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1.
BMC Res Notes ; 14(1): 245, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193271

RESUMO

OBJECTIVE: Sepsis is a major cause of mortality for critically ill patients. This study aimed to determine whether presepsin values can predict mortality in patients with sepsis. RESULTS: Receiver operating characteristic (ROC) curve analysis, Log-rank test, and multivariate analysis identified presepsin values and Prognostic Nutritional Index as predictors of mortality in sepsis patients. Presepsin value on Day 1 was a predictor of early mortality, i.e., death within 7 days of ICU admission; ROC curve analysis revealed an AUC of 0.84, sensitivity of 89%, and specificity of 77%; and multivariate analysis showed an OR of 1.0007, with a 95%CI of 1.0001-1.0013 (p = 0.0320).


Assuntos
Avaliação Nutricional , Sepse , Biomarcadores , Humanos , Unidades de Terapia Intensiva , Receptores de Lipopolissacarídeos , Fragmentos de Peptídeos , Projetos Piloto , Prognóstico , Curva ROC , Sepse/diagnóstico
2.
Int J Mol Sci ; 22(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199883

RESUMO

Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by progressive neuron losses in memory-related brain structures. The classical features of AD are a dysregulation of the cholinergic system, the accumulation of amyloid plaques, and neurofibrillary tangles. Unfortunately, current treatments are unable to cure or even delay the progression of the disease. Therefore, new therapeutic strategies have emerged, such as the exogenous administration of neurotrophic factors (e.g., NGF and BDNF) that are deficient or dysregulated in AD. However, their low capacity to cross the blood-brain barrier and their exorbitant cost currently limit their use. To overcome these limitations, short peptides mimicking the binding receptor sites of these growth factors have been developed. Such peptides can target selective signaling pathways involved in neuron survival, differentiation, and/or maintenance. This review focuses on growth factors and their derived peptides as potential treatment for AD. It describes (1) the physiological functions of growth factors in the brain, their neuronal signaling pathways, and alteration in AD; (2) the strategies to develop peptides derived from growth factor and their capacity to mimic the role of native proteins; and (3) new advancements and potential in using these molecules as therapeutic treatments for AD, as well as their limitations.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Fragmentos de Peptídeos/farmacologia , Doença de Alzheimer/metabolismo , Animais , Humanos
3.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200765

RESUMO

BacSp222 is a multifunctional peptide produced by Staphylococcus pseudintermedius 222. This 50-amino acid long peptide belongs to subclass IId of bacteriocins and forms a four-helix bundle molecule. In addition to bactericidal functions, BacSp222 possesses also features of a virulence factor, manifested in immunomodulatory and cytotoxic activities toward eukaryotic cells. In the present study, we demonstrate that BacSp222 is produced in several post-translationally modified forms, succinylated at the ε-amino group of lysine residues. Such modifications have not been previously described for any bacteriocins. NMR and circular dichroism spectroscopy studies have shown that the modifications do not alter the spatial structure of the peptide. At the same time, succinylation significantly diminishes its bactericidal and cytotoxic potential. We demonstrate that the modification of the bacteriocin is an effect of non-enzymatic reaction with a highly reactive intracellular metabolite, i.e., succinyl-coenzyme A. The production of succinylated forms of the bacteriocin depends on environmental factors and on the access of bacteria to nutrients. Our study indicates that the production of succinylated forms of bacteriocin occurs in response to the changing environment, protects producer cells against the autotoxicity of the excreted peptide, and limits the pathogenicity of the strain.


Assuntos
Bacteriocinas/química , Bacteriocinas/farmacologia , Macrófagos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Staphylococcus/fisiologia , Acil Coenzima A/metabolismo , Animais , Antibacterianos/farmacologia , Humanos , Lisina/química , Lisina/metabolismo , Macrófagos/patologia , Camundongos , Neutrófilos/patologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Processamento de Proteína Pós-Traducional
4.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201112

