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1.
Front Immunol ; 12: 728896, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34616396

RESUMO

A purified spike (S) glycoprotein of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) coronavirus was used to study its effects on THP-1 macrophages, peripheral blood mononuclear cells (PBMCs), and HUVEC cells. The S protein mediates the entry of SARS-CoV-2 into cells through binding to the angiotensin-converting enzyme 2 (ACE2) receptors. We measured the viability, intracellular cytokine release, oxidative stress, proinflammatory markers, and THP-1-like macrophage polarization. We observed an increase in apoptosis, ROS generation, MCP-1, and intracellular calcium expression in the THP-1 macrophages. Stimulation with the S protein polarizes the THP-1 macrophages towards proinflammatory futures with an increase in the TNFα and MHC-II M1-like phenotype markers. Treating the cells with an ACE inhibitor, perindopril, at 100 µM reduced apoptosis, ROS, and MHC-II expression induced by S protein. We analyzed the sensitivity of the HUVEC cells after the exposure to a conditioned media (CM) of THP-1 macrophages stimulated with the S protein. The CM induced endothelial cell apoptosis and MCP-1 expression. Treatment with perindopril reduced these effects. However, the direct stimulation of the HUVEC cells with the S protein, slightly increased HIF1α and MCP-1 expression, which was significantly increased by the ACE inhibitor treatment. The S protein stimulation induced ROS generation and changed the mitogenic responses of the PBMCs through the upregulation of TNFα and interleukin (IL)-17 cytokine expression. These effects were reduced by the perindopril (100 µM) treatment. Proteomic analysis of the S protein stimulated THP-1 macrophages with or without perindopril (100 µM) exposed more than 400 differentially regulated proteins. Our results provide a mechanistic analysis suggesting that the blood and vascular components could be activated directly through S protein systemically present in the circulation and that the activation of the local renin angiotensin system may be partially involved in this process. Graphical: Suggested pathways that might be involved at least in part in S protein inducing activation of inflammatory markers (red narrow) and angiotensin-converting enzyme inhibitor (ACEi) modulation of this process (green narrow).


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Apoptose/efeitos dos fármacos , COVID-19/imunologia , Macrófagos/imunologia , Estresse Oxidativo/efeitos dos fármacos , Perindopril/farmacologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , COVID-19/tratamento farmacológico , COVID-19/fisiopatologia , COVID-19/virologia , Linhagem Celular , Humanos , Macrófagos/efeitos dos fármacos , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Piroptose/efeitos dos fármacos , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética
2.
J Agric Food Chem ; 69(40): 12063-12071, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34581184

RESUMO

The angiotensin-converting enzyme (ACE) inhibitory peptide QIGLF derived from egg white was shown to have significant in vivo antihypertensive effects in our previous study, but the intervention mechanisms at the metabolic level are still unclear. The UPLC-QTOF/MS-based untargeted metabolomics approach was used to clarify the potential antihypertensive mechanisms of QIGLF in the serum of spontaneously hypertensive rats (SHRs). Multivariate statistical analysis showed a clear difference in the metabolite profiles between the QIGLF and model groups. The results suggested that eight potential biomarkers were identified, that is, adrenic acid, ursodeoxycholic acid, glycocholic acid, taurocholic acid, tryptophan, acetylindoxyl, tyrosine, and 2-phenylethanol, which were mainly involved in aromatic amino acid biosynthesis and metabolism, biosynthesis of bile acid, and biosynthesis of unsaturated fatty acids. QIGLF might exert antihypertensive effects by improving endothelial dysfunction. This study provides a theoretical basis for future research and application of ACE inhibitory peptides in the prevention and improvement of hypertension.


Assuntos
Anti-Hipertensivos , Hipertensão , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea , Clara de Ovo , Hipertensão/tratamento farmacológico , Metabolômica , Peptídeos/farmacologia , Ratos , Ratos Endogâmicos SHR
3.
J Agric Food Chem ; 69(35): 10350-10357, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34448567

RESUMO

As a membrane protein, the activity of angiotensin I-converting enzyme (ACE) can be modulated via regulation of its localization in the cell membrane with food-derived peptides. This study aimed to explore the effect of egg white peptides on the cell membrane localization and activity of ACE in human umbilical vein endothelial cells. ACE activity was found to be related to lipid rafts by using methyl-ß-cyclodextrin (MßCD). QVPLW and LCAY can inhibit ACE activity by preventing ACE recruitment into lipid rafts, with in situ IC50 values of 238.46 ± 11.35 µM and 31.55 ± 2.64 µM in the control groups, as well as 45.43 ± 6.15 µM and 34.63 ± 1.59 µM in the MßCD groups, respectively. QVPLW and LCAY may alter the cell membrane properties, including the fluidity, potential, and permeability, and eventually promote the transposition of ACE.


