RESUMO
The actual Coronavirus Disease (COVID 19) pandemic is due to Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a member of the coronavirus family. Besides the respiratory involvement, COVID 19 patients frequently develop a pro-coagulative state caused by virus-induced endothelial dysfunction, cytokine storm and complement cascade hyperactivation. It is common to observe diffuse microvascular thrombi in multiple organs, mostly in pulmonary microvessels. Thrombotic risk seems to be directly related to disease severity and worsens patients' prognosis. Therefore, the correct understanding of the mechanisms underlying COVID-19 induced prothrombotic state can lead to a thorough assessment of the possible management strategies. Hence, we review the pathogenesis and therapy of COVID 19-related thrombosis disease, focusing on the available evidence on the possible treatment strategies and proposing an algorithm for the anticoagulation strategy based on disease severity.
Assuntos
Anticoagulantes/uso terapêutico , Tratamento Farmacológico da COVID-19 , COVID-19/complicações , SARS-CoV-2/fisiologia , Trombofilia/virologia , Algoritmos , Interações Hospedeiro-Patógeno , HumanosRESUMO
OBJECTIVES: To evaluate the feasibility of the autoinflammatory disease activity index (AIDAI) as a tool to assess disease activity in patients with hereditary recurrent fever syndromes (HRFs) treated with canakinumab. METHODS: Patients with active colchicine-resistant familial Mediterranean fever (crFMF), mevalonate kinase deficiency (MKD), or tumor necrosis factor receptor-associated periodic syndrome (TRAPS) were enrolled in the phase III CLUSTER study and asked to complete the AIDAI questionnaire daily. All patients included in the analysis were treated with canakinumab, but regimens and periods of treatment varied per study protocol. The AIDAI for each patient was calculated weekly over the first 40 weeks of study, based on the diaries completed over 30 days. Disease-specific cut-off AIDAI values for inactive disease were calculated in a ROC analysis by comparing AIDAI scores with the occurrence of clinically inactive disease, based on the physician global assessments of disease activity and the occurrence of flares. RESULTS: Sixty patients with crFMF, 70 with MKD, and 43 with TRAPS were included in the analysis. Median AIDAI scores were high during the first 4 weeks for the three disease cohorts, and decreased afterwards, with some differences between disease cohorts. AIDAI values of 12.0, 9.6 and 15.5 were obtained as the most optimal thresholds to discriminate patients with inactive disease, with sensitivity and specificity values mostly over 75%. CONCLUSIONS: The AIDAI allows to discriminate between patients with active and inactive HRFs, and can be used in clinical practice to monitor the disease course of patients and the effect of medications.
Assuntos
Febre Familiar do Mediterrâneo , Doenças Hereditárias Autoinflamatórias , Deficiência de Mevalonato Quinase , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Deficiência de Mevalonato Quinase/tratamento farmacológico , Deficiência de Mevalonato Quinase/induzido quimicamenteRESUMO
Kidney injury may be a severe complication of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and contributes to worsen the prognosis. Various pathophysiological mechanisms can contribute to organ damage and impair renal function, proving the complexity of the virus activity and the resulting immunity response. We summarized the evidence of the literature on the prevalence of kidney involvement, on the pathogenic pathways and on its management.
RESUMO
Hydrogen sulfide (H2S) is a ubiquitous gaseous signaling molecule that has an important role in many physiological and pathological processes in mammalian tissues, with the same importance as two others endogenous gasotransmitters such as NO (nitric oxide) and CO (carbon monoxide). Endogenous H2S is involved in a broad gamut of processes in mammalian tissues including inflammation, vascular tone, hypertension, gastric mucosal integrity, neuromodulation, and defense mechanisms against viral infections as well as SARS-CoV-2 infection. These results suggest that the modulation of H2S levels has a potential therapeutic value. Consequently, synthetic H2S-releasing agents represent not only important research tools, but also potent therapeutic agents. This review has been designed in order to summarize the currently available H2S donors; furthermore, herein we discuss their preparation, the H2S-releasing mechanisms, and their -biological applications.
