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Translational Psychiatry Jan 2016Although different hypotheses have been formulated to explain schizophrenia pathogenesis, the links between them are weak. The observation that five psychotic patients... (Review)
Review
Although different hypotheses have been formulated to explain schizophrenia pathogenesis, the links between them are weak. The observation that five psychotic patients on chronic warfarin therapy for deep-vein thrombosis showed long-term remission of psychotic symptoms made us suspect that abnormalities in the coagulation pathway, specifically low tissue plasminogen activator (tPA) activity, could be one of the missing links. Our hypothesis is supported by a high prevalence of conditions affecting tPA activity in drug-naive schizophrenia, such as antiphospholipid antibodies, elevated cytokine levels, hyperinsulinemia and hyperhomocysteinemia. We recently screened a group of schizophrenia patients and controls for conditions affecting tPA activity. Free-protein S deficiency was highly prevalent among patients, but not found in controls. Free-protein S and functional protein C are natural anticoagulants that form complexes that inhibit tPA inhibitors. All participants had normal protein C levels, suggesting that protein S could have a role in schizophrenia, independent of protein C. Chronic patients and those studied during acute episodes had between three and six conditions affecting tPA and/or protein S activity, while patients in remission had up to two, which led us to postulate that multiple conditions affecting tPA and/or protein S activity could contribute to the full expression of schizophrenia phenotype. This paper describes the physiological roles of tPA and protein S, reviewing how their activity influences pathogenesis and comorbidity of schizophrenia. Next, it analyzes how activity of tPA and protein S is influenced by biochemical abnormalities found in schizophrenia. Last, it suggests future directions for research, such as studies on animal models and on therapeutic approaches for schizophrenia aiming at increasing tPA and protein S activity.
Topics: Blood Coagulation Disorders; Humans; Schizophrenia
PubMed: 26731441
DOI: 10.1038/tp.2015.204 -
Circulation Research May 2018
Topics: Glycogen Synthase Kinase 3 beta; Nitric Oxide; Phosphorylation; Protein S; Proteolysis
PubMed: 29798895
DOI: 10.1161/CIRCRESAHA.118.313109 -
Platelets Dec 2024Protein S (PS) is a vital endogenous anticoagulant. It plays a crucial role in regulating coagulation by acting as a cofactor for the activated protein C (APC) and... (Review)
Review
Protein S (PS) is a vital endogenous anticoagulant. It plays a crucial role in regulating coagulation by acting as a cofactor for the activated protein C (APC) and tissue factor pathway inhibitor (TFPI) pathways. Additionally, it possesses direct anticoagulant properties by impeding the intrinsic tenase and prothrombinase complexes. Protein S oversees the coagulation process in both the initiation and propagation stages through these roles. The significance of protein S in regulating blood clotting can be inferred from the significant correlation between deficits in protein S and an elevated susceptibility to venous thrombosis. This is likely because activated protein C and tissue factor pathway inhibitor exhibit low efficacy as anticoagulants when no cofactors exist. The precise biochemical mechanisms underlying the roles of protein S cofactors have yet to be fully elucidated. Nevertheless, recent scientific breakthroughs have significantly enhanced comprehension findings for these functions. The diagnosis of protein S deficiency, both from a technical and genetic standpoint, is still a subject of debate due to the complex structural characteristics of the condition. This paper will provide an in-depth review of the molecular structure of protein S and its hemostatic effects. Furthermore, we shall address the insufficiency of protein S and its methods of diagnosis and treatment.
Topics: Humans; Anticoagulants; Protein C; Blood Coagulation; Hemostatics
PubMed: 38602463
DOI: 10.1080/09537104.2024.2337907 -
British Journal of Pharmacology Apr 2018Hydrogen sulfide (H S), independently of any specific transporters, has a number of biological effects on the cardiovascular system. However, until now, the detailed... (Review)
Review
UNLABELLED
Hydrogen sulfide (H S), independently of any specific transporters, has a number of biological effects on the cardiovascular system. However, until now, the detailed mechanism of H S was not clear. Recently, a novel post-translational modification induced by H S, named S-sulfhydration, has been proposed. S-sulfhydration is the chemical modification of specific cysteine residues of target proteins by H S. There are several methods for detecting S-sulfhydration, such as the modified biotin switch assay, maleimide assay with fluorescent thiol modifying regents, tag-switch method and mass spectrometry. H S induces S-sulfhydration on enzymes or receptors (such as p66Shc, phospholamban, protein tyrosine phosphatase 1B, mitogen-activated extracellular signal-regulated kinase 1 and ATP synthase subunit α), transcription factors (such as specific protein-1, kelch-like ECH-associating protein 1, NF-κB and interferon regulatory factor-1), and ion channels (such as voltage-activated Ca channels, transient receptor potential channels and ATP-sensitive K channels) in the cardiovascular system. Although significant progress has been achieved in delineating the role of protein S-sulfhydration by H S in the cardiovascular system, more proteins with detailed cysteine sites of S-sulfhydration as well as physiological function need to be investigated in further studies. This review mainly summarizes the role and possible mechanism of S-sulfhydration in the cardiovascular system. The S-sulfhydrated proteins may be potential novel targets for therapeutic intervention and drug design in the cardiovascular system, which may accelerate the development and application of H S-related drugs in the future.