Assuntos
Clara de Ovo , Peptidil Dipeptidase A , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Microdomínios da Membrana , Peptídeos/farmacologia
4.
Int Heart J ; 62(4): 801-810, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34276005

RESUMO

Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) have been shown to prevent left ventricular remodeling and improve outcomes of patients with heart failure (HF). This study aimed to investigate whether the use of ACEi/ARB could be associated with HF with recovered ejection fraction (HFrecEF) in patients with dilated cardiomyopathy (DCM).We collected individual patient data regarding demographics, echocardiogram, and treatment in DCM between 2003 and 2014 from the clinical personal record, a national database of the Japanese Ministry of Health, Labour and Welfare. Patients with left ventricular ejection fraction (LVEF) < 40% were included. Eligible patients were divided into two groups according to the use of ACEi/ARB. A propensity score matching analysis was employed. The primary outcome was defined as LVEF ≥ 40% at 3 years of follow-up.Out of 5,955 patients with DCM and LVEF < 40%, propensity score matching yielded 830 pairs. The mean age was 58.8 years, and 1,184 (71.3%) of the patients were male. The primary outcome was observed more frequently in the ACEi/ARB group than in the no ACEi/ARB group (57.0% versus 49.3%; odds ratio 1.36; 95% confidence interval (CI) 1.12-1.65; P = 0.002). Subgroup analysis revealed that the use of ACEi and ARB was associated with recovery of LVEF regardless of atrial fibrillation. The change in LVEF from baseline to 3 years of follow-up was greater in the ACEi-ARB group (14.9% ± 0.6% versus 12.3% ± 0.5%; P = 0.001).The use of ACEi/ARB is associated with HFrecEF in patients with DCM and reduced LVEF.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Cardiomiopatia Dilatada/tratamento farmacológico , Sistema de Registros , Volume Sistólico/efeitos dos fármacos , Idoso , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
5.
Sci Transl Med ; 13(604)2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34321319

RESUMO

Angiotensin-converting enzyme inhibitors (ACEIs) are used by millions of patients to treat hypertension, diabetic kidney disease, and heart failure. However, these patients are often at increased risk of infection. To evaluate the impact of ACEIs on immune responses to infection, we compared the effect of an ACEI versus an angiotensin receptor blocker (ARB) on neutrophil antibacterial activity. ACEI exposure reduced the ability of murine neutrophils to kill methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Klebsiella pneumoniae in vitro. In vivo, ACEI-treated mice infected with MRSA had increased bacteremia and tissue bacteria counts compared to mice treated with an ARB or with no drug. Similarly, ACEIs, but not ARBs, increased the incidence of MRSA-induced infective endocarditis in mice with aortic valve injury. Neutrophils from ACE knockout (KO) mice or mice treated with an ACEI produced less leukotriene B4 (LTB4) upon stimulation with MRSA or lipopolysaccharide, whereas neutrophils overexpressing ACE produced more LTB4 compared to wild-type neutrophils. As a result of reduced LTB4 production, ACE KO neutrophils showed decreased survival signaling and increased apoptosis. In contrast, neutrophils overexpressing ACE had an enhanced survival phenotype. Last, in a cohort of human volunteers receiving the ACEI ramipril for 1 week, ACEI administration reduced neutrophil superoxide and reactive oxygen species production and neutrophils isolated from volunteers during ramipril treatment had reduced bactericidal activity. Together, these data demonstrate that ACEI treatment, but not ARB treatment, can reduce the bacterial killing ability of neutrophils.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , Staphylococcus aureus Resistente à Meticilina , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Humanos , Camundongos , Camundongos Knockout , Neutrófilos
6.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206708

