Search Results (1,120)

Background/Objectives: Infantile epileptic spasms syndrome (IESS) is a severe epilepsy of infancy. Corticotropin (ACTH) and vigabatrin are the only FDA-approved therapies. The efficacy of ACTH together with the strong convulsant effects of corticotropin-releasing hormone (CRH) suggests that excess CRH, secondary to impaired ACTH feedback, may contribute to spasms. We therefore hypothesized that CRH receptor 1 (CRHR1) antagonists would suppress spasms in a route- and drug-dependent manner. Methods: Using our validated rat model of IESS, in which prenatal priming with betamethasone was followed by postnatal triggering of spasms with N-methyl-D-aspartic acid (NMDA), we tested two CRHR1 antagonists, CP376395 and SN003, delivered intracranially (via intracerebroventricular or intraparenchymal infusion) or systemically. Results: Intracerebroventricular infusion of both antagonists suppressed spasms, with CP376395 providing more consistent effects. Intraparenchymal administration into the hypothalamic arcuate nucleus also reduced spasms, whereas misses into the mammillary bodies were ineffective, highlighting site specificity. Systemic administration yielded divergent results: SN003 robustly suppressed spasms, whereas CP376395 unexpectedly exacerbated them. No sex differences were observed. Conclusions: These findings demonstrate that CRHR1 blockade modifies experimental spasms in a route- and drug-specific manner and implicates discrete hypothalamic circuits, particularly those including the arcuate nucleus, in spasm generation. The divergent systemic responses between CP376395 and SN003 likely reflect differences in CRHR1 engagement (competitive and non-competitive antagonism, respectively) as well as differences in binding properties that may include differential network interactions beyond local CRH signaling or duration of receptor occupancy. In conclusion, SN003 may be a better option than CP376395 for further development as a CRHR1-targeted therapy pending additional pharmacokinetic/pharmacodynamic studies. Further work should explore dosing paradigms of CP376395 to determine if a therapeutic range for CP376395 exists. Full article

This study aimed to investigate the response mechanisms of liver and gill tissues in mandarin fish (Siniperca chuatsi) at the histological, apoptotic, and gene expression levels during the weaning process from live prey to artificial feed. By analyzing fish samples at different domestication stages (D0, D7, D14), the results revealed that: (1) Histologically, the gill filaments exhibited shortening and thickening post-domestication, while the liver showed increased vacuolation; (2) apoptosis detection (TUNEL assay) and analysis of apoptosis-related gene (Bax/Bcl-2) expression indicated that the gill tissue experienced a significant increase in apoptosis at the mid-domestication stage (D7), which returned to baseline levels later (D14), whereas hepatic apoptosis showed no significant changes throughout the process; (3) transcriptome sequencing identified 3405 and 881 differentially expressed genes (DEGs) in the liver and gill tissues, respectively, and the significantly enriched pathways were steroid biosynthesis in the liver and alanine, aspartate, and glutamate metabolism in the gills. The apoptosis pathway was also significantly enriched in both tissues. GO analysis further indicated that the DEGs were primarily associated with metabolic processes, oxidative stress, and cell apoptosis. In conclusion, artificial feed domestication induces adaptive changes in the tissue structure and molecular profiles of the gill and liver in mandarin fish. The gill response to dietary transition is more rapid and characterized by a reversible apoptotic process, providing a theoretical foundation for understanding the stress mechanisms associated with domestication and promoting healthy aquaculture practices for this species. Full article

