Expression of Concern: Sustained Oxidative Stress Causes Late Acute Renal Failure via Duplex Regulation on p38 MAPK and Akt Phosphorylation in Severely Burned Rats.
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ABSTRACT:
SUBMITTER: PLOS ONE Editors
PROVIDER: S-EPMC10833502 | biostudies-literature | 2024
REPOSITORIES: biostudies-literature
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Expression of Concern: Sustained Oxidative Stress Causes Late Acute Renal Failure via Duplex Regulation on p38 MAPK and Akt Phosphorylation in Severely Burned Rats.
PloS one 20240201 2
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Project description:BACKGROUND This study evaluated factors influencing early and late occurrence of AKI in severely burned patients and assessed the relationship between time of occurrence of AKI and mortality of AKI patients. MATERIAL AND METHODS Renal function was evaluated at 3 time points: at admission, at the critical point or middle point of hospitalization, and at the endpoint for which death or a discharge from the center was considered. AKI criteria were: decrease in GFR of less than 60 ml/min at admission, decrease in GFR of more than 75% compared to baseline, and decrease in the daily diuresis of less than 500 ml/24 h. RESULTS At admission, 15.1% of the patients had eGFR <60 ml/min. AKI occurred in 38.5% of cases. The occurrence of AKI was associated with: elderly age (p<0.001), female sex (p=0.017), overweight and obesity (p=0.055); extent and depth of burns, respiratory failure, low protein concentration (for all p<0.001), low blood pressure (p=0.014), and high WBC (p=0.010). Early AKI was detected in 28% of patients. Mortality was 100% with the initial GFR ?60, 100% with the initial GFR <60 and early deterioration of renal function, 80% with the initial GFR <60 and late worsening, and 60% with the initial GFR <60 and no worsening. Late AKI was observed in 10% of patients and mortality in this group was 79.2%. Mortality in the entire group with AKI was 88.0% versus 24.5%. CONCLUSIONS The frequent occurrence of AKI, especially early, worsens the prognosis for survival. Assessment of renal function should be included in the prognostic scales for burned patients.
| S-EPMC5070618 | biostudies-other
Project description:ObjectivesThe aim of this study was to determine the appropriate propranolol dosing strategy for reducing heart rate in severely burned adults.MethodsA total of 26 patients (≥18 years) with burns covering ≥30% of the total body surface area were included in this IRB-approved study. Plasma propranolol concentrations were determined in a placebo group (n=10) or following one of three dosing strategies: Q6 (n=4), Q8 (n=6), and Q24 (n=6). Blood was collected just before dosing and at regular intervals over two dosing periods with corresponding heart rate and blood pressure recordings. Statistical significance was determined by one-way ANOVA followed by the appropriate post-hoc test.ResultsHeart rate was 86±2 bpm for Q6, 93±3 bpm for Q8, and 90±4 bpm for Q24. The Q8 group had a significantly higher heart rate than the Q6 group (p=0.0001). Plasma propranolol concentrations were significantly higher in the Q6 dosing strategy than in the Q8 dosing strategy (p=0.02).ConclusionsHeart rate can be decreased to a similar degree with Q6 and Q24 dosing strategies, with the Q8 dosing strategy being less effective. Q6 dosing is recommended to maintain reduced heart rate throughout dosing periods.
| S-EPMC8173765 | biostudies-literature
Project description:BackgroundApart from the current understanding of enzyme function, the mechanism of ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) deficiency-associated osteoporosis is unknown. We aimed to explore the changes in the expression of signaling pathways of bone tissues involved in Enpp1 deficiency.MethodsThe body weights and morphology and histology of the bones of male Enpp1 knockout (KO) and wild-type (WT) mice were assessed. The humeri of WT and Enpp1 KO mice at 12 weeks of age were subjected to high-throughput quantitative molecular measurements, and bioinformatics analysis was performed. Proteins from humeri and calvarial pre-osteoblasts (Pobs) were used to verify the differentially expressed signaling pathways and to explain the mechanism of Enpp1 deficiency-associated osteoporosis.ResultsEnpp1 KO mice had significantly lower body weight and trabecular bone mass in the hindlimbs than WT mice. Proteomics and immunoblotting showed that Enpp1 deletion downregulated the expression of the p38 mitogen-activated protein kinase (MAPK) signaling pathway in bones. Lysophosphatidic acid (LPA) was involved in activating the MKK3/p38 MAPK/PCNA pathway and proliferating Pobs in Enpp1 KO mice, whereas a p38 MAPK inhibitor suppressed the LPA-induced pro-proliferation phenotype (p < 0.05).ConclusionThe inhibition of MKK3/p38 MAPK/PCNA pathway plays an important role in the development of osteoporosis caused by Enpp1 deficiency, and LPA partially rescued the proliferation of pre-osteoblasts via the MKK3/p38 MAPK/PCNA pathway.
