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Pediatric Research Oct 2023Hospital-acquired hyponatremia remains a feared event in patients receiving hypotonic fluid therapy. Our objectives were to assess post-operative plasma-sodium... (Observational Study)
Observational Study
BACKGROUND
Hospital-acquired hyponatremia remains a feared event in patients receiving hypotonic fluid therapy. Our objectives were to assess post-operative plasma-sodium concentration and to provide a physiological explanation for plasma-sodium levels over time in children with acute appendicitis.
METHODS
Thirteen normonatremic (plasma-sodium ≥135 mmol/L) children (8 males), median age 12.3 (IQR 11.5-13.5) years participated in this prospective observational study (ACTRN12621000587808). Urine was collected and analyzed. Blood tests, including renin, aldosterone, arginine-vasopressin, and circulating nitric oxide substrates were determined on admission, at induction of anesthesia, and at the end of surgery.
RESULTS
On admission, participants were assumed to be mildly dehydrated and were prescribed 50 mL/kg of Ringer's acetate intravenously followed by half-isotonic saline as maintenance fluid therapy. Blood tests, urinary indices, plasma levels of aldosterone, arginine-vasopressin, and net water-electrolyte balance indicated that participants were dehydrated on admission. Although nearly 50% of participants still had arginine-vasopressin levels that would have been expected to produce maximum antidiuresis at the end of surgery, electrolyte-free water clearance indicated that almost all participants were able to excrete net free water. No participant became hyponatremic.
CONCLUSIONS
The use of moderately hypotonic fluid therapy after correction of extracellular fluid deficit is not necessarily associated with post-operative hyponatremia.
IMPACT
Our observations show that in acutely ill normonatremic children not only the composition but also the amount of volume infused influence on the risk of hyponatremia. Our observations also suggest that perioperative administration of hypotonic fluid therapy is followed by a tendency towards hyponatremia if extracellular fluid depletion is left untreated. After correcting extracellular deficit almost all patients were able to excrete net free water. This occurred despite nearly 50% of the cohort having high circulating plasma levels of arginine-vasopressin at the end of surgery, suggesting a phenomenon of renal escape from arginine-vasopressin-induced antidiuresis.
Topics: Child; Humans; Male; Aldosterone; Arginine; Arginine Vasopressin; Hyponatremia; Sodium; Vasopressins; Water; Water-Electrolyte Balance; Prospective Studies
PubMed: 36759747
DOI: 10.1038/s41390-023-02509-1 -
Molecules (Basel, Switzerland) Aug 2023Among the toxic metabolites of the fungal world, those that, due to their strong biological effect, can seriously (even fatally) damage the life processes of humans (and... (Review)
Review
Among the toxic metabolites of the fungal world, those that, due to their strong biological effect, can seriously (even fatally) damage the life processes of humans (and certain groups of animals) stand out. Amatoxin-containing mushrooms and the poisonings caused by them stand out from the higher fungi, the mushrooms. There are already historical data and records about such poisonings, but scientific research on the responsible molecules began in the middle of the last century. The goals of this review work are as follows: presentation of the cosmopolitan mushroom species that produce amanitins (which are known from certain genera of four mushroom families), an overview of the chemical structure and specific properties of amanitins, a summary of the analytical methods applicable to them, a presentation of the "medical history" of poisonings, and a summary of the therapeutic methods used so far. The main responsible molecules (the amanitins) are bicyclic octapeptides, whose structure is characterized by an outer loop and an inner loop (bridge). It follows from the unusual properties of amanitins, especially their extreme stability (against heat, the acidic pH of the medium, and their resistance to human, and animal, digestive enzymes), that they are absorbed almost without hindrance and quickly transported to our vital organs. Adding to the problems is that accidental consumption causes no noticeable symptoms for a few hours (or even 24-36 h) after consumption, but the toxins already damage the metabolism of the target organs and the synthesis of nucleic acid and proteins. The biochemical catastrophe of the cells causes irreversible structural changes, which lead to necrotic damage (in the liver and kidneys) and death. The scientific topicality of the review is due to the recent publication of new data on the probable antidote molecule (ICR: indocyanine green) against amanitins. Further research can provide a new foundation for the therapeutic treatment of poisonings, and the toxicological situation, which currently still poses a deadly threat, could even be tamed into a controllable problem. We also draw attention to the review conclusions, as well as the mycological and social tasks related to amanitin poisonings (prevention of poisonings).
