Search Results (8,836)

The etiology of autism spectrum disorder (ASD) implicates genetic predispositions and environmental chemicals, such as polybrominated diphenyl ethers (PBDEs). We aimed to identify whether mitochondrial quality control (MQC) was involved in ASD-relevant behavioral changes induced by decabromodiphenyl ether (deca-BDE, BDE-209) and the alleviation by melatonin. Pregnant rats exposed to BDE-209 (50mg/kg i.g.) were administrated melatonin through drinking water (0.2 mg/mL) during gestation and lactation. Behavioral assessments integrated open-field test, three-chamber social test, and Morris water maze; mitochondrial detections took transmission electron microscopy, immunofluorescence, and homeostasis together; hippocampal molecular network was identified through transcriptomics profiles, combining dendritic morphology analysis after Golgi-Cox staining. Melatonin supplementation attenuated BDE-209-reduced social and cognitive ability, accompanied by improvements in hippocampal synaptic plasticity (dendritic spines, PSD95, SNAP25). Mitochondrial dysfunctions, shown as decreases in complex IV activity, ATP content, and mtDNA copies, plus redox imbalance (ROS/SOD2) and resultant mitochondrial membrane potential disruption and apoptosis, together with fusion/fission dynamic (MFN2/DRP1), biogenesis (SIRT1-PGC1α-TFAM), and mitophagy (SIRT3-FOXO3-PINK1) suppression, were reversed by melatonin partially through SIRT1 (Sirtuin-1)-dependent pathways, as these protections were abolished by inhibitor EX527. This study highlighted the SIRT1–SIRT3 axis in MQC and behavioral effects, providing novel intervention for PBDEs’ neurodevelopmental impairment. Full article

Heart failure (HF) with reduced ejection fraction is a systemic disorder that extends beyond cardiac dysfunction and involves peripheral organs, particularly skeletal muscle. Exercise intolerance and fatigue are the hallmark manifestations of HF that strongly predict morbidity and mortality. Accumulating evidence suggests that intrinsic skeletal muscle abnormalities are key contributors to exercise intolerance in HF. In HF, skeletal muscle undergoes metabolic remodeling characterized by shifts in fiber type composition, mitochondrial dysfunction, and increased oxidative stress. Mitochondrial dysfunction, characterized by decreased mitochondrial density, impaired biogenesis, and reduced respiratory capacity, further compromises skeletal muscle performance. These alterations impair adenosine triphosphate (ATP) generation via oxidative phosphorylation, forcing reliance on less efficient anaerobic glycolysis. The resulting metabolic shift exacerbates early lactate accumulation, muscle fatigue, and diminished exercise capacity. In parallel, an increase in oxidative and carbonyl stress, along with a decrease in antioxidant defenses as well as derangements in pathways that remove toxic lipid peroxidation, heightens oxidative and carbonyl stress perpetuating injury and establishing a vicious cycle of progressive muscle dysfunction. Thus, metabolic remodeling in skeletal muscle represents a central determinant of exercise intolerance in HF. While exercise training remains the most effective strategy to restore skeletal muscle health and exercise tolerance, emerging therapies offer novel avenues for intervention. Future research should focus on elucidating the molecular mechanisms underlying skeletal muscle dysfunction and developing therapies that restore metabolic integrity and functional capacity in HF. Full article

Background/Objectives: Diuretics are recommended for hemodynamically stable patients with COVID-19-associated acute respiratory distress syndrome (ARDS) who have a positive fluid balance. However, furosemide use may be limited by hypokalemia in this population. We aimed to evaluate the clinical and biochemical effects of spironolactone in critically ill patients with COVID-19-associated ARDS. Methods: In this retrospective cohort study, 60 patients with COVID-19-associated ARDS admitted to the intensive care unit (ICU) between March and May 2020 were grouped according to diuretic therapy (furosemide vs. spironolactone). Patients were followed for five days (T0–T4). Demographic characteristics and clinical/laboratory parameters were recorded. A two-sided p value < 0.05 was considered statistically significant. Results: Thirty-one patients received furosemide (F group) and 29 received spironolactone (S group). On day 5, in the F group, cumulative fluid balance and serum sodium increased significantly over time (p < 0.05). Lactate increased significantly over time in both groups (p < 0.05). N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels increased significantly from T0 to T4 in the F group (p < 0.05). Conclusions: Spironolactone use was associated with a more favorable trajectory of organ dysfunction and improved volume, electrolyte, and cardiac stress marker dynamics compared with furosemide in patients with COVID-19-associated ARDS. Although confirmation in larger prospective studies is needed, spironolactone may be considered a reasonable diuretic alternative in selected patients, particularly when potassium preservation and avoidance of hypernatremia are clinical priorities. Full article