| S-EPMC9571425 | biostudies-literature
Project description:This study aimed to investigate the differences in the trajectory of blood biomarkers routinely assessed through forward- and backward-looking approaches among burn patients. This cohort study included patients above 18 years of age from February 2007 to December 2018. All the biomarkers were estimated from admission to discharge from the intensive care unit. Significant differences were observed in the platelet count at 40 days, prothrombin time (PT) at 32 days, white blood cell count at 26 days, creatinine levels at 22 days, and lactate and total bilirubin levels at 19 days before death. In reverse order, significant differences were observed in the fitted model in platelet count at 44 days and in the platelet count and PT at 33 days. We obtained more valuable information from the longitudinal biomarker trajectory using the backward-looking method than using the forward-looking method. The platelet count served as the earliest predictor of mortality among burn patients.
| S-EPMC7530734 | biostudies-literature
Project description:Hypernatremia is common in critical care, especially in severely burned patients. Its occurrence has been linked to increased mortality. Causes of hypernatremia involve a net gain of sodium or a loss of free water. Renal loss of electrolyte-free water due to urea-induced osmotic diuresis has been described as causative in up to 10% of hypernatremic critical ill patients. In this context, excessive urea production due to protein catabolism acts as major contributor. In severe burn injury, muscle wasting occurs as result of hypermetabolism triggered by ongoing systemic inflammation. In this retrospective study, severely burned patients were analysed for the occurrence of hypernatremia and subsequent signs of hypermetabolism. The urea: creatinine ratio-as a surrogate for hypermetabolism-sufficiently discriminated between two groups. Four of nine hypernatremic burn patients (44%) had a highly elevated urea: creatinine ratio, which was clearly associated with an increased urea production and catabolic index. This hypermetabolism was linked to hypernatremia via an elevated urea- and reduced electrolyte-fraction in renal osmole excretion, which resulted in an increased renal loss of electrolyte-free water. In hypermetabolic severely burned patients, the electrolyte-free water clearance is a major contributor to hypernatremia. A positive correlation to serum sodium concentration was shown.
| S-EPMC7146173 | biostudies-literature
Project description:Recent studies have shown that constitutive activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in Schwann cells (SCs) increases myelin thickness in transgenic mice. In this secondary analysis, we report that these transgenic mice develop a postnatal corneal neurofibroma with the loss of corneal transparency by age six months. We show that expansion of non-myelinating SCs, under the control of activated ERK1/2, also drive myofibroblast differentiation that derives from both SC precursors and resident corneal keratocytes. Further, these mice also harbor activated mast cells in the central cornea, which contributes to pathological corneal neovascularization and fibrosis. This breach of corneal avascularity and immune status is associated with the growth of the tumor pannus, resulting in a corneal stroma that is nearly four times its normal size. In corneas with advanced disease, some axons became ectopically myelinated, and the disruption of Remak bundles is evident. To determine whether myofibroblast differentiation was linked to vimentin, we examined the levels and phosphorylation status of this fibrotic biomarker. Concomitant with the early upregulation of vimentin, a serine 38-phosphorylated isoform of vimentin (pSer38vim) increased in SCs, which was attributed primarily to the soluble fraction of protein-not the cytoskeletal portion. However, the overexpressed pSer38vim became predominantly cytoskeletal with the growth of the corneal tumor. Our findings demonstrate an unrecognized function of ERK1/2 in the maintenance of corneal homeostasis, wherein its over-activation in SCs promotes corneal neurofibromas. This study is also the first report of a genetically engineered mouse that spontaneously develops a corneal tumor.
| S-EPMC5586542 | biostudies-literature
Project description:Severe burn results in muscle wasting affecting quality of life in both children and adults. Biologic metabolic profiles are noticeably distinctive in childhood. We posit that muscle gene expression profiles are differentially regulated in response to severe burns in young animals. Twelve C57BL6 male mice, including young (5 weeks-old) and adults (11 weeks-old), received either scald burn, or sham procedure. Mouse muscle tissue was harvested 24 hours later for Next Generation Sequence (NGS) analysis. Our results showed 662 downregulated and 450 upregulated genes in gastrocnemius of young mice compared to adults without injury. After injury, we found 74/75 downregulated genes and 107/128 upregulated genes in both burned groups compared to respective uninjured age groups. VEGFA-VEGFR2, focal adhesion, and nuclear receptor meta-pathways were the top 3 gene pathways undergoing a differential change in response to age. Of note, the proteasome degradation pathway showed the most similar changes in both adult and young burned animals. This study demonstrates the characteristic profile of gene expression in skeletal muscle in young and adult burned mice. Prominent age effects were revealed in transcriptional levels with increased alterations of genes, miRNAs, pathways, and interactions.
