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European Review For Medical and... Oct 2023It is established that the balance of serum thiols is disrupted in favor of oxidants in coronary artery disease, and the cardiopulmonary bypass pump used during coronary...
OBJECTIVE
It is established that the balance of serum thiols is disrupted in favor of oxidants in coronary artery disease, and the cardiopulmonary bypass pump used during coronary artery bypass surgery disrupts this balance in favor of oxidants. In this study, we investigated the antioxidant effects of remifentanil or dexmedetomidine on thiol-disulfide balance and paraoxonase-1 (PON-1) levels during on-pump coronary artery bypass surgery.
PATIENTS AND METHODS
A total of 100 patients who underwent on-pump coronary artery bypass grafting surgery between May 2018 and December 2018 were included in the study. Patients were divided into two groups: the remifentanil group (Group R) and the dexmedetomidine group (Group D). Venous blood samples were obtained from the patients after induction of anesthesia [Time 1 (T-1)], then after cross-clamping of the aorta (T-2), after removal of the cross-clamp (T-3), 10 minutes after the end of protamine infusion (T-4), and 24 hours postoperatively (T-5). Serum total thiol, native thiol, disulfide, and PON-1 levels were evaluated.
RESULTS
Total thiol, disulfide, PON-1, native thiol/total thiol, total thiol/disulfide, and native thiol/disulfide levels were similar between the two groups. Native thiol levels were statistically significantly higher in group D compared to group R at T-3 and T-5 (p = 0.017 and p = 0.027, respectively). When T-1 and T-5 times were compared in intragroup measurements, disulfide levels were significantly lower, and native thiol/total thiol ratios were significantly higher at T-5 (p < 0.001).
CONCLUSIONS
In conclusion, in light of the data obtained from this study, it can be concluded that dexmedetomidine used during surgery has a better contribution to oxidant-antioxidant balance than remifentanil in patients undergoing coronary artery bypass surgery with the on-pump method.
Topics: Humans; Remifentanil; Dexmedetomidine; Disulfides; Sulfhydryl Compounds; Case-Control Studies; Coronary Artery Bypass; Oxidants
PubMed: 37843318
DOI: 10.26355/eurrev_202310_33930 -
Scientific Reports Oct 2023Insulin is proved to have angiogenic ability thereby may worsen the diabetic retinopathy (DR) progression. Insulin also triggers the expression of endogenous angiogenic...
Insulin is proved to have angiogenic ability thereby may worsen the diabetic retinopathy (DR) progression. Insulin also triggers the expression of endogenous angiogenic peptide, apelin. Since protamine was introduced as an inhibitor of the apelin receptor, we hypothesized that use of protaminated insulin instead of non-protaminated insulin can decrease the negative role of insulin in progression of DR. Firstly, the incidence of DR was compared among three diabetic patient groups: an oral medication, non-protaminated insulin, and protaminated insulin (PIns). Proliferation and migration rate of HUVECs was measured after insulin, apelin, and protamine exposure. In clinical study, the chance of developing DR was 8.5 and 4.1 times higher in insulin group and PIns groups compared with oral group respectively. Insulin group had a chance of 9.5-folds of non-proliferative DR compared to oral group. However, the difference of non-proliferative DR between PIns and oral group wasn't significant. In-vitro tests showed that concomitant use of insulin and apelin increases viability and migratory potential of HUVECs. However, protamine could reverse this effect. Protamine present in some insulins might show a promising protective role against diabetic retinopathy. Thus, protaminated insulins may be preferable in the treatment of diabetes.
Topics: Humans; Apelin; Apelin Receptors; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Insulin; Protamines
PubMed: 37828117
DOI: 10.1038/s41598-023-44639-w -
Cureus Sep 2023Infective endocarditis can be acute or subacute. It can be caused by viral, bacterial, fungal, and sometimes nonbacterial etiologies. It is an important cause of...
