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Indian Journal of Hematology & Blood... Jun 2015We carried out a retrospective cohort study to construct reference ranges for free protein S (FPS) levels during pregnancy and identify any conditions or factors that...
We carried out a retrospective cohort study to construct reference ranges for free protein S (FPS) levels during pregnancy and identify any conditions or factors that may affect FPS levels. Patients that were ordered thrombophilia screening tests during gestational period were identified. Patients demonstrated to have hereditary or acquired thrombophilia were excluded. Reference ranges were constructed using regression analysis. Outcome of the index pregnancy and pregnancy complications was used to identify any confounding factors. A total of 455 pregnant women were included. The quadratic equation for FPS according to gestational age (GA) was [75.497 + (-1.516*GA) + 0.018*GA*GA]. FPS level and GA were negatively correlated (Spearmans rho statistic [rs] = -0.436, p = 0.001). FPS level and fetal growth restriction (FGR) were negatively correlated ([rs] = -0.093, p = 0.049). FPS level and placental abruption were positively correlated ([rs] = 0.098, p = 0.039). Stepwise linear regression model constructed to predict FPS level with gestational age, placental abruption and FGR as the predictor variables. Gestational age was the only variable retaining statistically significant relation with FPS level (χ(2) = 0.216, df = 3, p = 0.001). FPS levels decrease significantly throughout gestation in gravidas without hereditary and/or acquired thrombophilias. In patients without thrombophilia FPS levels are not associated with pregnancy complications. The obtained reference intervals may be useful for the clinicians ordering FPS during pregnancy.
PubMed: 25825574
DOI: 10.1007/s12288-014-0448-3 -
Redox Biology May 2020The pathogenesis of many human diseases has been attributed to the over production of reactive oxygen species (ROS), particularly superoxide (O) and hydrogen peroxide... (Review)
Review
The pathogenesis of many human diseases has been attributed to the over production of reactive oxygen species (ROS), particularly superoxide (O) and hydrogen peroxide (HO), by-products of metabolism that are generated by the premature reaction of electrons with molecular oxygen (O) before they reach complex IV of the respiratory chain. To date, there are 32 known ROS generators in mammalian cells, 16 of which reside inside mitochondria. Importantly, although these ROS are deleterious at high levels, controlled and temporary bursts in HO production is beneficial to mammalian cells. Mammalian cells use sophisticated systems to take advantage of the second messaging properties of HO. This includes controlling its availability using antioxidant systems and negative feedback loops that inhibit the genesis of ROS at sites of production. At its core, ROS production depends on fuel metabolism. Therefore, desensitizing HO signals would also require the temporary inhibition of fuel combustion and fluxes through metabolic pathways that promote ROS production. Additionally, this would also demand the diversion of fuels and nutrients into pathways that generate NADPH and other molecules required to maintain cellular redox buffering capacity. Therefore, fuel selection and metabolic flux plays an integral role in dictating the strength and duration of cellular redox signals. In the present review I provide an updated view on the function of protein S-glutathionylation, a ubiquitous redox sensitive modification involving the formation of a disulfide between the small molecular antioxidant glutathione and a cysteine residue, in the regulation of cellular metabolism on a global scale. To date, these concepts have mostly been reviewed at the level of mitochondrial bioenergetics in the contexts of health and disease. Careful examination of the literature revealed that glutathionylation is a temporary inhibitor of most metabolic pathways including glycolysis, the Krebs cycle, oxidative phosphorylation, amino acid metabolism, and fatty acid combustion, resulting in the diversion of fuels towards NADPH-producing pathways and the inhibition of ROS production. Armed with this information, I propose that protein S-glutathionylation reactions desensitize HO signals emanating from catabolic pathways using a three-pronged regulatory mechanism; 1) inhibition of metabolic flux through pathways that promote ROS production, 2) diversion of metabolites towards pathways that support antioxidant defenses, and 3) direct inhibition of ROS-generating enzymes.