Assuntos
Descoberta de Drogas , Gasotransmissores/farmacologia , Sulfeto de Hidrogênio/farmacologia , Animais , Benzenossulfonatos/administração & dosagem , Benzenossulfonatos/metabolismo , Benzenossulfonatos/farmacologia , Benzenossulfonatos/uso terapêutico , Química Farmacêutica , Gasotransmissores/administração & dosagem , Gasotransmissores/metabolismo , Gasotransmissores/uso terapêutico , Humanos , Sulfeto de Hidrogênio/administração & dosagem , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/uso terapêutico , Morfolinas/administração & dosagem , Morfolinas/metabolismo , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Naproxeno/administração & dosagem , Naproxeno/análogos & derivados , Naproxeno/metabolismo , Naproxeno/farmacologia , Naproxeno/uso terapêutico , Compostos Organotiofosforados/administração & dosagem , Compostos Organotiofosforados/metabolismo , Compostos Organotiofosforados/farmacologia , Compostos Organotiofosforados/uso terapêuticoRESUMO
As of January 2020, a new pandemic has spread from Wuhan and caused thousands of deaths worldwide. Several studies have observed a relationship between coronavirus disease (COVID-19) infection and the cardiovascular system with the appearance of myocardial damage, myocarditis, pericarditis, heart failure and various arrhythmic manifestations, as well as an increase in thromboembolic risk. Cardiovascular manifestations have been highlighted especially in older and more fragile patients and in those with multiple cardiovascular risk factors such as cancer, diabetes, obesity and hypertension. In this review, we will examine the cardiac involvement associated with SARS-CoV-2 infection, focusing on the pathophysiological mechanism underlying manifestations and their clinical implication, taking into account the main scientific papers published to date.
RESUMO
17beta-Hydroxysteroid dehydrogenases (17beta-HSD) regulate the intracellular concentration of active sex steroid hormones in target tissues. To date, at least 14 different isozymes have been identified. The type 8 17beta-hydroxysteroid dehydrogenase (17beta-HSD8) selectively catalyzes the conversion of estradiol (E2) to estrone (E1). To map the promoter region and to investigate its regulation, we cloned and fused a 1600 bp DNA fragment upstream of the 17beta-HSD8 transcriptional start site to a luciferase reporter gene. After transient transfection in HepG2 cells, this fragment was shown to possess promoter activity. Deletion constructs of the 5' flanking region of the 17beta-HSD8 gene led to the identification of the minimal promoter region within the first 75 bp upstream of the transcriptional start site. This region included two CCAAT boxes and sequences closely resembling the consensus Sp1 and NF-kappaB motifs. Site directed mutagenesis revealed that the CCAAT boxes were essential for transcription in HepG2. EMSA, supershift and chromatin immunoprecipitation reflected that these sequences were binding sites for C/EBPbeta. Furthermore, promoter activity was increased by the co-transfection of a C/EBPbeta expression vector, and this transactivation was through both CCAAT boxes. Our studies indicate that C/EBPbeta is essential for the transcription of the 17beta-HSD8 gene in the liver.