RESUMO

Atherosclerosis has complex pathogenesis, which involves at least three serious aspects: inflammation, lipid metabolism alterations, and endothelial injury. There are no effective treatment options, as well as preventive measures for atherosclerosis. However, this disease has various severe complications, the most severe of which is cardiovascular disease (CVD). It is important to note, that CVD is among the leading causes of death worldwide. The renin-angiotensin-aldosterone system (RAAS) is an important part of inflammatory response regulation. This system contributes to the recruitment of inflammatory cells to the injured site and stimulates the production of various cytokines, such as IL-6, TNF-a, and COX-2. There is also an association between RAAS and oxidative stress, which is also an important player in atherogenesis. Angiotensin-II induces plaque formation at early stages, and this is one of the most crucial impacts on atherogenesis from the RAAS. Importantly, while stimulating the production of ROS, Angiotensin-II at the same time decreases the generation of NO. The endothelium is known as a major contributor to vascular function. Oxidative stress is the main trigger of endothelial dysfunction, and, once again, links RAAS to the pathogenesis of atherosclerosis. All these implications of RAAS in atherogenesis lead to an explicable conclusion that elements of RAAS can be promising targets for atherosclerosis treatment. In this review, we also summarize the data on treatment approaches involving cytokine targeting in CVD, which can contribute to a better understanding of atherogenesis and even its prevention.


Assuntos
Aterosclerose/etiologia , Aterosclerose/metabolismo , Suscetibilidade a Doenças , Sistema Renina-Angiotensina , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Aterosclerose/diagnóstico , Aterosclerose/terapia , Biomarcadores , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Avaliação Pré-Clínica de Medicamentos , Endotélio/metabolismo , Humanos , Terapia de Alvo Molecular , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos
7.
Int J Pharm ; 605: 120852, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34224842

RESUMO

LWHTH (Leu-Trp-His-Thr-His) is an antioxidant pentapeptide isolated from Styela clava tissue. Based on LWHTH, we designed and synthesized a series of novel peptides using the alanine scanning technique and determined the pharmacological activities of these derivatives. Among the ten newly synthesized LWHTH analogs, peptide CWHTH was identified as the most potent compound with prominent antioxidant activity. CWHTH not only showed the ability to scavenge several biologically important radicals, protected cells from H2O2 or APAP-induced damage by activating the PI3K/Akt and suppressing the JNK/c-Jun pathways, but also exerted strong in vivo hepatoprotective effects in an APAP-induced liver injury model in mice. Moreover, it was demonstrated that CWHTH possesses potent angiotensin converting enzyme (ACE) inhibitory activity and high stability against gastrointestinal proteases. In summary, CWHTH is a promising antioxidant peptide worthy of further investigation as a potential hepatoprotective and antihypertensive agent.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , Antioxidantes , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Antioxidantes/farmacologia , Peróxido de Hidrogênio , Camundongos , Peptídeos , Peptidil Dipeptidase A , Fosfatidilinositol 3-Quinases
8.
Sci Total Environ ; 797: 149150, 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34303979

RESUMO

The occurrence of antibiotic-resistant bacteria (ARB) in water bodies poses a sanitary and environmental risk. These ARB and other mobile genetic elements can be easily spread from hospital facilities, the point in which, for sure, they are more concentrated. For this reason, novel clean and efficient technologies are being developed for allowing to remove these ARB and other mobile genetic elements before their uncontrolled spread. In this paper, a review on the recent knowledge about the state of the art of the main disinfection technologies to control the antibiotic resistance spread from natural water, wastewater, and hospital wastewater (including urine matrices) is reported. These technologies involve not only conventional processes, but also the recent advances on advanced oxidation processes (AOPs), including electrochemical advanced oxidation processes (EAOPs). This review summarizes the state of the art on the applicability of these technologies and also focuses on the description of the disinfection mechanisms by each technology, highlighting the promising impact of EAOPs on the remediation of this important environmental and health problem.


