Search Results (28)

Traumatic brain injury (TBI) is a major global health concern and a leading cause of mortality and disability. Head computed tomography (CT) remains indispensable for the detection of intracranial hemorrhage; however, its indiscriminate use in mild trauma increases radiation exposure, cumulative oncogenic risk, and healthcare costs. Consequently, there is growing interest in tools capable of improving sensitivity in mild or early-stage TBI. Protein-based biomarkers are promising complements to conventional assessment. Molecules such as glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCH-L1), S100 calcium-binding protein B (S100B), and neurofilament light chain (NfL) reflect astroglial activation, neuronal injury, and axonal damage, enabling objective evaluation of neurotrauma. Beyond protein biomarkers, metabolomic and lipidomic approaches capture alterations associated with early metabolic distress, oxidative stress, mitochondrial dysfunction, and membrane disruption following TBI. High-resolution mass spectrometry studies have identified reproducible metabolite and lipid signatures correlating with injury severity and functional outcomes. Longitudinal profiling further reveals dynamic metabolic trajectories that distinguish secondary injury progression from stabilization, supporting predictive modeling and risk stratification. Together, these advances pave the way toward precision medicine in neurotrauma. Nevertheless, variability in assay performance and sampling timing continues to limit widespread clinical adoption. Future research should prioritize methodological standardization, analytical validation, and the integration of multi-omic data with machine learning–based predictive models. Full article

Background: Biomarker analysis in neurodegeneration with brain iron accumulation (NBIA) can offer valuable insights into the disease’s pathology and natural history. Methods: Twenty-five patients with C19orf12 mutations causing mitochondrial membrane protein-associated neurodegeneration (MPAN), 12 patients with PANK2 mutations causing pantothenate kinase-associated neurodegeneration (PKAN), and 30 age- and gender-matched controls were studied. Serum levels of MMP-9, S100B, ICAM-1, E- and P-selectins, total α-synuclein, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), Tau, ubiquitin-C-terminal hydrolase-L1 (UCH-L1), and brain-derived neurotrophic factor (BDNF) were measured. Clinical status was evaluated with dedicated rating scales. Results: Compared to the control group, MPAN patients had significantly higher serum levels of nearly all biomarkers, except BDNF. NfL, GFAP, and UCH-L1, were elevated by 5, 2, and 3.5 times, respectively. PKAN patients showed no significant differences in GFAP, UCH-L1, and S100B levels compared to controls. However, NfL and Tau levels were increased by 3 and 1.8 times, respectively. A correlation was observed between disease severity and levels of NfL, Tau, and UCH-L1 in MPAN, and GFAP, Tau, and UCH-L1 in PKAN. Conclusions: Patients with MPAN and PKAN showed increased levels of neurodegeneration biomarkers. Elevated inflammation and blood–brain barrier dysfunction biomarkers were specific to MPAN patients. Full article

Concussions, classified as a type of mild traumatic brain injury (mTBI), are frequently underdiagnosed due to the subjective nature of symptoms and limitations in existing diagnostic methodologies. Current clinical evaluations, including tools such as the Sport Concussion Assessment Tool 5 (SCAT5), Balance Error Scoring System (BESS), and Vestibular Ocular Motor Screening (VOMS), demonstrate high sensitivity and specificity but often fail to capture the full complexity of concussive injuries. Emerging diagnostic approaches, such as blood biomarkers (for example, glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), S100 calcium-binding protein B (S100B), and tau) and advanced neuroimaging techniques (for example, diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI)), show promise but remain impractical for routine clinical use due to accessibility and standardization challenges. This review examines objective markers, including neuroimaging, electrophysiological measures (for example, Electroencephalography (EEG), Magnetoencephalography (MEG)), and real-time diagnostic tools, as complementary strategies to enhance traditional clinical evaluations. Findings indicate that while clinical assessments remain central to concussion diagnosis, integrating them with advanced imaging and electrophysiological tools can provide more accurate diagnostics and recovery tracking. Biomarkers, although not yet ready for widespread use, hold significant potential for future applications. Further research is required to validate these methods and establish standardized protocols to facilitate their integration into clinical practice. Full article

