory cytokines IL-6 and IL-1ß. Here we review the literature that describes the pathogenesis of severe COVID-19 and NLRP3 activation and describe an important role in targeting this pathway for the treatment of severe COVID-19.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia Viral/metabolismo , Animais , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Imunidade Inata , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/metabolismo , Camundongos , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Piroptose/efeitos dos fármacos , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/etiologia , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Sesquiterpenos de Guaiano/farmacologia , Sesquiterpenos de Guaiano/uso terapêutico , Sulfonas/farmacologia , Sulfonas/uso terapêutico
4.
Med Hypotheses ; 143: 109906, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32505910

RESUMO

Most COVID-19 infected individuals present with mild flu-like symptoms; however, 5-10% of cases suffer from life-threatening pneumonia and respiratory failure. The pathogenesis of SARS-CoV-2 and its pathology of associated acute lung injury (ALI), acute respiratory distress syndrome (ARDS), sepsis, coagulopathy and multiorgan failure is not known. SARS-CoV-2 is an envelope virus with S (spike), M (membrane), N (nucleocapsid) and E (envelop) proteins. In a closely related coronavirus (SARS-CoV), the transmembrane E protein exerts an important role in membrane-ionic transport through viroporins, deletion of which reduced levels of IL-1ß and a remarkably reduced lung edema compared to wild type. IL-1ß is generated by macrophages upon activation of intracellular NLRP3 (NOD-like, leucine rich repeat domains, and pyrin domain-containing protein 3), part of the functional NLRP3 inflammasome complex that detects pathogenic microorganisms and stressors, while neutrophils are enhanced by increasing levels of IL-1ß. Expiring neutrophils undergo "NETosis", producing thread-like extracellular structures termed neutrophil extracellular traps (NETs), which protect against mild infections and microbes. However, uncontrolled NET production can cause acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), coagulopathy, multiple organ failure, and autoimmune disease. Herein, we present arguments underlying our hypothesis that IL-1ß and NETs, mediated via NLRP3 inflammasomes, form a feed-forward loop leading to the excessive alveolar and endothelial damage observed in severe cases of COVID-19. Considering such assertions, we propose potential drug candidates that could be used to alleviate such pathologies. Considering that recent efforts to ascertain effective treatments of COVID-19 in severe patients has been less than successful, investigating novel avenues of treating this virus are essential.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Armadilhas Extracelulares/efeitos dos fármacos , Interleucina-1beta/antagonistas & inibidores , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Infecções por Coronavirus/imunologia , Armadilhas Extracelulares/imunologia , Retroalimentação Fisiológica , Humanos , Inflamassomos/imunologia , Interleucina-1beta/imunologia , Modelos Biológicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Pandemias , Pneumonia Viral/imunologia
5.
Ann Intern Med ; 172(8): 523-532, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32203978

RESUMO

Background: Inflammatory cytokines, such as interleukin (IL)-1ß, alter iron homeostasis and erythropoiesis, resulting in anemia, but whether inhibition of IL-1ß can reverse these effects is unclear. Objective: To determine whether IL-1ß inhibition with canakinumab reduces incident anemia and improves hemoglobin levels among those with prevalent anemia. Design: Exploratory analysis of a randomized controlled trial. (ClinicalTrials.gov: NCT01327846). Setting: Many clinical sites in 39 countries. Participants: 8683 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants without anemia at trial entry and 1303 with prevalent anemia at trial entry. Intervention: Random assignment to receive placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months. Measurements: Primary outcome was incident anemia (hemoglobin level <130 g/L in men or <120 g/L in women). Results: Anemia incidence increased with rising baseline levels of high-sensitivity C-reactive protein (hsCRP), and both hsCRP and IL-6 decreased among participants receiving canakinumab compared with the placebo group. During a median follow-up of 3.7 years, participants without baseline anemia who received canakinumab at any dosage had significantly less incident anemia than those who received placebo (hazard ratio, 0.84 [95% CI, 0.77 to 0.93]; P < 0.001). Compared with placebo, the greatest benefits of IL-1ß inhibition on incident anemia were observed among participants with the most robust anti-inflammatory response, an effect corroborated in formal mediation analyses. Among those with baseline anemia, canakinumab increased mean hemoglobin levels by 11.3 g/L (P < 0.001) compared with placebo after 2 years of treatment. Canakinumab increased the risk for infection and was associated with mild cases of thrombocytopenia and neutropenia, none of which was grade 3 or higher. Limitation: CANTOS was not designed to assess the cause of anemia in individual trial participants. Conclusion: These exploratory analyses of randomized trial data provide proof of principle that inflammation inhibition, at least through the IL-1ß/IL-6 signaling pathway, reduces the incidence of anemia and improves hemoglobin levels in patients with anemia. Primary Funding Source: Novartis Pharmaceuticals.


