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Nutrients Jul 2021Dietary protamine can ameliorate hyperlipidemia; however, the protamine-derived active peptide and its hypolipidemic mechanism of action are unclear. Here, we report the...
Dietary protamine can ameliorate hyperlipidemia; however, the protamine-derived active peptide and its hypolipidemic mechanism of action are unclear. Here, we report the discovery of a novel anti-obesity and hypocholesterolemic peptide, RPR (Arg-Pro-Arg), derived from protamine in mice fed a high-fat diet for 50 days. Serum cholesterol levels were significantly lower in the protamine and RPR groups than in the control group. White adipose tissue weight was significantly decreased in the protamine and RPR groups. The fecal excretion of cholesterol and bile acid was significantly higher in the protamine and RPR groups than in the control group. We also observed a significant decrease in the expression of hepatic SCD1, SREBP1, and adipocyte FAS mRNA, and significantly increased expression of hepatic PPARα and adipocyte PPARγ1 mRNA in the protamine group. These findings demonstrate that the anti-obesity effects of protamine are linked to the upregulation of adipocyte PPARγ1 and hepatic PPARα and the downregulation of hepatic SCD1 via SREBP1 and adipocyte FAS. RPR derived from protamine has a crucial role in the anti-obesity action of protamine by evaluating the effective dose of adipose tissue weight loss.
Topics: Adipose Tissue, White; Adiposity; Animals; Anti-Obesity Agents; Anticholesteremic Agents; Biomarkers; Cholesterol; Diet, High-Fat; Disease Models, Animal; Fatty Acid Synthase, Type I; Liver; Male; Mice, Inbred C57BL; Obesity; Oligopeptides; PPAR alpha; PPAR gamma; Protamines; Stearoyl-CoA Desaturase; Sterol Regulatory Element Binding Protein 1; Weight Loss; Mice
PubMed: 34444660
DOI: 10.3390/nu13082501 -
EJHaem Feb 2022In this prospective, single-centre observational study of 30 patients undergoing cardiopulmonary bypass (CPB), the effect of unfractionated heparin (UFH), CPB surgery...
In this prospective, single-centre observational study of 30 patients undergoing cardiopulmonary bypass (CPB), the effect of unfractionated heparin (UFH), CPB surgery and protamine sulphate on complement and on post-operative blood loss were assessed. Although C3 and C4 levels decreased significantly immediately following the administration of UFH, C3a, C5a, Bb fragment and SC5b-9 remained unchanged. During CPB, C3 and C4 continued to fall whilst both alternative and classical pathways activation markers, Bb, C3a, C5a and SC5b-9 increased significantly. Protamine sulphate had no effect on classical pathway components or activation markers but decreased alternative pathway activation marker Bb. Over the 12-24 h post-surgery, both classical and alternative pathway activation markers returned to baseline, whilst C3 and C4 levels increased significantly but not to baseline values. Total drain volume 24 h after the surgery showed a moderate inverse correlation with post-protamine C3 ( = -0.46, = 0.01) and C4 ( = -0.57, = 0.0009) levels, whilst a moderate positive correlation was observed with post-protamine C3a ( = 0.46, = 0.009), C5a ( = 0.37, = 0.04) and SC5b-9 ( = 0.56, = 0.001) levels but not with Bb fragment ( = 0.25, = 0.17). Thus, inhibition of complement activation may be a therapeutic intervention to reduce post-operative blood in patients undergoing CPB.
PubMed: 35846208
DOI: 10.1002/jha2.371 -
Journal of Thrombosis and Haemostasis :... Oct 2018Essentials Heparin-protamine balance (HPB) modulates bleeding after neonatal cardiopulmonary bypass (CPB). HPB was examined in 44 neonates undergoing CPB. Post-operative... (Observational Study)
Observational Study
UNLABELLED
Essentials Heparin-protamine balance (HPB) modulates bleeding after neonatal cardiopulmonary bypass (CPB). HPB was examined in 44 neonates undergoing CPB. Post-operative bleeding occurred in 36% and heparin rebound in 73%. Thrombin-initiated fibrin clot kinetic assay and partial thromboplastin time best assessed HPB.