Post-traumatic stress disorder (PTSD) is frequently comorbid with persistent depressive disorder (dysthymia), indicating shared neurobiological pathways that influence stress modulation, emotional regulation, and neurohormonal adaptation. This study examines the roles of serum biomarkers—small ubiquitin-like modifier 1 (SUMO1), malondialdehyde (MDA), fractalkine (CX3CL1), and ubiquitin C-terminal hydrolase L1 (UCHL1)—involved in oxidative stress management, neuroimmune regulation, and neuronal proteostasis. In this cross-sectional analysis, biomarker expression was assessed in 92 male trauma-exposed participants aged 19–50 years, divided into three groups: PTSD duration ≤ 5 years (n = 33, median age 34.0 years [IQR 31.0–41.0]), PTSD duration > 5 years (n = 31, median age 36.0 years [IQR 29.5–41.0]), and controls without current or past PTSD (n = 28, median age 33.5 years [IQR 24.3–41.5]). Participants were stratified into younger (19–34 years) and older (35–50 years) cohorts to account for age-related neurobiological variability. Dysthymic symptomatology was evaluated using the Cornell Dysthymia Rating Scale (CDRS), focusing on chronic subthreshold depressive features. Results indicated a significant association between PTSD and elevated dysthymic symptom burden (p < 0.001), with both PTSD subgroups demonstrating mild to moderate CDRS severity compared to euthymic controls. Biomarker analysis revealed phase-dependent alterations: SUMO1 levels were significantly elevated in the ≤5 years PTSD group compared to controls (p = 0.002), suggesting early compensatory neuroprotection, whereas UCHL1 was markedly increased in the >5 years PTSD group (p = 0.015), which is indicative of chronic neuronal damage and proteostatic disruption. No significant differences were observed in MDA or CX3CL1 across groups (p > 0.05). These findings highlight PTSD’s contribution to sustained affective dysregulation, potentially mediated by temporal shifts in oxidative stress and protein homeostasis markers. Clinically, this supports the utility of biomarker profiling for risk stratification, early intervention, and personalized therapeutic strategies, such as targeted modulation of SUMOylation or UCHL1 activity, to enhance neuroresilience and mitigate progression to severe mood disorders. Full article

Background: Rapid identification and treatment of stroke are essential for the patient. Our objective was to determine the diagnostic utility of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) in the emergency department to identify and differentiate acute stroke within 4.5 h of symptom onset in patients admitted with a stroke code alert. Methods: This study included 85 patients with a “code stroke alert” upon arrival at the emergency department. Individuals were grouped in two categories: patients with stroke (including 69 patients) and patients without stroke (including 16 patients). The research was conducted at the Emergency Municipal Clinical Hospital in Timișoara, Romania, the county’s second-largest hospital, which lacks a neurologist and a dedicated stroke unit. Results: No significant differences were observed between the two groups (with stroke and without stroke) regarding most demographic or admission parameters. Significant differences were observed for the biomarkers GFAP (142.91 ± 102.19 pg/mL in patients with acute stroke vs. 37.76 ± 19.92 pg/mL in patients without stroke (p < 0.001)) and UCH-L1 (1307.68 ± 967.54 pg/mL in stroke patients vs. 189.81 ± 92.69 pg/mL in patients without stroke (p < 0.001)). Within the stroke group, 37 patients had acute ischemic stroke, while 32 patients were diagnosed with hemorrhagic stroke based on brain CT imaging. GFAP achieved an accuracy of 94.2% for differentiating hemorrhagic from ischemic stroke, with a cut-off value of 77.15 pg/mL. Conclusions: GFAP excellently differentiated acute stroke from stroke mimics, with high sensitivity, perfect specificity, and strong predictive values. Integrating GFAP and UCH-L1 measurements into emergency protocols may enhance stroke diagnosis, optimize patient triage, and ultimately improve outcomes by facilitating the faster initiation of appropriate therapies. Full article