Topics: Amanitins; Agaricales; Humans; Animals; Mushroom Poisoning
PubMed: 37570902
DOI: 10.3390/molecules28155932 -
Molecules (Basel, Switzerland) Dec 2023Ferroptosis is a form of regulated cell death that is characterized by the accumulation of iron-dependent lipid peroxides. The regulation of ferroptosis involves both... (Review)
Review
Ferroptosis is a form of regulated cell death that is characterized by the accumulation of iron-dependent lipid peroxides. The regulation of ferroptosis involves both non-enzymatic reactions and enzymatic mechanisms. Natural products have demonstrated potential effects on various enzymes, including GPX4, HO-1, NQO1, NOX4, GCLC, and GCLM, which are mainly involved in glutathione metabolic pathway or oxidative stress regulation, and ACSL3 and ACSL4, which mainly participate in lipid metabolism, thereby influencing the regulation of ferroptosis. In this review, we have provided a comprehensive overview of the existing literature pertaining to the effects of natural products on enzymes involved in ferroptosis and discussed their potential implications for the prevention and treatment of ferroptosis-related diseases. We also highlight the potential challenge that the majority of research has concentrated on investigating the impact of natural products on the expression of enzymes involving ferroptosis while limited attention is given to the regulation of enzyme activity. This observation underscores the considerable potential and scope for exploring the influence of natural products on enzyme activity.
Topics: Ferroptosis; Biological Products; Glutathione; Iron; Lipid Metabolism
PubMed: 38067658
DOI: 10.3390/molecules28237929 -
Frontiers in Cellular and Infection... 2023Malaria is a parasitic disease of global health significance and a leading cause of death in children living in endemic regions. Although various Plasmodium species are... (Review)
Review
Malaria is a parasitic disease of global health significance and a leading cause of death in children living in endemic regions. Although various Plasmodium species are responsible for the disease, infection accounts for most severe cases of the disease in humans. The mechanisms of cerebral malaria pathogenesis have been studied extensively in humans and animal malaria models; however, it is far from being fully understood. Recent discoveries indicate a potential role of bradykinin and the kallikrein kinin system in the pathogenesis of cerebral malaria. The aim of this review is to highlight how bradykinin is formed in cerebral malaria and how it may impact cerebral blood-brain barrier function. Areas of interest in this context include Plasmodium parasite enzymes that directly generate bradykinin from plasma protein precursors, cytoadhesion of infected red blood cells to brain endothelial cells, and endothelial cell blood-brain barrier disruption.
Topics: Animals; Humans; Bradykinin; Brain; Endothelial Cells; Malaria, Cerebral; Malaria, Falciparum
PubMed: 37637466
DOI: 10.3389/fcimb.2023.1184896 -
Scientific Reports Dec 2023To explore whether ferroptosis is involved in focal segmental glomerulosclerosis (FSGS) and its mechanism. The FSGS rat model was constructed by single nephrectomy...