SUMMARY
Background Neonates undergoing cardiopulmonary bypass (CPB) are at risk of excessive bleeding. Blood is anticoagulated with heparin during CPB. Heparin activity is reversed with protamine at the end of CPB. Paradoxically, protamine also inhibits blood coagulation when it is dosed in excess of heparin. Objectives To evaluate heparin-protamine balance in neonates undergoing CPB by using research and clinical assays, and to determine its association with postoperative bleeding. Patients/Methods Neonates undergoing CPB in the first 30 days of life were studied. Blood samples were obtained during and after surgery. Heparin-protamine balance was assessed with calibrated automated thrombography, thrombin-initiated fibrin clot kinetic assay (TFCK), activated partial thromboplastin time (APTT), anti-FXa activity, and thromboelastometry. Excessive postoperative bleeding was determined by measurement of chest tube output or the development of cardiac tamponade. Results and Conclusions Of 44 neonates enrolled, 16 (36%) had excessive postoperative bleeding. The TFCK value was increased. By heparin in neonatal blood samples, but was only minimally altered by excess protamine. Therefore, it reliably measured heparin in samples containing a wide range of heparin and protamine concentrations. The APTT most closely correlated with TFCK results, whereas anti-FXa and thromboelastometry assays were less correlative. The TFCK and APTT assay also consistently detected postoperative heparin rebound, providing an important continued role for these long-established coagulation tests in the management of postoperative bleeding in neonates requiring cardiac surgical repair. None of the coagulation tests predicted the neonates who experienced postoperative bleeding, reflecting the multifactorial causes of bleeding in this population.
Topics: Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Cardiopulmonary Bypass; Drug Monitoring; Female; Heparin; Heparin Antagonists; Humans; Infant, Newborn; Male; Postoperative Hemorrhage; Predictive Value of Tests; Prospective Studies; Protamines; Risk Factors; Treatment Outcome
PubMed: 30016577
DOI: 10.1111/jth.14245 -
Frontiers in Genetics 2020The genome of eukaryotes is highly organized within the cell nucleus, this organization elicits gene regulation and favors other mechanisms like cell memory throughout... (Review)
Review
The genome of eukaryotes is highly organized within the cell nucleus, this organization elicits gene regulation and favors other mechanisms like cell memory throughout histones and their post-translational modifications. In highly specialized cells, like sperm, the genome is mostly organized by protamines, yet a significant portion of it remains organized by histones. This protamine-histone-DNA organization, known as sperm epigenome, is established during spermiogenesis. Specific histones and their post-translational modifications are retained at specific genomic sites and during embryo development these sites recapitulate their histone profile that harbored in the sperm nucleus. It is known that histones are the conduit of epigenetic memory from cell to cell, hence histones in the sperm epigenome may have a role in transmitting epigenetic memory from the sperm to the embryo. However, the exact function and mechanism of histone retention remains elusive. During spermatogenesis, most of the histones that organize the genome are replaced by protamines and their retention at specific regions may be deeply intertwined with the eviction and replacement mechanism. In this review we will cover some relevant aspects of histone replacement that in turn may help us to contextualize histone retention. In the end, we focus on the architectonical protein CTCF that is, so far, the only factor that has been directly linked to the histone retention process.
PubMed: 32765595
DOI: 10.3389/fgene.2020.00780 -
BMC Cardiovascular Disorders May 2022Compared to simple percutaneous coronary intervention (PCI), complex PCI is associated with higher bleeding and thrombotic risk. No previous study has evaluated the use...
BACKGROUND
Compared to simple percutaneous coronary intervention (PCI), complex PCI is associated with higher bleeding and thrombotic risk. No previous study has evaluated the use of protamine after PCI with contemporary technologies. This study aimed to evaluate the safety and efficacy of manual compression with and without protamine after transfemoral complex PCI.
METHODS
We retrospectively analyzed 160 patients (protamine group, n = 92; non-protamine group, n = 68) who underwent complex PCI via the femoral artery. The primary outcome was a composite of in-hospital death, myocardial infarction, stent thrombosis, stroke/systemic embolism, bleeding requiring blood transfusion, and vascular access complications.
RESULTS
The primary outcome was significantly lower in the protamine group than in the non-protamine group (4.3% vs. 17.6%; p = 0.006). This was driven mainly by the lower incidences of hematoma in the protamine group (3.3% vs. 13.2%, p = 0.020). Furthermore, the protamine group had a significantly shorter hospital stay than the non-protamine group (4.8 ± 3.7 days vs. 8.4 ± 8.3 days, p = 0.001). While > 90% of the patients had acute coronary syndrome, there were no incidences of myocardial infarction or stent thrombosis in either group.
CONCLUSIONS
Among patients who underwent complex PCI via transfemoral access, immediate protamine administration was associated with a significantly lower rate of vascular access complications, especially hematoma, and shorter hospital stay than no protamine administration.
