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4.
J Pharmacol Sci ; 144(4): 218-228, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33070841

RESUMO

Myocardial ischemia initiates a chain of pathological conditions leading to cardiomyocyte death. Therefore, pharmacological treatment to stop ischemia-induced damage is necessary. Fibrates, have been reported to decrease inflammatory markers and to modulate the renin-angiotensin system (RAS). Our aim was to explore if clofibrate treatment, administered one week after myocardial event, decreases MI-induced cardiac damage. Wistar rats were assigned to: 1. Sham or 2. Coronary artery ligation (MI). Seven days after, rats were subdivided to receive vehicle (V) or clofibrate [100 mg/kg (C)] daily for 7 days. Blood samples and left ventricle were analyzed. RAS components [angiotensin II, angiotensin converting enzyme (ACE), and AT1-receptor] decreased in MI-C compared to MI-V, while [Ang-(1-7), bradykinin, ACE-2, and AT2-receptor] raised in response to clofibrate treatment. Oxidative stress markers increased in MI-V rats, a profile reverted in MI-C rats. Nitric oxide (NO) pathway (Akt, eNOS, and NO) exhibits a lower participation in MI-V, but clofibrate raised NO-pathway components and its production. MI-induced fibrosis and structural damage was also improved by clofibrate-treatment. In conclusion, clofibrate administration to 7 days MI-rats exerts an antioxidant, pro-vasodilator expression profile, and anti-fibrotic effect suggesting that PPARα activation can be considered a therapeutic target to improve cardiac condition posterior to ischemia.


Assuntos
Clofibrato/administração & dosagem , Clofibrato/farmacologia , Ventrículos do Coração/metabolismo , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/metabolismo , Miocárdio/patologia , Óxido Nítrico/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina II/metabolismo , Animais , Fibrose , Ventrículos do Coração/patologia , Masculino , Isquemia Miocárdica/patologia , Estresse Oxidativo/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo , Fatores de Tempo
5.
Nat Commun ; 11(1): 4549, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917889

RESUMO

Arterial macrophages have different developmental origins, but the association of macrophage ontogeny with their phenotypes and functions in adulthood is still unclear. Here, we combine macrophage fate-mapping analysis with single-cell RNA sequencing to establish their cellular identity during homeostasis, and in response to angiotensin-II (AngII)-induced arterial inflammation. Yolk sac erythro-myeloid progenitors (EMP) contribute substantially to adventitial macrophages and give rise to a defined cluster of resident immune cells with homeostatic functions that is stable in adult mice, but declines in numbers during ageing and is not replenished by bone marrow (BM)-derived macrophages. In response to AngII inflammation, increase in adventitial macrophages is driven by recruitment of BM monocytes, while EMP-derived macrophages proliferate locally and provide a distinct transcriptional response that is linked to tissue regeneration. Our findings thus contribute to the understanding of macrophage heterogeneity, and associate macrophage ontogeny with distinct functions in health and disease.


Assuntos
Artérias/citologia , Arterite/imunologia , Diferenciação Celular/fisiologia , Homeostase/fisiologia , Macrófagos/fisiologia , Envelhecimento/fisiologia , Angiotensina II/administração & dosagem , Angiotensina II/imunologia , Animais , Artérias/fisiologia , Medula Óssea/fisiologia , Transplante de Medula Óssea , Linhagem da Célula , Modelos Animais de Doenças , Feminino , Células-Tronco Hematopoéticas/fisiologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , RNA-Seq , Regeneração/fisiologia , Análise de Célula Única , Quimeras de Transplante
6.
Emerg Med Clin North Am ; 38(4): 807-818, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32981619

RESUMO

Sepsis care has evolved significantly since the initial early goal-directed therapy (EGDT) trials. Early fluid resuscitation, source control, and antibiotic therapy remain cornerstones of care but overall understanding is more nuanced, particularly regarding fluid selection, vasopressors, and inotropic support. Timely nutrition therapy and ventilatory support tend to receive less attention but also are important. Recent research has explored immunomodulation, ß-blockade, and vitamin supplementation. A renewed emphasis on early, aggressive resuscitation reaffirms the importance of emergency medicine providers knowledgeable and skilled in sepsis management.


