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Scientific Reports May 2021Protein S (PS) is a multifunctional glycoprotein that ameliorates the detrimental effects of diabetes mellitus (DM). The aim of this study was to evaluate the... (Observational Study)
Observational Study
Protein S (PS) is a multifunctional glycoprotein that ameliorates the detrimental effects of diabetes mellitus (DM). The aim of this study was to evaluate the distribution of PS in diabetic retinopathy (DR) and diabetic macular edema (DME). This was a study of 50 eyes with DM (37 with DME, 6 with proliferative DR, and 7 with no DR) and 19 eyes without DM. The level of PS was measured by enzyme immunoassay and was compared between eyes with or without DM, with or without DME, and with severe DME (≥ 350 μm) or mild DME (< 350 μm). We also performed immunohistopathologic evaluations of post-mortem eyes and the cystoid lesions excised during surgery. The aqueous free PS was significantly higher with DM (7.9 ± 1.2 ng/ml, P < 0.01) than without DM (6.1 ± 0.7). The aqueous free PS was significantly elevated with DME (8.2 ± 1.2, P < 0.05) compared to proliferative DR (7.0 ± 1.0) and no DR (7.0 ± 0.7). Eyes with severe DME had significantly higher aqueous free PS than mild DME (8.5 ± 1.3 vs. 7.7 ± 1.0, P < 0.05). Immunohistochemistry showed PS in the outer plexiform layer of the retina and cystoid lesion. The higher expression of PS with DR and DME suggests that PS is involved in their pathogenesis.
Topics: Aged; Aged, 80 and over; Aqueous Humor; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Female; Humans; Macular Edema; Male; Middle Aged; Protein S; Retina; Severity of Illness Index; Tomography, Optical Coherence
PubMed: 34001977
DOI: 10.1038/s41598-021-89870-5 -
Research and Practice in Thrombosis and... Feb 2022Low plasma levels of protein C or protein S are associated with venous thromboembolism rather than myocardial infarction. The high coagulant activity in patients with...
BACKGROUND
Low plasma levels of protein C or protein S are associated with venous thromboembolism rather than myocardial infarction. The high coagulant activity in patients with thrombophilia with a (familial) defect in protein C or S is explained by defective protein C activation, involving thrombomodulin and protein S. This causes increased plasmatic thrombin generation.
OBJECTIVE
Assess the role of platelets in the thrombus- and fibrin-forming potential in patients with familial protein C or protein S deficiency under high-shear flow conditions.
PATIENTS/METHODS
Whole blood from 23 patients and 15 control subjects was perfused over six glycoprotein VI-dependent microspot surfaces. By real-time multicolor microscopic imaging, kinetics of platelet thrombus and fibrin formation were characterized in 49 parameters.
RESULTS AND CONCLUSION
Whole-blood flow perfusion over collagen, collagen-like peptide, and fibrin surfaces with low or high GPVI dependency indicated an unexpected impairment of platelet activation, thrombus phenotype, and fibrin formation but unchanged platelet adhesion, observed in patients with protein C deficiency and to a lesser extent protein S deficiency, when compared to controls. The defect extended from diminished phosphatidylserine exposure and thrombus contraction to delayed and suppressed fibrin formation. The mechanism was thrombomodulin independent, and may involve negative platelet priming by plasma components.