Infective endocarditis can be acute or subacute. It can be caused by viral, bacterial, fungal, and sometimes nonbacterial etiologies. It is an important cause of mortality and morbidity in children as well as adolescents, despite advances in management. A 59-year-old male with a past medical history of aortic valve (AV) replacement on warfarin presented to the Emergency Department with dull right flank pain and poor dentition on examination. Computerized tomography (CT) scans of the abdomen revealed the presence of splenic and renal infarcts. Warfarin was held after the international normalized ratio (INR) was noted to be elevated at 11. Following the activation of the sepsis bundle in the ER, he received intravenous fluids (30 cc/kg) and was started on vancomycin and ceftriaxone. On further evaluation, the transesophageal echocardiogram revealed mobile densities on the aortic surface concerning vegetation. Antibiotics were transitioned to cefazolin, gentamycin, and rifampin for the management of prosthetic valve endocarditis. The patient's INR improved to 3.5 on the third day of hospitalization, and heparin was initiated to maintain anticoagulation for the prosthetic valve. However, on the eighth day of hospitalization, the patient developed left-sided weakness and slurred speech. The CT head showed acute frontoparietal intracranial hemorrhage (ICH), with an INR noted to be 5. Heparin was reversed with protamine sulfate, and vitamin K was administered, following which the INR improved to 2.3. The patient was transferred to intensive care, but on the second day of the ICU stay, the INR again shot up to 6 with normal LFTS. The patient received vitamin K, but the INR only improved to 5. Subsequently, antibiotics were changed from cefazolin to nafcillin. INR thus fell to 1.6 in two days after changing the antibiotics. The patient was soon transferred to a higher center for aortic valve replacement. While few case reports have described severe coagulopathy induced by cefazolin, it is particularly seen with impaired renal function; however, our patient's renal function was completely normal. Coagulopathy is due to the drug's effect on intestinal flora and its structural methyl-thiadiazole side chain, which has similar effects as epoxide reductase inhibitors and results in INR elevation. Patients on cefazolin need to be closely monitored for INR levels every day, as there is a high likelihood of developing complications like ICH, as noted in this patient. While the monitoring of cefazolin levels is not necessarily indicated, it is necessary to place patients on fall precautions and monitor INR levels every day, as mentioned above.
PubMed: 37814735
DOI: 10.7759/cureus.44875 -
International Journal of Pharmaceutics Nov 2023The current study aimed to develop enzyme-activated charge-reversal lipid nanoparticles (LNPs) as novel gene delivery systems.
AIM
The current study aimed to develop enzyme-activated charge-reversal lipid nanoparticles (LNPs) as novel gene delivery systems.
METHODS
Palmitic acid was covalently bound to protamine being utilised as transfection promoter to anchor it on the surfaces of LNPs. Green fluorescent protein (GFP) encoding plasmid DNA (pDNA) was ion paired with various cationic counter ions to achieve high encapsulation in LNPs. Protamine-decorated LNPs were prepared by solvent injection method followed by coating with sodium tripolyphosphate (TPP) to generate a bio-inert anionic outer surface. Resulting LNPs were characterised regarding size, polydispersity, zeta potential and encapsulation efficiency. Enzyme-triggered charge-reversal of LNPs was investigated using isolated alkaline phosphatase (ALP) monitoring changes in zeta potential as well as monophosphate release. Furthermore, monophosphate release, cell viability and transfection efficiency were evaluated on a human alveolar epithelial (A549) cell line.
RESULTS
Protamine-decorated and TPP-coated (Prot-pDNA/DcChol-TPP) LNPs displayed a mean size of 298.8 ± 17.4 nm and a zeta potential of -13.70 ± 0.61 mV. High pDNA encapsulation was achieved with hydrophobic ion pairs of pDNA with 3ß-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol hydrochloride (DcChol). Zeta potential of Prot-pDNA/DcChol-TPP LNPs reversed to positive values with a total Δ26.8 mV shift upon incubation with ALP. Conformably, a notable amount of monophosphate was released upon incubation of Prot-pDNA/DcChol-TPP LNPs with isolated as well as cell-associated ALP. A549 cells well tolerated LNPs displaying more than 95 % viability. Compared with naked pDNA, unmodified LNPs and control LNPs, Prot-pDNA/DcChol-TPP LNPs showed a significantly increased transfection efficiency.
CONCLUSION
Prot-pDNA/DcChol-TPP LNPs can be regarded as promising gene delivery systems.
Topics: Humans; Gene Transfer Techniques; Plasmids; Transfection; DNA; Nanoparticles; Protamines
PubMed: 37793466
DOI: 10.1016/j.ijpharm.2023.123474 -
Hormones (Athens, Greece) Dec 2023The objective of this retrospective study was to compare glycemic control, pregnancy outcomes, and neonatal outcomes in women with gestational diabetes mellitus (GDM)...
PURPOSE
The objective of this retrospective study was to compare glycemic control, pregnancy outcomes, and neonatal outcomes in women with gestational diabetes mellitus (GDM) treated with (a) insulin detemir and (b) insulin neutral protamine Hagedorn (NPH).
METHODS
A total of 192 women with GDM were included in the analysis. Ninety-eight women received detemir, while 94 women received NPH. Data regarding medical history, glycemic control, and time and mode of delivery, as well as neonatal outcomes, were recorded.
RESULTS
Baseline characteristics were comparable between the two groups. There were no differences with respect to the week of insulin initiation, total insulin dose, duration of insulin therapy, daily insulin dose/weight in early and late pregnancy, or the number of insulin injections per day. Maternal overall weight gain during pregnancy and weight gain per week did not differ either. The detemir group had slightly lower HbA1c levels at the end of gestation [median: det 5.2% (33 mmol/mol) vs NPH 5.4% (36 mmol/mol), p=0.035). There were no cases of hypoglycemia or allergic reactions in the two groups. There were also no differences regarding neonatal outcomes according to the available data, given that data in some cases were missing.
