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PubMed2002

Protamine P1 sequences in equids: comparison with even-toed animals.

Protamine P1 amino acid sequences were determined from semen samples of the Przewalski horse, donkey, Somali wild ass, Grevy's zebra, and Grant's zebra (odd-toed perissodactyls), and compared with those of the domestic horse. Although the rate of amino acid variation of protamine P1 is known to be among the most rapidly diverging polypeptides, the equid sequences revealed only little variation. The sequence from the Przewalski horse was identical with that from the domestic horse. The other sequences differed from the corresponding sequences of the domestic and Przewalski horses in two positions-Ser29 was replaced by Cys and Gln32 was replaced by Arg. The presence of the Cys residue at position 29 in the protamine P1 from the zebras, the donkey, and the Somali wild ass may allow formation of one extra protamine disulfide bridge during chromosome condensation in these species. Comparison with protamines from various even-toed animals (artiodactyls) indicated amino acid changes specific for those but different from the equid sequences.

Amino Acid Sequence↗
PubMed1998

Nucleosome positioning in the rat protamine 1 gene in vivo and in vitro.

The positions of the nucleosomes along the rat protamine 1 gene have been determined in vivo through micrococcal nuclease digestion of isolated nuclei followed by Southern analysis and indirect end labeling with a protamine 1 gene probe. Several strong positioning signals are detected in rat liver nuclei where the gene is repressed. In vitro reconstitution of nucleosomes along the cloned rat protamine 1 gene results in a precisely positioned nucleosome with a dyad axis at -109 bp upstream from the transcriptional start site. The position of this nucleosome reconstituted in vitro coincides with the position of one of the nucleosomes present in vivo in rat liver nuclei. Two important regulatory elements of the expression of the protamine 1 gene, the serum response element (CArG box) and the protamine 1 consensus (cAMP response element), are positioned over the -109 nucleosome with potential functional implications for transcriptional activation.

Animals↗
PubMed1987

Absence of prostaglandin changes associated with protamine administration in patients with pulmonary hypertension.

In patients with pre-existing pulmonary hypertension, severe pulmonary vasoconstriction has been observed following protamine administration. Thromboxane A2, a potent vasoconstrictor, is capable of producing increases in pulmonary vascular resistance, and animal studies suggest that heparin-protamine complexes stimulate thromboxane A2 synthesis. This study assessed the effect of protamine administration on hemodynamics and on plasma thromboxane A2 and its biologic antagonist, prostacyclin, by serial measurement of the stable metabolites, thromboxane B2 and 6-keto-prostaglandin F1 alpha, respectively. Ten adults with pulmonary artery hypertension undergoing elective mitral valve replacement were studied. After termination of cardiopulmonary bypass, baseline hemodynamic measurements were obtained and arterial blood for prostanoid analysis was sampled. Hemodynamic and prostanoid measurements were obtained 5, 10, 15, and 30 minutes after the protamine infusion began. Prostanoid levels were performed by double antibody radio-immunoassay. No significant hemodynamic changes occurred and no significant changes in prostanoid levels were observed. It is concluded that in patients with pulmonary hypertension, heparin-protamine complexes do not consistently raise circulating thromboxane levels, and the relationships among prostanoids, pulmonary hypertension, and systemic hypotension are still not clear.

6-Ketoprostaglandin F1 alpha↗
PubMed1998

Adverse events after protamine administration in patients undergoing cardiopulmonary bypass: risks and predictors of under-reporting.

A retrospective cohort study of patients undergoing cardiopulmonary bypass over 2 years at a single hospital was performed to determine the rate and predictors of attributing events to protamine and reporting them to a well-developed, hospital-based adverse drug reaction (ADR) program. Overall, 123 (12.9%) of 952 procedures were associated with an adverse event. Thirteen percent of these events were attributed to protamine in the medical record and 2.4% were reported to the ADR program. Only 19% of events attributed to protamine were reported. Even after excluding events with other measurable etiologies, the incidence of adverse events (2.6%) was still higher than that of attributed (0.8%) or reported (0.3%) events. Events that manifest as pulmonary hypertension occurred sooner after protamine, or were severe were significantly more likely to be attributed to protamine. These predictors demonstrated similar relationships with the probability of reporting events. Reliance on reporting of adverse events could not only underestimate the risk of these events, but might bias studies by identifying non-representative events.