Topics: Animals; Humans; Hydrogen Peroxide; Oxidation-Reduction; Protein S; Reactive Oxygen Species; Superoxides
PubMed: 32171726
DOI: 10.1016/j.redox.2020.101472 -
Polish Archives of Internal Medicine Aug 2017INTRODUCTION Inherited deficiencies of natural anticoagulants such as antithrombin (AT; gene: SERPINC1), protein C (PC; PROC), and protein S (PS; PROS1), with the...
INTRODUCTION Inherited deficiencies of natural anticoagulants such as antithrombin (AT; gene: SERPINC1), protein C (PC; PROC), and protein S (PS; PROS1), with the prevalence in the general European population of 0.02% to 0.17%, 0.2% to 0.3%, and 0.5%, respectively, are associated with increased risk of thromboembolic events. Only a few case reports of Polish deficient patients with known causal mutations have been published so far. OBJECTIVES The aim of the study was to characterize the frequency of SERPINC1, PROC, and PROS1 mutations and their thromboembolic manifestations in patients with AT, PC, or PS deficiencies, inhabiting southern Poland. PATIENTS AND METHODS Ninety unrelated patients (mean [SD] age, 40.1 [13.2] years) with AT (n = 35), PC (n = 28), or PS (n = 27) deficiencies, with a history of venous 73 (81%) or arterial 17 (19%) thromboembolism, were screened for mutations using the Sanger sequencing or multiplex ligation‑dependent probe amplification. RESULTS Twenty mutations (29%) described here were new, mostly in the SERPINC1 and PROC genes. Missense mutations accounted for 84% of all mutations in the PROC gene and approximately 50% of those in the SERPINC1 and PROS1 genes. In all 3 genes, the ratio of nonsense and splice-site mutations was 8% to 31% and 8% to 23%, respectively. The mutation detection rate was 90% for AT or PC when anticoagulant activity was below 70%, while for the PROS1 gene, the rate reached 80% at the free PS levels below 40%. CONCLUSIONS To our knowledge, this is the largest cohort of Polish patients deficient in natural anticoagulants and evaluated for the causal genetic background. Several new Polish detrimental mutations were detected, mostly in AT- and PC‑deficient patients.
Topics: Adolescent; Adult; Aged; Antithrombin III; Antithrombin III Deficiency; Blood Protein Disorders; Blood Proteins; DNA Mutational Analysis; Female; Humans; Male; Middle Aged; Mutation; Mutation, Missense; Poland; Protein C; Protein C Deficiency; Protein S; Protein S Deficiency; Young Adult
PubMed: 28607330
DOI: 10.20452/pamw.4045 -
Thrombosis Journal Sep 2021Protein S deficiency (PSD) is an autosomal dominant hereditary disease. In 1984, familial PSD was reported to be prone to recurrent thrombosis. Follow-up studies have...
BACKGROUND
Protein S deficiency (PSD) is an autosomal dominant hereditary disease. In 1984, familial PSD was reported to be prone to recurrent thrombosis. Follow-up studies have shown that heterozygous protein S (PROS1) mutations increase the risk of thrombosis. More than 300 PROS1 mutations have been identified; among them, only a small number of mutations have been reported its possible mechanism to reduce plasma protein S (PS) levels. However, whether PROS1 mutations affect protein structure and why it can induce PSD remains unknown.
METHODS
The clinical phenotypes of the members of a family with thrombosis were collected. Their PS activity was measured using the coagulation method, whereas their protein C and antithrombin III activities were measured using methods such as the chromogenic substrate method. The proband and her parents were screened for the responsible mutation using second-generation whole exon sequencing, and the members of the family were verified for suspected mutations using Sanger sequencing. Mutant and wild type plasmids were constructed and transfected into HEK293T cells to detect the mRNA and protein expression of PROS1.
RESULTS
In this family, the proband with venous thrombosis of both lower extremities, the proband's mother with pulmonary embolism and venous thrombosis of both lower extremities, and the proband's younger brother had significantly lower PS activity and carried a PROS1 c. 1820 T > C:p.Leu607Ser heterozygous mutation (NM_000313.3). However, no such mutations were found in family members with normal PS activity. The PS expression in the cell lysate and supernatant of the Leu607Ser mutant cells decreased, while mRNA expression increased. Immunofluorescence localization showed that there was no significant difference in protein localization before and after mutation.