RESUMO

The Semax (Met-Glu-His-Phe-Pro-Gly-Pro) peptide is a synthetic melanocortin derivative that is used in the treatment of ischemic stroke. Previously, studies of the molecular mechanisms underlying the actions of Semax using models of cerebral ischemia in rats showed that the peptide enhanced the transcription of neurotrophins and their receptors and modulated the expression of genes involved in the immune response. A genome-wide RNA-Seq analysis revealed that, in the rat transient middle cerebral artery occlusion (tMCAO) model, Semax suppressed the expression of inflammatory genes and activated the expression of neurotransmitter genes. Here, we aimed to evaluate the effect of Semax in this model via the brain expression profiling of key proteins involved in inflammation and cell death processes (MMP-9, c-Fos, and JNK), as well as neuroprotection and recovery (CREB) in stroke. At 24 h after tMCAO, we observed the upregulation of active CREB in subcortical structures, including the focus of the ischemic damage; downregulation of MMP-9 and c-Fos in the adjacent frontoparietal cortex; and downregulation of active JNK in both tissues under the action of Semax. Moreover, a regulatory network was constructed. In conclusion, the suppression of inflammatory and cell death processes and the activation of recovery may contribute to the neuroprotective action of Semax at both the transcriptome and protein levels.


Assuntos
Hormônio Adrenocorticotrópico/análogos & derivados , Isquemia Encefálica/prevenção & controle , Encéfalo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/farmacologia , Proteoma/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Transcriptoma/efeitos dos fármacos , Hormônio Adrenocorticotrópico/farmacologia , Animais , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Masculino , RNA-Seq , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
5.
Molecules ; 26(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204308

RESUMO

Globally, Alzheimer's disease (AD) is one of the most prevalent age-related neurodegenerative disorders associated with cognitive decline and memory deficits due to beta-amyloid deposition (Aß) and tau protein hyperphosphorylation. To date, approximately 47 million people worldwide have AD. This figure will rise to an estimated 75.6 million by 2030 and 135.5 million by 2050. According to the literature, the efficacy of conventional medications for AD is statistically substantial, but clinical relevance is restricted to disease slowing rather than reversal. Withaferin A (WA) is a steroidal lactone glycowithanolides, a secondary metabolite with comprehensive biological effects. Biosynthetically, it is derived from Withania somnifera (Ashwagandha) and Acnistus breviflorus (Gallinero) through the mevalonate and non-mevalonate pathways. Mounting evidence shows that WA possesses inhibitory activities against developing a pathological marker of Alzheimer's diseases. Several cellular and animal models' particulates to AD have been conducted to assess the underlying protective effect of WA. In AD, the neuroprotective potential of WA is mediated by reduction of beta-amyloid plaque aggregation, tau protein accumulation, regulation of heat shock proteins, and inhibition of oxidative and inflammatory constituents. Despite the various preclinical studies on WA's therapeutic potentiality, less is known regarding its definite efficacy in humans for AD. Accordingly, the present study focuses on the biosynthesis of WA, the epidemiology and pathophysiology of AD, and finally the therapeutic potential of WA for the treatment and prevention of AD, highlighting the research and augmentation of new therapeutic approaches. Further clinical trials are necessary for evaluating the safety profile and confirming WA's neuroprotective potency against AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Vitanolídeos/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Animais , Disfunção Cognitiva/tratamento farmacológico , Humanos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/uso terapêutico , Placa Amiloide/tratamento farmacológico , Solanaceae/metabolismo , Withania/metabolismo , Vitanolídeos/metabolismo , Proteínas tau/metabolismo
6.
Molecules ; 26(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204651

RESUMO

The driving forces and conformational pathways leading to amphitropic protein-membrane binding and in some cases also to protein misfolding and aggregation is the subject of intensive research. In this study, a chimeric polypeptide, A-Cage-C, derived from α-Lactalbumin is investigated with the aim of elucidating conformational changes promoting interaction with bilayers. From previous studies, it is known that A-Cage-C causes membrane leakages associated with the sporadic formation of amorphous aggregates on solid-supported bilayers. Here we express and purify double-labelled A-Cage-C and prepare partially deuterated bicelles as a membrane mimicking system. We investigate A-Cage-C in the presence and absence of these bicelles at non-binding (pH 7.0) and binding (pH 4.5) conditions. Using in silico analyses, NMR, conformational clustering, and Molecular Dynamics, we provide tentative insights into the conformations of bound and unbound A-Cage-C. The conformation of each state is dynamic and samples a large amount of overlapping conformational space. We identify one of the clusters as likely representing the binding conformation and conclude tentatively that the unfolding around the central W23 segment and its reorientation may be necessary for full intercalation at binding conditions (pH 4.5). We also see evidence for an overall elongation of A-Cage-C in the presence of model bilayers.