Adverse Drug Reaction Reporting Systems↗
PubMed1990

Reversal of depressed oxygen consumption accompanying in vivo protamine sulphate-heparin interactions by the prostacyclin analogue, iloprost.

Oxygen consumption (VO2) is known to be depressed 50 to 60% during protamine sulphate reversal of heparin anticoagulation. Accompanying this event are systemic hypotension, pulmonary artery hypertension and thrombocytopaenia. The effect of a pro-stacyclin analogue, iloprost, on protamine-induced changes in VO2 was assessed in this investigation. Three groups of anaesthetised adult mongrel dogs were studied: Group I--control subjects received i.v. normal saline infusions (n = 10); Group II--subjects received low-dose i.v. iloprost infusions (25-50 ng/kg/min) over 30 min (n = 7); and Group III--subjects received high-dose i.v. iloprost infusions (175 ng/kg/min) over 30 min (n = 7). All dogs initially received sodium heparin, 150 IU/kg i.v. Protamine sulphate, 1.5 mg/kg i.v., was subsequently administered over 10 s following the first 20 min of saline or iloprost infusion. Continuous measurements included: mixed venous (SvO2) and arterial (SaO2) oxygen saturation, arterial blood pressure, pulmonary artery pressure, heart rate and carotid artery flow (CaQ). Thermodilution cardiac output (CO) allowed calculation of VO2. Platelet counts were performed before and 3 min after protamine infusion. The VO2 declines in Group II and III subjects compared to Group I controls were markedly less. Maximum VO2 declines in Group I control dogs of -38.2 +/- 26.7% and Group II dogs of -34.1 +/- 36.8% at 75 to 90 s post-reversal contrasted to -2.9 +/- 31.9% in Group III animals at the same time interval. VO2 increases occurred 3 to 10 min after protamine exposure in Group III animals, as did attenuation of systemic hypotensive and pulmonary hypertensive responses in this group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Effect of sperm DNA damage and sperm protamine deficiency on fertilization and embryo development post-ICSI.

The aim of this study was to evaluate the effect of sperm DNA damage and protamine deficiency on fertilization and embryo development post-intracytoplasmic sperm injection (ICSI), and also to assess the effect of protamine deficiency on DNA damage. Semen samples were collected from 28 patients participating in the ICSI programme. Following sperm preparation and ICSI, the remaining processed semen samples were used to assess protamine deficiency and DNA damage employing chromomycin A3 (CMA3) staining and comet assay, respectively. Comet parameters, CMA3 percentage positivity, fertilization rate, embryo cleavage score and embryo quality score were assessed. Except for CMA3, none of the comet parameters showed significant correlation with fertilization rate. However, among comet parameters, head area and head intensity showed positive correlation with the embryo cleavage score, while comet mean intensity and head mean intensity showed a significant negative correlation with CMA3 positivity. Results of this study demonstrate that DNA fragmentation is more frequent in protamine-deficient spermatozoa. Unlike protamine deficiency, sperm DNA fragmentation does not preclude fertilization. Nonetheless, embryos derived from spermatozoa with high DNA damage have a lower potential to reach blastocyst stage.

Chromomycin A3↗
PubMedDate not supplied

Protamine as an efficient membrane-translocating peptide.

Protamine, a mixture of positively charged proteins from salmon roe used in diverse pharmaceutical applications, was reacted with the N-hydroxysuccinimide ester of tetramethylrhodamine to yield tetramethylrhodamine-labeled protamines (Pro(Rh)) containing one mole of fluorochrome per mole of protein. The internalization of tetramethylrhodamine-labeled protamine (Pro(Rh)) and the fluorescein-labeled tat peptide (Tat(Fl)) showed a similar dependence on time and concentration. Pro(Rh) and Tat(Fl) showed strong nuclear localizations, evident with both live cells and fixed cells co-stained with DAPI, a nuclear stain. The loss of fluorescence when cells were loaded with Pro(Rh) or Tat(Fl) was similar, further supporting a strong similarity between these two materials. Finally, when Pro(Ph) was covalently attached to the amino-CLIO nanoparticle, the cellular uptake of the nanoparticle was greatly enhanced. All experiments were performed with HeLa and CaCo-2 cells with similar results. These observations imply that protamine, a protein in regular clinical use, might be used for the design of novel membrane translocating/nuclear localizing pharmaceuticals whose development was initiated with other membrane-translocating peptides. In addition, the fluorescent protamines developed here might be used to further our understanding of this important pharmaceutical.