Assuntos
Anemia/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Interleucina-1beta/antagonistas & inibidores , Idoso , Anemia/complicações , Anemia/imunologia , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Método Duplo-Cego , Feminino , Hemoglobinas/análise , Humanos , Incidência , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações
7.
Sci Adv ; 6(6): eaay0589, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32076644

RESUMO

An acute myocardial infarction (AMI) induces a sterile inflammatory response that facilitates further heart injury and promotes adverse cardiac remodeling. Interleukin-1ß (IL-1ß) plays a central role in the sterile inflammatory response that results from AMI. Thus, IL-1ß blockage is a promising strategy for treatment of AMI. However, conventional IL-1ß blockers lack targeting specificity. This increases the risk of serious side effects. To address this problem herein, we fabricated platelet microparticles (PMs) armed with anti-IL-1ß antibodies to neutralize IL-1ß after AMI and to prevent adverse cardiac remodeling. Our results indicate that the infarct-targeting PMs could bind to the injured heart, increasing the number of anti-IL-1ß antibodies therein. The anti-IL-1ß platelet PMs (IL1-PMs) protect the cardiomyocytes from apoptosis by neutralizing IL-1ß and decreasing IL-1ß-driven caspase-3 activity. Our findings indicate that IL1-PM is a promising cardiac detoxification agent that removes cytotoxic IL-1ß during AMI and induces therapeutic cardiac repair.


Assuntos
Plaquetas/metabolismo , Micropartículas Derivadas de Células/metabolismo , Interleucina-1beta/antagonistas & inibidores , Animais , Apoptose , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Camundongos , Modelos Biológicos , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Ligação Proteica , Remodelação Ventricular
8.
Int J Oral Sci ; 12(1): 2, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31900383

RESUMO

Interleukin(IL)-1ß, a pro-inflammatory cytokine, was elevated and participates in periodontitis. Not only the link between IL-1ß and periodontitis was proved by clinical evidence, but also the increased IL-1ß triggers a series of inflammatory reactions and promotes bone resorption. Currently, IL-1ß blockage has been therapeutic strategies for autoimmune and autoinflammatory diseases such as rheumatoid arthritis, cryopyrin-associated periodic syndromes, gout and type II diabetes mellitus. It is speculated that IL-1ß be a potential therapeutic target for periodontitis. The review focuses on the production, mechanism, present treatments and future potential strategies for IL-1ß in periodontitis.


Assuntos
Inflamação/terapia , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/imunologia , Periodontite/terapia , Citocinas , Diabetes Mellitus Tipo 2 , Humanos , Inflamação/imunologia , Interleucina-1beta/efeitos dos fármacos , Periodontite/diagnóstico
9.
Phytochemistry ; 171: 112247, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31927201

RESUMO

Four previously undescribed acylated iridoid glucosides, linaburiosides A‒D, one undescribed iridoid, 7-deoxyiridolactonic acid, and one known acylated iridoid glucoside, iridolinarin C, were isolated from the aerial parts of a Mongolian traditional herbal medicine, Linaria buriatica. Linaburiosides A‒D had an acyl moiety corresponding to 7-deoxyiridolactonic acid. Detailed spectroscopic analyses of linaburiosides A‒D and 7-deoxyiridolactonic acid led to the assignment of their structures. The absolute configuration of 7-deoxyiridolactonic acid was elucidated by application of the PGME method; those of linaburiosides A‒D were assigned on the basis of chemical conversions, as well as application of the modified Mosher's method. The absolute configuration of iridolinarin C was also elucidated in this study. Anti-inflammatory and antiproliferative activities of isolated compounds and their derivatives were evaluated.


