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1.
J Korean Med Sci ; 35(39): e349, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33045772

RESUMO

BACKGROUNDS: The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has spread worldwide. Cardiac injury after SARS-CoV-2 infection is a major concern. The present study investigated impact of the biomarkers indicating cardiac injury in coronavirus disease 2019 (COVID-19) on patients' outcomes. METHODS: This study enrolled patients who were confirmed to have COVID-19 and admitted at a tertiary university referral hospital between February 19, 2020 and March 15, 2020. Cardiac injury was defined as an abnormality in one of the following result markers: 1) myocardial damage marker (creatine kinase-MB or troponin-I), 2) heart failure marker (N-terminal-pro B-type natriuretic peptide), and 3) electrical abnormality marker (electrocardiography). The relationship between each cardiac injury marker and mortality was evaluated. Survival analysis of mortality according to the scoring by numbers of cardiac injury markers was also performed. RESULTS: A total of 38 patients with COVID-19 were enrolled. Twenty-two patients (57.9%) had at least one of cardiac injury markers. The patients with cardiac injuries were older (69.6 ± 14.9 vs. 58.6 ± 13.9 years old, P = 0.026), and were more male (59.1% vs. 18.8%, P = 0.013). They showed lower initial oxygen saturation (92.8 vs. 97.1%, P = 0.002) and a trend toward higher mortality (27.3 vs. 6.3%, P = 0.099). The increased number of cardiac injury markers was significantly related to a higher incidence of in-hospital mortality which was also evidenced by Kaplan-Meier survival analysis (P = 0.008). CONCLUSION: The increased number of cardiac injury markers is related to in-hospital mortality in patients with COVID-19.


Assuntos
Infecções por Coronavirus/diagnóstico , Miocárdio/metabolismo , Pneumonia Viral/diagnóstico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Creatina Quinase Forma MB/metabolismo , Eletrocardiografia , Feminino , Traumatismos Cardíacos/metabolismo , Traumatismos Cardíacos/patologia , Mortalidade Hospitalar , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Peptídeo Natriurético Encefálico/metabolismo , Pandemias , Fragmentos de Peptídeos/metabolismo , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Fatores Sexuais , Centros de Atenção Terciária , Troponina I/metabolismo
2.
Nat Commun ; 11(1): 4790, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963242

RESUMO

Preventing aggregation of amyloid beta (Aß) peptides is a promising strategy for the treatment of Alzheimer's disease (AD), and gold nanoparticles have previously been explored as a potential anti-Aß therapeutics. Here we design and prepare 3.3 nm L- and D-glutathione stabilized gold nanoparticles (denoted as L3.3 and D3.3, respectively). Both chiral nanoparticles are able to inhibit aggregation of Aß42 and cross the blood-brain barrier (BBB) following intravenous administration without noticeable toxicity. D3.3 possesses a larger binding affinity to Aß42 and higher brain biodistribution compared with its enantiomer L3.3, giving rise to stronger inhibition of Aß42 fibrillation and better rescue of behavioral impairments in AD model mice. This conjugation of a small nanoparticle with chiral recognition moiety provides a potential therapeutic approach for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/efeitos dos fármacos , Ouro/farmacologia , Transtornos da Memória/tratamento farmacológico , Nanopartículas Metálicas/química , Fragmentos de Peptídeos/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Fragmentos de Peptídeos/metabolismo , Estereoisomerismo
3.
Mol Genet Genomics ; 295(6): 1529-1535, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32894358

RESUMO

Lanthipeptides are a subgroup of ribosomally encoded and post-translationally modified peptides (RiPPs) which frequently possess potent biological activity. Here we provide the first comprehensive bioinformatic analysis of the lanthipeptide-producing capability of the Salinispora genus, a marine actinomycete. One hundred twenty-two Salinispora arenicola, tropica, and pacifica genomic sequences were analyzed for lanthipeptide gene clusters, and the resulting 182 clusters were divided into seven groups based on sequence similarities. Group boundaries were defined based on LanB and LanM sequences with greater than 80% similarity within groups. Of the seven groups, six are predicted to encode class I lanthipeptides while only one group is predicted to encode class II lanthipeptides. Leader and core peptides were predicted for each cluster along with the number of possible lanthionine bridges. Notably, all of the predicted products of these clusters would represent novel lanthipeptide scaffolds. Of the 122 Salinispora genomes analyzed in this study, 92% contained at least one lanthipeptide gene cluster suggesting that Salinispora is a rich, yet untapped, source of lanthipeptides.