CONCLUSIONS
The analysis of family phenotype, gene association, and cell function tests suggest that the PROS1 Leu607Ser heterozygous mutation may be a pathogenic mutation. Serine substitution causes structural instability of the entire protein. These data indicate that impaired PS translation and synthesis or possible secretion impairment is the main pathogenesis of this family with hereditary PSD and thrombophilia.
PubMed: 34496879
DOI: 10.1186/s12959-021-00316-4 -
PloS One 2015Asthma is a chronic inflammatory disorder of the airways, involving oxidative stress. Upon oxidative stress, glutathione covalently binds to protein thiols to protect...
INTRODUCTION
Asthma is a chronic inflammatory disorder of the airways, involving oxidative stress. Upon oxidative stress, glutathione covalently binds to protein thiols to protect them against irreversible oxidation. This posttranslational modification, known as protein S-glutathionylation, can be reversed by glutaredoxin 1 (Glrx1) under physiological condition. Glrx1 is known to increase in the lung tissues of a murine model of allergic airway inflammation. However, the temporal relationship between levels of Glrx1, protein S-glutathionylation, and glutathione in the lungs with allergic airway inflammation is not clearly understood.
METHODS
BALB/c mice received 3 aerosol challenges with ovalbumin (OVA) following sensitization to OVA. They were sacrificed at 6, 24, 48, or 72 h, or 8 days (5 mice per group), and the levels of Glrx1, protein S-glutathionylation, glutathione, and 25 cytokines/chemokines were evaluated in bronchoalveolar lavage fluid (BALF) and/or lung tissue.
RESULTS
Levels of Glrx1 in BALF were significantly elevated in the OVA 6 h (final challenge) group compared to those in the control, with concurrent increases in protein S-glutathionylation levels in the lungs, as well as total glutathione (reduced and oxidized) and oxidized glutathione in BALF. Protein S-glutathionylation levels were attenuated at 24 h, with significant increases in Glrx1 levels in lung tissues at 48 and 72 h. Glrx1 in alveolar macrophages was induced after 6 h. Glrx1 levels concomitantly increased with Th2/NF-κB-related cytokines and chemokines in BALF.
CONCLUSIONS
The temporal relationships of Glrx1 with protein S-glutathionylation, glutathione, and cytokines/chemokines were observed as dynamic changes in lungs with allergic airway inflammation, suggesting that Glrx1 and protein-SSG redox status may play important roles in the development of allergic airway inflammation.
Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Glutaredoxins; Glutathione; Humans; Inflammation; Lung; Macrophages, Alveolar; Mice; Oxidative Stress
PubMed: 25874776
DOI: 10.1371/journal.pone.0122986 -
Cureus Jan 2023The dual coagulation disorder hereditary protein S deficiency and activated protein C (APC) resistance, which clinically manifests with recurrent venous thrombosis and...
The dual coagulation disorder hereditary protein S deficiency and activated protein C (APC) resistance, which clinically manifests with recurrent venous thrombosis and multifocal ischemic stroke, has only rarely been reported in the same patient. The patient is a 54-year-old male with a history of recurrent, asymptomatic ischemic stroke or transient ischemic attack (TIA) since age 14 and four episodes of deep vein thromboses (DVT), two complicated by pulmonary embolism, attributed to hereditary protein S deficiency and homozygous factor V Leiden mutation. In addition, the medical history was positive for obesity, previous chronic alcoholism, smoking, gynecomastia with left breast resection, arterial hypertension, hepatic steatosis, and cholecystolithiasis. Because of low compliance, long-term oral anticoagulation with phenprocoumon from the age of 38 was replaced by dabigatran (300 mg/d) after another stroke with bleeding at the age of 54. In summary, the simultaneous presence of two hereditary coagulation disorders can lead to multiple venous thromboses and recurrent ischemic stroke. An appealing therapeutic option in poorly compliant patients with these two hereditary clotting defects is the replacement of long-term anticoagulation with a vitamin K antagonist (VKA) by a direct oral anticoagulant.