Animals↗
PubMed1986

Marked differences in the ability of distinct protamines to disassemble nucleosomal core particles in vitro.

In accordance with the results of classical experiments performed in vitro with calf thymus chromatin and the fish protamine salmine, we have observed that this highly basic, small molecular weight protamine cannot cause major displacement of histones from nucleosomal core particles at concentrations several times higher than physiological (arginine/nucleotide ratios 1-8) and that hyperacetylation of histones facilitates nucleosome disassembly. However, the avian protamine galline, with molecular weight and number of arginine residues almost twice those of common fish protamines, is able to displace the nucleosomal core histones from DNA in vitro at concentrations (arginine/nucleotide ratios 0.6-1.2) within the physiological range (0.8). Our results suggest that the binding of the avian protamine galline to chromatin could be directly involved in the rapid disassembly of nucleosomes that takes place during the nucleohistone nucleoprotamine transition in chicken spermiogenesis.

Animals↗
PubMed1977

Identification and isolation of protamine messenger ribonucleoprotein particles from rainbow trout testis.

Treatment of rainbow trout testis polyribosomes with ethylenediaminetetraacetic acid released polyadenylated protamine messenger RNA in the form of a ribonucleoprotein (mRNP) particle. This mRNP particle which sedimented at 12-14 S could be identified by hybridization to [3H]poly(U) and was partially purified by two successive sucrose gradient sedimentations. When RNA was extracted from the mRNP particle and used as a template in the wheat germ cell-free protein synthesizing system the sole product of translation was protamine. Of this RNA, 30% contained poly(A) sequences and was shown to comigrate with polyadenylated protamine messenger RNA during polyacrylamide gel electrophoresis. When the proteins of the mRNP particle were examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the two prominent polypeptides with apparent molecular weights of 73 000 and 29 000 appeared reproducibly. Treatment of trout testis polyribosomes with puromycin in the presence of 0.5 M KCl released a smaller (8-10S) mRNP particle which was similarly shown to contain protamine messenger RNA. Trout testis postribosomal supernatant fraction possessed 16-18S mRNP particles containing polyadenylated RNA which cosedimented with protamine messenger RNA when the particles were dissociated with sodium dodecyl sulfate.

Animals↗
PubMed2003

A less toxic heparin antagonist--low molecular weight protamine.

A new thirteen amino acid peptide, named low molecular weight protamine (LMWP), was obtained through the enzymatic digestion of native protamine. Both in vitro and in vivo results showed that LMWP fully maintained the heparin neutralization function of protamine but had much lower immunogenicity and antigenicity. Unlike protamine, neither LMWP nor LMWP/heparin complexes caused significant blood platelet aggregation in rats. These results suggest that LMWP can be used as a substitute for protamine for developing a new generation of nontoxic heparin antagonists.

Animals↗
PubMed1999

Destruction of protamine in human sperm inhibits sperm binding and penetration in the zona-free hamster penetration test but increases sperm head decondensation and male pronuclear formation in the hamster-ICSI assay.

PURPOSE: Our purpose was to investigate the fertilizing ability of human protamine-damaged sperm in a heterologous system using hamster oocytes. METHODS: The protamine of the sperm were damaged by exposure to dithiothreitol, a disulfide-reducing agent. Their ability to penetrate and form male pronuclei were investigated using the zona-free hamster penetration test and the hamster-intracytoplasmic sperm injection assay, respectively. RESULTS: The zona-free hamster penetration test revealed that protamine-damaged sperm are unable to bind and penetrate the hamster oocyte. On the other hand, hamster-intracytoplasmic sperm injection assay results showed that 56.9% and 39.2% of the injected oocytes developed male pronuclei in protamine-damaged and live-intact sperm groups, respectively, with a significant difference in these rates (P < 0.01). CONCLUSIONS: This study shows that protamine-damaged sperm are able to undergo sperm head decondensation and male pronuclear formation only when injected into the ooplasm, although they cannot bind and penetrate through the zona and enter the ooplasm.

Acridine Orange↗
PubMed1982

Effect of protamine on the permeability and structure of rat peritoneum.