Assuntos
Desinfecção , Purificação da Água , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antibacterianos/farmacologia , Bactérias/genética , Resistência Microbiana a Medicamentos/genética , Genes Bacterianos , Tecnologia , Águas Residuárias
9.
J Food Biochem ; 45(7): e13779, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34060658

RESUMO

In this article, the selective inhibition of several tyrosine-containing dipeptides on N and C domain of ACE (angiotensin-converting enzyme) was studied, and the interaction mode of ACE and inhibitors was simulated by molecular docking. MTT assay was used to detect the effect of dipeptide on human umbilical vein endothelial cells (HUVEC). The results showed that the food-derived dipeptides AY (Ala-Tyr), LY (Leu-Tyr), and IY (Ile-Tyr) containing tyrosine at the C-terminal were favorable structures for selective inhibition of ACE C-domain. These dipeptides showed competitive and mixed inhibition patterns, while the dipeptides EY (Glu-Tyr), RY (Arg-Tyr), FY (Phe-Tyr), and SY (Ser-Tyr) showed noncompetitive inhibition. Food-derived dipeptides containing tyrosine have no cytotoxicity on HUVEC cells, which provides a basis for the application of food-derived tyrosine dipeptides as antihypertensive peptides. This study provides a theoretical basis for exploring the selective inhibition mechanism of ACE inhibitory peptides containing tyrosine residue. PRACTICAL APPLICATIONS: Angiotensin-converting enzyme (ACE) is a two-domain dipeptidyl carboxypeptidase, which is a key enzyme to regulate blood pressure. ACE has two active sites, C- and N-domain, which have high catalytic activity. Although the amino acid sequences of the two active sites have 60% similarity, there are some differences in structure and function. The action mechanism of ACE domain should be clarified, and the structure-activity relationship between inhibitors and ACE domain has not been systematically studied. The aim of this study was to identify the selective inhibitory effect of food-derived tyrosine dipeptides on the domain of ACE. This provides a new idea for finding new antihypertensive drugs with less side effects.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , Tirosina , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Angiotensinas , Dipeptídeos/farmacologia , Células Endoteliais , Humanos , Simulação de Acoplamento Molecular , Peptidil Dipeptidase A
10.
Adv Ther ; 38(7): 4013-4025, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34115328

RESUMO

INTRODUCTION: We evaluated the prevalence and predictors of ambulatory blood pressure (BP) control in patients taking a triple antihypertensive therapy (renin-angiotensin system inhibitor + calcium channel blocker + thiazide/thiazide-like diuretic, in either free or fixed-dose combinations) containing an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB). METHODS: We performed an observational cross-sectional study on 520 consecutive patients with essential hypertension taking a stable triple therapy in whom 24-h ambulatory BP was evaluated. Both number of pills and antihypertensive treatment intensity (ATI), as possible pharmacological predictors of ambulatory BP control, were taken into account. RESULTS: A total of 189 (36.3%) patients were taking triple therapy with ACEi and 331 (63.7%) patients were taking triple therapy with ARB. Mean age was 62.7 ± 12.2 years. Patients on triple therapy with ACEi had a significantly lower ATI and took fewer antihypertensive pills than patients on triple therapy with ARB (22.2% of patients took a single-pill triple fixed-dose combination). Patients taking triple therapy with ACEi had higher prevalence of both 24-h (54.8% vs 44.0%; p = 0.019) and daytime BP control (61.8% vs 49.2%; p = 0.006) than patients taking triple therapy with ARB, even after adjusting for age, sex, body mass index, smoking habit, type 2 diabetes mellitus, estimated glomerular filtration rate, and ATI [OR 1.5 (95% CI 1.1-2.2) and OR 1.6 (95% CI 1.1-2.4), respectively]. However, these independent associations with ambulatory BP control were lost when the number of antihypertensive pills was included in the model. CONCLUSION: The higher prevalence of ambulatory BP control found in patients taking a triple therapy with ACEi was affected by the lower number of antihypertensive pills taken, which was also the key predictor of ambulatory BP control in our study. This confirms the importance of fixed-dose combinations in the management of essential hypertension.