Topics: Anticoagulants; Hematoma; Hemorrhage; Heparin; Hospital Mortality; Humans; Myocardial Infarction; Percutaneous Coronary Intervention; Protamines; Retrospective Studies; Thrombosis; Treatment Outcome
PubMed: 35538419
DOI: 10.1186/s12872-022-02650-5 -
Reviews in Cardiovascular Medicine Jan 2022Perioperative anticoagulation management with uninterrupted or minimally interrupted anticoagulation during atrial fibrillation (AF) ablation is thought to be critical... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Perioperative anticoagulation management with uninterrupted or minimally interrupted anticoagulation during atrial fibrillation (AF) ablation is thought to be critical to minimize thromboembolic complications. Protamine is often administered to neutralize the effects of heparin and expedite vascular hemostasis post-procedure.
OBJECTIVE
We performed a systematic review and meta-analysis to determine the effectiveness of protamine to expedite vascular hemostasis and ambulation in patients undergoing AF ablation.
METHODS
Electronic searches on PubMed, The Cochrane Library, EMBASE, EBSCO, Web of Science, and CINAHL databases from the inception through August 7, 2021, were performed. The primary outcomes included-time to hemostasis (minutes) and time to ambulation (minutes). The secondary outcomes included - any vascular complications (excluding minor hematoma), minor hematoma, or cerebrovascular accidents (CVA).
RESULTS
A total of 5 eligible studies (3 retrospective cohort studies and two randomized trials) consisting of 1012 patients (515 patients received protamine group and 497 patients did not receive protamine group) were included in the meta-analysis. There was a significant reduction in time to ambulation [weighted mean difference (WMD) -176.6 minutes, 95% Confidence interval (CI) -266.9 to -86.3; < 0.01] and time to hemostasis (WMD -13.72 minutes, 95% CI -22 to -5.4, < 0.01) in the protamine group compared to the contrary. At a follow-up up to 3 months, there was no statistical difference between the two groups with regards to vascular complications (2.9% vs. 7.4%; Risk ratio (RR) 0.46 95% CI 0.17 to 1.24; = 0.12), minor hematoma (2.1% vs. 5.8%; RR 0.43, 95% CI 0.16 to 1.2; = 0.11) or CVA (0 vs. 0.3%; RR 0.62, 95% CI 0.08 to 4.98; = 0.65).
CONCLUSION
Protamine administration was associated with reduced time to ambulation (176 minutes reduction) and time to hemostasis (13 minutes reduction) without an increase in any adverse events.
Topics: Anticoagulants; Atrial Fibrillation; Catheter Ablation; Humans; Protamines; Retrospective Studies; Treatment Outcome
PubMed: 35092226
DOI: 10.31083/j.rcm2301034 -
Andrology Sep 2016Existing literature suggests evidence that protamine deficiency is related to DNA damage and male fertility. In this meta-analysis, we analyzed the relationship between... (Meta-Analysis)
Meta-Analysis Review
Existing literature suggests evidence that protamine deficiency is related to DNA damage and male fertility. In this meta-analysis, we analyzed the relationship between the ratio of protamine-1 and protamine-2 with male fertility and the association of protamine deficiency with sperm DNA damage. Quality of available cohort studies was evaluated using the Newcastle-Ottawa Scale checklist. Summary effect estimates with 95% confidence intervals (CI) were derived using a random effects model. The effect of the protamine ratio on male fertility was analyzed in nine studies demonstrating a significantly higher value of the protamine ratio in subfertile men (n = 633) when compared with controls (n = 453, SMD = 0.46, 95% CI 0.25-0.66, Z = 4.42, p < 0.00001). Both protamine mRNA (SMD = 0.45, 95% CI 0.11-0.79, Z = 2.63, p = 0.009) and protein ratio (SMD = 0.46, 95% CI 0.25-0.68, Z = 4.22, p < 0.0001) showed significantly increased values in subfertile patients. The association between protamine deficiency and DNA damage was analyzed in 12 studies (n = 845) exhibiting a combined overall correlation coefficient (COR) of 0.53 (95% CI 0.28-0.71, Z = 3.87, p < 0.001). Protamine deficiency measured by CMA3 staining was significantly associated with sperm DNA damage (COR = 0.71, 95% CI 0.48-0.85, Z = 4.87, p < 0.001), whereas the P1/P2 ratio was not (COR = 0.17, 95% CI -0.16 to 0.46, Z = 0.99, p = 0.33). It is concluded that the protamine ratio represents a suitable biomarker for the assessment of sperm quality and protamine deficiency is closely related with sperm DNA damage.