PubMed: 35284776
DOI: 10.1002/rth2.12678 -
Current Neuropharmacology 2021Hydrogen sulfide (H2S) and hydrogen polysulfides are recognized as important signaling molecules that are generated physiologically in the body, including the central... (Review)
Review
Hydrogen sulfide (H2S) and hydrogen polysulfides are recognized as important signaling molecules that are generated physiologically in the body, including the central nervous system (CNS). Studies have shown that these two molecules are involved in cytoprotection against oxidative stress and inflammatory response. In the brain system, H2S and polysulfides exert multiple functions in both health and diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), memory decline, and glioma. Mechanistically, S-Persulfidation (also known as S-sulfuration or S-sulfhydration) of target proteins is believed to be a fundamental mechanism that underlies H2S-regulated signaling pathways. Cysteine S-Persulfidation is an important paradigm of post translational protein modification in the process of H2S signaling. This model is established as a critical redox mechanism to regulate numerous biological functions, especially in H2S-mediated neuroprotection and neurogenesis. Although the current research of S-Persulfidation is still in its infancy, accumulative evidence suggests that protein S-Persulfidation may share similar characteristics with protein S-nitrosylation. In this review, we will provide a comprehensive insight into the S-Persulfidation biology of H2S and polysulfides in neurological ailments and presume potential avenues for therapeutic development in these disorders based on S-Persulfidation of target proteins.
Topics: Cysteine; Humans; Hydrogen Sulfide; Nervous System Diseases; Protein S; Sulfides
PubMed: 32888271
DOI: 10.2174/1570159X18666200905143550 -
Biomolecules Apr 2022Human S100B is a small, multifunctional protein. Its activity, inside and outside cells, contributes to the biology of the brain, muscle, skin, and adipocyte tissues....
Human S100B is a small, multifunctional protein. Its activity, inside and outside cells, contributes to the biology of the brain, muscle, skin, and adipocyte tissues. Overexpression of S100B occurs in Down Syndrome, Alzheimer's disease, Creutzfeldt-Jakob disease, schizophrenia, multiple sclerosis, brain tumors, epilepsy, melanoma, myocardial infarction, muscle disorders, and sarcopenia. Modulating the activities of S100B, related to human diseases, without disturbing its physiological functions, is vital for drug and therapy design. This work focuses on the extracellular activity of S100B and one of its receptors, the Receptor for Advanced Glycation End products (RAGE). The functional outcome of extracellular S100B, partially, depends on the activation of intracellular signaling pathways. Here, we used Biotin Switch Technique enrichment and mass-spectrometry-based proteomics to show that the appearance of the S100B protein in the extracellular milieu of the mammalian Chinese Hamster Ovary (CHO) cells, and expression of the membrane-bound RAGE receptor, lead to changes in the intracellular S-nitrosylation of, at least, more than a hundred proteins. Treatment of the wild-type CHO cells with nanomolar or micromolar concentrations of extracellular S100B modulates the sets of S-nitrosylation targets inside cells. The cellular S-nitrosome is tuned differently, depending on the presence or absence of stable RAGE receptor expression. The presented results are a proof-of-concept study, suggesting that S-nitrosylation, like other post-translational modifications, should be considered in future research, and in developing tailored therapies for S100B and RAGE receptor-related diseases.
Topics: Animals; CHO Cells; Cricetinae; Cricetulus; Humans; Protein S; Receptor for Advanced Glycation End Products; Receptors, Immunologic; S100 Calcium Binding Protein beta Subunit
PubMed: 35625541
DOI: 10.3390/biom12050613 -
BMC Nephrology May 2019Thrombophilia due to protein C (PC) and protein S (PS) deficiencies is highly prevalent among patients with stage 5 chronic kidney disease and is reported to arise due...
BACKGROUND
Thrombophilia due to protein C (PC) and protein S (PS) deficiencies is highly prevalent among patients with stage 5 chronic kidney disease and is reported to arise due to extracorporeal circulation during hemodialysis (HD). This study aimed to evaluate the relationship between HD treatment and thrombophilia.
METHODS
A total of 114 Japanese patients on maintenance HD (62 men, 52 women) were followed during 2008-2011. Their survival rates were compared against the duration of HD. Prior to each HD, coagulation/fibrinolysis parameters and PC and PS activities were measured using standard techniques. The patients were divided into two groups: Group 1, with PC and/or PS deficiencies (n = 32), and Group 2, without PC and PS deficiencies (n = 82). The influence of such deficiencies and duration of dialysis on survival was examined. Time-to-event analysis was applied using Kaplan-Meier estimates, and the log-rank test was proposed to test the equivalence of relative survival data. Hazard ratios and 95% confidence intervals (CI) were calculated.
