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1.
Br J Haematol ; 204(3): 988-1004, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38062782

RESUMO

Neonatal platelets present a reduced response to the platelet agonist, thrombin (Thr), thus resulting in a deficient Thr-induced aggregation. These alterations are more pronounced in premature newborns. Here, our aim was to uncover the causes underneath the impaired Ca2+ homeostasis described in neonatal platelets. Both Ca2+ mobilization and Ca2+ influx in response to Thr are decreased in neonatal platelets compared to maternal and control woman platelets. In neonatal platelets, we observed impaired Ca2+ mobilization in response to the PAR-1 agonist (SFLLRN) or by blocking SERCA3 function with tert-butylhydroquinone. Regarding SOCE, the STIM1 regulatory protein, SARAF, was found overexpressed in neonatal platelets, promoting an increase in STIM1/SARAF interaction even under resting conditions. Additionally, higher interaction between SARAF and PDCD61/ALG2 was also observed, reducing SARAF ubiquitination and prolonging its half-life. These results were reproduced by overexpressing SARAF in MEG01 and DAMI cells. Finally, we also observed that pannexin 1 permeability is enhanced in response to Thr in control woman and maternal platelets, but not in neonatal platelets, hence, leading to the deregulation of the Ca2+ entry found in neonatal platelets. Summarizing, we show that in neonatal platelets both Ca2+ accumulation in the intracellular stores and Thr-evoked Ca2+ entry through either capacitative channels or non-selective channels are altered in neonatal platelets, contributing to deregulated Ca2+ homeostasis in neonatal platelets and leading to the altered aggregation observed in these subjects.


Assuntos
Proteínas de Membrana , Trombina , Recém-Nascido , Humanos , Trombina/metabolismo , Proteínas de Membrana/metabolismo , Plaquetas/metabolismo , Homeostase , Cálcio/metabolismo , Sinalização do Cálcio
2.
Int J Mol Sci ; 24(19)2023 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-37833987

RESUMO

Hypoxia is considered to be a stressful physiological condition, which may occur during labor and the later stages of pregnancy as a result of, among other reasons, an aged placenta. Therefore, when gestation or labor is prolonged, low oxygen supply to the tissues may last for minutes, and newborns may present breathing problems and may require resuscitation maneuvers. As a result, poor oxygen supply to tissues and to circulating cells may last for longer periods of time, leading to life-threatening conditions. In contrast to the well-known platelet activation that occurs after reperfusion of the tissues due to an ischemia/reperfusion episode, platelet alterations in response to reduced oxygen exposition following labor have been less frequently investigated. Newborns overcome temporal hypoxic conditions by changing their organ functions or by adaptation of the intracellular molecular pathways. In the present review, we aim to analyze the main platelet modifications that appear at the protein level during hypoxia in order to highlight new platelet markers linked to complications arising from temporal hypoxic conditions during labor. Thus, we demonstrate that hypoxia modifies the expression and activity of hypoxic-response proteins (HRPs), including hypoxia-induced factor (HIF-1), endoplasmic reticulum oxidase 1 (Ero1), and carbonic anhydrase (CIX). Finally, we provide updates on research related to the regulation of platelet function due to HRP activation, as well as the role of HRPs in intracellular Ca2+ homeostasis.


Assuntos
Anidrases Carbônicas , Trabalho de Parto , Recém-Nascido , Gravidez , Feminino , Humanos , Idoso , Hipóxia/metabolismo , Oxigênio/metabolismo , Placenta/metabolismo , Anidrases Carbônicas/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
3.
J Cell Mol Med ; 22(1): 684-694, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28990324