Erythroid acute myeloid leukemia (AML) cell line OCI-M2 expresses a particular oncogenic network: IRF6, in concert with ETV2 and HEY1, aberrantly activates NKL homeobox gene NKX2-4, which in turn represses megakaryocytic lineage factor FLI1. Interestingly, in keratinocytes, IRF6 is able to bind glucose which promotes IRF6-dimerization and thus alters its binding site selection. Here, we used OCI-M2 as a model to investigate the role of glucose level and IRF6 in leukemogenesis. Treatment of OCI-M2 with high glucose or 2-deoxy-glucose resulted in the downregulation of IRF6 and NKX2-4, and the upregulation of FLI1, indicating that glucose-mediated dimerization of IRF6 altered its reported autoactivation. The screening of this cell line for genes encoding glycolytic enzymes identified aberrant overexpression of glucose-6-phosphate isomerase (GPI) and phosphofructokinase L (PFKL), which were targeted by genomic amplification and chromothripsis-like alterations, respectively. Furthermore, GPI was activated by NKX2-4 and ETV2, and PFKL by ETV2. Finally, siRNA-mediated downregulation of PFKL resulted in elevated glucose levels, suppressed expression of IRF6 and NKX2-4, and activated FLI1. Thus, we connected an oncogenic regulatory network with deregulated glycolytic enzymes and glucose metabolism, thereby establishing a new in vitro model to develop novel therapeutic avenues in AML subsets. Full article

Background and Objectives: Diabetes mellitus (DM) is a highly prevalent comorbidity among critically ill patients and may significantly influence intensive care unit (ICU) outcomes through metabolic, immune, and cardiovascular mechanisms. This study aimed to evaluate the impact of DM on clinical profile, comorbidities, complications, need for intensive support, and mortality in adult ICU patients. Materials and Methods: A retrospective observational study was conducted between January and December 2024 in a tertiary ICU, including 1344 adult patients. Among them, 435 (32.37%) had DM. Demographic data, admission diagnoses, laboratory parameters, comorbidities, complications, therapeutic interventions, and outcomes were analyzed. Comparative statistical analysis and multivariate logistic regression were performed to identify independent predictors of ICU mortality. Results: Patients with DM were significantly older than patients without diabetes mellitus (non-DM group) (69.62 ± 10.26 vs. 67.16 ± 14.26 years, p < 0.001) and more frequently female (57%, p = 0.0002). At admission, they presented higher glycemia (204.7 vs. 134.0 mg/dL, p < 0.00001), reduced glomerular filtration rate (47.2 vs. 59.5 mL/min/1.73 m², p < 0.00001), and more pronounced lymphocytopenia (p = 0.025). Cardiovascular and renal comorbidities were significantly more prevalent in DM, including hypertension (76.3%), heart failure (32.4%), and chronic kidney disease (33.1%) (all p < 0.01). DM was associated with increased odds of sepsis (OR 1.56), acute kidney injury (OR 1.51), and obesity (OR 2.57). ICU mortality was significantly higher in patients with DM (54.9% vs. 46.3%, p = 0.004; RR 1.19). Independent predictors of death included mechanical ventilation (OR 36.48), inotropic therapy (OR 4.74), hemodialysis (OR 2.57), elevated lactate, neutrophilia, and reduced glomerular filtration rate (GFR). Conclusions: DM was associated with increased ICU mortality and a higher burden of cardio-renal comorbidities and complications; however, mortality in the multivariate model was primarily driven by markers of organ dysfunction and the need for advanced supportive therapies. Early risk stratification and individualized management strategies are essential to improve outcomes in critically ill patients with diabetes. Full article