Assuntos
Anti-Inflamatórios/farmacologia , Glucosídeos/farmacologia , Iridoides/farmacologia , Linaria/química , Compostos Fitoquímicos/farmacologia , Células A549 , Acilação , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Glucosídeos/química , Glucosídeos/isolamento & purificação , Humanos , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/biossíntese , Iridoides/química , Iridoides/isolamento & purificação , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Células MCF-7 , Microglia/efeitos dos fármacos , Microglia/metabolismo , Conformação Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Células Tumorais Cultivadas
10.
Cancer Res ; 80(5): 1088-1101, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31915130

RESUMO

Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy typified by a highly stromal and weakly immunogenic tumor microenvironment that promotes tumor evolution and contributes to therapeutic resistance. Here, we demonstrate that PDA tumor cell-derived proinflammatory cytokine IL1ß is essential for the establishment of the protumorigenic PDA microenvironment. Tumor cell-derived IL1ß promoted the activation and secretory phenotype of quiescent pancreatic stellate cells and established an immunosuppressive milieu mediated by M2 macrophages, myeloid-derived suppressor cells, CD1dhiCD5+ regulatory B cells, and Th17 cells. Loss of tumor cell-derived IL1 signaling in tumor stroma enabled intratumoral infiltration and activation of CD8+ cytotoxic T cells, attenuated growth of pancreatic neoplasia, and conferred survival advantage to PDA-bearing mice. Accordingly, antibody-mediated neutralization of IL1ß significantly enhanced the antitumor activity of α-PD-1 and was accompanied by increased tumor infiltration of CD8+ T cells. Tumor cell expression of IL1ß in vivo was driven by microbial-dependent activation of toll-like receptor 4 (TLR4) signaling and subsequent engagement of the NLRP3 inflammasome. Collectively, these findings identify a hitherto unappreciated role for tumor cell-derived IL1ß in orchestrating an immune-modulatory program that supports pancreatic tumorigenesis. SIGNIFICANCE: These findings identify a new modality for immune evasion in PDA that depends on IL1ß production by tumor cells through TLR4-NLRP3 inflammasome activation. Targeting this axis might provide an effective PDA therapeutic strategy.


Assuntos
Carcinogênese/imunologia , Carcinoma Ductal Pancreático/imunologia , Interleucina-1beta/metabolismo , Neoplasias Pancreáticas/imunologia , Evasão Tumoral/imunologia , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Sinergismo Farmacológico , Células Epiteliais , Feminino , Humanos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Transgênicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ductos Pancreáticos/citologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Cultura Primária de Células , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/metabolismo , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
12.
Reumatol. clín. (Barc.) ; 16: 0-0, 2020. ilus
Artigo em Espanhol | IBECS | ID: ibc-187742

RESUMO

El desenlace de la infección por SARS-CoV-2 (COVID-19) afecta fundamentalmente al campo pulmonar, ocasionando un cuadro de SÍNDROME DE DISTRÉS RESPIRATORIO AGUDO (SDRA). Este proceso es un cuadro inflamatorio, protagonizado por una cascada de citocinas bajo el amparo del INFLAMOSOMA NLRP3, responsable principal de la destrucción alveolar. De entre todas las citocinas que se desencadenan en este cuadro destaca la IL beta. ANAKINRA es un potente fármaco biológico, capaz de bloquear esta IL 1 beta. Proponemos su uso, de cara a controlar el SDRA secundario a la infección por COVID-19


The outcome of the SARS-CoV-2 (COVID-19) infection fundamentally affects the lung field, causing ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS). This process is an inflammatory picture, involving an NLRP3 INFLAMOSOME-triggered cytokine storm, the main player in alveolar destruction. IL-1 beta stands out among the cytokines that are triggered in this picture. ANAKINRA is a potent biological drug, capable of blocking this IL 1 beta. We propose its use in controlling ARDS secondary to COVID-19 infection