Background: Severe hypertriglyceridemia (SHTG) in children is a rare but clinically significant disorder associated with recurrent acute pancreatitis and substantial morbidity. Early identification and prompt management are essential to prevent pancreatic and systemic complications. Methods: We report the case of an 11-year-old female with a history of xanthogranulomatous pancreatitis who presented with extreme hypertriglyceridemia, with fasting triglyceride levels exceeding 4000 mg/dL. Results: The patient was treated acutely with continuous intravenous aspart insulin (0.1 U/kg/hour) and adjusted 10% glucose infusion, with hourly glucose and potassium monitoring, leading to a rapid and marked reduction in triglyceride levels—55% reduction within the first 24 h, 76% at 48 h, and 82% after 96 h of treatment. No hypoglycemia or other adverse effects were observed. Nutritional management included a low–long-chain triglyceride (LCT) diet enriched with medium-chain triglycerides (MCTs) and omega-3 fatty acids, providing essential calories while minimizing chylomicron production. Over a 12-month follow-up, the patient remained asymptomatic, with sustained lipid normalization and no recurrence of pancreatitis. Conclusions: This case underscores the therapeutic value of combining pharmacologic and dietary strategies in pediatric SHTG. Evidence from pediatric and adult studies supports the role of insulin infusion for acute triglyceride lowering and MCT-based nutritional therapy for long-term control. Our findings highlight the need for early, individualized, and multidisciplinary management and emphasize the potential future role of emerging targeted therapies in addressing refractory pediatric hypertriglyceridemia. Full article

The aggregation of tau protein is a central pathological event in Alzheimer’s disease, and this pathology is hypothesized to spread via a prion-like mechanism driven by tau “seeds”. While aggregated tau from Alzheimer’s disease brains is known to contain age-related d-isomerized aspartic acid (d-Asp) residues, it remains unknown how this modification affects the seeding activity that drives disease propagation. Here, we investigated the impact of site-specific d-isomerization within R2 and R3 tau repeat-domain peptides, which form the core of tau fibrils. We demonstrate that the stereochemical integrity of these peptides is critical for their seeding function. d-isomerization at Asp314 within the R3 peptide seed severely impaired its ability to template the fibrillization of full-length tau in vitro. This finding was validated in a cellular model, where R3 seeds containing d-Asp314 were significantly less potent at inducing the formation of phosphorylated tau aggregates compared to wild-type seeds. Our results establish that Asp d-isomerization within tau seeds acts as a potent attenuator of their pathological seeding activity, suggesting this spontaneous modification may intrinsically modulate the progression of Alzheimer’s disease. Full article

Background/Objectives: There is no definitive consensus regarding the effects of melatonin on cardiometabolic risk factors (CMRFs). This systematic review and dose–response meta-analysis of randomized controlled trials (RCTs) evaluated the impacts of melatonin supplementation on CMRFs, including anthropometric, lipid, glycemic, inflammatory, oxidative, and liver function parameters. Methods: A systematic search across multiple databases retrieved 63 eligible RCTs published up to October 2025. Results: This random-effects meta-analysis indicated that melatonin supplementation significantly reduced hip circumference (weighted mean difference (WMD): −1.18 cm, 95% confidence interval (CI): −2.28, −0.08), systolic blood pressure (WMD: −2.34 mmHg, 95% CI: −4.13, −0.55), fasting blood glucose (WMD: −11.63 mg/dL, 95% CI: −19.16, −4.10), low-density lipoprotein cholesterol (WMD: −6.28 mg/dL, 95% CI: −10.53, −2.03), total cholesterol (WMD: −6.97 mg/dL, 95% CI: −12.20, −1.74), C-reactive protein (WMD: −0.59 mg/L, 95% CI: −0.94, −0.23), malondialdehyde (WMD: −1.54 μmol/L, 95% CI: −2.07, −1.01), tumor necrosis factor-alpha (WMD: −1.61 pg/mL, 95% CI: −2.31, −0.90), interleukin-6 (WMD: −6.43 pg/mL, 95% CI: −10.72, −2.15), and alanine aminotransferase (WMD: −2.61 IU/L, 95% CI: −4.87, −0.34). Supplementation with melatonin substantially increased serum total antioxidant capacity (WMD: 0.15 mmol/L, 95% CI: 0.08, 0.22) and high-density lipoprotein cholesterol (WMD: 2.04 mg/dL, 95% CI: 0.50, 3.57). No significant effects of melatonin were observed on body weight, waist circumference, body fat percentage, body mass index, fasting insulin, homeostasis model assessment of insulin resistance, hemoglobin A1c, triglycerides, diastolic blood pressure, aspartate aminotransferase, or gamma-glutamyl transferase. Conclusions: Melatonin supplementation significantly ameliorated multiple CMRFs. Full article