Assuntos
Ressuscitação/métodos , Sepse/terapia , Angiotensina II/uso terapêutico , Antibacterianos/uso terapêutico , Antioxidantes/uso terapêutico , Ácido Ascórbico/uso terapêutico , Glicemia/análise , Pressão Sanguínea , Cardiomiopatias/etiologia , Cardiomiopatias/terapia , Cardiotônicos/uso terapêutico , Estado Terminal , Serviço Hospitalar de Emergência , Nutrição Enteral , Hidratação , Glucocorticoides/uso terapêutico , Hemodinâmica , Humanos , Escores de Disfunção Orgânica , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração Artificial , Vasoconstritores/uso terapêutico
7.
Clin Sci (Lond) ; 134(18): 2489-2501, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32990314

RESUMO

Angiotensin-converting enzyme (ACE) is a zinc membrane metallopeptidase that plays a key role in regulating vasoactive peptide levels and hence cardiovascular activity through its conversion of angiotensin I (Ang I) to Ang II and its metabolism of bradykinin. The discovery of its homologue, ACE2, 20 years ago has led to intensive comparisons of these two enzymes revealing surprising structural, catalytic and functional distinctions between them. ACE2 plays multiple roles not only as a vasopeptidase but also as a regulator of amino acid transport and serendipitously as a viral receptor, mediating the cellular entry of the coronaviruses causing severe acute respiratory syndrome (SARS) and, very recently, COVID-19. Catalytically, ACE2 functions as a monocarboxypeptidase principally converting the vasoconstrictor angiotensin II to the vasodilatory peptide Ang-(1-7) thereby counterbalancing the action of ACE on the renin-angiotensin system (RAS) and providing a cardioprotective role. Unlike ACE, ACE2 does not metabolise bradykinin nor is it inhibited by classical ACE inhibitors. However, it does convert a number of other regulatory peptides in vitro and in vivo. Interest in ACE2 biology and its potential as a possible therapeutic target has surged in recent months as the COVID-19 pandemic rages worldwide. This review highlights the surprising discoveries of ACE2 biology during the last 20 years, its distinctions from classical ACE and the therapeutic opportunities arising from its multiple biological roles.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Angiotensina II/efeitos dos fármacos , Angiotensina II/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Infecções por Coronavirus/metabolismo , Humanos , Pandemias , Pneumonia Viral/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Vasoconstritores/farmacologia
9.
Nihon Yakurigaku Zasshi ; 155(5): 319-322, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32879173

RESUMO

In Japan, hypertensive patients are speculated to be 40 million, and 30 million among them are poor controlled. Moreover, 20% of them are estimated as "resistant hypertension" those are above their target blood pressure even in the simultaneous use of three different classes anti-hypertensive drugs. Recently, aldosterone is recognized as one of the main causes of the etiology of "resistant hypertension." Therefore, it is important to discover novel drugs that inhibit the synthesis and secretion of aldosterone. We recently generated a stable H295R cell line expressing aldosterone synthase gene (CYP11B2) promoter (-1521~+2)/luciferase cDNA chimeric reporter construct. We thereafter established a high-throughput screening (HTS) system for the discovery of novel anti-hypertensive drugs that inhibit angiotensin II-induced CYP11B2 expression using the cell line. After confirmation of its validation (Z' score > 0.5), we performed HTS using Core Library (9,600 chemical compounds) and Validated Compound Library (1,979 chemical compounds) obtained from Drug Discovery Initiative (The University of Tokyo), and Tohoku University Chemical Library (5,562 chemical compounds), respectively. We obtained several hit compounds from each library, and focused on one compound (bortezomib) obtained from Validated Compound Library. The compound did not affect cell viability by WST-1 assay, and was demonstrated to lower blood pressure of Tsukuba Hypertensive Mice, significantly. The compound may therefore be a potential candidate of novel anti-hypertensive drugs in the future.