RESUMO

Stanniocalcins are expressed in the pancreas tissue, and it was suggested a direct correlation between circulating insulin and STC2 concentrations in human. Here, we show a significant correlation between STC1 and both glycaemia and glycosylated haemoglobin among DM2 patients, while DM2 patients who present the greatest glycosylated haemoglobin values exhibited the lowest STC2 expression. However, treatment of patients with antiglycaemic drugs does not significantly modify the expression of both STCs. On the other hand, STC2-/- mice that exhibited neonatal and adult overweight further presented deregulated glycaemia when they were feed with a hypercaloric diet (breeding pellet, BP). This alteration is more evident at the early stages of the animal life. Deregulated glycaemia in these mice was confirmed using glucose oral test. In addition, STC2-/- mice present enhanced pancreas size; thus, the histological analysis reveals that WT mice respond to BP diet by increasing the size of the pancreatic islets through inducing cell division, and STC2-/- mice lack this compensatory mechanism. Contrary, BP fed STC2-/- mice show enhanced number of islets but of similar size than those fed with regular pellet. Histopathological analysis demonstrates tissue structure disruption and erythrocytes infiltrations in STC2-/- mice, possibly due to the stress evoked by the BP diet. Finally, enhanced glucagon immunostaining was observed in the islet of STC2-/- mice, and the glucagon ELISA assay confirmed the increase in the circulating glucagon. Summarizing, we present evidence of the role of STCs, mainly STC2, as a possible early marker during development of diabetes mellitus.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Glicoproteínas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Adulto , Idoso , Animais , Glucagon/sangue , Glicoproteínas/deficiência , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos Endogâmicos C57BL , Camundongos Obesos , Pessoa de Meia-Idade , Tamanho do Órgão , Pâncreas/metabolismo , Pâncreas/patologia
4.
J Cell Mol Med ; 17(5): 636-47, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23577651

RESUMO

The use of the mammal target of rapamycin (mTOR) inhibitors has been consolidated as the therapy of election for preventing graft rejection in kidney transplant patients, despite their immunosuppressive activity is less strong than anti-calcineurin agents like tacrolimus and cyclosporine A. Furthermore, as mTOR is widely expressed, rapamycin (a macrolide antibiotic produced by Streptomyces hygroscopicus) is recommended in patients presenting neoplasia due to its antiproliferative actions. Hence, we have investigated whether rapamycin presents side effects in the physiology of other cell types different from leucocytes, such as platelets. Blood samples were drawn from healthy volunteers and kidney transplant patients long-term medicated with rapamycin: sirolimus and everolimus. Platelets were either loaded with fura-2 or directly stimulated, and immunoassayed or fixed with Laemmli's buffer to perform the subsequent analysis of platelet physiology. Our results indicate that rapamycin evokes a biphasic time-dependent alteration in calcium homeostasis and function in platelets from kidney transplant patients under rapamycin regime, as demonstrated by the reduction in granule secretion observed and subsequent impairment of platelet aggregation in these patients compared with healthy volunteers. Platelet count was also reduced in these patients, thus 41% of patients presented thrombocytopenia. All together our results show that long-term administration of rapamycin to kidney transplant patients evokes alteration in platelet function.


Assuntos
Plaquetas/patologia , Cálcio/metabolismo , Homeostase/efeitos dos fármacos , Transplante de Rim , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Idoso , Plaquetas/efeitos dos fármacos , Demografia , Ativação Enzimática/efeitos dos fármacos , Everolimo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Fatores de Tempo
6.
Haematologica ; 89(9): 1142-4, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15377479

RESUMO

We clearly show that plasma membrane Ca2+ ATPase (PMCA) activity is lower in platelets from patients with non-insulin-dependent diabetes mellitus (NIDDM) than in those from healthy controls. The lower activity is likely due to reduced PMCA expression and increased tyrosine phosphorylation. These findings provide an explanation for the cellular ionic defects occurring in insulin resistant conditions.


Assuntos
Plaquetas/enzimologia , ATPases Transportadoras de Cálcio/deficiência , Proteínas de Transporte de Cátions/deficiência , Diabetes Mellitus Tipo 2/sangue , Processamento de Proteína Pós-Traducional , Adulto , Plaquetas/efeitos dos fármacos , Cálcio/sangue , ATPases Transportadoras de Cálcio/sangue , ATPases Transportadoras de Cálcio/química , Proteínas de Transporte de Cátions/sangue , Proteínas de Transporte de Cátions/química , Diabetes Mellitus Tipo 2/enzimologia , Feminino , Humanos , Resistência à Insulina , Ionomicina/farmacologia , Masculino , Fosforilação , Fosfotirosina/análise , ATPases Transportadoras de Cálcio da Membrana Plasmática , Ativação Plaquetária , Tapsigargina/farmacologia
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