Assuntos
Diabetes Mellitus Tipo 2 , Hipertensão , Idoso , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Monitorização Ambulatorial da Pressão Arterial , Bloqueadores dos Canais de Cálcio/uso terapêutico , Estudos Transversais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Pessoa de Meia-Idade , Sistema Renina-Angiotensina
11.
J Food Sci ; 86(7): 3046-3060, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34146413

RESUMO

This study aimed to assess the biological properties of peptide fractions isolated from dried fermented dairy products (jameed) as influenced by processing. Peptide fractions were separated by reversed-phase high-performance liquid chromatography (RP-HPLC) from salted (Sa) and unsalted (Us) cow milk jameed after drying the fermented curd by sun drying (Sd) or freeze-drying (Fd) and were characterized for their antioxidant capacity and inhibitory activity toward angiotensin I-converting enzyme (ACE) and α-amylase. Sd samples showed more numerous peptide peaks in RP-HPLC chromatograms than Fd samples, regardless of the salt content. High antioxidant activity was evidenced in several peptide fractions from FdUs jameed (including fractions 1, 2, 4, 7, 8, 9, and 10), SdUs jameed (1, 2, 5, 7, and 9), and FdSa jameed (2, 5, 6, and 9). By contrast, peptide fractions from SdSa (1, 2, 3, 5, 8, and 9), SdUs (4, 5, and 10), and FdUs (5, 6, and 8) jameed displayed the highest ACE inhibitory activity. Similarly, the highest inhibition of α-amylase was obtained with fractions from SdSa (1, 2, 3, 4, 5, 6, 8, and 9), SdUs (2 and 6), and FdUs (1, 7 and 9) jameed. A significant negative correlation was evidenced between antioxidant activity and anti-α-amylase activity of peptide fractions from SdSa jameed. These findings demonstrate that cow milk jameed is a source of bioactive peptides with antioxidant, anti-ACE, and anti-α-amylase properties in vitro, which can be tailored by adjusting the salt content and the drying conditions. PRACTICAL APPLICATION: This study shows that cow milk jameed, a staple fermented food in several Mediterranean countries, can serve as a useful source of multifunctional bioactive peptides with potential antioxidant, hypotensive, and hypoglycemic effects, which may help prevent and manage chronic health conditions such as hypertension, type 2 diabetes, and the metabolic syndrome. The bioactivities of certain peptide fractions were enhanced by lowering the salt content of jameed or by the drying method. The relatively simple RP-HPLC method described in this study can be used to isolate the peptide fractions of interest for further characterization and use as functional ingredients.


Assuntos
Aminoácidos/análise , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/farmacocinética , Antioxidantes/farmacologia , Produtos Fermentados do Leite , Hipoglicemiantes/farmacologia , Leite/química , Fragmentos de Peptídeos/farmacologia , Inibidores da Enzima Conversora de Angiotensina/química , Animais , Anti-Hipertensivos/química , Antioxidantes/química , Bovinos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipertensão/tratamento farmacológico , Hipoglicemiantes/química , Fragmentos de Peptídeos/química , Peptidil Dipeptidase A/metabolismo
12.
J Reprod Immunol ; 146: 103344, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34146892

RESUMO

The pandemic COVID-19 presents a major challenge to identify effective drugs for treatment. Clinicians need evidence based on randomized trials regarding effective medical treatments for this infection. Currently no effective therapies exist for the progression of the mild forms to severe disease. Knowledge however is rapidly expanding. Remdesivir, an anti- retroviral agent has in vitro activity against this virus and has shown to decrease the duration of ICU care in patients with severe disease, while low dose dexamethasone also showed a decrease in the duration of stay in cases of severe disease requiring assisted ventilation. At the time of writing this article, two mRNA-based vaccines have shown an approximate 95 % efficacy in preventing infection in large clinical trials. At least one of these drugs has regulatory permission for vaccination in high-income countries. Low and middle-income countries may have difficulties in initiating vaccine programs on large scales because of availability, costs, refrigeration and dissemination. Adequately powered randomized trials are required for drugs with in vitro activity against the virus. Supportive care should be provided for stable, hypoxia and pneumonia free patients on imaging. Vaccines are of obvious benefit and given the preliminary evidence of the efficacy of over 95 %, Low and middle-income countries must develop links with the WHO COVAX program to ensure global distribution of vaccines.