The effect of protamine, a polycationic protein, on the mesothelial permeability and ultrastructure was evaluated in a rat model of peritoneal dialysis. The peritoneal permeability to urea and inulin were measured after the intraperitoneal instillation of protamine sulfate in varying concentrations. A functional correlation was made with the ultrastructure of omentum. Protamine concentrations between 5 and 30 micrograms/ml decreased the permeability to inulin without significantly altering that of urea. At concentrations from 30 to 75 micrograms/ml, protamine increased permeability to urea by 50% and to inulin by 20%. Mesothelial cells revealed a loss of microvilli and minor degrees of disorganization of submembranous, cytoplasmic microfilaments without significant changes in the intramembranous structure of occluding junctions. Effects were partially reversible. At a concentration of 100 micrograms/ml, there was an irreversible doubling in permeability to inulin without a comparable effect on permeability to urea associated with the disruption of occluding junctions in focal areas. This complex response to protamine suggests at least two transperitoneal diffusion pathways, transcellular and paracellular. The mesothelial cell occluding junctions may be a diffusion barrier in the latter pathway.

Animals↗
PubMed1970

The use of protamine to study [6,7-3H] oestradiol-17-beta binding in rat uterus.

1. The binding of [6,7-(3)H]oestradiol-17beta to uteri has been studied by using sucrose-gradient analysis and also the property of oestradiol receptors to form insoluble complexes with protamine. 2. Protamine precipitates the 8S and part of the 4S oestradiol-binding proteins in uterine cytoplasm from mature rats. It does not precipitate the oestradiol-17beta-binding proteins present in cytoplasm from non-target tissues or serum. No tritium-labelled material was precipitated by protamine after equilibration of [6,7-(3)H]oestradiol-17beta with either serum albumin or phosvitin. 3. Protamine precipitated a small amount of progesterone but not testosterone or cortisol that had been equilibrated with uterine cytoplasm. It did not precipitate any tritium radioactivity from muscle cytoplasm that had been equilibrated with either [1,2-(3)H]testosterone sulphate or [1,2-(3)H]dehydroepiandrosterone. 4. A simple method has been devised for measuring binding constants of tissue extracts for [6,7-(3)H]oestradiol-17beta, based on precipitation with protamine. Reasonable agreement was obtained between the values obtained by this method and those obtained by sucrose-gradient analysis. 5. This method has been used to study the effect of maturity, ovariectomy, adrenalectomy and hypophysectomy on the cytoplasmic binding of [6,7-(3)H]oestradiol-17beta. None of these procedures affected the dissociation constant K(d) or the number of binding sites/mg of cytoplasmic protein. When measured per uterus or per mg of DNA, ovariectomy and hypophysectomy decreased the number of binding sites. Adrenalectomy had no effect. 6. The properties of the 4S oestradiol-binding protein present in cytoplasm from mature uteri have been studied. It is not present in uteri from immature, ovariectomized, or hypophysectomized rats and it does not bind testosterone or cortisol. Unlabelled oestradiol-17beta, U-11,100A, N-ethylmaleimide and N-bromosuccinimide all decrease the binding of [6,7-(3)H]oestradiol-17beta to both 8S and 4S receptors. Binding to both 8S and 4S receptors decreases when oestradiol is transported to the nucleus. The 4S receptor is not the same as the 4S binding component formed by salt dissociation of the 8S receptor.

Adrenal Glands↗
PubMed1992

Protein phosphatase 2A is a specific protamine-kinase-inactivating phosphatase.

Purified preparations of a protamine protein kinase from bovine kidney cytosol [Damuni, Amick & Sneed (1989) J. Biol. Chem. 264, 6412-6416] were inactivated after incubation with near-homogeneous preparations of protein phosphatase 2A1 and protein phosphatase 2A2. These protein phosphatase 2A-mediated inactivations of the protamine kinase were unaffected by highly purified preparations of inhibitor 2, but were prevented when the incubations were performed in the presence of 100 nM microcystin-LR, 100 nM okadaic acid or 0.2 mM-ATP. By contrast, highly purified preparations of protein phosphatase 2B, protein phosphatase 2C, the catalytic subunit of protein phosphatase 1, and two forms of a protein tyrosine phosphatase, designated PTPase 1B and T-cell PTPase, had little effect, if any, on protamine kinase activity. Purified preparations of the protamine kinase did not react with anti-phosphotyrosine antibodies, as determined by Western blotting and immunoprecipitation analysis. The results indicate that protein phosphatase 2A is a specific protamine-kinase-inactivating phosphatase.

Animals↗
PubMed2002

A preliminary report on the implication of RT-PCR detection of DAZ, RBMY1, USP9Y and Protamine-2 mRNA in testicular biopsy samples from azoospermic men.