Objective: To evaluate the economic impact associated with the use of specific brain biomarkers glial fibrillary acid protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) in adult patients with suspected mild traumatic brain injury (TBI) in a standard Spanish hospital setting. Methods: We used a budget impact analysis (BIA) to compare the cost of standard of care using head computed tomography (CT) to evaluate intracranial injury with a scenario incorporating specific biomarkers GFAP and UCH-L1 in an estimated population of 3500 adult patients attending the hospital emergency department with a score of 13 to 15 on the Glasgow Coma Scale (GCS). The probabilities associated with clinical procedures were obtained from a multidisciplinary group of experts from Spanish hospitals and supplemented with data from the literature. Costs were estimated using hospital tariffs from the Spanish autonomous communities and other official sources. Results: The incorporation of specific biomarkers GFAP and UCH-L1 in the management of mild TBI could generate an estimated annual savings of EUR 696,634 in a standard Spanish hospital, mainly due to reduced CT use. The average savings per patient would be EUR 199.04, and the care time would be reduced by 111 min. Sensitivity analysis, with variations of ±20% in the parameters, confirms these savings. Conclusions: This study suggests that the use of specific biomarkers GFAP and UCH-L1 in the management of mild TBI patients in Spain could reduce the average cost per patient, generating significant savings for hospitals. Future studies that incorporate data from clinical records will help validate these results. Full article

As acute ischemic stroke (AIS) is still a significant cause of morbidity globally, new methods of rapid diagnostics are continually being researched and improved. Still, the only definite way to diagnose AIS is radiological imaging. Lately, serum biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) have shown their usefulness in AIS as potential complementary tools in early recognition. We aimed to investigate if GFAP and UCH-L1 can correlate with comprehensive diagnostic information provided by computed tomography (CT) and several clinical parameters in AIS severity assessment and subsequently with clinical outcomes. Fifty-two patients with AIS and a potential for mechanical thrombectomy (MT) were included in our study. Thirty-seven patients underwent MT. Results showed no correlation of biomarkers with any analyzed CT parameter (thrombus length, volume, and density, clot burden score, collateral score, AIS core and penumbra volume, differences in perfusion between healthy and affected brain tissue). In addition, none of the clinical parameters, such as sex, symptom onset time, or the National Institutes of Health Stroke Scale, correlated with biomarkers. However, lower biomarker levels corresponded with a good clinical outcome, and higher levels to a poor outcome following hospital discharge, irrespective of the performed MT (p = 0.005 for GFAP, p = 0.001 for UCH-L1). In patients with successful MT, there were also differences between patients with a good clinical outcome compared with patients with a poor clinical outcome (p = 0.007 for GFAP, p = 0.004 for UCH-L1). In conclusion, these biomarkers cannot replace imaging modalities but can provide complementary diagnostic information in the setting of AIS. Full article

The proteasomal system of protein degradation is crucial for various cellular processes, including transduction of signals and differentiation of cells. Proteasome activity rises after various traumatic stressors such as hyperoxia, radiation, or oxidative damage. Removal of damaged proteins is essential to provide the necessary conditions for cell repair. Several studies report the activation of the proteasomal degradation system after thermal injury, CNS injury, abdominal trauma, ischemia-reperfusion injury, and possible clinical implications of the use of proteasome inhibitors. It is important to highlight the distinct and crucial roles of UCHL1, 26S, and 20S proteasome subunits as biomarkers. UCHL1 appears to be particularly relevant for identifying brain and neuronal damage and in advancing the diagnosis and prognosis of traumatic brain injury (TBI) and other neurological conditions. Meanwhile, the 26S and 20S proteasomes may serve as markers for peripheral tissue damage. This differentiation enhances our understanding and ability to target specific types of tissue damage in clinical settings. Full article