Chronic stress disrupts neuroendocrine regulation, neurotransmitter balance, and neuronal redox homeostasis, thereby contributing to the development of anxiety-related neuropathology. Arecoline, the predominant alkaloid of Areca catechu L., displays diverse neuropharmacological properties, yet its role in stress-induced emotional dysfunction has not been fully elucidated. This study examined the anxiolytic-like and neuroprotective effects of arecoline in mice exposed to chronic unpredictable mild stress (CUMS). Arecoline administration markedly improved behavioral outcomes, reflected by increased central exploration in the open-field test, prolonged time in the light compartment, and enhanced open-arm activity in the elevated plus maze. These behavioral benefits were accompanied by normalization of serum corticosterone levels, restoration of hippocampal neurotransmitters, reinforcement of antioxidant enzyme activities, and attenuation of pro-inflammatory cytokines. At the molecular level, arecoline elevated brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), cAMP response element-binding protein (CREB), N-methyl-D-aspartate receptor (NMDAR), and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), indicating enhanced synaptic plasticity, while concurrently diminishing oxidative and inflammatory stress. Collectively, the findings suggest that arecoline exerts multifaceted neuroprotective actions under chronic stress by coordinating neuroendocrine modulation, neurotransmitter homeostasis, antioxidant defenses, and synaptic plasticity. This study provides new mechanistic evidence supporting the potential relevance of arecoline as a functional neuroactive compound for managing stress-induced anxiety disorders. Full article

Currently, there is no report on prediction models of standardized ileal amino acid digestibilities (SIAADs) in soybean meals (SBMs) for medium-growing yellow-feathered chickens. This study firstly analyzed the chemical compositions of 10 SBMs, then determined their SIAADs in chickens, and finally established and verified prediction models for SBM SIAADs based on their chemical compositions and amino acid (AA) profiles. A total of 276 55 d-old Tianluma roosters were selected and randomly divided by body weight into 11 treatment groups. On d 63, chickens were fed either a nitrogen-free diet (NFD) or one of 10 SBM diets for 5 d. On d 67, ileal chyme samples were collected to determine SIAADs. Data from nine SBM samples and stepwise regressions were employed to build prediction models, while one SBM sample was randomly selected to validate model accuracy. Different SBM sources affected (p ≤ 0.007) SIAADs in medium-growing yellow-feathered chickens. The standardized ileal digestibility (SID) of glutamic acid (Glu) was the highest (93.9%), whereas that of cysteine (Cys) was the lowest (81.7%). Fifteen prediction models (R² = 0.567–0.993, p < 0.03) for the SIDs of methionine (Met), isoleucine (Ile), leucine (Leu), phenylalanine (Phe), lysine (Lys), histidine (His), arginine (Arg), aspartic acid (Asp), serine (Ser), Glu, glycine (Gly), alanine (Ala), Cys, tyrosine (Tyr), and proline (Pro) in SBMs for medium-growing yellow-feathered chickens were effectively established based on chemical compositions and AA profiles. Among them, the prediction model for the SID of Cys showed the best fit (R² = 0.993, p = 0.002), while the model for the SID of Ala had the lowest fit (R² = 0.567, p = 0.019). Except for His and Pro, which exhibited poor predictive accuracy, all other models showed good accuracy. These prediction models thus provide a valuable reference for rapidly estimating the SIDs of key AAs in SBMs for medium-growing yellow-feathered chickens. Full article

Adverse pregnancy outcomes (APOs) such as prematurity, low birth weight, stillbirth, and birth defects remain significant global health challenges. While many risk factors are known, APOs encompass a wide range of outcomes with diverse, sometimes poorly understood etiologies. Pregnancy-related acute kidney injury (PR-AKI) and liver injury are particularly associated with increased maternal and fetal mortality. This study investigated the association between hematological parameters, kidney and liver injury markers and adverse pregnancy outcomes. This cross-sectional study involved 714 pregnant women aged 18–40 years, conducted between August 2021 and August 2022. Maternal blood samples were collected before and after delivery to compare hematological parameters. Kidney and liver injury markers were measured using standard methods. The study analysed the association of these parameters with adverse pregnancy outcomes. The median age of participants was 24 years (Q1, Q3: 21, 26). Women with adverse pregnancy outcomes had statistically significant serum creatinine levels [0.52 mg/dL (0.45, 0.58)] compared to those without [0.50 mg/dL (0.44, 0.56)], although the difference was not clinically significant. Elevated Aspartate Transaminase (AST) levels (>90th percentile) were statistically associated with adverse pregnancy outcomes. Pairwise comparisons with Bonferroni corrections revealed significant differences in Hemoglobin (Hb), White Blood Cell (WBC), Red Blood Cell (RBC), platelet, and Packed Cell Volume (PCV) levels before and after delivery (p < 0.05) in both groups. Elevated AST levels, but not other hematological or biochemical parameters, were independently associated with adverse pregnancy outcomes, whereas creatinine differences lacked clinical impact. Full article