To explore whether ferroptosis is involved in focal segmental glomerulosclerosis (FSGS) and its mechanism. The FSGS rat model was constructed by single nephrectomy combined with fractional tail vein injection of doxorubicin. 24-hour urine protein, serum biochemistry, HE, PAS and Masson pathological staining were measured to assess renal injury. Glomerular and morphological changes of ferroptosis were observed by transmission electron microscopy. Iron content in renal tissue was assessed by Prussian blue staining and iron detection. GSH/GSSG kit was used to detect the content and proportion of reduced/oxidized glutathione. Lipid peroxidation related proteins including MDA expression was assessed by colorimetry. The iron metabolism biomarkers such as hepcidin, ferroportin and TFR, ferroptosis biomarkers such as GPX4, ACSL4, and ferritinophagy biomarkers such as LC3II/LC3I, NCOA4, and FTH1 were detected by Western blot. Significant urinary protein, hyperlipidemia, azotemia, increased serum creatinine and hypoproteinemia were observed in FSGS rats. Histology and electron microscopy showed segmental sclerosis of glomeruli, compensatory enlargement of some glomeruli, occlusion of capillary lumen, balloon adhesion, increased mesangial matrix, atrophy of some tubules, and renal interstitial fibrosis in renal tissue of FSGS rats. The morphology of glomerular foot processes disappeared; the foot processes were extensively fused and some foot processes detached. Mitochondria became smaller, membrane density increased, and mitochondrial cristae decreased or disappeared. In addition, iron deposition was observed in renal tissue of FSGS rats. Compared with the control group, the levels of GSH, GSH/GSSG, GPX4, and ferroportin were reduced and the expression of GSSG, MDA, ACSL4, hepcidin, and TFR was increased in the renal tissue of FSGS rats; meanwhile, the expression of LC3II/LC3I and NCOA4 was increased and the expression of FTH1 was decreased. Ferroptosis is involved in the pathological progression of FSGS, which is probably associated with activation of ferritinophagy. This represents a potential therapeutic target for FSGS.
Topics: Rats; Animals; Glomerulosclerosis, Focal Segmental; Hepcidins; Ferroptosis; Glutathione Disulfide; Biomarkers; Iron
PubMed: 38097813
DOI: 10.1038/s41598-023-49697-8 -
Frontiers in Immunology 2023Malignant tumors have a unique tumor microenvironment (TME), which includes mild acidity, hypoxia, overexpressed reactive oxygen species (ROS), and high glutathione... (Review)
Review
Malignant tumors have a unique tumor microenvironment (TME), which includes mild acidity, hypoxia, overexpressed reactive oxygen species (ROS), and high glutathione (GSH) levels, among others. Recently, TME regulation approaches have attracted widespread attention in cancer immunotherapy. Nanoparticles as drug delivery systems have ability to modulate the hydrophilicity of drugs to affect drug uptake and efflux in tumor. Especially, the metal nanoparticles have been extensive applied for tumor immunotherapy due to their unique physical properties and elaborate design. However, the potential deficiencies of metal nanoparticles due to their low biodegradability, toxicity and treatment side effects restrict their clinical application. In this review, we briefly introduce the feature characteristics of the TME and the recent advances in tumor microenvironment responsive metal nanoparticles for tumor immunotherapy. In addition, nanoparticles could be combined with other treatments, such as chemotherapy, radiotherapy and photodynamic therapy also is presented. Finally, the challenges and outlook for improving the antitumor immunotherapy efficiency, side effect and potential risks of metal nanoparticles has been discussed.
Topics: Humans; Tumor Microenvironment; Immunotherapy; Metal Nanoparticles; Drug-Related Side Effects and Adverse Reactions; Drug Delivery Systems; Glutathione; Neoplasms
PubMed: 37575228
DOI: 10.3389/fimmu.2023.1237361 -
EBioMedicine Nov 2023Polycystic ovary syndrome (PCOS) is the most common endocrine disorder leading to anovulatory infertility. Abnormalities in the central neuroendocrine system governed by...
BACKGROUND
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder leading to anovulatory infertility. Abnormalities in the central neuroendocrine system governed by gonadotropin-releasing hormone (GnRH) neurons might be related to ovarian dysfunction in PCOS, although the link in this disordered brain-to-ovary communication remains unclear. Here, we manipulated GnRH neurons using chemogenetics in adult female mice to unveil whether chronic overaction of these neurons would trigger PCOS-like hormonal and reproductive impairments.
METHODS
We used adult Gnrh1 female mice to selectively target and express the designer receptors exclusively activated by designer drugs (DREADD)-based chemogenetic tool hM3D(Gq) in hypophysiotropic GnRH neurons. Chronic chemogenetic activation protocol was carried out with clozapine N-oxide (CNO) i.p. injections every 48 h over a month. We evaluated the reproductive and hormonal profile before, during, and two months after chemogenetic manipulations.