Assuntos
Alanina/análogos & derivados , Proteínas de Bactérias/metabolismo , Genoma Bacteriano , Micromonosporaceae/metabolismo , Fragmentos de Peptídeos/metabolismo , Sulfetos/metabolismo , Alanina/isolamento & purificação , Alanina/metabolismo , Proteínas de Bactérias/genética , Genômica , Micromonosporaceae/genética , Micromonosporaceae/crescimento & desenvolvimento , Fragmentos de Peptídeos/isolamento & purificação , Sulfetos/isolamento & purificação
4.
Ecotoxicol Environ Saf ; 203: 111044, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888613

RESUMO

BACKGROUND: Exposure to ambient fine particulate matter (PM2.5) is associated with various adverse health outcomes. Although several mechanisms have been proposed including oxidative stress and inflammatory responses, the exact mechanism is still unknown. Few studies have investigated the mechanism linking PM2.5 and blood pressure (BP). In this study, we measured urinary metabolites and BP -related renin-angiotensin-aldosterone system (RAAS) to investigate the associations between ambient PM2.5 exposure and BP in healthy C57BL/6 mice. METHODS: The C57BL/6 mice were exposed to ambient concentrated PM2.5 or filtered air (FA) for 16 weeks. Systolic BP and diastolic BP were measured by noninvasive BP system. The urine metabolites were quantified using the untargeted metabolomics approach. The expression of RAAS-related proteins angiotensin-converting enzyme (ACE)2, angiotensin (Ang) II, Ang (1-7) and aldosterone (ALD) were measured using Western blot and ELISA kits. RESULTS: The metabolomics analysis demonstrated that PM2.5 exposure induced significant changes of some metabolites in urine, including stress hormones, amino acids, fatty acids, and lipids. Furthermore, there was an elevation of BP, increase of serous Ang II and ALD, along with the decrease of ACE2 and Ang (1-7) in kidney in the PM2.5-exposed mice compared with FA-exposed mice. CONCLUSIONS: The results demonstrated that PM2.5 exposure-induced BP elevation might be associated with RAAS activation. Meanwhile, PM2.5 exposure-induced changes of stress hormone and lipid metabolism might mediate the activation of RAAS. The results suggested that the systemic stress hormone and lipid metabolism was associated with the development of hypertension.


Assuntos
Poluentes Atmosféricos/toxicidade , Angiotensina I/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/induzido quimicamente , Material Particulado/toxicidade , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/metabolismo , Acetilglucosaminidase/urina , Angiotensina I/sangue , Animais , Biomarcadores/sangue , Biomarcadores/urina , Hipertensão/urina , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Metaboloma/efeitos dos fármacos , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/sangue , Peptidil Dipeptidase A/sangue , Sistema Renina-Angiotensina/efeitos dos fármacos , beta-Galactosidase/urina
5.
Acta Odontol Latinoam ; 33(2): 125, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32920615

RESUMO

Melatonin (MLT) is a potential signaling molecule in the homeostasis of bone metabolism and may be an important mediator of bone formation and stimulation. The aim of this in vitro study was to evaluate the effect of MLT on the viability, mRNA/protein expression and mineralization of pre-osteoblastic cells. The concentrations 5, 2.5, 1, 0.1 and 0.01 mM MLT were tested on pre-osteoblastic cells (MC3T3) compared to control (no MLT), evaluating proliferation and cell viability (C50), gene expression (RT-PCR) and secretion (ELISA) of COL-I and OPN at 24h, 48h and 72h, and the formation of mineral nodules (alizarin red and fast red) after 10 days of treatment. MLT at 5 and 2.5 mM proved to be cytotoxic (C50), so only 0.01, 0.1 and 1 mM were used for the subsequent analyses. OPN mRNA expression increased with MLT at 0.1 mM - 1 mM, which was followed by increased secretion of OPN both at 24h and 72h compared to the remaining groups (p <0.05). COL-I mRNA and COL-1 secretion followed the same pattern as OPN at 0.1 mM MLT at 72h of treatment (p <0.05). Regarding mineralization, all MLT doses (except 1mM) caused an increase (p <0.05) in the formation of mineral nodules compared to the control. Melatonin at 0.01mM - 1mM had a stimulatory effect on osteoblasts by upregulating COL-I and OPN expression/ secretion and mineralization, thereby fostering osteogenesis.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Metaloproteinase 2 da Matriz/metabolismo , Melatonina/farmacologia , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Osteopontina/metabolismo , Fragmentos de Peptídeos/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Ensaio de Imunoadsorção Enzimática , Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Metaloproteinase 2 da Matriz/genética , Osteoblastos/metabolismo , Osteopontina/genética , Fragmentos de Peptídeos/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real
6.
Nature ; 584(7821): 479-483, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32788728