Assuntos
Anti-Hipertensivos , Citocromo P-450 CYP11B2 , Aldosterona , Angiotensina II , Animais , Anti-Hipertensivos/farmacologia , Citocromo P-450 CYP11B2/genética , Humanos , Japão , Camundongos
11.
J Cardiovasc Magn Reson ; 22(1): 57, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32758255

RESUMO

BACKGROUND: Myocardial fibrosis is observed in multiple cardiac conditions including hypertension and aortic stenosis. Excessive fibrosis is associated with adverse clinical outcomes, but longitudinal human data regarding changes in left ventricular remodelling and fibrosis over time are sparse because of the slow progression, thereby making longitudinal studies challenging. The purpose of this study was to establish and characterize a mouse model to study the development and regression of left ventricular hypertrophy and myocardial fibrosis in response to increased blood pressure and to understand how these processes reverse remodel following normalisation of blood pressure. METHODS: We performed a longitudinal study with serial cardiovascular magnetic resonance (CMR) imaging every 2 weeks in mice (n = 31) subjected to angiotensin II-induced hypertension for 6 weeks and investigated reverse remodelling following normalisation of afterload beyond 6 weeks (n = 9). Left ventricular (LV) volumes, mass, and function as well as myocardial fibrosis were measured using cine CMR and the extracellular volume fraction (ECV) s. RESULTS: Increased blood pressure (65 ± 12 vs 85 ± 9 mmHg; p < 0.001) resulted in higher indices of LV hypertrophy (0.09 [0.08, 0.10] vs 0.12 [0.11, 0.14] g; p < 0.001) and myocardial fibrosis (ECV: 0.24 ± 0.03 vs 0.30 ± 0.02; p < 0.001) whilst LV ejection fraction fell (LVEF, 59.3 [57.6, 59.9] vs 46.9 [38.5, 49.6] %; p < 0.001). We found a strong correlation between ECV and histological myocardial fibrosis (r = 0.89, p < 0.001). Following cessation of angiotensin II and normalisation of blood pressure (69 ± 5 vs baseline 65 ± 12 mmHg; p = 0.42), LV mass (0.11 [0.10, 0.12] vs 0.09 [0.08, 0.11] g), ECV (0.30 ± 0.02 vs 0.27 ± 0.02) and LVEF (51.1 [42.9, 52.8] vs 59.3 [57.6, 59.9] %) improved but remained impaired compared to baseline (p < 0.05 for all). There was a strong inverse correlation between LVEF and %ECV during both systemic hypertension (r = - 0.88, p < 0.001) and the increases in ECV observed in the first two weeks of increased blood pressure predicted the reduction in LVEF after 6 weeks (r = - 0.77, p < 0.001). CONCLUSIONS: We have established and characterized angiotensin II infusion and repeated CMR imaging as a model of LV hypertrophy and reverse remodelling in response to systemic hypertension. Changes in myocardial fibrosis and alterations in cardiac function are only partially reversible following relief of hypertension.


Assuntos
Pressão Sanguínea , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/etiologia , Miocárdio/patologia , Função Ventricular Esquerda , Remodelação Ventricular , Angiotensina II , Animais , Modelos Animais de Doenças , Progressão da Doença , Fibrose , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Imagem Cinética por Ressonância Magnética , Masculino , Camundongos Endogâmicos C57BL , Fatores de Tempo
12.
Am J Physiol Lung Cell Mol Physiol ; 319(4): L596-L602, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32783619

RESUMO

A new form of severe acute respiratory syndrome (SARS) caused by SARS-coronavirus 2 (CoV-2), called COVID-19, has become a global threat in 2020. The mortality rate from COVID-19 is high in hypertensive patients, making this association especially dangerous. There appears to be a consensus, despite the lack of experimental data, that angiotensin II (ANG II) is linked to the pathogenesis of COVID-19. This process may occur due to acquired deficiency of angiotensin-converting enzyme 2 (ACE2), resulting in reduced degradation of ANG II. Furthermore, ANG II has a critical role in the genesis and worsening of hypertension. In this context, the idea that there is a surge in the level of ANG II with COVID-19 infection, causing multiple organ injuries in hypertensive patients becomes attractive. However, the role of other components of the renin angiotensin system (RAS) in this scenario requires elucidation. The identification of other RAS components in COVID-19 hypertension may provide both diagnostic and therapeutic benefits. Here, we summarize the pathophysiologic contributions of different components of RAS in hypertension and their possible correlation with poor outcome observed in hypertensive patients with COVID-19.