Background: Hypoxic–ischemic encephalopathy (HIE) remains a major cause of neonatal mortality and long-term neurodevelopmental impairment despite advances in perinatal care and the widespread use of therapeutic hypothermia. Reliable early prognostic markers are essential for risk stratification and long-term follow-up planning. This study aimed to evaluate long-term neurodevelopmental outcomes and associated prognostic factors in neonates with HIE treated in the era of therapeutic hypothermia. Methods: This retrospective cohort study was conducted in a tertiary neonatal intensive care unit between January 2020 and June 2024. Neonates with gestational age ≥ 35 weeks diagnosed with HIE were included. Clinical characteristics, laboratory parameters, neurophysiological findings, neuroimaging results, and indicators of multiorgan dysfunction were recorded. Long-term neurodevelopmental outcomes were assessed at 18 to 24 months of age. The primary outcome was death or severe neurodevelopmental impairment. Multivariable logistic regression analysis was performed to identify independent predictors of adverse outcomes. Results: A total of 99 neonates were included. Therapeutic hypothermia was administered to 86 (86.9%) infants. Severe neurodevelopmental impairment or death occurred in 18 (18.2%) patients. Cerebral palsy was diagnosed in 19 (20.9%) survivors, developmental delay in 12 (13.2%), epilepsy in 16 (17.6%), and feeding difficulties in 9 (9.9%). In multivariable analysis, higher lactate levels (adjusted OR = 1.239, 95% CI = 1.052–1.458), lower Apgar score at 5 min (adjusted OR = 0.570, 95% CI = 0.344–0.944), and renal dysfunction (adjusted OR = 7.947, 95% CI = 2.027–31.164) were independently associated with severe neurodevelopmental impairment or death. Multiorgan dysfunction and abnormal neurophysiological and neuroimaging findings were significantly associated with adverse outcomes. Conclusions: Early biochemical markers, neurological assessments, neurophysiological recordings, neuroimaging patterns, and systemic organ dysfunction are closely associated with long-term neurodevelopmental outcomes in neonates with HIE. A multidimensional approach to early prognostic evaluation may improve risk stratification and guide targeted follow-up and intervention strategies. Full article

Severe hypercalcemia is a life-threatening condition requiring immediate treatment alongside a systematic evaluation to identify the underlying cause. Although malignancy is a common etiology among hospitalized patients, alternative causes must be considered to guide targeted therapy, as illustrated in these cases. The first case involved a 31-year-old postpartum woman with corrected calcium levels of 14.5 mg/dL and suppressed PTH. Hypercalcemia resolved after tapering and temporary cessation of breastfeeding, consistent with lactation-associated hypercalcemia that is likely PTHrP-mediated. The second case describes a 30-year-old woman who presented with hypotension, hypercalcemia, hyperphosphatemia, and low PTH. A systematic evaluation revealed severe glucocorticoid deficiency consistent with primary adrenal insufficiency (Addison’s disease). The final case featured a 47-year-old man with severe symptomatic hypercalcemia (18.5 mg/dL) and markedly elevated PTH. Imaging revealed a 3 cm parathyroid tumor. Selective parathyroidectomy produced a rapid intraoperative PTH decline, and pathology supported parathyroid adenoma rather than carcinoma. Together, these cases highlight that symptomatic severe hypercalcemia is a medical emergency warranting prompt clinical intervention, followed by an early PTH-based stratification to direct a focused, stepwise diagnostic workup and definitive management. Full article

Background: Congested tournament schedules impose substantial physiological stress in team sports; however, the integrated endocrine and inflammatory responses to real competitive match load in female handball players remain insufficiently characterized. Objective: This study aimed to characterize the acute biochemical responses, including hormonal, inflammatory, muscle damage, and bone metabolism markers, elicited by competitive tournament load in female handball players and to provide practical insights for optimizing recovery strategies and load management during short-term competitive periods. Methods: In a pre–post study design, venous blood samples were collected from competitive female athletes (n = 8; age 20.83 ± 2.93 years) before the first match and after the fourth consecutive match of an official university qualification tournament. Biochemical analyses included cortisol, insulin, IL-6, creatine kinase (CK), IGF-1, irisin, lactate dehydrogenase (LDH), osteocalcin, and testosterone. Pre-to-post changes were assessed using paired t-tests and effect sizes. Results: Tournament load induced substantial multisystem physiological perturbations. Significant increases were observed in cortisol (p < 0.001), insulin (p = 0.044), IL-6 (p < 0.001), CK (p < 0.001), and osteocalcin (p = 0.005), indicating activation of the hypothalamic–pituitary–adrenal axis, systemic inflammation, muscle membrane disruption, and enhanced bone turnover. Conversely, IGF-1 (p < 0.001) and testosterone (p = 0.004) significantly decreased, reflecting suppression of anabolic signaling and a shift toward a catabolic hormonal environment under cumulative match stress. LDH significantly decreased (p = 0.002), while irisin showed no significant change (p > 0.05). Conclusions: These findings demonstrate that congested tournament schedules provoke an integrated endocrine–inflammatory stress response in female handball players. Importantly, the observed anabolic–catabolic imbalance highlights the need for individualized recovery strategies, optimized load management, and adequate recovery periods to mitigate maladaptation and reduce injury risk during short-term competitive tournaments. Full article