Assuntos
Proteína Oncogênica pp60(v-src)/química , Fragmentos de Peptídeos/química , Peptídeos/química , Lactalbumina/química , Espectroscopia de Ressonância Magnética/métodos , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Membranas , Simulação de Dinâmica Molecular , Proteína Oncogênica pp60(v-src)/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptídeos/metabolismo , Ligação Proteica , Conformação Proteica
7.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206089

RESUMO

Amyloid-ß (Aß) 1-40 and 1-42 peptides are key mediators of synaptic and cognitive dysfunction in Alzheimer's disease (AD). Whereas in AD, Aß is found to act as a pro-epileptogenic factor even before plaque formation, amyloid pathology has been detected among patients with epilepsy with increased risk of developing AD. Among Aß aggregated species, soluble oligomers are suggested to be responsible for most of Aß's toxic effects. Aß oligomers exert extracellular and intracellular toxicity through different mechanisms, including interaction with membrane receptors and the formation of ion-permeable channels in cellular membranes. These damages, linked to an unbalance between excitatory and inhibitory neurotransmission, often result in neuronal hyperexcitability and neural circuit dysfunction, which in turn increase Aß deposition and facilitate neurodegeneration, resulting in an Aß-driven vicious loop. In this review, we summarize the most representative literature on the effects that oligomeric Aß induces on synaptic dysfunction and network disorganization.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Sinapses/genética , Transmissão Sináptica/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/efeitos adversos , Peptídeos beta-Amiloides/ultraestrutura , Proteínas Amiloidogênicas/efeitos adversos , Proteínas Amiloidogênicas/genética , Animais , Humanos , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Multimerização Proteica/genética , Sinapses/metabolismo
8.
Front Immunol ; 12: 625732, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34194422

RESUMO

The etiological agent of COVID-19 SARS-CoV-2, is primarily a pulmonary-tropic coronavirus. Infection of alveolar pneumocytes by SARS-CoV-2 requires virus binding to the angiotensin I converting enzyme 2 (ACE2) monocarboxypeptidase. ACE2, present on the surface of many cell types, is known to be a regulator of blood pressure homeostasis through its ability to catalyze the proteolysis of Angiotensin II (Ang II) into Angiotensin-(1-7) [Ang-(1-7)]. We therefore hypothesized that SARS-CoV-2 could trigger variations of ACE2 expression and Ang II plasma concentration in SARS-CoV-2-infected patients. We report here, that circulating blood cells from COVID-19 patients express less ACE2 mRNA than cells from healthy volunteers. At the level of circulating cells, this ACE2 gene dysregulation mainly affects the monocytes, which also show a lower expression of membrane ACE2 protein. Moreover, soluble ACE2 (sACE2) plasma concentrations are lower in prolonged viral shedders than in healthy controls, while the concentration of sACE2 returns to normal levels in short viral shedders. In the plasma of prolonged viral shedders, we also found higher concentrations of Ang II and angiotensin I (Ang I). On the other hand, the plasma levels of Ang-(1-7) remains almost stable in prolonged viral shedders but seems insufficient to prevent the adverse effects of Ang II accumulation. Altogether, these data evidence that the SARS-CoV-2 may affect the expression of blood pressure regulators with possible harmful consequences on COVID-19 outcome.


Assuntos
Angiotensina II/sangue , Angiotensina I/sangue , Enzima de Conversão de Angiotensina 2/sangue , COVID-19/sangue , Fragmentos de Peptídeos/sangue , Adulto , Enzima de Conversão de Angiotensina 2/genética , COVID-19/virologia , Feminino , Perfilação da Expressão Gênica , Antígenos HLA-DR , Humanos , Receptores de Lipopolissacarídeos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Projetos Piloto , Estudos Prospectivos , RNA Mensageiro , Eliminação de Partículas Virais
9.
Nat Commun ; 12(1): 4077, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210970