Assuntos
Infecções por Coronavirus/fisiopatologia , Hipertensão/fisiopatologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/fisiopatologia , Sistema Renina-Angiotensina/fisiologia , Angiotensina II/metabolismo , Betacoronavirus , Infecções por Coronavirus/mortalidade , Humanos , Hipertensão/mortalidade , Pandemias , Pneumonia Viral/mortalidade , Fatores de Risco
13.
Medicine (Baltimore) ; 99(31): e21492, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756181

RESUMO

Activation of the renin angiotensin system and renal oxidative stress (OS) are critical contributors in the progression of chronic kidney disease(CKD). Recent studies have confirmed that the angiotensin-converting enzyme 2-angiotensin (1-7)-Mas(ACE2/Ang(1-7)/Mas) axis, the important components of renin angiotensin system, protected kidneys against damage by antagonizing angiotensin II and attenuating OS in rats with several nephropathy models, but its effect needs to be further evaluated in clinic. In this study, we aimed to detected serum ACE2/Ang (1-7)/Mas axis, OS conditions and described its clinical associations in patients with CKD at different stages.A total of 48 patients with CKD and 6 healthy controls (CT) were enrolled, and serum angiotensin converting enzyme (ACE), ACE2, Ang (1-7), 8-hydroxy-2'-deoxyguanosine (8-OHdG) were determined by ELISA. Serum extracellular glutathione peroxidase(eGSH-Px) activity and renal functions were determined by the biochemical method.Serum ACE and ACE2 levels in CKD stages 3 to 5 and serum Ang(1-7) levels in CKD stages 4 to 5 without Ang II receptor blockers treatment significantly increased compared to those in the CT group. However, ACE2 was decreased and Ang(1-7) level increased in early CKD stage with Ang II receptor blockers treatment. Higher serum 8-OHdG levels and lower eGSH-Px activity were noted in CKD stages 4 to 5. Serum 8-OHdG level was correlated with serum ACE2, Ang(1-7) expression. Estimated glomerular filtration rate (eGFR) was correlated with serum ACE, ACE2, Ang(1-7), 8-OHdG, Hcy levels and serum eGSH-Px activity. Multiple-regression analysis eGFR was predicted by ACE, Hcy, eGSH-Px, and also can be predicted by ACE2, Ang(1-7), Hcy in CT subgroup.The ACE2/Ang(1-7)/Mas axis is associated with OS, and both them were associated with eGFR in the progression of CKD. Activation of ACE2/Ang(1-7)/Mas axis may have renoprotective effect and can be a potential therapeutic target in patients with early CKD stages.


Assuntos
Angiotensina II/sangue , Angiotensina I/sangue , Estresse Oxidativo/fisiologia , Fragmentos de Peptídeos/sangue , Peptidil Dipeptidase A/sangue , Insuficiência Renal Crônica/sangue , 8-Hidroxi-2'-Desoxiguanosina/sangue , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Sistema Renina-Angiotensina/fisiologia
14.
A A Pract ; 14(6): e01221, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32784326

RESUMO

The rapid spread of Coronavirus Disease 2019 (COVID-19) has sparked a search for effective therapies. The discovery that the virus binds the angiotensin-converting enzyme 2 (ACE2) receptor has led to investigation of the renin-angiotensin system for possible therapeutic targets. We present a case of an elderly woman with multiple comorbidities who developed severe acute respiratory distress syndrome (ARDS), a cardiomyopathy, and vasodilatory shock secondary to COVID-19 and was treated with exogenous angiotensin II. She rapidly demonstrated significant hemodynamic improvement without noted adverse effects. Thus, we propose further investigation into possible benefits of angiotensin II in shock secondary to COVID-19.


