Translational research : the journal of laboratory and clinical medicine
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Thrombomodulin (TM) functions in coagulation, fibrinolysis and inflammation by its cofactor activity for protein C, thrombin-activatable fibrinolysis inhibitor (TAFI) activation and high mobility group box 1 (HMGB1) degradation induced by thrombin. It has been widely reported that mutations in TM are related to thromboembolic diseases but hardly in lectin domain. Here we report our findings about the functional deficiencies in TM caused by substitution of aspartate with tyrosine at residue 126. ⋯ And the study with thrombosis models of mice suggested the decreased inhibition of thrombus development of the mutant. Together the results showed deleterious changes on TM function caused by this mutation, which may explain the thrombophilia tendency of the patients. This work provided supportive evidence that mutation in lectin domain of TM might be related to thrombotic diseases and may help us better understand the physiological roles of TM.
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After an attack of pancreatitis, individuals may develop metabolic sequelae (eg, new-onset diabetes) and/or pancreatic cancer. These new-onset morbidities are, at least in part, driven by low-grade inflammation. The aim was to study the profiles of cytokines/chemokines in individuals after an attack of pancreatitis. ⋯ Pancreatitis-related factors, body composition, and other studied parameters did not differ significantly between the 2 endotypes. Individuals with a similar phenotype and clinical course of pancreatitis have differing cytokine/chemokine profiles after clinical resolution of the disease. People with the inflammatory endotype have distinct changes in the pancreatic and gut hormones known to be involved in the pathogenesis of new-onset morbidities after an attack of pancreatitis.
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Dysregulation of the splicing machinery is emerging as a hallmark in cancer due to its association with multiple dysfunctions in tumor cells. Inappropriate function of this machinery can generate tumor-driving splicing variants and trigger oncogenic actions. However, its role in pancreatic neuroendocrine tumors (PanNETs) is poorly defined. ⋯ Notably, key splicing factors were overexpressed in PanNETs samples, wherein their levels correlated with clinical and malignancy features. Using in vivo and in vitro assays, we demonstrate that one of those altered factors, NOVA1, is tightly related to cell proliferation, alters pivotal signaling pathways and interferes with responsiveness to drug treatment in PanNETs, suggesting a role for this factor in the aggressiveness of these tumors and its suitability as therapeutic target. Altogether, our results unveil a severe alteration of the splicing machinery in PanNETs and identify the putative relevance of NOVA1 in tumor development/progression, which could provide novel avenues to develop diagnostic biomarkers and therapeutic tools for this pathology.
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As the COVID-19 pandemic continues into its third year, emerging data indicates increased risks associated with SARS-CoV-2 infection during pregnancy, including pre-eclampsia, intrauterine growth restriction, preterm birth, stillbirth, and risk of developmental defects in neonates. Here, we review clinical reports to date that address different COVID-19 pregnancy complications. We also document placental pathologies induced by SARS-CoV-2 infection, entry mechanisms in placental cells, and immune responses at the maternal-fetal interface. ⋯ However, because pregnant individuals were not included in the vaccine clinical trials, some pregnant individuals have safety concerns and are hesitant to take these vaccines. We describe the recent studies that have addressed the effectiveness and safety of the current vaccines during pregnancy. This review also sheds light on important areas that need to be carefully or more fully considered with respect to understanding SARS-CoV-2 disease mechanisms of concern during pregnancy.
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Multicenter Study Observational Study
SERPINA5 may promote the development of preeclampsia by disruption of the uPA/uPAR pathway.
Preeclampsia (PE) is the leading cause of maternal and fetal morbidity or mortality but lacks reliable methods for early diagnosis. In a previous study, serum SERPINA5 levels were higher in women with PE before the clinical manifestation of the disease. This study aimed to evaluate the efficacy of SERPINA5 in predicting PE and investigate its role in trophoblast cell biology. ⋯ It also demonstrated that SERPINA5 inhibited primary EVT cell invasion by disrupting the urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor (uPA/uPAR) pathway, in turn, is involved in the development of PE. In vivo experiments also proved that overexpression of SERPINA5 induced a PE-like syndrome (hypertension and proteinuria) in pregnant rats. Therefore, serum SERPINA5 is a promising early biomarker of PE, suggesting that it may be involved in placental development through its action on the uPA/uPAR system prior to the clinical manifestation of PE.