2022-11-04 | GSE208548 | GEO
Project description:Severe burn results in muscle wasting affecting quality of life in both children and adults. Biologic metabolic profiles are noticeably distinctive in childhood. We posit that muscle gene expression profiles are differentially regulated in response to severe burns in young animals. Twelve C57BL6 male mice, including young (5 weeks-old) and adults (11 weeks-old), received either scald burn, or sham procedure. Mouse muscle tissue was harvested 24 h later for Next Generation Sequence analysis. Our results showed 662 downregulated and 450 upregulated genes in gastrocnemius of young mice compared to adults without injury. After injury, we found 74/75 downregulated genes and 107/128 upregulated genes in both burned groups compared to respective uninjured age groups. VEGFA-VEGFR2, focal adhesion, and nuclear receptor meta-pathways were the top 3 gene pathways undergoing a differential change in response to age. Of note, the proteasome degradation pathway showed the most similar changes in both adult and young burned animals. This study demonstrates the characteristic profile of gene expression in skeletal muscle in young and adult burned mice. Prominent age effects were revealed in transcriptional levels with increased alterations of genes, miRNAs, pathways, and interactions.
| S-EPMC9748408 | biostudies-literature
Project description:BackgroundPost-burn hyperglycemia leads to graft failure, multiple organ failure, and death. A hyperinsulinemic-euglycemic clamp is used to keep serum glucose between 60 and 110 mg/dL. Because of frequent hypoglycemic episodes, a less-stringent sliding scale insulin protocol is used to maintain serum glucose levels between 80 and 160 mg/dL after elevations >180 mg/dL.Study designWe randomized pediatric patients with massive burns into 2 groups, patients receiving sliding scale insulin to lower blood glucose levels (n = 145) and those receiving no insulin (n = 98), to determine the differences in morbidity and mortality. Patients 0 to 18 years old with burns covering ≥ 30% of the total body surface area and not randomized to receive anabolic agents were included in this study. End points included glucose levels, infections, resting energy expenditure, lean body mass, bone mineral content, fat mass, muscle strength, and serum inflammatory cytokines, hormones, and liver enzymes.ResultsMaximal glucose levels occurred within 6 days of burn injury. Blood glucose levels were age dependent, with older children requiring more insulin (p < 0.05). Daily maximum and daily minimum, but not 6 am, glucose levels were significantly different based on treatment group (p < 0.05). Insulin significantly increased resting energy expenditure and improved bone mineral content (p < 0.05). Each additional wound infection increased incidence of hyperglycemia (p = 0.004). There was no mortality in patients not receiving insulin, only in patients who received insulin (p < 0.004). Muscle strength was increased in patients receiving insulin (p < 0.05).ConclusionsBurn-induced hyperglycemia develops in a subset of severely burned children. Length of stay was reduced in the no insulin group, and there were no deaths in this group. Administration of insulin positively impacted bone mineral content and muscle strength, but increased resting energy expenditure, hypoglycemic episodes, and mortality. New glucose-lowering strategies might be needed.
| S-EPMC4045114 | biostudies-literature
Project description:Continuous renal replacement therapy (CRRT) is administered to critically ill patients with renal injuries as renal replacement or renal support. We aimed to identify predictors of mortality among burn patients receiving CRRT, and to investigate clinical differences according to acute kidney injury (AKI) status. This retrospective observational study evaluated 216 Korean burn patients who received CRRT at a burn intensive care unit. Patients were categorized by AKI status. Data were collected regarding arterial pH, laboratory results, ratio of arterial oxygen partial pressure to fractional inspired oxygen (PF ratio), and urine production. Among surviving patients, CRRT duration and the sequential organ failure assessment score were 6.5 days and 4.7 in the non-AKI group and 23.4 days and 7.4 in the AKI group, respectively (p = 0.003 and p = 0.008). On logistic regression analyses, mortality was significantly associated with a pH of <7.2 (p = 0.004), potassium levels of >5.0 mEg/L (p = 0.045), creatinine levels of >2.0 mg/dL (p = 0.011), lactate levels of >2 mmol/L (p<0.001), a PF ratio of <200 (p = 0.042), and a platelet count of <100,000/μL (p<0.001). In the AKI group, poor outcomes were associated with a pH of <7.2, potassium levels of <5.0 mEg/L, lactate levels of >2 mmol/L, and a platelet count of <100,000/μL, while good outcomes were associated with creatinine levels of >2 mg/dL. In the non-AKI group, poor outcomes were associated with lactate levels of >1.5 mmol/L, a PF ratio of <200, and a platelet count of <100,000/μL, while good outcomes were associated with creatinine levels of >1.2 mg/dL. Duration of the CRRT application and the requirement for either renal replacement or renal support at the initiation of CRRT application are important considerations depending on its application.
| S-EPMC5708827 | biostudies-literature