RESULTS
Of the 114 patients, 37 died (Group 1, 22; Group 2, 15). The hazard ratio (95% CI) was higher (p = 0.004) in Group 1 than Group 2. Gene analyses of PC and PS were performed in 14 patients from Group 1. No mutations in either protein were observed. We analyzed the causes of death in both groups; however, the estimated thrombophilia-related incidence of death could not be determined due to small sample size of HD patients.
CONCLUSIONS
Our results suggest that PC and PS deficiencies may be related to survival in HD patients. However, this finding warrants additional research.
Topics: Aged; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Male; Middle Aged; Protein C Deficiency; Protein S Deficiency; Renal Dialysis; Survival Rate
PubMed: 31138132
DOI: 10.1186/s12882-019-1344-8 -
Biomolecules Mar 2022Covalent binding between nitric oxide (NO) and a protein's free thiol group (SH) is termed protein S-nitrosylation. Protein S-nitrosylation is involved in cellular...
Covalent binding between nitric oxide (NO) and a protein's free thiol group (SH) is termed protein S-nitrosylation. Protein S-nitrosylation is involved in cellular regulation mechanisms that underlie a wide range of critical functions, such as apoptosis, alteration of enzyme activities, and transcription-factor stability. Impaired protein S-nitrosylation is associated with a growing list of pathophysiological conditions, such as cardiovascular disease, multiple sclerosis, pulmonary hypertension, and sickle cell disease. The enzyme paraoxonase 1 (PON1) binds to high-density lipoprotein to provide many of its antiatherogenic properties. The enzyme has a strong antioxidant capacity, which protects fats, lipids, and lipoproteins from oxidation, in addition to breaking down oxidized fats. We investigated the effect of S-S transnitrosylation on PON1 activities. Incubation of recombinant PON1 (rePON1) with nitrosylated human serum albumin (HSA-NO) resulted in S-nitrosylation of about 70% of the rePON1, as measured by Q-TOF LC/MS. S-nitrosylation significantly increased rePON1 hydrolytic activities. It also increased rePON1's ability to inhibit low-density lipoprotein oxidation induced by Cu. Finally, it increased the enzyme's penetration into macrophage cells by 31%. Our findings suggest that S-nitrosylation of rePON1 improves its biological functions which may positively affect atherosclerosis disease progression.
Topics: Antioxidants; Aryldialkylphosphatase; Humans; Lipoproteins, HDL; Lipoproteins, LDL; Protein S
PubMed: 35327606
DOI: 10.3390/biom12030414 -
Oral Diseases Nov 2017All living tissues require essential nutrients such as amino acids, fatty acids, carbohydrates, minerals, vitamins, and water. The skeleton requires nutrients for... (Review)
Review
All living tissues require essential nutrients such as amino acids, fatty acids, carbohydrates, minerals, vitamins, and water. The skeleton requires nutrients for development, maintaining bone mass and density. If the skeletal nutritional requirements are not met, the consequences can be quite severe. In recent years, there has been growing interest in promotion of bone health and inhibition of vascular calcification by vitamin K2. This vitamin regulates bone remodeling, an important process necessary to maintain adult bone. Bone remodeling involves removal of old or damaged bone by osteoclasts and its replacement by new bone formed by osteoblasts. The remodeling process is tightly regulated, when the balance between bone resorption and bone formation shifts to a net bone loss results in the development of osteoporosis in both men and women. In this review, we focus on our current understanding of the effects of vitamin K2 on bone cells and its role in prevention and treatment of osteoporosis.