RESUMO

Lipopolysaccharide (LPS) resides in the outer membrane of Gram-negative bacteria where it is responsible for barrier function1,2. LPS can cause death as a result of septic shock, and its lipid A core is the target of polymyxin antibiotics3,4. Despite the clinical importance of polymyxins and the emergence of multidrug resistant strains5, our understanding of the bacterial factors that regulate LPS biogenesis is incomplete. Here we characterize the inner membrane protein PbgA and report that its depletion attenuates the virulence of Escherichia coli by reducing levels of LPS and outer membrane integrity. In contrast to previous claims that PbgA functions as a cardiolipin transporter6-9, our structural analyses and physiological studies identify a lipid A-binding motif along the periplasmic leaflet of the inner membrane. Synthetic PbgA-derived peptides selectively bind to LPS in vitro and inhibit the growth of diverse Gram-negative bacteria, including polymyxin-resistant strains. Proteomic, genetic and pharmacological experiments uncover a model in which direct periplasmic sensing of LPS by PbgA coordinates the biosynthesis of lipid A by regulating the stability of LpxC, a key cytoplasmic biosynthetic enzyme10-12. In summary, we find that PbgA has an unexpected but essential role in the regulation of LPS biogenesis, presents a new structural basis for the selective recognition of lipids, and provides opportunities for future antibiotic discovery.


Assuntos
Membrana Celular/química , Escherichia coli/química , Escherichia coli/patogenicidade , Lipopolissacarídeos/química , Lipopolissacarídeos/metabolismo , Amidoidrolases/química , Amidoidrolases/metabolismo , Motivos de Aminoácidos , Membrana Externa Bacteriana/química , Membrana Externa Bacteriana/metabolismo , Sítios de Ligação , Membrana Celular/metabolismo , Estabilidade Enzimática , Escherichia coli/citologia , Escherichia coli/efeitos dos fármacos , Genes Essenciais , Hidrolases/química , Hidrolases/metabolismo , Lipídeo A/química , Lipídeo A/metabolismo , Lipopolissacarídeos/biossíntese , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Modelos Moleculares , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Periplasma/química , Periplasma/metabolismo , Ligação Proteica , Virulência
7.
Life Sci ; 258: 118206, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32758623

RESUMO

Scientists are looking for new therapies to cope with the rise in cancer worldwide. Since cancer cells overexpress peptide receptors and owing to small size, easy uptake by tumor cells, easy preparation, and with no toxicity, the use of radiolabeled peptides with high specificity and affinity for accurate imaging and therapy has attracted much attention. To develop an ideal imaging or treatment radiolabeled peptide, there are some aspects in the components of radiolabeled peptide including radionuclide, peptide, chelator, and spacer that should be considered. Some peptides, including somatostatin, RGD, neurotensin, bombesin, exendin, vasoactive intestinal peptide, and gastrin are currently under (pre)clinical investigations. Today, nanoparticles are suitable tools for targeting peptide for molecular imaging and therapy of tumors with low toxicity. This paper presents some essential aspects in developing a valuable radiolabeled peptide and some radiolabeled peptides with regard to their applications in tumor imaging and therapy in pre-clinical and clinical phases.


Assuntos
Diagnóstico por Imagem/métodos , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Fragmentos de Peptídeos/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Animais , Diagnóstico por Imagem/tendências , Humanos , Mediadores da Inflamação/metabolismo
8.
Adv Exp Med Biol ; 1272: 1-16, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32845499

RESUMO

Elastic fibers are found in the extracellular matrix (ECM) of tissues requiring resilience and depend on elasticity. Elastin and its degradation products have multiple roles in the oncologic process. In many malignancies, the remodeled ECM expresses high levels of the elastin protein which may have either positive or negative effects on tumor growth. Elastin cross-linking with other ECM components and the enzymes governing this process all have effects on tumorigenesis. Elastases, and specifically neutrophil elastase, are key drivers of invasion and metastasis and therefore are important targets for inhibition. Elastin degradation leads to the generation of bioactive fragments and elastin-derived peptides that further modulate tumor growth and spread. Interestingly, elastin-like peptides (ELP) and elastin-derived peptides (EDP) may also be utilized as nano-carriers to combat tumor growth. EDPs drive tumor development in a variety of ways, and specifically targeting EDPs and their binding proteins are major objectives for ongoing and future anti-cancer therapies. Research on both the direct anti-cancer activity and the drug delivery capabilities of ELPs is another area likely to result in novel therapeutic agents in the near future.