Assuntos
17-Hidroxiesteroide Desidrogenases/genética , Proteína beta Intensificadora de Ligação a CCAAT/fisiologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Transcrição Gênica/fisiologia , Animais , Sequência de Bases , Linhagem Celular , Imunoprecipitação da Cromatina , DNA , Ensaio de Desvio de Mobilidade Eletroforética , Humanos , Fígado/metabolismo , Camundongos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Regiões Promotoras Genéticas , Homologia de Sequência do Ácido NucleicoAssuntos
Injúria Renal Aguda , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , Injúria Renal Aguda/virologia , Idoso de 80 Anos ou mais , COVID-19 , Teste para COVID-19 , Deterioração Clínica , Técnicas de Laboratório Clínico/métodos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/terapia , Feminino , Humanos , Testes de Função Renal , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Oxigenoterapia/métodos , Administração dos Cuidados ao Paciente/métodos , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Pneumonia Viral/terapia , SARS-CoV-2 , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento , Tratamento Farmacológico da COVID-19RESUMO
Human Ag-specific CD8(+) T lymphocytes are heterogeneous and include functionally distinct populations. In this study, we report that at least two distinct mechanisms control the expansion of circulating naive, memory, and effector CD8(+) T lymphocytes when exposed to mitogen or Ag stimulation. The first one leads to apoptosis and occurs shortly after in vitro stimulation. Susceptibility to cell death is prominent among primed T cell subsets, and it is inversely correlated with the size of the ex vivo Bcl-2(high) population within these subsets. Importantly, the Bcl-2(high) phenotype is associated to the proportion of responsive CD8(+) T cells, independently of their differentiation stage. The second one depends on the expression of newly synthesized cyclin-dependent kinase inhibitor p16(INK4a) that occurs in a significant fraction of T cells that had been actively cycling, leading to their cell cycle arrest upon stimulation. Strikingly, accumulation of p16(INK4a) protein preferentially occurs in naive as opposed to primed derived T lymphocytes and is not related to apoptosis. Significant levels of p16 are readily detectable in a small number of ex vivo CD8(+) T cells. Our observations reveal that activation-induced p16 expression represents an alternative process to apoptosis, limiting the proliferation potential of activated naive derived T lymphocytes.
Assuntos
Antígenos/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Adulto , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Humanos , Cinética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoRESUMO
In human somatic cells, including T lymphocytes, telomeres progressively shorten with each cell division, eventually leading to a state of cellular senescence. Ectopic expression of telomerase results in the extension of their replicative life spans without inducing changes associated with transformation. However, it is yet unknown whether somatic cells that overexpress telomerase are physiologically indistinguishable from normal cells. Using CD8+ T lymphocyte clones overexpressing telomerase, we investigated the molecular mechanisms that regulate T cell proliferation. In this study, we show that early passage T cell clones transduced or not with human telomerase reverse transcriptase displayed identical growth rates upon mitogenic stimulation and no marked global changes in gene expression. Surprisingly, reduced proliferative responses were observed in human telomerase reverse transcriptase-transduced cells with extended life spans. These cells, despite maintaining high expression levels of genes involved in the cell cycle progression, also showed increased expression in several genes found in common with normal aging T lymphocytes. Strikingly, late passage T cells overexpressing telomerase accumulated the cyclin-dependent inhibitors p16Ink4a and p21Cip1 that have largely been associated with in vitro growth arrest. We conclude that alternative growth arrest mechanisms such as those mediated by p16Ink4a and p21Cip1 still remained intact and regulated the growth potential of cells independently of their telomere status.
Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/enzimologia , Proliferação de Células , Expressão Gênica/imunologia , Telomerase/biossíntese , Telomerase/genética , Células Cultivadas , Cromossomos Humanos , Células Clonais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Cariotipagem , Mitose/genética , Mitose/imunologia , Telomerase/metabolismo , Transdução GenéticaRESUMO
Human T lymphocytes can be numerically expanded in vitro only to a limited extent. The cyclin-dependent kinase inhibitor p16(INK4a) is essential in the control of cellular proliferation, and its expression, in epithelial cells, is associated with irreversible growth arrest. Using long-term cultured CD8+ T lymphocytes, we have investigated the role of the p16/pRb pathway in the regulation of T cell proliferation and senescence. In this study, we describe at least two mechanisms that cause replicative growth arrest in cultured lymphocytes. The first one depends on the expression of p16(INK4a) and is directly responsible for the exit of a significant proportion of CD8+ T cells from the proliferative population. This induced p16 expression pattern is observed during each round of mitogen stimulation and is not related to activation-induced cell death. Importantly, knocking down p16(INK4a) expression allows increased proliferation of T cells. The second one is a phenomenon that resembles human fibroblast senescence, but is independent of p16(INK4a) and of telomere attrition. Interestingly, virtually all pRb proteins in the senescent population are found in the active form. Our data indicate that newly synthesized p16(INK4a) limits the proliferation of T lymphocytes that respond to mitogen, but is not required for the loss of mitogen responsiveness called senescence.