Topics: Animals; Bone Development; Bone Remodeling; Bone and Bones; Calcium-Binding Proteins; Extracellular Matrix Proteins; Humans; Osteoblasts; Osteocalcin; Osteoclasts; Osteocytes; Protein S; Vitamin K 2; Matrix Gla Protein
PubMed: 27976475
DOI: 10.1111/odi.12624 -
Open Biology Apr 2022Protein S-acylation, more commonly known as protein palmitoylation, is a biological process defined by the covalent attachment of long chain fatty acids onto cysteine... (Review)
Review
Protein S-acylation, more commonly known as protein palmitoylation, is a biological process defined by the covalent attachment of long chain fatty acids onto cysteine residues of a protein, effectively altering the local hydrophobicity and influencing its stability, localization and overall function. Observed ubiquitously in all eukaryotes, this post translational modification is mediated by the 23-member family of zDHHC protein acyltransferases in mammals. There are thousands of proteins that are S-acylated and multiple zDHHC enzymes can potentially act on a single substrate. Since its discovery, numerous methods have been developed for the identification of zDHHC substrates and the individual members of the family that catalyse their acylation. Despite these recent advances in assay development, there is a persistent gap in knowledge relating to zDHHC substrate specificity and recognition, that can only be thoroughly addressed through reconstitution. Herein, we will review the various methods currently available for reconstitution of protein S-acylation for the purposes of identifying enzyme-substrate pairs with a particular emphasis on the advantages and disadvantages of each approach.
Topics: Acetyltransferases; Acylation; Animals; Mammals; Protein Processing, Post-Translational; Protein S; Substrate Specificity
PubMed: 35414257
DOI: 10.1098/rsob.210390 -
Yakugaku Zasshi : Journal of the... 2016Nitric oxide (NO) plays a pivotal function in neurotransmission, vasodilation, proliferation, and apoptosis in various types of cells via protein S-nitrosylation.... (Review)
Review
Nitric oxide (NO) plays a pivotal function in neurotransmission, vasodilation, proliferation, and apoptosis in various types of cells via protein S-nitrosylation. Previously we demonstrated that protein disulfide isomerase (PDI) is S-nitrosylated in brains manifesting sporadic neurodegenerative diseases. This modification results in dysfunction of its enzymatic activity and consequently the accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER). The aim of this study was to clarify the detailed function of NO on unfolded protein response (UPR) branches. We here found that the ER stress sensor IRE1α is S-nitrosylated. Interestingly, NO specifically abrogates ribonuclease activity, but not oligomerization or autophosphorylation of IRE1α. Site-directed mutagenesis revealed that Cys 931 and Cys951 in IRE1 are targets for S-nitrosylation. These mutants expressing in IRE1α knockout MEF showed a resistant role to the inhibition of nuclease activity by NO. Thus, we elucidated the effects of S-nitrosylation on ER stress sensors that mediate the UPR, and thus contribute to cell death pathways.
Topics: Animals; Apoptosis; Brain; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Endoribonucleases; Mutagenesis, Site-Directed; Neurodegenerative Diseases; Nitric Oxide; Protein Disulfide-Isomerases; Protein S; Protein Serine-Threonine Kinases; Ribonucleases; Unfolded Protein Response
PubMed: 27252058
DOI: 10.1248/yakushi.15-00292-1 -
Cureus Oct 2023Protein S is a glycoprotein created by the body that aids in the prevention of a hypercoagulable state. Protein S-deficient patients are placed on anticoagulant...
Protein S is a glycoprotein created by the body that aids in the prevention of a hypercoagulable state. Protein S-deficient patients are placed on anticoagulant regimens, as there is no current definitive cure. Failure to bring balance to the hematological system in these patients will lead to complications such as widespread clot formation and pulmonary embolisms. Here, we present a 74-year-old female who was admitted to the ICU after collapsing. She presented with respiratory failure, urinary tract infection (UTI), and pneumonia. Magnetic resonance imaging (MRI) scans depicted a thrombus in the distal right transverse sinus and sigmoid sinus. Her hematologic workup showed normal levels of homocysteine, fibrinogen, and protein C levels but protein S levels were reduced to 24%. This case displays the intricate presentation of a rare hematological disease as well as the importance of routine follow-up to maintain patient health.
PubMed: 37954832
DOI: 10.7759/cureus.46864