Assuntos
Antivirais/uso terapêutico , Vacinas contra COVID-19/uso terapêutico , COVID-19/terapia , Medicina Baseada em Evidências/métodos , Pandemias/prevenção & controle , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Antivirais/farmacologia , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/virologia , Vacinas contra COVID-19/imunologia , Ensaios Clínicos como Assunto , Medicina Baseada em Evidências/tendências , Saúde Global , Humanos , Cooperação Internacional , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/metabolismo , Resultado do Tratamento , Internalização do Vírus/efeitos dos fármacos
13.
Front Cell Infect Microbiol ; 11: 639177, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34178717

RESUMO

Several comorbidities, including hypertension, have been associated with an increased risk of developing severe disease during SARS-CoV-2 infection. Angiotensin II receptor blockers (ARBs) are currently some of the most widely-used drugs to control blood pressure by acting on the angiotensin II type 1 receptor (AT1R). ARBs have been reported to trigger the modulation of the angiotensin I converting enzyme 2 (ACE2), the receptor used by the virus to penetrate susceptible cells, raising concern that such treatments may promote virus capture and increase their viral load in patients receiving ARBs therapy. In this in vitro study, we reviewed the effect of ARBs on ACE2 and AT1R expression and investigated whether treatment of permissive ACE2+/AT1R+ Vero E6 cells with ARBs alters SARS-CoV-2 replication in vitro in an angiotensin II-free system. After treating the cells with the ARBs, we observed an approximate 50% relative increase in SARS-CoV-2 production in infected Vero E6 cells that correlates with the ARBs-induced up-regulation of ACE2 expression. From this data, we believe that the use of ARBs in hypertensive patients infected by SARS-CoV-2 should be carefully evaluated.


Assuntos
Antagonistas de Receptores de Angiotensina , COVID-19 , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/farmacologia , Humanos , Sistema Renina-Angiotensina , SARS-CoV-2
15.
J Mol Model ; 27(7): 206, 2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34169390

RESUMO

The interaction between SARS-CoV-2 Spike protein and angiotensin-converting enzyme 2 (ACE2) is essential to viral attachment and the subsequent fusion process. Interfering with this event represents an attractive avenue for the development of therapeutics and vaccine development. Here, a hybrid approach of ligand- and structure-based virtual screening techniques were employed to disclose similar analogues of a reported antiviral phytochemical, glycyrrhizin, targeting the blockade of ACE2 interaction with the SARS-CoV-2 Spike. A ligand-based similarity search using a stringent cut-off revealed 40 FDA-approved compounds in DrugBank. These filtered hits were screened against ACE2 using a blind docking approach to determine the natural binding tendency of the compounds with ACE2. Three compounds, deslanoside, digitoxin, and digoxin, were reported to show strong binding with ACE2. These compounds bind at the H1-H2 binding pocket, in a manner similar to that of glycyrrhizin which was used as a control. To achieve consistency in the docking results, docking calculations were performed via two sets of docking software that predicted binding energy as ACE2-Deslanoside (AutoDock, -10.3 kcal/mol and DockThor, -9.53 kcal/mol), ACE2-Digitoxin (AutoDock, -10.6 kcal/mol and DockThor, -8.84 kcal/mol), and ACE2-Digoxin (AutoDock, -10.6 kcal/mol and DockThor, -8.81 kcal/mol). The docking results were validated by running molecular simulations in aqueous solution that demonstrated the stability of ACE2 with no major conformational changes in the ligand original binding mode (~ 2 Å average RMSD). Binding interactions remained quite stable with an increased potential for getting stronger as the simulation proceeded. MMGB/PBSA binding free energies were also estimated and these supported the high stability of the complexes compared to the control (~ -50 kcal/mol net MMGB/PBSA binding energy versus ~ -30 kcal/mol). Collectively, the data demonstrated that the compounds shortlisted in this study might be subjected to experimental evaluation to uncover their real blockade capacity of SARS-CoV-2 host ACE2 receptor.