CONCLUSION
The use of insulin detemir was found to be equally effective and safe compared to NPH in women with GDM.
Topics: Infant, Newborn; Humans; Female; Pregnancy; Hypoglycemic Agents; Insulin Detemir; Insulin, Long-Acting; Diabetes, Gestational; Insulin, Isophane; Retrospective Studies; Diabetes Mellitus, Type 2; Pregnancy Outcome; Glycemic Control; Insulin; Weight Gain
PubMed: 37775682
DOI: 10.1007/s42000-023-00490-2 -
Journal of Nutritional Science 2023This review discusses epigenetic mechanisms and the relationship of infertility in men and women in relation to parameters pertaining to nutrition. The prevalence of... (Review)
Review
This review discusses epigenetic mechanisms and the relationship of infertility in men and women in relation to parameters pertaining to nutrition. The prevalence of infertility worldwide is 8-12 %, and one out of every eight couples receives medical treatment. Epigenetic mechanisms, aging, environmental factors, dietary energy and nutrients and non-nutrient compounds; more or less energy intake, and methionine come into play in the occurrence of infertility. It also interacts with vitamins B12, D and B6, biotin, choline, selenium, zinc, folic acid, resveratrol, quercetin and similar factors. To understand the molecular mechanisms regulating the expression of genes that affect infertility, the environment, the role of genotype, age, health, nutrition and changes in the individual's epigenotype must first be considered. This will pave the way for the identification of the unknown causes of infertility. Insufficient or excessive intake of energy and certain macro and micronutrients may contribute to the occurrence of infertility as well. In addition, it is reported that 5-10 % of body weight loss, moderate physical activity and nutritional interventions for improvement in insulin sensitivity contribute to the development of fertility. Processes that pertain to epigenetics carry alterations which are inherited yet not encoded via the DNA sequence. Nutrition is believed to have an impact over the epigenetic mechanisms which are effective in the pathogenesis of several diseases like infertility. Epigenetic mechanisms of individuals with infertility are different from healthy individuals. Infertility is associated with epigenetic mechanisms, nutrients, bioactive components and numerous other factors.
Topics: Humans; Male; Female; Infertility, Female; Epigenesis, Genetic; Genotype
PubMed: 37771507
DOI: 10.1017/jns.2023.62 -
Frontiers in Cell and Developmental... 2023Protamines (PRM1 and PRM2) are small, arginine-rich, nuclear proteins that replace histones in the final stages of spermiogenesis, ensuring chromatin compaction and...
Protamines (PRM1 and PRM2) are small, arginine-rich, nuclear proteins that replace histones in the final stages of spermiogenesis, ensuring chromatin compaction and nuclear remodeling. Defects in protamination lead to increased DNA fragmentation and reduced male fertility. Since efficient sperm production requires the translocation of protamines from the cytoplasm to the nucleus, we investigated whether SPAG17, a protein crucial for intracellular protein trafficking during spermiogenesis, participates in protamine transport. Initially, we assessed the protein-protein interaction between SPAG17 and protamines using proximity ligation assays, revealing a significant interaction originating in the cytoplasm and persisting within the nucleus. Subsequently, immunoprecipitation and mass spectrometry (IP/MS) assays validated this initial observation. Sperm and spermatids from knockout mice exhibited abnormal protamination, as revealed by chromomycin A3 staining, suggesting defects in protamine content. However, no differences were observed in the expression of and mRNA or in protein levels between testes of wild-type and knockout mice. Conversely, immunofluorescence studies conducted on isolated mouse spermatids unveiled reduced nuclear/cytoplasm ratios of protamines in knockout spermatids compared to wild-type controls, implying transport defects of protamines into the spermatid nucleus. In alignment with these findings, experiments involving somatic cells, including mouse embryonic fibroblasts, exhibited compromised nuclear translocation of PRM1 and PRM2 in the absence of SPAG17. Collectively, our results present compelling evidence that SPAG17 facilitates the transport of protamines from the cytoplasm to the nucleus.
PubMed: 37766963
DOI: 10.3389/fcell.2023.1125096 -
Animals : An Open Access Journal From... Sep 2023This study explored the effects of hyperbaric oxygen therapy (HBOT) on the cardiovascular system and oxidative stress in streptozotocin-induced diabetic rats. Wistar...