LINKED ARTICLES
This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.
Topics: Animals; Cardiovascular System; Humans; Hydrogen Sulfide; Protein Processing, Post-Translational; Protein S
PubMed: 28432761
DOI: 10.1111/bph.13825 -
Amino Acids Jan 2023Some glycoproteins contain carbohydrates S-linked to cysteine (Cys) residues. However, relatively few S-glycosylated proteins have been detected, due to the lack of an...
Some glycoproteins contain carbohydrates S-linked to cysteine (Cys) residues. However, relatively few S-glycosylated proteins have been detected, due to the lack of an effective research methodology. This work outlines a general concept for the detection of S-glycosylation sites in proteins. The approach was verified by exploratory experiments on a model mixture of β-S-glucosylated polypeptides obtained by the chemical transformation of lysozyme P00698. The model underwent two processes: (1) oxidative hydrolysis of S-glycosidic bonds under alkaline conditions to expose the thiol group of Cys residues; (2) thiol S-alkylation leading to thiol S-adduct formation at the former S-glycosylation sites. Oxidative hydrolysis was conducted in aqueous urea, dimethyl sulfoxide, or trifluoroethanol, with silver nitrate as the reaction promoter, in the presence of triethylamine and/or pyridine. The concurrent formation of stable protein silver thiolates, gluconic acid, and silver nanoclusters was observed. The essential de-metalation of protein silver thiolates using dithiothreitol preceded the S-labeling of Cys residues with 4-vinyl pyridine or a fluorescent reagent. The S-labeled model was sequenced by tandem mass spectrometry to obtain data on the modifications and their distribution over the protein chains. This enabled the efficiency of both S-glycosidic bonds hydrolysis and S-glycosylation site labeling to be evaluated. Suggestions are also given for testing this novel strategy on real proteomic samples.
Topics: Glycosylation; Cysteine; Protein S; Glycosides; Hydrolysis; Proteomics; Proteins; Oxidative Stress
PubMed: 36460841
DOI: 10.1007/s00726-022-03208-7 -
Biomedical Journal 2015Cancer is a worldwide health problem leading to a high incidence of morbidity and mortality. Malignant transformation can occur by expression of oncogenes,... (Review)
Review
Cancer is a worldwide health problem leading to a high incidence of morbidity and mortality. Malignant transformation can occur by expression of oncogenes, over-expression and deregulated activation of proto-oncogenes, and inactivation of tumor suppressor genes. These cellular actions occur through stimulation of oncogenic signaling pathways. Nitric oxide (NO) can induce genetic changes in cells and its intracellular generation can lead to tumor formation and progression. It can also promote anti-tumor activities. The pro- and anti-tumor activities of NO are dependent on its intracellular concentration, cell compartmentalization, and cell sensitivity. NO affects a number of oncogenic signaling pathways. This review focuses on two oncogenic signaling pathways: NO-EGFR-Src-FAK and NO-Ras-EGFR-ERK1/2 MAP kinases. In these pathways, low to intermediate concentrations of NO/S-nitrosothiols (RSNOs) stimulate oncogenic signaling, while high concentrations of NO/RSNO stimulate anti-oncogenic signaling. Increasing knowledge on pro- and anti-tumorigenic activities of NO and related reactive species such as RSNOs has fostered the research and synthesis of novel NO-based chemotherapeutic agents. RSNOs, effective as NO donors and trans-nitrosylating agents under appropriate conditions, may operate as potential chemotherapeutic agents.