Assuntos
Humanos , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Infecções por Coronavirus/complicações , Vírus da SARS/patogenicidade , Pneumonia Viral/tratamento farmacológico , Interleucina-1alfa/antagonistas & inibidores , Interleucina-1beta/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Inflamassomos/imunologia , Terapia Biológica/métodos , Interleucina-1alfa/imunologia , Interleucina-1beta/imunologia
13.
Hypertension ; 75(2): 477-482, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31884854

RESUMO

While hypertension and inflammation are physiologically inter-related, the effect of therapies that specifically target inflammation on blood pressure is uncertain. The recent CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) afforded the opportunity to test whether IL (interleukin)-1ß inhibition would reduce blood pressure, prevent incident hypertension, and modify relationships between hypertension and cardiovascular events. CANTOS randomized 10 061 patients with prior myocardial infarction and hsCRP (high sensitivity C-reactive protein) ≥2 mg/L to canakinumab 50 mg, 150 mg, 300 mg, or placebo. A total of 9549 trial participants had blood pressure recordings during follow-up; of these, 80% had a preexisting diagnosis of hypertension. In patients without baseline hypertension, rates of incident hypertension were 23.4, 26.6, and 28.1 per 100-person years for the lowest to highest baseline tertiles of hsCRP (P>0.2). In all participants random allocation to canakinumab did not reduce blood pressure (P>0.2) or incident hypertension during the follow-up period (hazard ratio, 0.96 [0.85-1.08], P>0.2). IL-1ß inhibition with canakinumab reduces major adverse cardiovascular event rates. These analyses suggest that the mechanisms underlying this benefit are not related to changes in blood pressure or incident hypertension. Clinical Trial Registration- URL: https://clinicaltrials.gov. Unique identifier: NCT01327846.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Pressão Sanguínea/fisiologia , Hipertensão/tratamento farmacológico , Interleucina-1beta/metabolismo , Idoso , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Injeções Subcutâneas , Interleucina-1beta/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade
14.
Pediatr Rheumatol Online J ; 17(1): 84, 2019 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-31864380

RESUMO

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is the most catastrophic form of heterotopic ossification, due to ongoing intracellular signaling through the bone morphogenic protein pathway. The paroxysmal appearance of inflammatory lumps and elevated inflammatory markers during flares, suggest that FOP is an auto-inflammatory disease. Based on evidence, demonstrating a role for interleukin-1ß (IL-1ß) in other forms of heterotopic ossification, we hypothesized that treating FOP patients with anti-IL-1 agents could help lower the rate of FOP paroxysms and/or limit the symptoms and residual lesions. CASE PRESENTATION: A 13.5-year-old Arab boy was diagnosed with FOP. Treatment with anti-inflammatory drugs did not change the disease course. New lumps appeared in a rate of approximately one every 8 days. Treatment with the anti-IL-1 agents anakinra and canakinumab resulted in significantly lower rate of paroxysms (every 22-25 days, of which almost all involved only 2 existing lumps), as well as shorter duration. High levels of IL-1ß were found in the patient's plasma samples, collected during a paroxysm that appeared 8 weeks after the last canakinumab dose. In contrast, IL-1ß plasma levels were undetectable in the previous three plasma samples, obtained while he was treated with anti-IL-1 agents. CONCLUSIONS: Our data demonstrate the efficacy of anti-IL-1 agents in the treatment of a patient with FOP. Results showing the marked increase in IL-1ß plasma levels during a paroxysm support a role for IL-1ß in the pathogenesis of FOP and further provide the rationale for the use of anti-IL-1 agents in FOP treatment.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Interleucina-1beta/sangue , Miosite Ossificante/sangue , Adolescente , Biomarcadores/sangue , Progressão da Doença , Humanos , Interleucina-1beta/antagonistas & inibidores , Imagem por Ressonância Magnética , Masculino , Miosite Ossificante/diagnóstico , Miosite Ossificante/tratamento farmacológico , Tomografia Computadorizada por Raios X
15.
J Neuroinflammation ; 16(1): 234, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31771613