Assuntos
Elastina , Matriz Extracelular , Neoplasias/metabolismo , Microambiente Tumoral , Elastina/metabolismo , Humanos , Neoplasias/terapia , Fragmentos de Peptídeos/metabolismo
9.
PLoS Pathog ; 16(7): e1008669, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32702076

RESUMO

Hepatitis B virus (HBV) replicates its genomic DNA via viral DNA polymerase self-primed reverse transcription of a RNA pre-genome in the nucleocapsid assembled by 120 core protein (Cp) dimers. The arginine-rich carboxyl-terminal domain (CTD) of Cp plays an important role in the selective packaging of viral DNA polymerase-pregenomic (pg) RNA complex into nucleocapsid. Previous studies suggested that the CTD is initially phosphorylated at multiple sites to facilitate viral RNA packaging and subsequently dephosphorylated in association with viral DNA synthesis and secretion of DNA-containing virions. However, our recent studies suggested that Cp is hyper-phosphorylated as free dimers and its dephosphorylation is associated with pgRNA encapsidation. Herein, we provide further genetic and biochemical evidence supporting that extensive Cp dephosphorylation does take place during the assembly of pgRNA-containing nucleocapsids, but not empty capsids. Moreover, we found that cellular protein phosphatase 1 (PP1) is required for Cp dephosphorylation and pgRNA packaging. Interestingly, the PP1 catalytic subunits α and ß were packaged into pgRNA-containing nucleocapsids, but not empty capsids, and treatment of HBV replicating cells with core protein allosteric modulators (CpAMs) promoted empty capsid assembly and abrogated the encapsidation of PP1 α and ß. Our study thus identified PP1 as a host cellular factor that is co-packaged into HBV nucleocapsids, and plays an essential role in selective packaging of the viral DNA-polymerase-pgRNA complex through catalyzing Cp dephosphorylation.


Assuntos
Vírus da Hepatite B/fisiologia , Nucleocapsídeo/metabolismo , Proteína Fosfatase 1/metabolismo , RNA Viral/metabolismo , Montagem de Vírus/fisiologia , Linhagem Celular , Hepatite B/virologia , Humanos , Fragmentos de Peptídeos/metabolismo , Fosforilação , Proteínas do Core Viral/metabolismo
10.
JACC Heart Fail ; 8(10): 789-799, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32641226

RESUMO

The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial reported that sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, significantly reduced mortality and heart failure (HF) hospitalization in HF patients with a reduced ejection fraction (HFrEF). However, fewer than 1% of patients in the PARADIGM-HF study had New York Heart Association (NYHA) functional class IV symptoms. Accordingly, data that informed the use of S/V among patients with advanced HF were limited. The LIFE (LCZ696 in Hospitalized Advanced Heart Failure) study was a 24-week prospective, multicenter, double-blinded, double-dummy, active comparator trial that compared the safety, efficacy, and tolerability of S/V with those of valsartan in patients with advanced HFrEF. The trial planned to randomize 400 patients ≥18 years of age with advanced HF, defined as an EF ≤35%, New York Heart Association functional class IV symptoms, elevated natriuretic peptide concentration (B-type natriuretic peptide [BNP] ≥250 pg/ml or N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥800 pg/ml), and ≥1 objective finding of advanced HF. Following a 3- to 7-day open label run-in period with S/V (24 mg/26 mg twice daily), patients were randomized 1:1 to S/V titrated to 97 mg/103 mg twice daily versus 160 mg of V twice daily. The primary endpoint was the proportional change from baseline in the area under the curve for NT-proBNP levels measured through week 24. Secondary and tertiary endpoints included clinical outcomes and safety and tolerability. Because of the COVID-19 pandemic, enrollment in the LIFE trial was stopped prematurely to ensure patient safety and data integrity. The primary analysis consists of the first 335 randomized patients whose clinical follow-up examination results were not severely impacted by COVID-19. (Entresto [LCZ696] in Advanced Heart Failure [LIFE STUDY] [HFN-LIFE]; NCT02816736).


Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Tetrazóis/uso terapêutico , Betacoronavirus , Cardiotônicos/uso terapêutico , Infecções por Coronavirus , Relação Dose-Resposta a Droga , Método Duplo-Cego , Término Precoce de Ensaios Clínicos , Taxa de Filtração Glomerular , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Transplante de Coração , Coração Auxiliar , Hospitalização/estatística & dados numéricos , Humanos , Hipotensão/induzido quimicamente , Peptídeo Natriurético Encefálico/metabolismo , Pandemias , Fragmentos de Peptídeos/metabolismo , Pneumonia Viral , Volume Sistólico
11.
PLoS One ; 15(7): e0236740, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32722706

RESUMO

Tryptic digestion of proteins followed by liquid chromatography with tandem mass spectrometry analysis is an extensively used approach in proteomics research and biopharmaceutical product characterization, owing to the high level of cleavage fidelity produced with this technique. However, nonspecific trypsin cleavages have been frequently reported and shown to be related to a number of digestion conditions and predigestion sample treatments. In this work, we reveal that, for a number of commercial trypsins, reconstitution and storage conditions can have a significant impact on the occurrence of trypsin nonspecific cleavages. We analyzed the tryptic digestion of a variety of biotherapeutics, using trypsins reconstituted under different conditions. The results indicate that, for many commercial trypsins, commonly recommended reconstitution/storage conditions (mildly acidic, e.g., 50 mM acetic acid, 1 mM HCl) can actually promote nonspecific trypsin activities, which are time dependent and can be as high as 20% in total relative abundance. In contrast, using water for reconstitution and storage can effectively limit nonspecific cleavages to 1%. Interestingly, the performances of different commercial trypsins were found to be quite distinct in their levels of nonspecific cleavages and responses to the two reconstitution conditions. Our findings demonstrate the importance of choosing the appropriate trypsin for tryptic digestion and the necessity of assessing the impact of trypsin reconstitution and storage on nonspecific cleavages. We advocate for manufacturers of commercial trypsins to reevaluate manufacturing processes and reconstitution/storage conditions to provide good cleavage specificity.


Assuntos
Ácidos/química , Fragmentos de Peptídeos/metabolismo , Proteínas/metabolismo , Proteólise , Proteômica/métodos , Tripsina/metabolismo , Humanos , Fragmentos de Peptídeos/análise , Fragmentos de Peptídeos/isolamento & purificação
12.
J Immunol ; 205(5): 1198-1206, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32680957

RESUMO

Fever in infections correlates with inflammation, macrophage infiltration into the affected organ, macrophage activation, and release of cytokines involved in immune response, hematopoiesis, and homeostatic processes. Angiotensin-converting enzyme 2 (ACE2) is the canonical cell surface receptor for SARS-CoV-2. ACE2 together with angiotensin receptor types 1 and 2 and ACE2 are components of the renin-angiotensin system (RAS). Exacerbated production of cytokines, mainly IL-6, points to macrophages as key to understand differential COVID-19 severity. SARS-CoV-2 may modulate macrophage-mediated inflammation events by altering the balance between angiotensin II, which activates angiotensin receptor types 1 and 2, and angiotensin 1-7 and alamandine, which activate MAS proto-oncogene and MAS-related D receptors, respectively. In addition to macrophages, lung cells express RAS components; also, some lung cells are able to produce IL-6. Addressing how SARS-CoV-2 unbalances RAS functionality via ACE2 will help design therapies to attenuate a COVID-19-related cytokine storm.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/imunologia , Interleucina-6/biossíntese , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/imunologia , Sistema Renina-Angiotensina , Angiotensina I/metabolismo , Animais , Betacoronavirus/imunologia , Infecções por Coronavirus/virologia , Humanos , Inflamação/imunologia , Macrófagos/imunologia , Pandemias , Fragmentos de Peptídeos/metabolismo , Pneumonia Viral/virologia , Proteínas Proto-Oncogênicas/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Virais/metabolismo
13.
Life Sci ; 257: 118067, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32652140

RESUMO

Although renin-angiotensin system (RAS) imbalance is manifested in cardiomyopathies with different etiologies, the impact of RAS effectors on Chagas cardiomyopathy and skeletal myositis is poorly understood. Given that diminazene aceturate (DMZ) shares trypanocidal, angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1-7) stimulatory effects, we investigated the impact of DMZ on cardiomyocytes infection in vitro, renin-angiotensin system, Chagas cardiomyopathy and skeletal myositis in vivo. Cardiomyocytes and T. cruzi were used to evaluate DMZ toxicity in vitro. The impact of 20-days DMZ treatment (1 mg/kg) was also investigated in uninfected and T. cruzi-infected mice as follows: control uninfected and untreated, uninfected treated with DMZ, infected untreated and infected treated with DMZ. DMZ had low toxicity on cardiomyocytes, induced dose-dependent antiparasitic activity on T. cruzi trypomastigotes, and reduced parasite load but not infection rates in cardiomyocytes. DMZ increased ACE2 activity and angiotensin-(1-7) plasma levels but exerted no interference on angiotensin-converting enzyme (ACE) activity, ACE, ACE2 and angiotensin II levels in uninfected and infected mice. DMZ treatment also reduced IFN-γ and IL-2 circulating levels but was ineffective in attenuating parasitemia, MCP-1, IL-10, anti-T. cruzi IgG, nitrite/nitrate and malondialdehyde production, myocarditis and skeletal myositis compared to infected untreated animals. As the antiparasitic effect of DMZ in vitro did not manifest in vivo, this drug exhibited limited relevance to the treatment of Chagas disease. Although DMZ is effective in upregulating angiotensin-(1-7) levels, this molecule does not act as a potent modulator of T. cruzi infection, which can establish heart and skeletal muscle parasitism, lipid oxidation and inflammatory damage, even in the presence of high concentrations of this RAS effector.