Background and Objectives: In previous studies, we reported that the assessment of the cumulative thermal dose in the crystalline lens, conducted through computational modeling utilizing a supercomputer and the biothermal transport equation, exhibited a significant association with the incidence of nuclear cataracts. In this study, we have investigated the types of proteins that expressed underlying 35.0 °C (normal-temp) and 37.5 °C (warming-temp) by using the shotgun liquid chromatography (LC) with tandem mass spectrometry (MS/MS)-based global proteomic approach. Materials and Methods: We have discussed the changes in protein expression in warmed iHLEC-NY2 cells using Gene Ontology analysis and a label-free semiquantitative method based on spectral counting. Results: In iHLEC-NY2, 615 proteins were detected, including 307 (49.9%) present in both lenses cultured at normal-temp and warming-temp, 130 (21.1%) unique to the lens cultured at normal-temp, and 178 (29.0%) unique to the lens cultured at warming-temp. Furthermore, LC–MS/MS analysis showed that warming decreased the expression of actin, alpha cardiac muscle 1, actin-related protein 2, putative tubulin-like protein alpha-4B, ubiquitin carboxyl-terminal hydrolase 17-like protein 1, ubiquitin-ribosomal protein eL40 fusion protein, ribosome biogenesis protein BMS1 homolog, histone H2B type 1-M, and histone H2A.J. in iHLEC-NY2. Conclusions: The decreases in the specific protein levels of actin, tubulin, ubiquitin, ribosomes, and histones may be related to cataract development under warming conditions. This investigation could provide a critical framework for understanding the correlation between temperature dynamics and the development of nuclear cataracts. Full article

Impaired renal function can influence biomarker levels through mechanisms involving blood–brain barrier integrity and clearance pathways; however, the impact of variations within normal renal function remains unclear. The main aim of this study was to determine whether adjustment for the specific level of renal function is necessary when renal function remains within physiological levels. We studied n = 183 patients (NID n = 122; other neurological diseases n = 39; somatoform controls n = 22) who underwent lumbar puncture at University Hospital Frankfurt. Serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), total tau protein (tTAU), and ubiquitin C-terminal hydrolase-L1 (UCHL1) were measured using the single molecule array (SIMOA) technique. Estimated glomerular filtration rate (eGFR) correlated negatively with CSF GFAP (r = −0.217, p = 0.004) and serum NfL (r = −0.164, p = 0.032). Patients with impaired renal function exhibited higher CSF NfL (p = 0.036) and CSF GFAP (p = 0.026) levels. However, these findings did not remain significant after adjusting for BMI and age. Importantly, in patients with normal renal function, no significant correlations with eGFR and biomarker levels were observed after adjustment. Our findings indicate that serum and CSF concentrations of NfL, GFAP, tTAU, and UCHL1 are not significantly affected by fluctuations in physiological kidney function but emphasize the importance of considering comorbidities in impaired renal function when interpreting biomarker levels. Full article

FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations in acute myeloid leukemia (AML) are associated with poor prognosis and therapy resistance. This study aimed to demonstrate that inhibiting the deubiquitinating enzymes ubiquitin-specific peptidase 14 (USP14) and ubiquitin C-terminal hydrolase L5 (UCHL5) (USP14/UCHL5) with b-AP15 or the organogold compound auranofin (AUR) induces apoptosis in the ITD-transformed human leukemia cell line MV4-11 and mononuclear leukocytes derived from patients with FLT3-ITD-positive AML. This study included patients diagnosed with AML at Tokyo Medical and Dental University Hospital between January 2018 and July 2024. Both treatments blocked downstream FLT3 pathway events, with the effects potentiated by USP14 knockdown. Both treatments inhibited FLT3 deubiquitination via K48 and disrupted translation initiation via 4EBP1, a downstream FLT3 target. FLT3 was downregulated in the leukemic cells, with the associated activation of stress-related MAP kinase pathways and increased NF-E2-related factor 2. Furthermore, the overexpression of B-cell lymphoma-extra-large and myeloid cell leukemia-1 prevented the cell death caused by b-AP15 and AUR. These results suggest that inhibiting USP14/UCHL5, which involves multiple regulatory mechanisms, is a promising target for novel therapies for treatment-resistant FLT3-ITD-positive AML. Full article