Assuntos
Angiotensina II/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Choque/tratamento farmacológico , Choque/etiologia , Vasoconstritores/uso terapêutico , Idoso de 80 Anos ou mais , Feminino , Humanos , Pandemias
15.
PLoS Biol ; 18(8): e3000808, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32817651

RESUMO

Although dysregulation of mitochondrial dynamics has been linked to cellular senescence, which contributes to advanced age-related disorders, it is unclear how Krüppel-like factor 5 (Klf5), an essential transcriptional factor of cardiovascular remodeling, mediates the link between mitochondrial dynamics and vascular smooth muscle cell (VSMC) senescence. Here, we show that Klf5 down-regulation in VSMCs is correlated with rupture of abdominal aortic aneurysm (AAA), an age-related vascular disease. Mice lacking Klf5 in VSMCs exacerbate vascular senescence and progression of angiotensin II (Ang II)-induced AAA by facilitating reactive oxygen species (ROS) formation. Klf5 knockdown enhances, while Klf5 overexpression suppresses mitochondrial fission. Mechanistically, Klf5 activates eukaryotic translation initiation factor 5a (eIF5a) transcription through binding to the promoter of eIF5a, which in turn preserves mitochondrial integrity by interacting with mitofusin 1 (Mfn1). Accordingly, decreased expression of eIF5a elicited by Klf5 down-regulation leads to mitochondrial fission and excessive ROS production. Inhibition of mitochondrial fission decreases ROS production and VSMC senescence. Our studies provide a potential therapeutic target for age-related vascular disorders.


Assuntos
Aneurisma da Aorta Abdominal/genética , Células Endoteliais/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Mitocôndrias/metabolismo , Fatores de Iniciação de Peptídeos/genética , Proteínas de Ligação a RNA/genética , Idoso , Angiotensina II/genética , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Animais , Aorta/diagnóstico por imagem , Aorta/metabolismo , Aorta/patologia , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Senescência Celular/efeitos dos fármacos , Ecocardiografia , Células Endoteliais/patologia , Feminino , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/deficiência , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/patologia , Dinâmica Mitocondrial/efeitos dos fármacos , Fatores de Iniciação de Peptídeos/deficiência , Cultura Primária de Células , Regiões Promotoras Genéticas , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo
16.
Life Sci ; 258: 118175, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32750436

RESUMO

AIMS: Human podocytes (hPC) play an important role in the pathogenesis of renal diseases. In this context, angiotensin II (Ang II) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) play a crucial role in podocyte injury. Recently, transmembrane protein (Tmem) 63c, a member of the Tmem-family was found to be expressed in kidney and associated with podocyte function. In this study, we analysed the expression regulation and functional impact of Tmem63c on cell viability and apoptosis in hPC in the context of Ang II activation. MATERIALS AND METHODS: Expression of Tmem63c in response to Ang II and the NFκB inhibitor Bay 11-7082 was analysed by Real-Time PCR and Western blotting. Cellular functions were determined by functional assays. KEY FINDINGS: We found Ang II to induce Tmem63c expression in hPC in a concentration-dependent manner. Inhibition of NFκB by Bay 11-7082 reduced basal as well as Ang II-induced Tmem63c expression. SiRNA-mediated down-regulation of Tmem63c diminished cell viability and protein kinase B (Akt) signaling and increased cell apoptosis of resting as well as Ang II-activated hPC. SIGNIFICANCE: These data show that Ang II induced the expression of Tmem63c in hPC, possibly via NFκB-dependent mechanisms. Moreover, down-regulation of Tmem63c was associated with reduced cell viability, indicating Tmem63c to be a potential pro-survival factor in hPC.


Assuntos
Angiotensina II/farmacologia , Canais de Cálcio/metabolismo , Podócitos/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Humanos , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Podócitos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
Am J Pathol ; 190(10): 2013-2017, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32735889