In this research, we sought to methodically examine the protective effects of Gastrodia elata extract (GEE) on liver damage induced by D-galactose (D-gal) in mice and clarify the underlying mechanisms. The chemical composition of GEE was characterized using Ultra-Performance Liquid Chromatography–Tandem Mass Spectrometry (UPLC-MS/MS), while network pharmacology analysis was employed to predict potential molecular targets and signaling pathways. A mouse model of liver injury was established through daily intraperitoneal injection of D-gal over a 42-day period, during which the hepatoprotective efficacy of GEE was evaluated. Biochemical, histopathological, and molecular analyses were subsequently performed. UPLC-MS/MS identified ingredients such as amino acids, aromatic compounds, fatty acids, and terpenoids in GEE. A network pharmacology analysis enabled the identification of 272 common targets linked to GEE and liver damage, demonstrating notable enrichment within the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. In vivo experiments demonstrated that GEE effectively alleviated D-gal-induced body weight loss and elevated liver index values, alleviated hepatic histological damage, and reduced serum levels of Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), and Alkaline Phosphatase (ALP). Furthermore, GEE enhanced the activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), decreased malondialdehyde (MDA) levels, and downregulated the mRNA expression of the pro-inflammatory cytokines Interleukin-6 (IL-6), Interleukin-1 beta (IL-1β), and Tumor Necrosis Factor-alpha (TNF-α). Western blot analysis confirmed that GEE activated the PI3K/Akt pathway, as evidenced by increased ratios of phosphorylated Phosphatidylinositol 3-kinase/Phosphatidylinositol 3-kinase (p-PI3K/PI3K) and phosphorylated AKT/Protein Kinase B (p-AKT/AKT); restored the B-cell lymphoma 2-associated X protein/B-cell lymphoma-2 (Bax/Bcl-2) balance; and reduced cyclin-dependent kinase inhibitor 1 (p21) expression. The results suggest that GEE protects against D-gal-induced liver damage by reducing oxidative stress, inhibiting inflammatory responses, and modulating apoptosis through the activation of the PI3K/Akt signaling pathway, providing support for its potential use in hepatoprotection. Full article

Magnesium ions regulate synaptic and nonsynaptic neuronal excitability from intracellular (Mg²⁺_i) and extracellular (Mg²⁺_o) domains, modulating voltage- and ligand-gated ion channels. K+ inward rectifier (Kir) channel inward rectification arises from Mg²⁺_i blocking the pore and outward K⁺ current, while Mg²⁺_o targets external sites. Mg²⁺_i causes voltage-dependent Ca²⁺ voltage-gated (Ca_V) and Na⁺ voltage-gated (Na_V) channel block while phosphorylation modulates channel activity. Mg²⁺_o elicits direct voltage-dependent Ca_V channel block, and screens surface charge, and in Na_V channels reduces conduction and may cause depolarization by quantum tunneling across closed channels. Mg²⁺_i is an allosteric large conductance Ca²⁺-activated K⁺ (BK) channel activator, binding to low-affinity sites to alter Ca²⁺ and voltage sensitivity but reduces small conductance Ca²⁺-activated K⁺ (SK) channels’ outward K⁺ current and induces inward rectification. N-Methyl-D-aspartate receptor (NMDAR) channels are inhibited by Mg²⁺_i binding within the pore, while Mg²⁺_o stabilizes excitability through voltage-dependent block, Mg²⁺_o forms Mg-ATP complex modifying purinergic P2X receptor (P2XR) channel affinity and gating and directly blocks the pore. Mg²⁺_o reduces gamma-aminobutyric acid type A receptor (GABA_AR) channel Cl⁻ current amplitude and augments susceptibility to blockers. Mg²⁺_o and Mg²⁺_i block nicotinic acetylcholine receptor (nAChR) channels through voltage-dependent pore binding and surface charge screening, impeding current flow and altering gating. Full article