PubMed: 36824536
DOI: 10.7759/cureus.34012 -
Redox Biology Jun 2023Oxidative stress drives protein S-glutathionylation, which regulates the structure and function of target proteins and is implicated in the pathogenesis of many...
Glutaredoxin 1 protects lens epithelial cells from epithelial-mesenchymal transition by preventing casein kinase 1α S-glutathionylation during posterior capsular opacification.
Oxidative stress drives protein S-glutathionylation, which regulates the structure and function of target proteins and is implicated in the pathogenesis of many diseases. Glutaredoxin 1 (Grx1), a cytoplasmic deglutathionylating enzyme, maintains a reducing environment within the cell under various conditions by reversing S-glutathionylation. Grx1 performs a wide range of antioxidant activities in the lens and prevents protein-thiol mixed disulfide accumulation, reducing protein-protein aggregation, insolubilization, and apoptosis of lens epithelial cells. Oxidative stress is related to epithelial-mesenchymal transition (EMT) during posterior capsular opacification (PCO). However, whether Grx1-regulated protein S-glutathionylation plays an essential role in PCO remains unclear. In this study, we revealed that Grx1 expression was decreased in mice following cataract surgery. Furthermore, the absence of Grx1 elevated oxidative stress and protein S-glutathionylation and aggravated EMT in both in vitro and in vivo models. Concurrently, these results could be reversed by Grx1 overexpression. Notably, liquid chromatography-tandem mass spectrometry results showed that casein kinase 1α (CK1α) was susceptible to S-glutathionylation under oxidative stress, and CK1α S-glutathionylation (CK1α-SSG) was mediated at Cys249. The absence of Grx1 upregulated CK1α-SSG, subsequently decreasing the CK1α-induced phosphorylation of β-catenin at Ser45. The consequential downregulation of degradative β-catenin and upregulation of its nuclear translocation activated the Wnt/β-catenin signaling pathway and aggravated EMT. In conclusion, the downregulated expression of Grx1 in mice following cataract surgery aggravated EMT by upregulating the extent of CK1α-SSG. To the best of our knowledge, our study is the first to report how S-glutathionylation regulates CK1α activity under oxidative stress.
Topics: Animals; Mice; beta Catenin; Casein Kinases; Cataract; Epithelial Cells; Epithelial-Mesenchymal Transition; Glutaredoxins; Glutathione; Protein S
PubMed: 36989576
DOI: 10.1016/j.redox.2023.102676 -
Journal of Thrombosis and Haemostasis :... Aug 2016Essentials Epithelial cell apoptosis is critical in the pathogenesis of idiopathic pulmonary fibrosis. Protein S, a circulating anticoagulant, inhibited apoptosis of...
UNLABELLED
Essentials Epithelial cell apoptosis is critical in the pathogenesis of idiopathic pulmonary fibrosis. Protein S, a circulating anticoagulant, inhibited apoptosis of lung epithelial cells. Overexpression of protein S in lung cells reduced bleomycin-induced pulmonary fibrosis. Intranasal therapy with exogenous protein S ameliorated bleomycin-induced pulmonary fibrosis.
SUMMARY
Background Pulmonary fibrosis is the terminal stage of interstitial lung diseases, some of them being incurable and of unknown etiology. Apoptosis plays a critical role in lung fibrogenesis. Protein S is a plasma anticoagulant with potent antiapoptotic activity. The role of protein S in pulmonary fibrosis is unknown. Objectives To evaluate the clinical relevance of protein S and its protective role in pulmonary fibrosis. Methods and Results The circulating level of protein S was measured in patients with pulmonary fibrosis and controls by the use of enzyme immunoassays. Pulmonary fibrosis was induced with bleomycin in transgenic mice overexpressing human protein S and wild-type mice, and exogenous protein S or vehicle was administered to wild-type mice; fibrosis was then compared in both models. Patients with pulmonary fibrosis had reduced circulating levels of protein S as compared with controls. Inflammatory changes, the levels of profibrotic cytokines, fibrosis score, hydroxyproline content in the lungs and oxygen desaturation were significantly reduced in protein S-transgenic mice as compared with wild-type mice. Wild-type mice treated with exogenous protein S showed significant decreases in the levels of inflammatory and profibrotic markers and fibrosis in the lungs as compared with untreated control mice. After bleomycin infusion, mice overexpressing human protein S showed significantly low caspase-3 activity, enhanced expression of antiapoptotic molecules and enhanced Akt and Axl kinase phosphorylation as compared with wild-type counterparts. Protein S also inhibited apoptosis of alveolar epithelial cells in vitro. Conclusions These observations suggest clinical relevance and a protective role of protein S in pulmonary fibrosis.