In this study, reverse transcription-polymerase chain reaction (RT-PCR) was optimized to analyse the presence of DAZ, RBMY1, USP9Y, protamine-2, SRY and actin messenger RNA (mRNA) in testicular cells of men suffering from idiopathic azoospermia. All samples (n=28), including five controls, showed normal expression of actin, SRY and USP9Y. Sperm was not recovered from eight patients after testicular biopsy. Of these, four patients showed altered mRNA levels for the fertility genes, DAZ, RBMY1 and protamine-2. One patient, who was previously shown to be azoospermia factor region (AZF)b deleted, lacked RBM mRNA and presented with reduced amplification of protamine-2 mRNA. This correlated with previous studies, which proposed that RBM expression is exclusive to AZFb and that the lack of testicular RBMY1 mRNA results in suppressed spermatogenesis. Two patients were each lacking DAZ mRNA but did show expression of RBMY1 mRNA at a reduced level, suggesting that there might be residual spermatogenesis in the absence of DAZ expression. Protamine-2 mRNA was detected in one patient and was absent in the second patient. Finally, one patient lacked DAZ, RBMY1 and protamine-2 mRNA. The 19 remaining azoospermic patients presented with normal expression patterns for each of the fertility genes studied. This study demonstrates that the expression of spermatogenesis-specific genes varies in azoospermia. The study of the expression of such genes in a larger number of patients might be useful in characterizing and identifying subpopulations of azoospermic men.

Biopsy↗
PubMed1995

Ultrastructural immunolocalisation of histones (H2B, H3, H4), transition protein (TP1) and protamine in rabbit spermatids and spermatozoa nuclei. Relation to condensation of the chromatin.

The histones H2B, H3 and H4, the transition protein TP1 and protamine were localised using ultrastructural immunocytochemistry in nuclei of rabbit spermatids and spermatozoa. Histones are present in round spermatid nuclei and are lost during the elongation of nuclei. TP1 and protamine appear simultaneously in all nuclei during this period. TP1 is located at the periphery of chromatin cords, while protamine seems to be located at random in the same cords. TP1 is lost in most elongated spermatids during step 13 of spermiogenesis, and the protamine stays in all sperm nuclei. TP1 remains present in some old spermatids and ejaculated spermatozoa. In the rabbit, 3-6% of sperm nuclei decondense spontaneously. Most are characterised by a retention of TP1. Respective roles of TP1 and the protamine in spermatid nuclear condensation are discussed.

Animals↗
PubMed1985

In vivo neutralization of low-molecular weight heparin fraction CY 216 by protamine.

The neutralization in vivo of a low molecular weight heparin by protamine was investigated. Large doses and excessive doses of intravenously administered CY 216 were studied. An intravenous injection of protamine given 10 minutes after the administration of CY 216 did not cause the studied biologic parameters to return to normal levels, but merely attenuated them, whatever the protamine dosage tested. In contrast, the bleeding time and the volume of blood loss resumed normal values that were close to those observed in the controls. This dissociation of actions cannot be explained at present. The ratio of protamine to CY 216 dosage that produced the best results was 1 antiheparin U of protamine to 2 anti-Xa U of CY 216. Nevertheless CY 216 appeared to have a small hemorrhagic potential.

Animals↗
PubMed2002

Intraoperative transesophageal echocardiographic assessment of the effect of protamine on paraprosthetic aortic insufficiency immediately after stentless tissue aortic valve replacement.

Mild paravalvular aortic insufficiency (AI) is common immediately after stentless bioprosthetic aortic valve replacement. Although resolution of paraprosthetic jets with protamine has been described, the predictability of resolution has not been addressed. Intraoperative transesophageal echocardiography was performed before and after protamine administration among 2 groups. The first group (n = 20) was used to define the prevalence and severity of paravalvular AI after stentless tissue AVR, and define a threshold value for jet size associated with resolution with protamine. A second group (n = 18) was used to prospectively test the determined threshold. Paravalvular AI occurred in 13 of 20 (65%) patients. Using a threshold value of 0.3 cm or less jet width, prospective testing revealed positive and negative predictive values for AI resolution with protamine of 93% (14 of 15) and 100% (3 of 3), respectively. Protamine administration is associated with resolution of small AI jets immediately after implantation of a stentless aortic bioprosthesis, with a jet width 0.3 cm or less strongly predictive of resolution.

Adult↗