RESUMO

Coronavirus disease 2019 has markedly varied clinical presentations, with most patients being asymptomatic or having mild symptoms. However, severe acute respiratory disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is common and associated with mortality in patients who require hospitalization. The etiology of susceptibility to severe lung injury remains unclear. Angiotensin II, converted by angiotensin-converting enzyme (ACE) from angiotensin I and metabolized by ACE 2 (ACE2), plays a pivotal role in the pathogenesis of lung injury. ACE2 is identified as an essential receptor for SARS-CoV-2 to enter the cell. The binding of ACE2 and SARS-CoV-2 leads to the exhaustion and down-regulation of ACE2. The interaction and imbalance between ACE and ACE2 result in an unopposed angiotensin II. Considering that the ACE insertion (I)/deletion (D) gene polymorphism contributes to the ACE level variability in general population, in which mean ACE level in DD carriers is approximately twice that in II carriers, we propose a hypothesis of genetic predisposition to severe lung injury in patients with coronavirus disease 2019. It is plausible that the ACE inhibitors and ACE receptor blockers may have the potential to prevent and to treat the acute lung injury after SARS-CoV-2 infection, especially for those with the ACE genotype associated with high ACE level.


Assuntos
Infecções por Coronavirus , Predisposição Genética para Doença , Lesão Pulmonar/etiologia , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Frequência do Gene , Genótipo , Humanos , Lesão Pulmonar/virologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/fisiopatologia , Polimorfismo Genético , Receptores Virais/metabolismo , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiologia
19.
J Ovarian Res ; 13(1): 79, 2020 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-32684166

RESUMO

The outbreak and continued spread of the novel coronavirus disease 2019 (COVID-19) is a preeminent global health threat that has resulted in the infection of over 11.5 million people worldwide. In addition, the pandemic has claimed the lives of over 530,000 people worldwide. Age and the presence of underlying comorbid conditions have been found to be key determinants of patient mortality. One such comorbidity is the presence of an oncological malignancy, with cancer patients exhibiting an approximate two-fold increase in mortality rate. Due to a lack of data, no consensus has been reached about the best practices for the diagnosis and treatment of cancer patients. Interestingly, two independent research groups have discovered that Withaferin A (WFA), a steroidal lactone with anti-inflammatory and anti-tumorigenic properties, may bind to the viral spike (S-) protein of SARS-CoV-2. Further, preliminary data from our research group has demonstrated that WFA does not alter expression of ACE2 in the lungs of tumor-bearing female mice. Downregulation of ACE2 has recently been demonstrated to increase the severity of COVID-19. Therefore, WFA demonstrates real potential as a therapeutic agent to treat or prevent the spread of COVID-19 due to the reported interference in viral S-protein to host receptor binding and its lack of effect on ACE2 expression in the lungs.


Assuntos
Angiotensina II/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Peptidil Dipeptidase A/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Vitanolídeos/farmacologia , Angiotensina II/metabolismo , Animais , Betacoronavirus/metabolismo , Caquexia/metabolismo , Feminino , Humanos , Camundongos , Neoplasias Ovarianas/tratamento farmacológico , Pandemias , Peptidil Dipeptidase A/metabolismo , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Endocrinology ; 161(9)2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32652001

RESUMO

The current COVID-19 pandemic is the most disruptive event in the past 50 years, with a global impact on health care and world economies. It is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a coronavirus that uses angiotensin-converting enzyme 2 (ACE2) as an entry point to the cells. ACE2 is a transmembrane carboxypeptidase and member of the renin-angiotensin system. This mini-review summarizes the main findings regarding ACE2 expression and function in endocrine tissues. We discuss rapidly evolving knowledge on the potential role of ACE2 and SARS coronaviruses in endocrinology and the development of diabetes mellitus, hypogonadism, and pituitary and thyroid diseases.


Assuntos
Angiotensina II/metabolismo , Betacoronavirus/fisiologia , Complicações do Diabetes/virologia , Doenças do Sistema Endócrino/virologia , Peptidil Dipeptidase A/fisiologia , Animais , Betacoronavirus/patogenicidade , Encéfalo , Infecções por Coronavirus/complicações , Doenças do Sistema Endócrino/complicações , Expressão Gênica , Humanos , Hipogonadismo/complicações , Hipogonadismo/virologia , Camundongos , Pandemias , Peptidil Dipeptidase A/genética , Doenças da Hipófise/complicações , Doenças da Hipófise/virologia , Pneumonia Viral/complicações , Ratos , Sistema Renina-Angiotensina , Serina Endopeptidases/genética , Doenças da Glândula Tireoide/complicações , Doenças da Glândula Tireoide/virologia
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