RESUMO

BACKGROUND: Inflammation and apoptosis caused by intracerebral hemorrhage (ICH) are two important factors that affect patient prognosis and survival. Toll-like receptor 4 (TLR4) triggers activation of the inflammatory pathway, causing synthesis and release of inflammatory factors. The inflammatory environment also causes neuronal apoptosis. However, no studies have reported the role of TLR4 in inflammation and apoptosis. METHODS: We performed survival curve analysis and behavioral scores on TLR4 knockout mice and wild-type mice after inducing ICH. We used TLR4 knockout mice and wild-type mice to make ICH models with type VII collagenase and explored the link between TLR4 in inflammation and apoptosis. We used Western blot to detect the expression of apoptosis-related proteins, inflammatory factors, and their receptors at different time points after ICH induction. The effects of TLR4 on apoptosis were observed by TUNEL, Hoechst, and HE staining techniques. The association with TLR4 in inflammation and apoptosis was explored using IL-1ß and TNF-α antagonists. Data conforming to a normal distribution are expressed as mean ± standard deviation. Grade and quantitative data were compared with rank sum test and t test between two groups. P < 0.05 was considered statistically significant. RESULTS: TLR4 knockout significantly increased the survival rate of ICH mice. The scores of TLR4 knockout mice were significantly lower than those of wild-type mice. We found that TLR4 knockout mice significantly inhibited apoptosis and the expression of inflammatory factors after the induction of ICH. The apoptosis of ICH-induced mice was significantly improved after injecting IL-1ß and TNF-α antagonists. Moreover, the anti-apoptotic effect of the antagonist in wild-type mice is more pronounced. A single injection of the antagonist failed to improve apoptosis in TLR4 knockout mice. CONCLUSIONS: We conclude that TLR4-induced inflammation after ICH promotes neuronal apoptosis. IL-1ß and TNF-α antagonists attenuate this apoptotic effect. Therefore, targeting TLR4 in patients with clinical ICH may attenuate inflammatory response, thereby attenuating apoptosis and improving prognosis.


Assuntos
Apoptose/fisiologia , Encéfalo/metabolismo , Hemorragia Cerebral/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Hemorragia Cerebral/genética , Colagenases/metabolismo , Interleucina-1beta/antagonistas & inibidores , Camundongos , Camundongos Knockout , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/antagonistas & inibidores
16.
Physiol Res ; 68(Suppl 1): S17-S30, 2019 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-31755287

RESUMO

Improvement in the prognosis of patients at risk of atherothrombotic events is based on three pillars - slowing down the process of atherogenesis (i.e. the development of atherosclerotic plaque), stabilizing the current atherosclerotic plaque, and reducing the risk of thrombotic occlusion in cases with unstable atherosclerotic plaque. The current prophylaxis has so far taken into consideration the adjustment of several risk factors, including dyslipidemia, arterial hypertension, smoking, and diabetes through lifestyle changes or pharmacological therapies. An essential part of prophylaxis is the anti-thrombotic strategy, especially anti-platelet therapy. Recently, a new pathway has been developed, based on reducing the activity of the inflammatory process with NLRP3 inflammasome, specifically a monoclonal antibody against interleukin 1beta (canakinumab). The efficacy and safety of this treatment, in secondary prevention, were documented in the CANTOS study. Other therapeutic procedures, including suppression of the inflammatory component of atherogenesis, are at the stage of clinical assessment.