Background/Objectives: Acute kidney injury (AKI) remains a significant complication following cardiac surgery, associated with increased morbidity and mortality. The early detection of AKI is limited by the cost, availability, and unclear clinical utility of the current biomarkers. This study aimed to evaluate the red cell distribution width (RDW) on ICU admission as a predictor of postoperative AKI. Methods: We conducted a retrospective analysis of adult patients undergoing isolated coronary artery bypass grafting (CABG) or combined CABG and aortic valve surgery at a tertiary cardiac surgery centre (University Hospital of Siena, Italy) between January 2015 and December 2020. AKI was defined according to the KDIGO criteria. The RDW was measured preoperatively (T0), at ICU admission (T1), and at 24 (T2) and 48 h (T3) postoperatively. Temporal RDW changes (ΔRDW) were also calculated. Multivariate logistic regression identified independent predictors of AKI, and receiver operating characteristic (ROC) analysis evaluated the predictive accuracy. Results: A total of 456 patients were included, with an overall AKI incidence of 31%. Patients developing AKI exhibited significantly higher RDW at all measured time points, especially at ICU admission. Multivariate analysis identified age, RDW (OR 1.19, 95% CI: 1.03–1.37, p = 0.016) and serum creatinine at ICU admission, and elevated lactate at T2 as independent AKI predictors. In subgroup analyses, RDW at ICU admission remained significantly associated with AKI in patients who were not transfused, but not in patients who were. Conclusions: In this study, a high RDW at ICU admission represented an early postoperative marker independently associated with AKI after cardiac surgery, particularly in patients who did not receive transfusion. Full article

Background: The perioperative period in cancer surgery is characterized by transient metabolic and inflammatory perturbations that may influence early postoperative biochemical dynamics. Surgical stress induces insulin resistance, hyperglycemia, cytokine activation, and metabolic shifts that interact with tumor cell signaling pathways. Intravenous lidocaine has been associated with anti-inflammatory and systemic stabilizing effects beyond analgesia. We investigated whether perioperative lidocaine administration during robotic-assisted radical prostatectomy (RARP) is associated with early postoperative prostate-specific antigen (PSA) dynamics within the context of perioperative metabolic–inflammatory modulation. Methods: In this single-center retrospective cohort study, 180 patients undergoing RARP for localized or locally advanced prostate cancer were stratified according to perioperative intravenous lidocaine exposure. The primary endpoint was undetectable PSA (<0.1 ng/mL) at 6–12 weeks postoperatively. Secondary endpoints included PSA detectability at 3 and 6 months and time to first detectable PSA. Multivariable logistic and Cox regression models were adjusted for established oncologic risk factors. Perioperative glycemic variation, intraoperative lactate dynamics, and postoperative IL-6 levels were analyzed as indicators of stress-induced metabolic activation. Results: Lidocaine exposure was independently associated with higher odds of undetectable PSA at 6–12 weeks (OR 2.10, 95% CI 1.15–3.85) and at subsequent time points. In Cox analysis, lidocaine was associated with a reduced hazard of PSA detectability (HR 0.58, 95% CI 0.37–0.92). Patients receiving lidocaine demonstrated significantly attenuated perioperative hyperglycemia, lower lactate elevation, and reduced IL-6 response. Conclusions: Perioperative intravenous lidocaine administration during RARP was associated with more favorable early PSA dynamics and attenuation of perioperative metabolic–inflammatory activation. Given the retrospective and non-randomized design of the study, these findings should be interpreted as associative and hypothesis-generating, and warrant confirmation in prospective controlled investigations. Full article