Assuntos
Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Ácido Glicirrízico/farmacologia , Receptores Virais/antagonistas & inibidores , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/metabolismo , Inibidores da Enzima Conversora de Angiotensina/química , Animais , Antivirais/química , Sítios de Ligação , COVID-19/enzimologia , COVID-19/virologia , Descoberta de Drogas , Reposicionamento de Medicamentos , Ácido Glicirrízico/análogos & derivados , Ácido Glicirrízico/química , Interações Hospedeiro-Patógeno , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica , Receptores Virais/química , Receptores Virais/metabolismo , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Relação Estrutura-Atividade
16.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34068941

RESUMO

Diabetic nephropathy (DN) is the most frequent cause of end-stage renal disease. Tubulointerstitial accumulation of lysine 63 (K63)-ubiquitinated (Ub) proteins is involved in the progression of DN fibrosis and correlates with urinary miR-27b-3p downregulation. We explored the renoprotective effect of an inhibitor of K63-Ub (NSC697923), alone or in combination with the ACE-inhibitor ramipril, in vitro and in vivo. Proximal tubular epithelial cells and diabetic DBA/2J mice were treated with NSC697923 and/or ramipril. K63-Ub protein accumulation along with α-SMA, collagen I and III, FSP-1, vimentin, p16INK4A expression, SA-α Gal staining, Sirius Red, and PAS staining were measured. Finally, we measured the urinary albumin to creatinine ratio (uACR), and urinary miR-27b-3p expression in mice. NSC697923, both alone and in association with ramipril, in vitro and in vivo inhibited hyperglycemia-induced epithelial to mesenchymal transition by significantly reducing K63-Ub proteins, α-SMA, collagen I, vimentin, FSP-1 expression, and collagen III along with tubulointerstitial and glomerular fibrosis. Treated mice also showed recovery of urinary miR-27b-3p and restored expression of p16INK4A. Moreover, NSC697923 in combination with ramipril demonstrated a trend in the reduction of uACR. In conclusion, we suggest that selective inhibition of K63-Ub, when combined with the conventional treatment with ACE inhibitors, might represent a novel treatment strategy to prevent the progression of fibrosis and proteinuria in diabetic nephropathy and we propose miR-27b-3p as a biomarker of treatment efficacy.


Assuntos
Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/prevenção & controle , Fibrose/prevenção & controle , Lisina/química , Nitrofuranos/farmacologia , Ramipril/farmacologia , Sulfonas/farmacologia , Ubiquitinação , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Quimioterapia Combinada , Feminino , Fibrose/etiologia , Fibrose/metabolismo , Fibrose/patologia , Camundongos , Camundongos Endogâmicos DBA
18.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069880

RESUMO

This research focuses on the proteolytic capacity of sea bass byproduct (SB) and their hypocholesterolemic activity via the cholesterol micelle formation (CMF) inhibition. SB was fermented with seven mixed lactic acid bacteria for 5 h at 42 °C. The lactic fermented SB was hydrolyzed with Protease N for 6 h under HHP to obtain the SB hydrolysates (HHP-assisted Protease N hydrolysis after fermentation, F-HHP-PN6). The supernatant was separated from the SB hydrolysate and freeze-dried. As the hydrolysis time extended to 6 h, soluble protein content increased from 187.1 to 565.8 mg/g, and peptide content increased from 112.8 to 421.9 mg/g, while inhibition of CMF increased from 75.0% to 88.4%. Decreasing the CMF inhibitory activity from 88.4% to 42.1% by simulated gastrointestinal digestion (FHHP-PN6 was further hydrolyzed by gastrointestinal enzymes, F-HHP-PN6-PP) reduced the CMF inhibitory activity of F-HHP-PN6. Using gel filtration chromatography, the F-HHP-PN6-PP was fractioned into six fractions. The molecular weight of the fifth fraction from F-HHP-PN6-PP was between 340 and 290 Da, and the highest inhibitory efficiency ratio (IER) on CMF was 238.9%/mg/mL. Further purification and identification of new peptides with CMF inhibitory activity presented the peptide sequences in Ser-Ala-Gln, Pro-Trp, and Val-Gly-Gly-Thr; the IERs were 361.7, 3230.0, and 302.9%/mg/mL, respectively.