Assuntos
Cardiomiopatia Chagásica/tratamento farmacológico , Doença de Chagas/tratamento farmacológico , Diminazena/análogos & derivados , Miócitos Cardíacos/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina I/metabolismo , Animais , Linhagem Celular , Cardiomiopatia Chagásica/parasitologia , Doença de Chagas/parasitologia , Diminazena/administração & dosagem , Diminazena/farmacologia , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocardite/tratamento farmacológico , Miocardite/parasitologia , Miócitos Cardíacos/parasitologia , Miosite/tratamento farmacológico , Miosite/parasitologia , Fragmentos de Peptídeos/metabolismo , Ratos , Tripanossomicidas/administração & dosagem , Tripanossomicidas/farmacologia
14.
Dtsch Med Wochenschr ; 145(11): 755-760, 2020 Jun.
Artigo em Alemão | MEDLINE | ID: covidwho-545794

RESUMO

Current pandemic caused by SARS-CoV-2 inducing viral COVID-19 pneumonia, is categorized in 3 stages. Some biomarkers could be assigned to one of these stages, showing a correlation to mortality in COVID-19 patients. Laboratory findings in COVID-19, especially when serially evaluated, may represent individual disease severity and prognosis. These may help planning and controlling therapeutic interventions. Biomarkers for myocardial injury (high sensitive cardiac troponin, hsTn) or hemodynamic stress (NTproBNP) may occur in COVID-19 pneumonia such as in other pneumonias, correlating with severity and prognosis of the underlying disease. In hospitalized COVID-19 patients' mild increases of hsTn or NTproBNP may be explained by cardiovascular comorbidities and direct or indirect cardiac damage or stress caused by or during COVID-19 pneumonia. In case of suspected NSTE-ACS and COVID-19, indications for echocardiography or reperfusion strategy should be carefully considered against the risk of contamination.


Assuntos
Cardiomiopatias/virologia , Infecções por Coronavirus/complicações , Pandemias/classificação , Pneumonia Viral/classificação , Adulto , Biomarcadores , Cardiomiopatias/epidemiologia , Cardiomiopatias/patologia , Comorbidade , Infecções por Coronavirus/classificação , Infecções por Coronavirus/genética , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/fisiopatologia , Humanos , Masculino , Peptídeo Natriurético Encefálico/metabolismo , Fragmentos de Peptídeos/metabolismo , Fenótipo , Pneumonia Viral/genética , Risco , Troponina C/metabolismo
15.
Dtsch Med Wochenschr ; 145(11): 755-760, 2020 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-32492745

RESUMO

Current pandemic caused by SARS-CoV-2 inducing viral COVID-19 pneumonia, is categorized in 3 stages. Some biomarkers could be assigned to one of these stages, showing a correlation to mortality in COVID-19 patients. Laboratory findings in COVID-19, especially when serially evaluated, may represent individual disease severity and prognosis. These may help planning and controlling therapeutic interventions. Biomarkers for myocardial injury (high sensitive cardiac troponin, hsTn) or hemodynamic stress (NTproBNP) may occur in COVID-19 pneumonia such as in other pneumonias, correlating with severity and prognosis of the underlying disease. In hospitalized COVID-19 patients' mild increases of hsTn or NTproBNP may be explained by cardiovascular comorbidities and direct or indirect cardiac damage or stress caused by or during COVID-19 pneumonia. In case of suspected NSTE-ACS and COVID-19, indications for echocardiography or reperfusion strategy should be carefully considered against the risk of contamination.