Assuntos
Anti-Inflamatórios/uso terapêutico , Aterosclerose/tratamento farmacológico , Inflamação/prevenção & controle , Placa Aterosclerótica/prevenção & controle , Trombose/prevenção & controle , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Humanos , Interleucina-1beta/antagonistas & inibidores , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Fatores de Risco
17.
Drug Des Devel Ther ; 13: 3559-3568, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686786

RESUMO

Background: Osteoarthritis (OA) is a prevalent degenerative joint disease, which was characterized by inflammation and cartilage degradation. Accumulating evidence has demonstrated that Tanshinone I has an anti-inflammatory effect in various diseases. However, the efficacy of Tanshinone I as an anti-inflammatory agent in OA remains unclear. This study aimed to explore the role of Tanshinone I on OA both in vitro and in vivo. Methods: CHON-001 cells were treated with IL-1ß (10 ng/mL) for 72 hrs to induce OA model in vitro. Meanwhile, CHON-001 cells were pre-treated with 20 µM Tanshinone I for 24 hrs and then stimulated with IL-1ß (10 ng/mL) for 72 hrs. CCK-8, immunofluorescence and flow cytometry assays were used to detect the viability, proliferation and apoptosis in CHON-001 cells, respectively. Western blotting assay was used to detect the levels of collagen II, aggrecan, MMP-13, cleaved caspase 1, Gasdermin D, SOX11 and p-NF-κB in CHON-001 cells. In addition, the mouse model of OA was built by anterior cruciate ligament transection (ACLT) in the right knee. Meanwhile, the mice were administrated with 10 or 30 mg/kg Tanshinone I for 8 weeks. Safranin-O/Fast Green staining was used to assess cartilage destruction in a mouse model of OA. Results: In this study, IL-1ß significantly induced apoptosis, extracellular matrix degradation and inflammatory response in CHON-001 cells. Tanshinone I significantly inhibited IL-1ß-induced apoptosis in CHON-001 cells. In addition, the IL-1ß-induced collagen II, aggrecan degradation, SOX11 downregulation, and MMP-13 and p-NF-κB upregulation in CHON-001 cells were notably reversed by Tanshinone I treatment. Moreover, Tanshinone I alleviated cartilage destruction and synovitis and reduced OARSI scores and subchondral bone thickness in a mouse model of OA. Conclusion: Our findings showed that Tanshinone I could alleviate the progression of OA in vitro and in vivo. These results demonstrated that Tanshinone I might be regarded as a promising therapeutic agent for the treatment of OA.


Assuntos
Abietanos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Inflamação/tratamento farmacológico , Interleucina-1beta/antagonistas & inibidores , Osteoartrite/tratamento farmacológico , Abietanos/química , Animais , Anti-Inflamatórios não Esteroides/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Condrócitos/metabolismo , Matriz Extracelular/metabolismo , Feminino , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoartrite/metabolismo
18.
Lipids Health Dis ; 18(1): 171, 2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31521168

RESUMO

Psoriasis is a chronic, systemic, hyper-proliferative immune-mediated inflammatory skin disease. The results of epidemiological investigations have shown that psoriasis affects around 2% of the general population worldwide, and the total number of psoriasis patients is more than 6 million in China. Apart from the skin manifestations, psoriasis has been verified to associate with several metabolic comorbidities, such as insulin resistance, diabetes and obesity. However, the underlying mechanism is still not elucidated. Adipocytes, considered as the active endocrine cells, are dysfunctional in obesity which displays increased synthesis and secretion of adipokines with other modified metabolic properties. Currently, growing evidence has pointed to the central role of adipokines in adipose tissue and the immune system, providing new insights into the effect of adipokines in linking the pathophysiology of obesity and psoriasis. In this review, we summarize the current understanding of the pathological role of adipokines and the potential mechanisms whereby different adipokines link obesity and psoriasis. Furthermore, we also provide evidence which identifies a potential therapeutic target aiming at adipokines for the management of these two diseases.


Assuntos
Adipócitos/imunologia , Adiponectina/imunologia , Citocinas/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Lectinas/imunologia , Obesidade/imunologia , Psoríase/imunologia , Adipócitos/efeitos dos fármacos , Adipócitos/patologia , Adiponectina/agonistas , Adiponectina/genética , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/imunologia , Tecido Adiposo/patologia , Citocinas/agonistas , Citocinas/genética , Proteínas Ligadas por GPI/agonistas , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Regulação da Expressão Gênica/imunologia , Humanos , Sistema Imunitário/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Interleucina-6/imunologia , Lectinas/agonistas , Lectinas/genética , Leptina/antagonistas & inibidores , Leptina/genética , Leptina/imunologia , Terapia de Alvo Molecular/métodos , Obesidade/tratamento farmacológico , Obesidade/genética , Obesidade/fisiopatologia , Psoríase/tratamento farmacológico , Psoríase/genética , Psoríase/fisiopatologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
19.
Rev. esp. cardiol. (Ed. impr.) ; 72(9): 760-766, sept. 2019. ilus
Artigo em Espanhol | IBECS | ID: ibc-189135