FINDINGS
We discovered that the overactivation of GnRH neurons was sufficient to disrupt reproductive cycles, promote hyperandrogenism, and induce ovarian dysfunction. These PCOS features were detected with a long-lasting neuroendocrine dysfunction through abnormally high luteinizing hormone (LH) pulse secretion. Additionally, the GnRH-R blockade prevented the establishment of long-term neuroendocrine dysfunction and androgen excess in these animals.
INTERPRETATION
Taken together, our results show that hyperactivity of hypothalamic GnRH neurons is a major driver of reproductive and hormonal impairments in PCOS and suggest that antagonizing the aberrant GnRH signaling could be an efficient therapeutic venue for the treatment of PCOS.
FUNDING
European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement n◦ 725149).
Topics: Humans; Female; Mice; Animals; Polycystic Ovary Syndrome; Luteinizing Hormone; Gonadotropin-Releasing Hormone; Neurons
PubMed: 37898094
DOI: 10.1016/j.ebiom.2023.104850 -
International Journal of Molecular... Jan 2024Mitochondria are critical for providing energy to maintain cell viability. Oxidative phosphorylation involves the transfer of electrons from energy substrates to oxygen... (Review)
Review
Mitochondria are critical for providing energy to maintain cell viability. Oxidative phosphorylation involves the transfer of electrons from energy substrates to oxygen to produce adenosine triphosphate. Mitochondria also regulate cell proliferation, metastasis, and deterioration. The flow of electrons in the mitochondrial respiratory chain generates reactive oxygen species (ROS), which are harmful to cells at high levels. Oxidative stress caused by ROS accumulation has been associated with an increased risk of cancer, and cardiovascular and liver diseases. Glutathione (GSH) is an abundant cellular antioxidant that is primarily synthesized in the cytoplasm and delivered to the mitochondria. Mitochondrial glutathione (mGSH) metabolizes hydrogen peroxide within the mitochondria. A long-term imbalance in the ratio of mitochondrial ROS to mGSH can cause cell dysfunction, apoptosis, necroptosis, and ferroptosis, which may lead to disease. This study aimed to review the physiological functions, anabolism, variations in organ tissue accumulation, and delivery of GSH to the mitochondria and the relationships between mGSH levels, the GSH/GSH disulfide (GSSG) ratio, programmed cell death, and ferroptosis. We also discuss diseases caused by mGSH deficiency and related therapeutics.
Topics: Reactive Oxygen Species; Glutathione; Mitochondria; Oxidative Stress; Homeostasis; Oxidation-Reduction
PubMed: 38279310
DOI: 10.3390/ijms25021314 -
Journal of the International Society of... Dec 2023Accumulation of body fat and dyslipidemia are associated with the development of obesity and cardiometabolic diseases. Moreover, the degree to which lipids can be... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Accumulation of body fat and dyslipidemia are associated with the development of obesity and cardiometabolic diseases. Moreover, the degree to which lipids can be metabolized has been cited as a determinant of cardiometabolic health and prolonged endurance capacity. In the backdrop of increasing obesity and cardiometabolic diseases, lipid metabolism and its modulation by physical activity, dietary adjustments, and supplementation play a significant role in maintaining health and endurance. Food-derived oligopeptides, such as rice and soybean peptides, have been shown to directly regulate abnormal lipid metabolism or promote hypolipidemia and fat oxidation in cell culture models, animal models, and human studies. However, whether supplementation with oligopeptides derived from multiple food sources can promote lipid degradation and fat oxidation in athletes remains unclear. Therefore, in a randomized controlled crossover trial, we investigated the impact of food-derived oligopeptide supplementation before and during exercise on lipid metabolism in young male cyclists.
METHODS
Sixteen young male cyclists (age: 17.0 ± 1.0 years; height: 178.4 ± 6.9 cm; body mass: 68.7 ± 12.7 kg, body mass index: 21.5 ± 3.4 kg/m; maximum oxygen uptake: 56.3 ± 5.8 mL/min/kg) participated in this randomized controlled crossover trial. Each participant drank two beverages, one containing a blend of three food-derived oligopeptides (treatment, 0.5 g/kg body weight in total) and the other without (control), with a 2-week washout period between two experiments. The cyclists completed a one-day pattern protocol that consisted of intraday fasting, 30 min of sitting still, 85 min of prolonged exercise plus a 5-min sprint (PE), a short recovery period of 60 min, a 20-min time trial (TT), and recovery till next morning. Blood samples were collected for biochemical analyses of serum lipids and other biomarkers. We analyzed plasma triglyceride species (TGs), free amino acids (FAAs), and tricarboxylic acid (TCA) cycle intermediates using omics methods. In addition, exhaled gas was collected to assess the fat oxidation rate.