RESUMO

Emerging data demonstrate that the activity of immune cells can be modulated by microbial molecules. Here, we show that the short-chain fatty acids (SCFAs) pentanoate and butyrate enhance the anti-tumor activity of cytotoxic T lymphocytes (CTLs) and chimeric antigen receptor (CAR) T cells through metabolic and epigenetic reprograming. We show that in vitro treatment of CTLs and CAR T cells with pentanoate and butyrate increases the function of mTOR as a central cellular metabolic sensor, and inhibits class I histone deacetylase activity. This reprogramming results in elevated production of effector molecules such as CD25, IFN-γ and TNF-α, and significantly enhances the anti-tumor activity of antigen-specific CTLs and ROR1-targeting CAR T cells in syngeneic murine melanoma and pancreatic cancer models. Our data shed light onto microbial molecules that may be used for enhancing cellular anti-tumor immunity. Collectively, we identify pentanoate and butyrate as two SCFAs with therapeutic utility in the context of cellular cancer immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Ácidos Graxos Voláteis/metabolismo , Fatores Imunológicos/metabolismo , Imunoterapia Adotiva/métodos , Microbiota/fisiologia , Neoplasias/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Butiratos/metabolismo , Linhagem Celular Tumoral , Citocinas/metabolismo , Feminino , Imunoterapia , Interferon gama , Subunidade alfa de Receptor de Interleucina-2 , Megasphaera , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase , Receptores Acoplados a Proteínas G/genética , Fator de Necrose Tumoral alfa
10.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281277

RESUMO

The aim of this research was to analyze the heterologous expression, purification, and immunoregulatory activity of recombinant YGP40 (rYGP40), the potential precursor of the yolkin peptide complex. The ygp40 coding sequence was codon optimized, successfully expressed in the E. coli system, and purified from inclusion bodies with a yield of about 1.1 mg/L of culture. This study showed that the protein exhibits immunomodulatory activity, expressed by the stimulation of TNF-α and IL-10 production and nitric oxide induction at a level comparable to that of the natural yolkin peptide complex obtained by other authors from hen egg yolk. At the highest dose of 100 µg/mL, rYGP40 also caused the up-regulation of iNOS expression in murine bone marrow-derived macrophages (BMDM). Moreover, no cytotoxic effects of rYGP40 on the BMDM cell line were observed.


Assuntos
Vitelogeninas/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Galinhas , Clonagem Molecular , Gema de Ovo/química , Feminino , Humanos , Fatores Imunológicos/química , Fatores Imunológicos/genética , Fatores Imunológicos/farmacologia , Técnicas In Vitro , Interleucina-10/biossíntese , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Peso Molecular , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/metabolismo , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/farmacologia , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia , Fator de Necrose Tumoral alfa/biossíntese , Vitelogeninas/genética , Vitelogeninas/farmacologia
11.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281279

RESUMO

(1) Background: Autophagy, the major cytoplasmic process of substrate turnover, declines with age, contributing to proteostasis decline, accumulation of harmful protein aggregates, damaged mitochondria and to ROS production. Accordingly, abnormalities in the autophagic flux may contribute to many different pathophysiological conditions associated with ageing, including neurodegeneration. Recent data have shown that extra-virgin olive oil (EVOO) polyphenols stimulate cell defenses against plaque-induced neurodegeneration, mainly, through autophagy induction. (2) Methods: We carried out a set of in vitro experiments on SH-SY5Y human neuroblastoma cells exposed to toxic Aß1-42 oligomers to investigate the molecular mechanisms involved in autophagy activation by two olive oil polyphenols, oleuropein aglycone (OleA), arising from the hydrolysis of oleuropein (Ole), the main polyphenol found in olive leaves and drupes and its main metabolite, hydroxytyrosol (HT). (3) Results: Our data show that the mixture of the two polyphenols activates synergistically the autophagic flux preventing cell damage by Aß1-42 oligomers., in terms of ROS production, and impairment of mitochondria. (4) Conclusion: Our results support the idea that EVOO polyphenols act synergistically in autophagy modulation against neurodegeneration. These data confirm and provide the rationale to consider these molecules, alone or in combination, as promising candidates to contrast ageing-associated neurodegeneration.