RESUMO

Múltiples ensayos clínicos han demostrado de forma inequívoca que los medicamentos hipocolesterolemiantes disminuyen el riesgo de enfermedad cardiovascular ateroesclerótica de una muy amplia variedad de personas. A pesar de esto, muchas personas tratadas de manera óptima según los estándares actuales presentan eventos isquémicos potencialmente letales. Evidencia experimental y clínica reciente indica que la inflamación persistente en la placa ateroesclerótica es uno de los principales mecanismos subyacentes a este riesgo residual, lo que ha abierto la puerta a la aplicación de fármacos antiinflamatorios para la prevención de la enfermedad cardiovascular. En este artículo se repasa el conocimiento actual sobre la biología de la citocina interleucina 1beta, un regulador clave de la respuesta inflamatoria en la placa ateroesclerótica y la diana del primer ensayo clínico que ha demostrado que un fármaco antiinflamatorio puede reducir de forma efectiva el riesgo cardiovascular. Se discuten los importantes retos a los que se enfrentan los inhibidores de la interleucina 1beta y otros compuestos antiinflamatorios en su traslación al ámbito clínico y se identifican otras posibles dianas en esta vía de señalización, prometedoras en el contexto cardiovascular


Clinical trials have unequivocally shown that cholesterol-lowering drugs decrease the risk of atherosclerotic cardiovascular disease in an exceptionally wide range of individuals. Yet, even when treated optimally according to current standards, many individuals still experience life-threatening ischemic events. Emerging experimental and clinical evidence strongly suggests that persistent inflammation is a major driver of this residual risk, which has opened the door to the application of anti-inflammatory drugs for cardiovascular disease prevention. Here, we review our current knowledge of the biology of interleukin-1Beta, a key regulator of inflammation in atherosclerotic plaque and the target of the first clinical trial to demonstrate that an anti-inflammatory drug can effectively reduce cardiovascular risk. We discuss the challenges faced by interleukin-1Beta inhibitors and other anti-inflammatory compounds in their translation to the clinical scenario, and identify other potential targets within this signaling pathway that hold promise in the cardiovascular setting


Assuntos
Humanos , Doença da Artéria Coronariana/tratamento farmacológico , Aterosclerose/tratamento farmacológico , Placa Aterosclerótica/tratamento farmacológico , Interleucina-1beta/antagonistas & inibidores , Inflamassomos/uso terapêutico , Interleucina-1beta/efeitos dos fármacos , Anticolesterolemiantes/farmacocinética , Inflamação/fisiopatologia , Hematopoese/efeitos dos fármacos
20.
F1000Res ; 82019.
Artigo em Inglês | MEDLINE | ID: mdl-31448091

RESUMO

Atherosclerotic cardiovascular disease is a leading cause of death and morbidity globally. Over the past several years, arterial inflammation has been implicated in the pathophysiology of athero-thrombosis, substantially confirming what pathologist Rudolf Virchow had observed in the 19th century. Lipid lowering, lifestyle changes, and modification of other risk factors have reduced cardiovascular complications of athero-thrombosis, but a substantial residual risk remains. In view of the pathogenic role of inflammation in athero-thrombosis, directly targeting inflammation has emerged as an additional potential therapeutic option; and some early promising results have been suggested by the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS), in which canakinumab, a fully human monoclonal antibody targeting the pro-inflammatory and pro-atherogenic cytokine interleukin 1 beta, was shown to reduce cardiovascular events.


Assuntos
Aterosclerose/patologia , Doenças Cardiovasculares/patologia , Inflamação/patologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Humanos , Interleucina-1beta/antagonistas & inibidores
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