Assuntos
Bass/metabolismo , Colesterol/química , Hidrolisados de Proteína/farmacologia , Sequência de Aminoácidos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Anticolesterolemiantes/farmacologia , Antioxidantes/farmacologia , Fermentação , Hidrólise , Pressão Hidrostática , Micelas , Peso Molecular , Oligopeptídeos , Peptídeo Hidrolases/metabolismo , Peptídeos/química , Peptídeos/metabolismo , Hidrolisados de Proteína/metabolismo , Proteínas/química , Proteínas/metabolismo , Proteólise
19.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069441

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel emerging pathogen causing an unprecedented pandemic in 21st century medicine. Due to the significant health and economic burden of the current SARS-CoV-2 outbreak, there is a huge unmet medical need for novel interventions effectively blocking SARS-CoV-2 infection. Unknown details of SARS-CoV-2 cellular biology hamper the development of potent and highly specific SARS-CoV-2 therapeutics. Angiotensin-converting enzyme-2 (ACE2) has been reported to be the primary receptor for SARS-CoV-2 cellular entry. However, emerging scientific evidence suggests the involvement of additional membrane proteins, such as heparan sulfate proteoglycans, in SARS-CoV-2 internalization. Here, we report that syndecans, the evolutionarily conserved family of transmembrane proteoglycans, facilitate the cellular entry of SARS-CoV-2. Among syndecans, the lung abundant syndecan-4 was the most efficient in mediating SARS-CoV-2 uptake. The S1 subunit of the SARS-CoV-2 spike protein plays a dominant role in the virus's interactions with syndecans. Besides the polyanionic heparan sulfate chains, other parts of the syndecan ectodomain, such as the cell-binding domain, also contribute to the interaction with SARS-CoV-2. During virus internalization, syndecans colocalize with ACE2, suggesting a jointly shared internalization pathway. Both ACE2 and syndecan inhibitors exhibited significant efficacy in reducing the cellular entry of SARS-CoV-2, thus supporting the complex nature of internalization. Data obtained on syndecan specific in vitro assays present syndecans as novel cellular targets of SARS-CoV-2 and offer molecularly precise yet simple strategies to overcome the complex nature of SARS-CoV-2 infection.


Assuntos
COVID-19/metabolismo , Receptores de Coronavírus/metabolismo , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/metabolismo , Sindecanas/metabolismo , Internalização do Vírus , Amilorida/farmacologia , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , COVID-19/virologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Bloqueadores do Canal de Sódio Epitelial/farmacologia , Humanos , Peptídeos/farmacologia , Domínios Proteicos , SARS-CoV-2/metabolismo , Sindecana-4/antagonistas & inibidores , Sindecana-4/metabolismo , Sindecanas/antagonistas & inibidores
20.
Muscle Nerve ; 64(2): 163-171, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34050938

RESUMO

INTRODUCTION/AIMS: The DMD Care Considerations Working Group Guidelines 2010 recommended treating cardiac dystrophinopathy with angiotensin-converting enzyme-inhibitor (ACEi) and beta-blocker (BB) therapy to prevent the progressive decline in left ventricular function expected from earlier, natural history studies. The aim of this research was to audit change in measures of left ventricular function over 8 years to 4 years before and 4 years after deploying an ACEi/BB combination systematically at a dedicated "cardiology-muscle" clinic. METHODS: This is an institutionally registered, retrospective, case-file-based audit of serial echocardiographic measures of left ventricular fractional shortening accumulated over the period 1995 to 2015. RESULTS: Data from 104 genetically confirmed Duchenne muscular dystrophy (DMD) patients, aged 22.2 ± 5.3 years at data censure, were included. Mean age at first detection of left ventricular dysfunction was 15.1 ± 4.2 years, but older in those on maintenance steroid therapy (16.8 ± 4.2 vs 14.5 ± 4.1 years; P = .04). Group mean fractional shortening fell by 1.5%/year over the 4 years before therapy, but this decreased to 0.9%/year over the first 4 years after starting therapy. Analysis of limited left ventricular ejection fraction measures showed similar but nonsignificant changes. Neither age at detection of left ventricular dysfunction nor fractional shortening percent at time of therapy initiation affected the beneficial response. DISCUSSION: The results support the international DMD recommendations of the time. This combination of cardiac medications helps stabilize heart function. For the best long-term effects, therapy needs to be initiated no later than on first detection left ventricular impairment.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Cardiomiopatias/tratamento farmacológico , Distrofia Muscular de Duchenne/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Adolescente , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Cardiomiopatias/diagnóstico , Criança , Humanos , Masculino , Distrofia Muscular de Duchenne/diagnóstico , Estudos Retrospectivos , Volume Sistólico/efeitos dos fármacos , Disfunção Ventricular Esquerda/tratamento farmacológico , Função Ventricular/efeitos dos fármacos , Adulto Jovem
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