Assuntos
Doença de Alzheimer/dietoterapia , Azeite de Oliva/farmacologia , Polifenóis/farmacologia , Acetatos/administração & dosagem , Acetatos/química , Acetatos/farmacologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Autofagia/efeitos dos fármacos , Linhagem Celular , Monoterpenos Ciclopentânicos/administração & dosagem , Monoterpenos Ciclopentânicos/química , Monoterpenos Ciclopentânicos/farmacologia , Dieta Mediterrânea , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Neurológicos , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Degeneração Neural/prevenção & controle , Neurônios/efeitos dos fármacos , Neurônios/patologia , Azeite de Oliva/administração & dosagem , Azeite de Oliva/química , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/toxicidade , Álcool Feniletílico/administração & dosagem , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Polifenóis/administração & dosagem , Polifenóis/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Piranos/administração & dosagem , Piranos/química , Piranos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Ubiquitina/metabolismo
12.
Molecules ; 26(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34201982

RESUMO

During the last three decades, a variety of different studies on bioactive peptides that are opioid receptor ligands, have been carried out, with regard to their isolation and identification, as well as their molecular functions in living organisms. Thus, in this review, we would like to summarize the present state-of-the art concerning hemorphins, methodological aspects of their identification, and their potential role as therapeutic agents. We have collected and discussed articles describing hemorphins, from their discovery up until now, thus presenting a very wide spectrum of their characteristic and applications. One of the major assets of the present paper is a combination of analytical and pharmacological aspects of peptides described by a team who participated in the initial research on hemorphins. This review is, in part, focused on the analysis of endogenous opioid peptides in biological samples using advanced techniques, description of the identification of synthetic/endogenous hemorphins, their involvement in pharmacology, learning, pain and other function. Finally, the part regarding hemorphin analogues and their synthesis, has been added.


Assuntos
Peptídeos Opioides/metabolismo , Dor/metabolismo , Fragmentos de Peptídeos/metabolismo , Receptores Opioides/metabolismo , Animais , Humanos
13.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209299

RESUMO

Alzheimer's disease (AD)-associated neurodegeneration is triggered by different fragments of amyloid beta (Aß). Among them, Aß (25-35) fragment plays a critical role in the development of neurodegeneration-it reduces synaptic integrity by disruption of excitatory/inhibitory ratio across networks and alters the growth factors synthesis. Thus, in this study, we aimed to identify the involvement of neurotrophic factors-the insulin-like growth factor 1 (IGF-1) and nerve growth factor (NGF)-of AD-like neurodegeneration induced by Aß (25-35). Taking into account our previous findings on the neuroprotective effects of the mix of proteoglycans of embryonic genesis (PEG), it was suggested to test its regulatory effect on IGF-1 and NGF levels. To evaluate the progress of neurodegeneration, in vivo electrophysiological investigation of synaptic activity disruption of the entorhinal cortex-hippocampus circuit at AD was performed and the potential recovery effects of PEG with relative structural changes were provided. To reveal the direct effects of PEG on brain functional activity, the electrophysiological pattern of the single cells from nucleus supraopticus, sensomotor cortex and hippocampus after acute injection of PEG was examined. Our results demonstrated that after i.c.v. injection of Aß (25-35), the level of NGF decreased in cerebral cortex and hypothalamus, and, in contrast, increased in hippocampus, prompting its multidirectional role in case of brain damage. The concentration of IGF-1 significantly increased in all investigated brain structures. The administration of PEG balanced the growth factor levels accompanied by substantial restoration of neural tissue architecture and synaptic activity. Acute injection of PEG activated the hypothalamic nucleus supraopticus and hippocampal neurons. IGF-1 and NGF levels were found to be elevated in animals receiving PEG in an absence of amyloid exposure. We suggest that IGF-1 and NGF play a critical role in the development of AD. At the same time, it becomes clear that the neuroprotective effects of PEG are likely mediated via the regulation of neurotrophins.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Encéfalo , Eletrocardiografia , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Neural/metabolismo , Fragmentos de Peptídeos/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley
14.
J Stroke Cerebrovasc Dis ; 30(8): 105933, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34157668