Extracellular vesicles (EVs), particularly exosomes, have emerged as critical mediators of intercellular communication, yet the metabolite fraction of their cargo remains substantially underexplored relative to proteins and nucleic acids. This review synthesizes current knowledge on the exosomal metabolome as a functionally distinct intercellular signaling system with unique biophysical properties. We review the mechanisms proposed to govern metabolite encapsulation into exosomes, encompassing membrane transporter involvement, lipid raft partitioning, and binding to luminal proteins, and discuss the unresolved question of whether metabolite loading is selective or stochastic. Critically, we present a quantitative framework evaluating whether delivered metabolite quantities are sufficient to alter recipient cell metabolic pools, distinguishing receptor-mediated signaling from bulk substrate delivery. We also address methodological considerations including contamination artifacts and isolation-method biases that complicate interpretation of EV metabolomics data. Exosomal metabolites are reviewed across four functional categories: energy substrates (ATP, lactate, amino acids), signaling molecules (TCA cycle intermediates, eicosanoids, nucleotides), redox cofactors and antioxidants (NADH, glutathione), and oncometabolites. For each category, available evidence is critically appraised, distinguishing metabolites with direct mass spectrometric detection from those whose roles are inferred from parent-cell biology. The review examines the roles of exosomal metabolites in tumor-stroma metabolic symbiosis, immunometabolic regulation, inter-organ crosstalk in metabolic diseases including type 2 diabetes and non-alcoholic fatty liver disease, cancer metastasis, viral infections, and immune evasion. A quantitative framework is discussed to evaluate whether delivered metabolite quantities are sufficient to alter recipient cell metabolic pools, distinguishing receptor-mediated signaling from bulk substrate delivery. Technical challenges in exosomal metabolomics are reviewed, including the impact of isolation method on data quality, contamination artifacts, and current standardization gaps. Therapeutic implications of exosomal metabolite signaling are discussed, encompassing metabolite-loaded exosomes as therapeutic vehicles and exosomal metabolite loading as a pharmacological target. Integration of single-vesicle technologies with systems biology approaches is highlighted as a promising direction for advancing this field toward precision medicine applications in oncological and metabolic disorders. Full article

The objective of this research was to examine how varying dietary inclusion levels of Lactobacillus plantarum influence the muscle composition, hemolymph biochemical indices, lipid metabolism, and the mTOR signaling pathway in red claw crayfish (Cherax quadricarinatus). Four diets with 0 (CK), 0.10 (LG), 1.00 (MG), and 10.00 (HG) g/kg L. plantarum were formulated, with three replicates of 40 crayfish (average weight: 0.13 ± 0.01 g, average length: 0.58 ± 0.01 cm) in a 56-day trial. Results showed that no significant differences in muscle crude protein, crude lipid, ash, or moisture were observed between experimental and CK groups (p > 0.05), while the contents of multiple essential amino acids (e.g., arginine up to 6.05%, histidine up to 7.52%) and non-essential amino acids (e.g., aspartic acid up to 3.70%, glutamic acid up to 1.76%) were significantly elevated, and the content of muscle C18:0 (a saturated fatty acid) was notably reduced (p < 0.05), while total saturated fatty acids showed no significant variation among all groups (p > 0.05). Hemolymph alkaline phosphatase, transaminases, lactate dehydrogenase, and lysozyme activities, as well as glucose, total protein, and albumin levels, were significantly higher in experimental groups (p < 0.05). Lipid metabolism was upregulated, and the mTOR pathway was inhibited in experimental crayfish (p < 0.05). This study demonstrates that dietary L. plantarum enhances lipid metabolism in red claw crayfish, with 1.0 g/kg L. plantarum identified as the optimal supplementation level. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, arising from profound metabolic reprogramming and widespread epigenetic dysregulation. However, the role of epigenetic aberrations in modulating metabolic reprogramming and the interplay between cis-regulatory elements (CREs), such as promoters, enhancers and super-enhancers, and metabolic adaptation have not been systematically summarized. Therefore, this review aims to integrate current evidence to elucidate the mechanisms of how cis-regulatory elements (CREs) drive oncogenic and metabolic signals in HCC progression. For instance, enhancers and super-enhancers transcriptionally activate key metabolic genes involved in aerobic glycolysis (GLUT1, HK2, PKM2, LDHA), de novo lipogenesis (ACLY, FASN, ACC), glutaminolysis (SLC1A5, GLS), and nucleotide synthesis. Meanwhile, many metabolic intermediates, including acetyl-CoA, succinyl-CoA and lactate, act as cofactors or substrates for epigenetic modifiers, creating bidirectional feedback loops that reinforce CRE-driven malignant phenotypes. Therefore, aberrant CREs acts as “metabolic switches” that sense and respond to various metabolic conditions to sustain HCC growth. Consequently, targeted intervention against oncogenic CREs, such as super-enhancers or their co-activators, to disrupt CRE-mediated metabolic vulnerabilities, has emerged as a highly promising new paradigm for precision therapy in HCC. Full article