RESULTS
Five of 20 plasma FAAs were elevated pre-exercise (pre-Ex) only 20 min after oligopeptide ingestion, and most FAAs were markedly increased post PE and TT. Serum levels of TG and non-esterified fatty acids were lower in the experimental condition than in the control condition at the post PE and TT assessments, respectively. Further, the omics analysis of plasma TGs for the experimental condition demonstrated that most TGs were lower post PE and at the next fasting when compared with control levels. Simultaneously, the fat oxidation rate began to increase only 20 min after ingestion and during the preceding 85 min of PE. Levels of TCA cycle intermediates did not differ between the conditions.
CONCLUSIONS
The study noted that continuous ingestion of food-derived oligopeptides accelerated total body triglyceride breakdown, non-esterified fatty acid uptake, and fat oxidation during both sedentary and exercise states. Elevated circulating and intracellular FAA flux may modulate the selection of substrates for metabolic pathways in conjunction with the release of neuroendocrinological factors that slow down carbohydrate metabolism via acetyl coenzyme A feedback inhibition. This may increase the availability of fatty acids for energy production, with FAAs supplying more substrates for the TCA cycle. The findings of this study provide novel insight into strategies for promoting lipid metabolism in populations with dyslipidemia-related metabolic disorders such as obesity and for improving physiological functioning during endurance training. However, the absence of a non-exercising control group and verification of long-term supplementation effects was a limitation. Future studies will emphasize the impacts of whole protein supplementation as a control and of combined food-derived peptides or oligopeptides with probiotics and healthy food components on lipid metabolism in individuals who exercise.
Topics: Animals; Humans; Male; Adolescent; Lipid Metabolism; Cross-Over Studies; Oxygen Consumption; Oxygen; Oligopeptides; Amino Acids; Cardiovascular Diseases; Dietary Supplements; Lipids
PubMed: 37674290
DOI: 10.1080/15502783.2023.2254741 -
Journal of Nanobiotechnology Aug 2023Iron sulfide nanomaterials have been successfully employed as therapeutic agents for bacterial infection therapy and catalytic-ferroptosis synergistic tumor therapy due...
BACKGROUND
Iron sulfide nanomaterials have been successfully employed as therapeutic agents for bacterial infection therapy and catalytic-ferroptosis synergistic tumor therapy due to their unique structures, physiochemical properties, and biocompatibility. However, biomedical research and understanding of the biological functions of iron sulfides are insufficient, and how iron sulfide nanomaterials affect reactive oxygen species (ROS) in diseases remains unknown. Acute kidney injury (AKI) is associated with high levels of ROS, and therefore nanomedicine-mediated antioxidant therapy has emerged as a novel strategy for its alleviation.
RESULTS
Here, mackinawite nanozymes were synthesized from glutathione (GSH) and iron ions (Fe) (denoted as GFeSNs) using a hydrothermal method, and then evaluated as ROS scavengers for ROS-related AKI treatment. GFeSNs showed broad-spectrum ROS scavenging ability through synergistic interactions of multiple enzymes-like and hydrogen polysulfide-releasing properties. Furthermore, both in vitro and in vivo experiments demonstrated that GFeSNs exhibited outstanding cytoprotective effects against ROS-induced damage at extremely low doses and significantly improved treatment outcomes in AKI.
CONCLUSIONS
Given the synergetic antioxidant properties and high biocompatibility, GFeSNs exhibit great potential for the treatment of AKI and other ROS-associated diseases.
Topics: Animals; Antioxidants; Reactive Oxygen Species; Acute Kidney Injury; Iron; Fishes; Glutathione
PubMed: 37598162
DOI: 10.1186/s12951-023-02034-7