RESUMO

OBJECTIVES: The study aimed to investigate whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration and/or left atrial volume index (LAVI), as atrial cardiopathy biomarkers, were associated with infarct patterns on diffusion-weighted imaging in patients with embolic strokes of undetermined source (ESUS). MATERIALS AND METHOD: We retrospectively evaluated patient with ESUS from our stroke registry between January 2018 and November 2019. Cut-off values for atrial cardiopathy biomarkers were defined as >250 pg/mL for NT-proBNP and >34 mL/m2 for LAVI. Eligible patients were then assigned to 3 groups and infarct patterns were compared according to their atrial cardiopathy markers: Group 1 (no atrial cardiopathy markers), Group 2 (one marker), and Group 3 (both markers). RESULTS: Among 194 eligible patients with ESUS (76 women; mean age, 69.2 years), simultaneous increases of NT-proBNP concentration and LAVI were identified in 39 (20.1%). Group 3 had a significantly larger infarct volume, relative to Group 1 and Group 2 (P=0.043) Multivariable logistic regression analyses revealed that these patients (Group 3) were significantly more likely to have multi-territorial infarcts (adjusted odds ratio [aOR]: 3.03, 95% confidence interval [CI]: 1.05-8.72; P=0.04), a maximal lesion diameter >15mm (aOR: 4.51, 95% CI: 1.70-11.93; P=0.001), and large cortical infarctions (aOR: 4.17, 95% CI: 1.75-9.96; P=0.001). CONCLUSION: We found that simultaneously increased values for NT-proBNP concentration and LAVI were independently associated with multi-territorial and large cortical infarct patterns in patients with ESUS. These findings suggest that NT-proBNP and LAVI may be useful biomarkers for identifying cardioembolic subtypes and guiding treatment selection in patients with ESUS.


Assuntos
Função do Átrio Esquerdo , Remodelamento Atrial , Infarto Encefálico/diagnóstico por imagem , Cardiomiopatias/complicações , Imagem de Difusão por Ressonância Magnética , Ecocardiografia , AVC Embólico/diagnóstico por imagem , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Infarto Encefálico/etiologia , Cardiomiopatias/sangue , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/fisiopatologia , AVC Embólico/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sistema de Registros , Estudos Retrospectivos , Fatores de Tempo
15.
FASEB J ; 35(7): e21727, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34117802

RESUMO

We previously discovered the implication of membrane-type 5-matrix metalloproteinase (MT5-MMP) in Alzheimer's disease (AD) pathogenesis. Here, we shed new light on pathogenic mechanisms by which MT5-MMP controls the processing of amyloid precursor protein (APP) and the fate of amyloid beta peptide (Aß) as well as its precursor C99, and C83. We found in human embryonic kidney cells (HEK) carrying the APP Swedish familial mutation (HEKswe) that deleting the C-terminal non-catalytic domains of MT5-MMP hampered its ability to process APP and release the soluble 95 kDa form (sAPP95). Catalytically inactive MT5-MMP variants increased the levels of Aß and promoted APP/C99 sorting in the endolysosomal system, likely through interactions of the proteinase C-terminal portion with C99. Most interestingly, the deletion of the C-terminal domain of MT5-MMP caused a strong degradation of C99 by the proteasome and prevented Aß accumulation. These discoveries reveal new control of MT5-MMP over APP by proteolytic and non-proteolytic mechanisms driven by the C-terminal domains of the proteinase. The targeting of these non-catalytic domains of MT5-MMP could, therefore, provide new insights into the therapeutic regulation of APP-related pathology in AD.


Assuntos
Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Metaloproteinases da Matriz Associadas à Membrana/metabolismo , Fragmentos de Peptídeos/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Linhagem Celular , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteólise
16.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071276

RESUMO

Cardiovascular disease is the leading cause of death worldwide, and its prevalence is increasing due to the aging of societies. Atherosclerosis, a type of chronic inflammatory disease that occurs in arteries, is considered to be the main cause of cardiovascular diseases such as ischemic heart disease or stroke. In addition, the inflammatory response caused by atherosclerosis confers a significant effect on chronic inflammatory diseases such as psoriasis and rheumatic arthritis. Here, we review the mechanism of action of the main causes of atherosclerosis such as plasma LDL level and inflammation; furthermore, we review the recent findings on the preclinical and clinical effects of antibodies that reduce the LDL level and those that neutralize the cytokines involved in inflammation. The apolipoprotein B autoantibody and anti-PCSK9 antibody reduced the level of LDL and plaques in animal studies, but failed to significantly reduce carotid inflammation plaques in clinical trials. The monoclonal antibodies against PCSK9 (alirocumab, evolocumab), which are used as a treatment for hyperlipidemia, lowered cholesterol levels and the incidence of cardiovascular diseases. Antibodies that neutralize inflammatory cytokines (TNF-α, IL-1ß, IL-6, IL-17, and IL-12/23) have shown promising but contradictory results and thus warrant further research.


