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1.
Front Endocrinol (Lausanne) ; 12: 747744, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34867791

RESUMO

This paper suggests that ATP release induced by the SARS-CoV-2 virus plays a key role in the genesis of the major symptoms and complications of COVID-19. Infection of specific cells which contain the Angiotensin-Converting Enzyme 2 (ACE2) receptor results in a loss of protection of the Mineralocorticoid Receptor (MR). Local activation by cortisol stimulates the release of ATP initially into the basolateral compartment and then by lysosomal exocytosis from the cell surface. This then acts on adjacent cells. In the nose ATP acts as a nociceptive stimulus which results in anosmia. It is suggested that a similar paracrine mechanism is responsible for the loss of taste. In the lung ATP release from type 2 alveolar cells produces the non-productive cough by acting on purinergic receptors on adjacent neuroepithelial cells and activating, via the vagus, the cough reflex. Infection of endothelial cells results in the exocytosis of WeibelPalade bodies. These contain the Von Willebrand Factor responsible for micro-clotting and angiopoietin-2 which increases vascular permeability and plays a key role in the Acute Respiratory Distress Syndrome. To test this hypothesis this paper reports proof of concept studies in which MR blockade using spironolactone and low dose dexamethasone (SpiDex) was given to PCR-confirmed COVID-19 patients. In 80 patients with moderate to severe respiratory failure 40 were given SpiDex and 40 conventional treatment with high dose dexamethasone (HiDex). There was 1 death in the HiDex group and none in the SpiDex. As judged by clinical, biochemical and radiological parameters there were clear statistically significant benefits of SpiDex in comparison to HiDex. A further 20 outpatients with COVID-19 were given SpiDex. There was no control group and the aim was to demonstrate safety. No adverse effects were noted and no patient became hyperkalaemic. 90% were asymptomatic at 10 days. The very positive results suggest that blockade of the MR can produce major benefit in COVID19 patients. Further larger controlled studies of inpatients and outpatients are required not only for SARS-CoV-2 infection per se but also to determine if this treatment affects the incidence of Long COVID.


Assuntos
Anosmia/complicações , COVID-19/diagnóstico , COVID-19/terapia , Nociceptividade , SARS-CoV-2 , Avaliação de Sintomas , Trifosfato de Adenosina/metabolismo , Adulto , Idoso , Angiopoietina-2/biossíntese , Enzima de Conversão de Angiotensina 2/biossíntese , Animais , COVID-19/sangue , Dexametasona/administração & dosagem , Dexametasona/sangue , Dexametasona/uso terapêutico , Células Endoteliais/metabolismo , Feminino , Humanos , Hidrocortisona/metabolismo , Rim/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Reação em Cadeia da Polimerase , Ratos , Receptores de Mineralocorticoides/biossíntese , Espironolactona/sangue , Fator de von Willebrand/biossíntese
2.
Blood ; 111(7): 3514-21, 2008 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-18216296

RESUMO

The potential role of dietary fats in cancer is attracting considerable interest within the community. Both epidemiologic and experimental findings suggest that omega-3 polyunsaturated fatty acids (omega-3 PUFAs), which are almost absent from typical Western diets, exert protective effects against cancer progression, although the precise mechanism of this suppression remains unknown. One of the potential targets for omega-3 PUFAs in cancer suppression is angiogenesis, a process of new blood vessel formation within rapidly growing tumors. Here, we demonstrate that omega-6 PUFAs stimulate and omega-3 PUFAs inhibit major proangiogenic processes in human endothelial cells, including the induction of angiopoietin-2 (Ang2) and matrix metalloprotease-9, endothelial invasion, and tube formation, that are usually activated by the major omega-6 PUFA arachidonic acid. The cyclooxygenase (COX)-mediated conversion of PUFAs to prostanoid derivatives participated in modulation of the expression of Ang2. Thus, the omega-6 PUFA-derived prostaglandin E2 augmented, whereas the omega-3 PUFA-derived prostaglandin E3 suppressed the induction of Ang2 by growth factors. Our findings are consistent with the suggestion that PUFAs undergo biotransformation by COX-2 to lipid mediators that modulate tumor angiogenesis, which provides new insight into the beneficial effects of omega-3 PUFAs.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Células Endoteliais/enzimologia , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Neoplasias/enzimologia , Neovascularização Patológica/metabolismo , Alprostadil/análogos & derivados , Alprostadil/metabolismo , Angiopoietina-2/biossíntese , Ácido Araquidônico/metabolismo , Células Cultivadas , Dinoprostona/metabolismo , Células Endoteliais/patologia , Ácidos Graxos Ômega-6/metabolismo , Ácidos Graxos Ômega-6/farmacologia , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico
3.
J Biol Chem ; 279(13): 12171-80, 2004 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-14702352