Background: Anti-N-methyl-D-aspartate IgM and IgA antibodies (NMDAR1-abs) are associated with unfavorable stroke outcomes and may be risk factors thereof. However, to utilize NMDAR1-abs serostatus for risk assessment in acute stroke, it is crucial to understand the robustness of serostatus during this phase. Therefore, we investigated the robustness of NMDAR1-abs serostatus and titer levels up to seven days after stroke. Methods: In this exploratory analysis of the multicenter STRAWINSKI trial (identifier: NCT01264549), patients with severe ischemic stroke (NIHSS ≥ 9) in the middle cerebral artery territory were included. The first blood sample was taken within 36 h and then daily from day two to seven after stroke. NMDAR1-abs immunoglobulin (Ig)A and IgM were assessed in serum using cell-based assays. We initially measured NMDAR1-abs in the total cohort on day 1. Subsequently, in samples from seropositive and matched seronegative patients, we measured NMDAR1-abs on each following day. Titer dilutions started from 1:10 up to 1:1000. Seropositivity was defined as any titer > 0. Results: Out of 171 patients (mean age = 76 [SD = 11], median NIHSS = 15 [IQR = 12–18]), 16 (9%) individuals were seropositive. Seropositive patients remained seropositive and matched seronegative participants remained seronegative over sequential measurements. Although titer levels remained largely unchanged, some patients showed fluctuating titers. Conclusions: The status of NMDAR1-abs seropositivity is stable during acute stroke, with little to no variation in titer levels. Full article

Additive manufacturing (AM), also known as 3D printing, is a rapidly growing field in industry. AM technologies include sintering, melting, and stereolithography. With steadily rising utilization, evaluating the environmental impact of AM materials has become essential, as these materials may act as emerging pollutants. Photopolymerizing resins (PRs) used in stereolithography can enter terrestrial ecosystems in polymerized and unpolymerized forms due to improper disposal. Insects are likely to be among the first organisms exposed to these contaminants in land ecosystems. This study evaluates the physiological effects of photopolymerizing resin particles (PRPs) produced via sanding on tropical house crickets (Gryllodes sigillatus) that were fed PRPs-contaminated agarose gels for 10 days. Effects were evaluated through mortality observations and enzymatic activity assays of cell transport mediating enzymes, digestive enzymes, and antioxidative stress enzymes. PRPs exposure caused sex-dependent differences in survival; an increase in amylase, alanine aminotransferase, aspartate aminotransferase, and trypsin; and a decrease in alkaline phosphatase, glutathione peroxidase, and superoxide dismutase activity, indicating molecular and cellular damage. PRPs’ toxicity might be enhanced due to a sex-dependent pulverization capability exhibited by G. sigillatus. These findings underscore the potential ecological risks associated with PRPs in terrestrial environments and the need for further research on their environmental impact. Full article

Adolescent-onset schizophrenia (AOS; onset between ages 13 and 18) represents a rare but severe subtype of schizophrenia that disrupts crucial neurodevelopmental and psychosocial milestones. Marked by prominent cognitive deficits, negative symptoms, and poor long-term outcomes, AOS poses unique diagnostic and therapeutic challenges distinct from adult-onset cases. A comprehensive search of PubMed/MEDLINE (January 2003–February 2025) and reference lists of prior reviews identified twenty-four primary studies addressing pharmacological, psychosocial, and neurobiological aspects of AOS. Synthesis of this evidence highlights atypical antipsychotics such as aripiprazole and brexpiprazole as well-tolerated first-line options for positive symptom reduction, while clozapine remains the most effective treatment for resistant AOS. High-dose olanzapine offers comparable efficacy but carries greater metabolic risk. Psychosocial approaches—including cognitive behavioral therapy (CBT) and motivational enhancement therapy (MET)—enhance adherence, insight, and functional recovery when integrated with pharmacotherapy. Converging neuroimaging and biomarker data reveal persistent neuroinflammatory and glutamatergic dysregulation, characterized by elevated interleukin-6 (IL-6), C-C motif chemokine ligand 11 (CCL11), and dorsomedial prefrontal hypoglutamatergia, suggesting immune-mediated and developmental mechanisms underlying symptom persistence. Emerging research on neuromodulation and N-methyl-D-aspartate (NMDA)-targeted strategies further broadens the therapeutic landscape. Collectively, these findings highlight the importance of early, developmentally informed, and multidisciplinary interventions tailored to adolescents. Strengthening longitudinal, biomarker-guided, and neuromodulation-inclusive studies will be critical for refining precision treatment models and informing future clinical and policy frameworks for adolescent psychosis care. Full article