Topics: DNA Damage; DNA Fragmentation; Humans; Infertility, Male; Male; Protamines; Spermatozoa
PubMed: 27231200
DOI: 10.1111/andr.12216 -
Frontiers in Genetics 2019Spermiogenesis is a complex cellular differentiation process that the germ cells undergo a distinct morphological change, and the protamines replace the core histones to... (Review)
Review
Spermiogenesis is a complex cellular differentiation process that the germ cells undergo a distinct morphological change, and the protamines replace the core histones to facilitate chromatin compaction in the sperm head. Recent studies show the essential roles of epigenetic events during the histone-to-protamine transition. Defects in either the replacement or the modification of histones might cause male infertility with azoospermia, oligospermia or teratozoospermia. Here, we summarize recent advances in our knowledge of how epigenetic regulators, such as histone variants, histone modification and their related chromatin remodelers, facilitate the histone-to-protamine transition during spermiogenesis. Understanding the molecular mechanism underlying the modification and replacement of histones during spermiogenesis will enable the identification of epigenetic biomarkers of male infertility, and shed light on potential therapies for these patients in the future.
PubMed: 31649732
DOI: 10.3389/fgene.2019.00962 -
Cellular and Molecular Life Sciences :... Jun 2017Pronuclear/zygotic stage is the very first stage of life. In this period, paternal pronucleus undergoes massive chromatin remodeling called "paternal reprogramming"... (Review)
Review
Pronuclear/zygotic stage is the very first stage of life. In this period, paternal pronucleus undergoes massive chromatin remodeling called "paternal reprogramming" including protamine-histone replacement and subsequent acquisition of epigenetic modifications. Although these consecutive events are required for the initiation of maternal-zygotic transition, the precise role of paternal reprogramming and its effect on subsequent embryonic development has been largely unknown to date. Recently, various new techniques, especially next-generation sequencing (NGS) and RNAi microinjection contribute to unveil the epigenetic transition from both paternal and maternal to early preimplantation embryos, suggesting not only the simple transcriptional regulation by transcription factors but also dynamic structural alteration of chromatin to initiate the wave of zygotic gene transcription. This review summarizes such recent progress for understanding the epigenetic transition in sperm and preimplantation embryos, and further argue about its transgenerational effect.
Topics: Animals; Blastocyst; Cellular Reprogramming; Epigenesis, Genetic; Gene Expression Regulation, Developmental; Humans; Male; Spermatozoa; Zygote
PubMed: 28050628
DOI: 10.1007/s00018-016-2447-z -
Annals of Cardiac Anaesthesia 2021Protamine is routinely administered to neutralize the anticlotting effects of heparin, traditionally at a dose of 1 mg for every 100 IU of heparin-a 1:1 ratio protamine... (Observational Study)
Observational Study
CONTEXT
Protamine is routinely administered to neutralize the anticlotting effects of heparin, traditionally at a dose of 1 mg for every 100 IU of heparin-a 1:1 ratio protamine sparing effects-but this is based more on experience and practice than literature evidence. The use of Hemostasis Management System (HMS) allows an individualized heparin and protamine titration. This usually results in a decreased protamine dose, thus limiting its side effects, including paradox anticoagulation.
AIMS
This study aims to assess how the use of HMS allows to reduction of protamine administration while restoring the basal activated clotting time (ACT) at the end of cardiac surgery.
SETTINGS AND DESIGN
A retrospective observational study in a tertiary care university hospital.
SUBJECTS AND METHODS
We analyzed data from 42 consecutive patients undergoing cardiopulmonary bypass (CPB) for cardiac surgery. For all patients HMS tests were performed before and after CPB, to determine how much heparin was needed to reach target ACT, and how much protamine was needed to reverse it.
RESULTS
At the end of cardiopulmonary bypass, 2.2 ± 0.5 mg/kg of protamine was sufficient to reverse heparin effects. The protamine-to-heparin ratio was 0.56:1 over heparin total dose (a 44% reduction) and 0.84:1 over heparin initial dose (a 16% reduction).
CONCLUSION
A lower dose of protamine was sufficient to revert heparin effects after cardiopulmonary bypass. While larger studies are needed to confirm these findings and detect differences in clinically relevant outcomes, the administration of a lower protamine dose is endorsed by current guidelines and may help to avoid the detrimental effects of protamine overdose, including paradox bleeding.
Topics: Anticoagulants; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Heparin; Heparin Antagonists; Humans; Protamines; Whole Blood Coagulation Time
PubMed: 33884973
DOI: 10.4103/aca.ACA_26_19