Topics: Animals; Humans; Neoplasms; Nitric Oxide; Phosphorylation; Protein S; Signal Transduction; Tyrosine
PubMed: 26068128
DOI: 10.4103/2319-4170.158624 -
Frontiers in Plant Science 2017S-acylation, also known as S-palmitoylation or palmitoylation, is a reversible post-translational lipid modification in which long chain fatty acid, usually the... (Review)
Review
S-acylation, also known as S-palmitoylation or palmitoylation, is a reversible post-translational lipid modification in which long chain fatty acid, usually the 16-carbon palmitate, covalently attaches to a cysteine residue(s) throughout the protein via a thioester bond. It is involved in an array of important biological processes during growth and development, reproduction and stress responses in plant. S-acylation is a ubiquitous mechanism in eukaryotes catalyzed by a family of enzymes called Protein S-Acyl Transferases (PATs). Since the discovery of the first PAT in yeast in 2002 research in S-acylation has accelerated in the mammalian system and followed by in plant. However, it is still a difficult field to study due to the large number of PATs and even larger number of putative S-acylated substrate proteins they modify in each genome. This is coupled with drawbacks in the techniques used to study S-acylation, leading to the slower progress in this field compared to protein phosphorylation, for example. In this review we will summarize the discoveries made so far based on knowledge learnt from the characterization of protein S-acyltransferases and the S-acylated proteins, the interaction mechanisms between PAT and its specific substrate protein(s) in yeast and mammals. Research in protein S-acylation and PATs in plants will also be covered although this area is currently less well studied in yeast and mammalian systems.
PubMed: 28392791
DOI: 10.3389/fpls.2017.00346 -
Anales de Pediatria May 2023The objective of the study was to establish the normal range for the levels of antithrombin (AT), protein C (PC), and protein S (PS) in the first week post birth in...
INTRODUCTION
The objective of the study was to establish the normal range for the levels of antithrombin (AT), protein C (PC), and protein S (PS) in the first week post birth in mother-infant pairings, adjusting for obstetric and perinatal factors, based on 2 different laboratory methods.
METHODS
Determinations were carried out in 83 healthy term neonates and their mothers, establishing 3 postpartum age groups: 1-2 days, 3 days, and 4-7 days.
RESULTS
There were no differences in the levels of any of the proteins between the different age groups in neonates or mothers in the first week post birth. The adjusted analysis found no association with obstetric or perinatal factors. The AT and PC levels were higher in mothers compared to infants (P < .001), while the PS levels were similar in both. Overall, the correlation of maternal and infant protein values was poor, except for the levels of free PS in the first 2 days after delivery. Although we found no differences based on which of the 2 laboratory methods was applied, the absolute values did differ.
Topics: Child, Preschool; Female; Humans; Infant; Infant, Newborn; Pregnancy; Mothers; Postpartum Period; Protein C; Thrombin; Protein S; Antithrombins
PubMed: 37076369
DOI: 10.1016/j.anpede.2023.03.005 -
Nature Apr 2016Microglia are damage sensors for the central nervous system (CNS), and the phagocytes responsible for routine non-inflammatory clearance of dead brain cells. Here we...
Microglia are damage sensors for the central nervous system (CNS), and the phagocytes responsible for routine non-inflammatory clearance of dead brain cells. Here we show that the TAM receptor tyrosine kinases Mer and Axl regulate these microglial functions. We find that adult mice deficient in microglial Mer and Axl exhibit a marked accumulation of apoptotic cells specifically in neurogenic regions of the CNS, and that microglial phagocytosis of the apoptotic cells generated during adult neurogenesis is normally driven by both TAM receptor ligands Gas6 and protein S. Using live two-photon imaging, we demonstrate that the microglial response to brain damage is also TAM-regulated, as TAM-deficient microglia display reduced process motility and delayed convergence to sites of injury. Finally, we show that microglial expression of Axl is prominently upregulated in the inflammatory environment that develops in a mouse model of Parkinson's disease. Together, these results establish TAM receptors as both controllers of microglial physiology and potential targets for therapeutic intervention in CNS disease.
Topics: Animals; Apoptosis; Brain; Brain Injuries; Disease Models, Animal; Female; Inflammation; Intercellular Signaling Peptides and Proteins; Ligands; Male; Mice; Microglia; Neurogenesis; Parkinson Disease; Phagocytosis; Protein S; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Signal Transduction; Stem Cell Niche; Up-Regulation; c-Mer Tyrosine Kinase; Axl Receptor Tyrosine Kinase
PubMed: 27049947
DOI: 10.1038/nature17630 -
Frontiers in Neurology 2014
Review
PubMed: 25071708
DOI: 10.3389/fneur.2014.00120