Ubiquitin C-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme originally found in the brain. Our previous work revealed that UCHL1 was also expressed in skeletal muscle and affected myoblast differentiation and metabolism. In this study, we further tested the role of UCHL1 in myogenesis and muscle regeneration following muscle ischemia-reperfusion (IR) injury. In the C2C12 myoblast, UCHL1 knockdown upregulated MyoD and myogenin and promoted myotube formation. The skeletal muscle-specific knockout (smKO) of UCHL1 increased muscle fiber sizes in young mice (1 to 2 months old) but not in adult mice (3 months old). In IR-injured hindlimb muscle, UCHL1 was upregulated. UCHL1 smKO ameliorated tissue damage and injury-induced inflammation. UCHL1 smKO also upregulated myogenic factors and promoted functional recovery in IR injury muscle. Moreover, UCHL1 smKO increased Akt and Pink1/Parkin activities. The overall results suggest that skeletal muscle UCHL1 is a negative factor in skeletal muscle development and recovery following IR injury and therefore is a potential therapeutic target to improve muscle regeneration and functional recovery following injuries. Full article

Postconcussion syndrome (PCS) is one of the leading complications that may appear in patients after mild head trauma. Every day, thousands of people, regardless of age, gender, and race, are diagnosed in emergency departments due to head injuries. Traumatic Brain Injury (TBI) is a significant public health problem, impacting an estimated 1.5 million people in the United States and up to 69 million people worldwide each year, with 80% of these cases being mild. An analysis of the available research and a systematic review were conducted to search for a solution to predicting the occurrence of postconcussion syndrome. Particular biomarkers that can be examined upon admission to the emergency department after head injury were found as possible predictive factors of PCS development. Setting one unequivocal definition of PCS is still a challenge that causes inconsistent results. Neuron Specific Enolase (NSE), Glial Fibrillary Acidic Protein (GFAP), Ubiquitin C-terminal Hydrolase-L1 (UCH-L1), Serum Protein 100 B (s100B), and tau protein are found to be the best predictors of PCS development. The presence of all mentioned biomarkers is confirmed in severe TBI. All mentioned biomarkers are used as predictors of PCS. A combined examination of NSE, GFAP, UCH-1, S100B, and tau protein should be performed to detect mTBI and predict the development of PCS. Full article

In mammals, hearing loss is irreversible due to the lack of the regenerative capacity of the auditory epithelium. However, stem/progenitor cells in mammalian cochleae may be a therapeutic target for hearing regeneration. The ubiquitin proteasome system plays an important role in cochlear development and maintenance. In this study, we investigated the role of ubiquitin C-terminal hydrolase L1 (UCHL1) in the process of the transdifferentiation of auditory supporting cells (SCs) into hair cells (HCs). The expression of UCHL1 gradually decreased as HCs developed and was restricted to inner pillar cells and third-row Deiters’ cells between P2 and P7, suggesting that UCHL1-expressing cells are similar to the cells with Lgr5-positive progenitors. UCHL1 expression was decreased even under conditions in which supernumerary HCs were generated with a γ-secretase inhibitor and Wnt agonist. Moreover, the inhibition of UCHL1 by LDN-57444 led to an increase in HC numbers. Mechanistically, LDN-57444 increased mTOR complex 1 activity and allowed SCs to transdifferentiate into HCs. The suppression of UCHL1 induces the transdifferentiation of auditory SCs and progenitors into HCs by regulating the mTOR pathway. Full article

Acute ischemic stroke (AIS) is one of the leading causes of morbidity worldwide, thus, early recognition is essential to accelerate treatment. The only definite way to diagnose AIS is radiological imaging, which is limited to hospitals. However, two serum neuromarkers, glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1), have been proven as indicators of brain trauma and AIS. We aimed to investigate the potential utility of these markers in distinguishing between large vessel occlusion (LVO) and small vessel occlusion (SVO), considering differences in treatment. Sixty-nine AIS patients were included in our study and divided into LVO and SVO groups based on radiological imaging. Control group consisted of 22 participants without history of neurological disorders. Results showed differences in serum levels of both GFAP and UHC-L1 between all groups; control vs. SVO vs. LVO (GFAP: 30.19 pg/mL vs. 58.6 pg/mL vs. 321.3 pg/mL; UCH-L1: 117.7 pg/mL vs. 251.8 pg/mL vs. 573.1 pg/mL; p < 0.0001), with LVO having the highest values. Other prognostic factors of stroke severity were analyzed and did not correlate with serum biomarkers. In conclusion, a combination of GFAP and UCH-L1 could potentially be a valuable diagnostic tool for differentiating LVO and SVO in AIS patients. Full article