BACKGROUND
This study explored the effects of hyperbaric oxygen therapy (HBOT) on the cardiovascular system and oxidative stress in streptozotocin-induced diabetic rats. Wistar albino rats were divided into four groups: DM group (diabetic rats), DM+HBOT group (diabetic rats exposed to HBOT for 1 h daily, five days a week, at 2.8 atmosphere absolute (ATA) with 100% oxygen for two weeks), DM+INS group (diabetic rats treated with neutral protamine hagedorn (NPH) insulin at a dosage of 3-5 U/day), and DM+HBOT+INS group (diabetic rats treated with both NPH insulin and HBOT for two weeks).
METHODS
Evaluations included glycemic control, oxidative stress parameters, and cardiac function measurements.
RESULTS
NPH insulin treatment reduced blood glucose levels, although normoglycemia was not achieved. The DM+HBOT+INS group demonstrated the lowest pro-oxidative marker levels. NPH insulin treatment improved cardiac function, and combination therapy effectively restored cardiac function in diabetic animals.
CONCLUSIONS
NPH insulin treatment reduced hyperglycemia and improved cardiac function in diabetic rats. The combined approach of NPH insulin and HBOT resulted in decreased pro-oxidative markers. These findings provide valuable insights for managing cardiovascular complications and oxidative stress in diabetes.
PubMed: 37760247
DOI: 10.3390/ani13182847 -
The Veterinary Quarterly Dec 2023The objective of this study was to investigate the effect of etamsylate on canine blood and heparinised canine blood from healthy dogs using thromboelastography (TEG)....
The objective of this study was to investigate the effect of etamsylate on canine blood and heparinised canine blood from healthy dogs using thromboelastography (TEG). Citrated blood was obtained from twenty healthy client-owned dogs, and 3 experiments were performed. Experiment 1 compared TEG in blood versus blood with etamsylate (250 mM). Experiment 2 evaluated TEG in heparinised blood (1 U/mL) with and without the addition of etamsylate (250 mM). Experiment 3 evaluated dose escalation of etamsylate (control, 250 μM, 500 μM and 1000 μM) in heparinised blood (1 U/mL). The addition of etamsylate to canine blood in experiment 1 increased the percentage of clot lysis at 30 min (z = -2.103, = .035) and 60 min (z = -1.988, = .047), suggesting that etamsylate could have a fibrinolytic effect. When etamsylate was added to heparinised canine blood (1 U/mL), etamsylate produced a dose-dependent inhibition of the effect of heparin when higher concentrations of etamsylate were used (500 μM and 1000 μM). The linear mixed effects model showed significant increases in α angle and maximal amplitude when high dose etamsylate was added compared to the control. In conclusion, etamsylate could be used at higher doses to inhibit the effect of heparin in dogs when protamine might not be available. However, etamsylate might have a fibrinolytic effect when used in healthy dogs.
Topics: Animals; Dogs; Ethamsylate; Heparin; Thrombelastography
PubMed: 37715947
DOI: 10.1080/01652176.2023.2260449 -
Nanoscale Advances Sep 2023Protamine, a small, strongly positively-charged protein, plays a key role in achieving chromatin condensation inside sperm cells and is also involved in the formulation...
Protamine, a small, strongly positively-charged protein, plays a key role in achieving chromatin condensation inside sperm cells and is also involved in the formulation of nanoparticles for gene therapy and packaging of mRNA-based vaccines against viral infection and cancer. The detailed mechanisms of such condensations are still poorly understood especially under low salt conditions where electrostatic interaction predominates. Our previous study, with a refined coarse-grained model in full consideration of the long-range electrostatic interactions, has demonstrated the crucial role of electrostatic interaction in protamine-controlled reversible DNA condensation. Therefore, we herein pay our attention only to the electrostatic interaction and devise a coarser-grained bead-spring model representing the right linear charge density on protamine and DNA chains but treating other short-range interactions as simply as possible, which would be suitable for real-scale simulations. Effective pair potential calculations and large-scale molecular dynamics simulations using this extremely simple model reproduce the phase behaviour of DNA in a wide range of protamine concentrations under low salt conditions, again revealing the importance of the electrostatic interaction in this process and providing a detailed nanoscale picture of bundle formation mediated by a charge disproportionation mechanism. Our simulations also show that protamine length alters DNA overcharging and in turn redissolution thresholds of DNA condensates, revealing the important role played by entropies and correlated fluctuations of condensing agents and thus offering an additional opportunity to design tailored nanoparticles for gene therapy. The control mechanism of DNA-protamine condensates will also provide a better microscopic picture of biomolecular condensates, , membraneless organelles arising from liquid-liquid phase separation, that are emerging as key principles of intracellular organization. Such condensates controlled by post-translational modification of protamine, in particular phosphorylation, or by variations in protamine length from species to species may also be responsible for the chromatin-nucleoplasm patterning observed during spermatogenesis in several vertebrate and invertebrate species.
PubMed: 37705794
DOI: 10.1039/d2na00847e