Antibiotic residues in water buffalo milk are a food-safety concern, yet depletion data are scarce. The purpose of this study was to characterize the depletion profiles of amoxicillin (AMOX) and its two major metabolites, amoxicilloic acid (AMA) and amoxicillin diketopiperazine-2′,5′-dione (2,5-DKP), in Anatolian water buffalo milk after a single intramuscular administration and to estimate a milk withdrawal time relative to the EU MRL. We tested the hypothesis that AMOX concentrations would decrease below the EU MRL over successive milkings and that AMA and 2,5-DKP would exhibit depletion kinetics distinct from the parent compound. Five lactating Anatolian water buffaloes received a single intramuscular injection of amoxicillin (15 milligrams per kilogram). Milk was collected at each milking (twice daily) for seven days and analyzed by liquid chromatography–tandem mass spectrometry with quantification limits below the European Union maximum residue limit for amoxicillin in milk (4 micrograms per kilogram). Amoxicillin peaked at the second milking (mean 13.65 micrograms per kilogram), mean concentrations fell below the maximum residue limit from the sixth milking, and they became non-quantifiable from the tenth milking onward. Two major metabolites, amoxicillinic acid and amoxicillin diketopiperazine-2′,5′-dione, peaked earlier (2,5-DKP Tmax 12 h) or at higher concentrations (AMA Cmax 32.64 µg/kg vs. AMOX 13.65 µg/kg) and remained detectable up to the thirteenth milking, with longer apparent terminal half-lives (32.0 and 52.8 h) than amoxicillin (23.5 h); the mixed-effects model confirmed different depletion rates among analytes (milking × analyte interaction p = 4.63 × 10⁻⁵). A log-linear withdrawal model applying the EMA 95/95 tolerance limit indicated that the first time point at which the upper tolerance limit fell below the EU MRL was 84.7 h after dosing; rounded up to the next 12 h milking interval, this corresponds to a reported withdrawal period of 96 h (≈8 milkings). These results provide species-specific residue kinetics for amoxicillin in Anatolian buffalo milk and support considering metabolites in monitoring and withdrawal-time decisions. Full article

Colic is a leading cause of mortality in horses, particularly when associated with systemic inflammation and organ dysfunction. In human medicine, these complications are associated with sepsis, defined as organ dysfunction caused by a dysregulated, life-threatening host response to infection. However, no consensus sepsis score exists for adult horses. This retrospective study aimed to develop a diagnostic sepsis score for adult horses. Medical records from 295 horses admitted for colic to the Oniris equine emergency department (Nantes, France) between July 2011 and November 2021 were analyzed. Horses were classified as having sepsis or colic based on their final diagnosis. Clinical and laboratory parameters were assessed, and univariate and multivariate logistic regression analyses yielded a predictive score. The optimal threshold was determined by maximizing sensitivity and specificity. Sepsis was diagnosed in 89 horses (30.2%). Six parameters—temperature, heart rate, leukocyte count, red blood cells, creatine kinase, and lactate—were included in the model. The score showed 79% accuracy, with 59% sensitivity and 88% specificity. At a threshold of 3, sensitivity was 52.7%, specificity was 91.6%, and the Youden index was 0.44. This study proposes a rapid, practical sepsis diagnostic score for adult horses with acute gastrointestinal disease, serving as a highly specific tool for confirming sepsis. Full article