Topics: A549 Cells; Aged; Animals; Apoptosis; Bleomycin; Blood Proteins; Bronchoalveolar Lavage Fluid; Caspase 3; Epithelial Cells; Female; Fibrosis; Gene Expression Profiling; Humans; Idiopathic Pulmonary Fibrosis; Immunoenzyme Techniques; Inflammation; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Phosphorylation; Protein S
PubMed: 27172994
DOI: 10.1111/jth.13362 -
Journal of Cardiology Mar 2018It is well known that warfarin inhibits the synthesis of vitamin K-dependent anticoagulants, including thrombin, protein C and S, and factor Xa, leading, paradoxically,...
BACKGROUND
It is well known that warfarin inhibits the synthesis of vitamin K-dependent anticoagulants, including thrombin, protein C and S, and factor Xa, leading, paradoxically, to an initial hypercoagulable state. Edoxaban, a direct inhibitor of activated factor X is widely used for the treatment of acute venous thromboembolism (VTE). However, the effect of edoxaban on circulating coagulation factors, in patients with acute VTE, remains unknown.
METHODS AND RESULTS
We enrolled 57 patients with acute VTE with/without pulmonary embolism treated with edoxaban (n=37) or warfarin (n=20) in a clinical setting. Before treatment and 2 weeks after treatment, we evaluated thrombotic burden using ultrasound or computed tomography angiography. We also evaluated thrombin generation, represented by prothrombin fragment F1+2; thrombus degradation, represented by D-dimer; and levels of anticoagulants, including protein C, protein S, and antithrombin III. Both edoxaban and warfarin treatment improved thrombotic burden and decreased prothrombin fragment F1+2, and D-dimer. Edoxaban treatment preserved protein C and protein S levels. In contrast, warfarin decreased protein C and protein S levels. Neither treatment affected antithrombin III.
CONCLUSIONS
Edoxaban improves VTE while preserving protein C and protein S levels, thereby indicating that edoxaban improves thrombotic burden while maintaining levels of anticoagulants.
Topics: Acute Disease; Aged; Anticoagulants; Antithrombin III; Female; Humans; Male; Middle Aged; Protein C; Protein S; Pulmonary Embolism; Pyridines; Thiazoles; Treatment Outcome; Venous Thromboembolism; Warfarin
PubMed: 29100817
DOI: 10.1016/j.jjcc.2017.09.009 -
JSM Biochemistry and Molecular Biology 2016Protein S (PS), a γ-carboxyglutamate-containing serum protein, was unexpectedly discovered in 1977. Soon after its discovery, PS gained the attention of researchers...
Protein S (PS), a γ-carboxyglutamate-containing serum protein, was unexpectedly discovered in 1977. Soon after its discovery, PS gained the attention of researchers because of its physiological importance, acting as a multifunctional protein at the intersection of blood coagulation, inflammation, and other cellular processes. Protein S functions as an anticoagulant by directly inhibiting procoagulants, such as Factor Xa (FXa), FVa, and FIXa, while also serving as a cofactor for anticoagulants such as Activated Protein C and Tissue Factor Pathway Inhibitor. By associating with C4b binding protein (C4BP), PS has also been shown to minimize the effect of inflammation. Finally, PS promotes efferocytosis through TAM family protein kinase receptors. Mutations in the PS gene cause pathological conditions such as deep vein thrombosis and hereditary ischemia. In this review, we summarize studies regarding the multiple functions of PS.
PubMed: 29854880
DOI: No ID Found