RESUMO

Exposure of endothelial cells to hypoxia-induced angiopoietin-2 (Ang2) expression. The increase in Ang2 mRNA levels occurred by transcriptional regulation and by post-transcriptional increase in mRNA stability. Induction of Ang2 mRNA resulted in an increase of intracellular and secreted Ang2 protein levels. Since the transcriptional regulation of several genes involved in angiogenesis during hypoxia is mediated by hypoxia-inducible factor-1 (HIF-1), it was conceivable that Ang2 expression might be regulated by the same oxygen-dependent mechanism. However, our data showed that pharmacological HIF inducers, CoCl(2) and DFO, did not affect Ang2 expression. Moreover, HIF-1-deficient hepatoma cell (Hepa1 c4) and its wild-type counterpart (Hepa1 c1c4) up-regulates Ang2 during hypoxia. These results indicated that hypoxia-driven Ang2 expression may be independent of the HIF pathway. Using neutralizing VEGF antibody or pharmacological inhibitors of VEGF receptors, we showed that hypoxia-induced VEGF participates but could not account completely for Ang2 expression during hypoxia. In addition, hypoxia elicited an increase of cyclooxygenase-2 (COX-2) expression and a parallel increase in prostanglandin E(2) (PGE(2)) and prostacyclin (PGI(2)) production. COX-2 inhibitors decreased the hypoxic induction of Ang2 and the hypoxic induction of PGE(2) and PGI(2) in a dose-dependent manner. Similarly, COX-2 but not COX-1 antisense treatment decreased hypoxic induction of Ang2 expression, and this effect was reversed by exogenous PGE(2). Finally, exogenous PGE(2) and PGI(2) were able to stimulate Ang2 under normoxic conditions. These findings suggest that COX-2-dependent prostanoids may play an important role in the regulation of hypoxia-induced Ang2 expression.


Assuntos
Angiopoietina-2/biossíntese , Proteínas de Ligação a DNA/metabolismo , Endotélio Vascular/enzimologia , Hipóxia , Proteínas Nucleares/metabolismo , Oxigênio/metabolismo , Fatores de Transcrição , Transcrição Gênica , Western Blotting , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Sobrevivência Celular , Células Cultivadas , Cobalto/farmacologia , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/farmacologia , DNA Complementar/metabolismo , Desferroxamina/farmacologia , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Ensaio de Imunoadsorção Enzimática , Epoprostenol/metabolismo , Humanos , Hipóxia/metabolismo , Fator 1 Induzível por Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia , Concentração Inibidora 50 , Quelantes de Ferro/farmacologia , Isoenzimas/biossíntese , Lactonas/farmacologia , Proteínas de Membrana , Oligonucleotídeos Antissenso/farmacologia , Prostaglandina-Endoperóxido Sintases/biossíntese , Prostaglandinas/metabolismo , RNA Mensageiro/metabolismo , Proteínas Recombinantes/química , Sulfonas , Fatores de Tempo , Ativação Transcricional , Veias Umbilicais/citologia , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismo
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