Multi-drug resistance in Acinetobacter baumannii poses a significant human health threat. For multidrug-resistant pathogens, ‘last line of defense’ antibiotics like the polymyxins are implemented. Concerningly, polymyxin-resistance is evidenced in Acinetobacter baumannii and is mediated by the PmrAB two-component system. The response regulator PmrA upregulates pmrC, leading to lipooligosaccharide modifications that reduce polymyxin binding. Sequencing of A. baumannii resistant isolates has identified point mutations in the receiver domain of PmrA that correlate with increased resistance. To investigate functional impacts of these mutations, we characterized five PmrA mutations (D10N, M12I, I13M, G54E, and S119T) by assessing changes in PmrA DNA-binding affinity, dimerization, phosphorylation, and structure. Our findings suggest that these mutations impact the ability of PmrA to receive the activating phosphoryl group from the sensor kinase PmrB. The slow phosphoryl uptake is likely due to (1) disruption of the PmrB-PmrA interaction by interfering with the recognition site on PmrA, or (2) perturbation of PmrA’s active site via steric hindrance or displacement of residues and ions necessary for coordination within the aspartic acid pocket. Slowed phosphorylation of a response regulator can lead to enhanced gene transcription through several mechanisms. These insights advance our understanding of PmrA-mediated resistance in A. baumannii. Full article

Background: Dotinurad (DOT) has demonstrated beneficial metabolic effects in preclinical models as a selective uric acid reabsorption inhibitor. However, its clinical impact on steatotic liver disease (SLD) with hyperuricemia (HU-SLD) remains unclear. Methods: This observational pilot study evaluated 33 patients with HU-SLD (Metabolic dysfunction-associated steatotic liver disease: n = 20; Metabolic dysfunction-associated alcohol-related liver disease: n = 1; Alcohol-related liver disease: n = 12) treated with DOT for at least 6 months. Laboratory parameters were assessed at baseline and at 6 months. The primary outcomes were changes in serum uric acid levels, hepatobiliary function markers, and renal function markers. Results: DOT significantly reduced serum uric acid levels from 8.4 (7.7–9.0) to 6.0 (5.9–6.8) mg/dL at 6 months (p < 0.001). Regarding hepatobiliary markers, gamma-glutamyl transferase decreased from 47 (30–78) to 43 (27–54) U/L (p = 0.042) and total bilirubin decreased from 0.6 (0.5–1.0) to 0.6 (0.4–0.7) mg/dL (p = 0.023). Significant but modest improvements in renal function were also observed, with serum creatinine decreasing from 1.1 (0.9–1.3) to 1.0 (0.9–1.1) mg/dL (p = 0.010) and estimated glomerular filtration rate increasing from 55.6 (44–67.3) to 56.6 (48.8–71.5) mL/min/1.73 m² (p = 0.007). No significant changes were observed for aspartate aminotransferase, alanine aminotransferase, fibrosis-related markers, lipid profiles, or glycemic markers. Moreover, no treatment discontinuations or adverse events were recorded during the study period. Conclusions: DOT effectively reduced serum uric acid and modestly improved renal and hepatobiliary parameters in HU-SLD without any patient-reported complications. These real-world findings support the potential of DOT as a well-tolerated therapeutic option beyond urate lowering and warrant further investigation in larger, controlled studies. Full article