Assuntos
Anticorpos/farmacologia , Aterosclerose/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Imunização Passiva/métodos , Animais , Anticorpos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/uso terapêutico , Apolipoproteínas B , Autoanticorpos , LDL-Colesterol/sangue , Citocinas/imunologia , Humanos , Inflamação/tratamento farmacológico , Fragmentos de Peptídeos , Pró-Proteína Convertase 9/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico
17.
Nat Commun ; 12(1): 3555, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34117234

RESUMO

Plasma biomarkers of amyloid, tau, and neurodegeneration (ATN) need to be characterized in cognitively unimpaired (CU) elderly individuals. We therefore tested if plasma measurements of amyloid-ß (Aß)42/40, phospho-tau217 (P-tau217), and neurofilament light (NfL) together predict clinical deterioration in 435 CU individuals followed for an average of 4.8 ± 1.7 years in the BioFINDER study. A combination of all three plasma biomarkers and basic demographics best predicted change in cognition (Pre-Alzheimer's Clinical Composite; R2 = 0.14, 95% CI [0.12-0.17]; P < 0.0001) and subsequent AD dementia (AUC = 0.82, 95% CI [0.77-0.91], P < 0.0001). In a simulated clinical trial, a screening algorithm combining all three plasma biomarkers would reduce the required sample size by 70% (95% CI [54-81]; P < 0.001) with cognition as trial endpoint, and by 63% (95% CI [53-70], P < 0.001) with subsequent AD dementia as trial endpoint. Plasma ATN biomarkers show usefulness in cognitively unimpaired populations and could make large clinical trials more feasible and cost-effective.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Biomarcadores/sangue , Disfunção Cognitiva/sangue , Disfunção Cognitiva/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/sangue , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Fragmentos de Peptídeos/sangue , Proteínas tau/sangue
18.
Ann Palliat Med ; 10(6): 6455-6466, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34154350

RESUMO

BACKGROUND: The aim of the present study was to investigate the value of parameters related to right heart function combined with N-terminal pro-B-type natriuretic peptide (NT-proBNP) in acute radiation-induced right heart injury. METHODS: Seventy patients who received chest radiotherapy (RT) in the RT department of our hospital between September 2015 and March 2019 were included in the study. RESULTS: Of the included 70 patients, 19, 32, 4, and 15 had thoracic esophageal cancer, central lung cancer, thymoma, and left breast cancer, respectively. The Tei index, tricuspid annular displacement, right ventricular ejection fraction, and NT-proBNP of the 70 patients were measured 1 week before RT, at weeks 2 and 4 during RT, and 4 weeks after RT. Differences in the Tei index, the tricuspid annular displacement, and NT-proBNP were significant (P<0.01, P<0.05, and P<0.05, respectively). The Tei index significantly increased in the second week of RT. Tricuspid annular displacement decreased significantly 4 weeks after RT. NT-proBNP reached its peak value in the fourth week of RT. However, there was no significant difference in right ventricular ejection fraction (P>0.05). CONCLUSIONS: The Tei index of the right ventricle can be used as a sensitive indicator for the early detection of right heart injury after RT for thoracic tumors. Additionally, tricuspid annular displacement can be used as an index for the early detection of right ventricular damage after RT for thoracic tumors. However, right ventricular ejection fraction showed no significant change in the early stage of right heart damage after RT. Finally, it is important to consider NT-proBNP for the detection of acute radiation-induced heart injury. In acute radiation-induced right heart injury, the combined application of right ventricular Tei index, tricuspid annular displacement, and NT-proBNP is clinically relevant.