Assuntos
Cardiomiopatias/virologia , Infecções por Coronavirus/complicações , Pandemias/classificação , Pneumonia Viral/classificação , Adulto , Biomarcadores , Cardiomiopatias/epidemiologia , Cardiomiopatias/patologia , Comorbidade , Infecções por Coronavirus/classificação , Infecções por Coronavirus/genética , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/fisiopatologia , Humanos , Masculino , Peptídeo Natriurético Encefálico/metabolismo , Fragmentos de Peptídeos/metabolismo , Fenótipo , Pneumonia Viral/genética , Risco , Troponina C/metabolismo
16.
Rev Med Virol ; 30(5): e2119, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32584474

RESUMO

The novel coronavirus disease 2019 (COVID-19) is rapidly expanding and causing many deaths all over the world with the World Health Organization (WHO) declaring a pandemic in March 2020. Current therapeutic options are limited and there is no registered and/or definite treatment or vaccine for this disease or the causative infection, severe acute respiratory coronavirus 2 syndrome (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2), a part of the renin-angiotensin system (RAS), serves as the major entry point into cells for SARS-CoV-2 which attaches to human ACE2, thereby reducing the expression of ACE2 and causing lung injury and pneumonia. Vitamin D, a fat-soluble-vitamin, is a negative endocrine RAS modulator and inhibits renin expression and generation. It can induce ACE2/Ang-(1-7)/MasR axis activity and inhibits renin and the ACE/Ang II/AT1R axis, thereby increasing expression and concentration of ACE2, MasR and Ang-(1-7) and having a potential protective role against acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Therefore, targeting the unbalanced RAS and ACE2 down-regulation with vitamin D in SARS-CoV-2 infection is a potential therapeutic approach to combat COVID-19 and induced ARDS.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Peptidil Dipeptidase A/genética , Pneumonia Viral/tratamento farmacológico , Receptores Virais/genética , Vitamina D/uso terapêutico , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/virologia , Angiotensina I/genética , Angiotensina I/metabolismo , Betacoronavirus/genética , Betacoronavirus/metabolismo , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Pandemias , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Ligação Proteica , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Virais/antagonistas & inibidores , Receptores Virais/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo
17.
Neuron ; 107(3): 417-435, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32579881

RESUMO

Identifying effective treatments for Alzheimer's disease (AD) has proven challenging and has instigated a shift in AD research focus toward the earliest disease-initiating cellular mechanisms. A key insight has been an increase in soluble Aß oligomers in early AD that is causally linked to neuronal and circuit hyperexcitability. However, other accumulating AD-related peptides and proteins, including those derived from the same amyloid precursor protein, such as Aη or sAPPα, and autonomously, such as tau, exhibit surprising opposing effects on circuit dynamics. We propose that the effects of these on neuronal circuits have profound implications for our understanding of disease complexity and heterogeneity and for the development of personalized diagnostic and therapeutic strategies in AD. Here, we highlight important peptide-specific mechanisms of dynamic pathological disequilibrium of cellular and circuit activity in AD and discuss approaches in which these may be further understood, and theoretically and experimentally leveraged, to elucidate AD pathophysiology.


Assuntos
Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Neurônios/metabolismo , Convulsões/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/fisiopatologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Astrócitos/metabolismo , Segmento Inicial do Axônio/metabolismo , Encéfalo/fisiopatologia , Humanos , Microglia/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Vias Neurais , Fragmentos de Peptídeos/metabolismo , Receptores de Glutamato/metabolismo , Convulsões/fisiopatologia , Sinapses/metabolismo
18.
Proc Natl Acad Sci U S A ; 117(25): 14482-14492, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32518112

RESUMO

Cerebral amyloid angiopathy (CAA), where beta-amyloid (Aß) deposits around cerebral blood vessels, is a major contributor of vascular dysfunction in Alzheimer's disease (AD) patients. However, the molecular mechanism underlying CAA formation and CAA-induced cerebrovascular pathology is unclear. Hereditary cerebral amyloid angiopathy (HCAA) is a rare familial form of CAA in which mutations within the (Aß) peptide cause an increase in vascular deposits. Since the interaction between Aß and fibrinogen increases CAA and plays an important role in cerebrovascular damage in AD, we investigated the role of the Aß-fibrinogen interaction in HCAA pathology. Our work revealed the most common forms of HCAA-linked mutations, Dutch (E22Q) and Iowa (D23N), resulted in up to a 50-fold stronger binding affinity of Aß for fibrinogen. In addition, the stronger interaction between fibrinogen and mutant Aßs led to a dramatic perturbation of clot structure and delayed fibrinolysis. Immunofluorescence analysis of the occipital cortex showed an increase of fibrin(ogen)/Aß codeposition, as well as fibrin deposits in HCAA patients, compared to early-onset AD patients and nondemented individuals. Our results suggest the HCAA-type Dutch and Iowa mutations increase the interaction between fibrinogen and Aß, which might be central to cerebrovascular pathologies observed in HCAA.


Assuntos
Peptídeos beta-Amiloides/genética , Encéfalo/patologia , Angiopatia Amiloide Cerebral Familiar/patologia , Fibrina/metabolismo , Fibrinogênio/metabolismo , Fragmentos de Peptídeos/genética , Peptídeos beta-Amiloides/metabolismo , Angiopatia Amiloide Cerebral Familiar/genética , Feminino , Fibrinogênio/isolamento & purificação , Fibrinólise/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fragmentos de Peptídeos/metabolismo , Ligação Proteica/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo
19.
Travel Med Infect Dis ; 36: 101782, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32526372

RESUMO

INTRODUCTION: There are currently no satisfactory methods for predicting the outcome of Coronavirus Disease-2019 (COVID-19). The aim of this study is to establish a model for predicting the prognosis of the disease. METHODS: The laboratory results were collected from 54 deceased COVID-19 patients on admission and before death. Another 54 recovered COVID-19 patients were enrolled as control cases. RESULTS: Many laboratory indicators, such as neutrophils, AST, γ-GT, ALP, LDH, NT-proBNP, Hs-cTnT, PT, APTT, D-dimer, IL-2R, IL-6, IL-8, IL-10, TNF-α, CRP, ferritin and procalcitonin, were all significantly increased in deceased patients compared with recovered patients on admission. In contrast, other indicators such as lymphocytes, platelets, total protein and albumin were significantly decreased in deceased patients on admission. Some indicators such as neutrophils and procalcitonin, others such as lymphocytes and platelets, continuously increased or decreased from admission to death in deceased patients respectively. Using these indicators alone had moderate performance in differentiating between recovered and deceased COVID-19 patients. A model based on combination of four indicators (P = 1/[1 + e-(-2.658+0.587×neutrophils - 2.087×lymphocytes - 0.01×platelets+0.004×IL-2R)]) showed good performance in predicting the death of COVID-19 patients. When cutoff value of 0.572 was used, the sensitivity and specificity of the prediction model were 90.74% and 94.44%, respectively. CONCLUSIONS: Using the current indicators alone is of modest value in differentiating between recovered and deceased COVID-19 patients. A prediction model based on combination of neutrophils, lymphocytes, platelets and IL-2R shows good performance in predicting the outcome of COVID-19.


Assuntos
Infecções por Coronavirus/mortalidade , Pneumonia Viral/mortalidade , Idoso , Idoso de 80 Anos ou mais , Fosfatase Alcalina/metabolismo , Aspartato Aminotransferases/metabolismo , Betacoronavirus , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Infecções por Coronavirus/sangue , Infecções por Coronavirus/metabolismo , Feminino , Ferritinas/metabolismo , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , L-Lactato Desidrogenase/metabolismo , Contagem de Leucócitos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Peptídeo Natriurético Encefálico/metabolismo , Neutrófilos , Pandemias , Tempo de Tromboplastina Parcial , Fragmentos de Peptídeos/metabolismo , Pneumonia Viral/sangue , Pneumonia Viral/metabolismo , Pró-Calcitonina/metabolismo , Prognóstico , Tempo de Protrombina , Curva ROC , Receptores de Interleucina-2/metabolismo , Troponina T/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , gama-Glutamiltransferase/metabolismo
20.
J Mol Cell Cardiol ; 145: 84-87, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32562701

RESUMO

We believe that, in parallel to the attempts for direct blockade of the SARS-CoV-2 penetration into host cell and repurposing drugs, finding new therapeutic strategies for patients with lung injury or cardiovascular complications/coagulopathies associated with COVID-19 should be paid particular attention. Apelin or its receptor agonists are of great potential treatment for COVID-19 through suppressing angiotensin-converting enzyme (ACE) and angiotensin II (Ang-II) production, as well as, down-regulating angiotensin receptor 1 (AT1R) and ACE2 up-regulation. These drugs have potential to improve acute lung injury and cardiovascular/coagulopathy complications in COVID-19 which are associated with elevated Ang-II/Ang(1-7) ratio.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Receptores de Apelina/uso terapêutico , Apelina/uso terapêutico , Betacoronavirus/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Angiotensina I/metabolismo , Angiotensina II/biossíntese , Angiotensina II/sangue , Animais , Apelina/metabolismo , Receptores de Apelina/agonistas , Receptores de Apelina/metabolismo , Infecções por Coronavirus/virologia , Reposicionamento de Medicamentos/métodos , Humanos , Camundongos , Pandemias , Fragmentos de Peptídeos/metabolismo , Pneumonia Viral/virologia , Receptor Tipo 1 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/imunologia
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