Assuntos
Traumatismos Cardíacos , Peptídeo Natriurético Encefálico , Biomarcadores , Humanos , Fragmentos de Peptídeos , Volume Sistólico , Função Ventricular Direita
19.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069596

RESUMO

Acinetobacter baumannii is a serious nosocomial pathogen with multiple drug resistance (MDR), the control of which has become challenging due to the currently used antibiotics. Our main objective in this study is to determine the antibacterial and antibiofilm activities of the antimicrobial peptide, Octominin, against MDR A. baumannii and derive its possible modes of actions. Octominin showed significant bactericidal effects at a low minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of 5 and 10 µg/mL, respectively. Time-kill kinetic analysis and bacterial viability tests revealed that Octominin showed a concentration-dependent antibacterial activity. Field-emission scanning electron microscopy (FE-SEM) analysis revealed that Octominin treatment altered the morphology and membrane structure of A. baumannii. Propidium iodide (PI) and reactive oxygen species (ROS) generation assays showed that Octominin increased the membrane permeability and ROS generation in A. baumannii, thereby causing bacterial cell death. Further, a lipopolysaccharides (LPS) binding assay showed an Octominin concentration-dependent LPS neutralization ability. Biofilm formation inhibition and eradication assays further revealed that Octominin inhibited biofilm formation and showed a high biofilm eradication activity against A. baumannii. Furthermore, up to a concentration of 100 µg/mL, Octominin caused no hemolysis and cell viability changes in mammalian cells. An in vivo study in zebrafish showed that the Octominin-treated group had a significantly higher relative percentage survival (54.1%) than the untreated group (16.6%). Additionally, a reduced bacterial load and fewer alterations in histological analysis confirmed the successful control of A. baumannii by Octominin in vivo. Collectively, these data suggest that Octominin exhibits significant antibacterial and antibiofilm activities against the multidrug-resistant A. baumannii, and this AMP can be developed further as a potent AMP for the control of antibiotic resistance.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Peptídeos Catiônicos Antimicrobianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/metabolismo , Animais , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Peptídeos Catiônicos Antimicrobianos/metabolismo , Biofilmes/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Sinergismo Farmacológico , Cinética , Viabilidade Microbiana/efeitos dos fármacos , Modelos Animais , Fragmentos de Peptídeos/metabolismo , Peixe-Zebra
20.
J Clin Anesth ; 73: 110379, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34087659

RESUMO

STUDY OBJECTIVE: Supplemental oxygen is a simple method to improve arterial oxygen saturation and might therefore improve myocardial oxygenation. Thus, we tested whether intraoperative supplemental oxygen reduces the risk of impaired cardiac function diagnosed with NT-proBNP and myocardial injury after noncardiac surgery (MINS) diagnosed with high-sensitivity Troponin T. DESIGN: Parallel-arm double-blinded single-centre superiority randomized trial. SETTING: Operating room and postoperative recovery area. PATIENTS: 260 patients over the age of 45 years at-risk for cardiovascular complications undergoing major abdominal surgery. INTERVENTION: Administration of 80% versus 30% oxygen throughout surgery and for the first two postoperative hours. MEASUREMENTS: The primary outcome was the postoperative maximum NT-proBNP concentration in both groups, which was assessed within 2 h after surgery, and on the first and third postoperative day. The secondary outcome was the incidence of MINS in both groups. MAIN RESULTS: 128 patients received 80% oxygen and 130 received 30% oxygen throughout surgery and for the first two postoperative hours. There was no significant difference in the median postoperative maximum NT-proBNP concentration between the 80% and the 30% oxygen group (989 pg.mL-1 [IQR 499; 2005] and 810 pg.mL-1 [IQR 409; 2386], effect estimate: 159 pg.mL-1, 95%CI -123, 431, p = 0.704). There was no difference in the incidence of MINS between both groups. (p = 0.703). CONCLUSIONS: There was no beneficial effect of perioperative supplemental oxygen administration on postoperative NT-proBNP concentration and MINS. It seems likely that supplemental oxygen has no effect on the release of NT-proBNP in patients at-risk for cardiovascular complications undergoing major abdominal surgery. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03366857. https://clinicaltrials.gov/ct2/results?cond=NCT+03366857&term=&cntry=&state=&city=&dist=.


Assuntos
Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Biomarcadores , Humanos , Pessoa de Meia-Idade , Oxigênio , Estudos Prospectivos , Medição de Risco
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