Search Results (108)

Background: Gastric cancer is one of the most prevalent malignancies worldwide and the fourth leading cause of cancer-related mortality. Protein ubiquitination and deubiquitination regulate protein stability as post-translational modifications, playing essential roles in tumorigenesis. Although UCHL1, a deubiquitinating enzyme (DUB), is implicated in the progression of several cancer types, its role in gastric cancer remains unclear. Methods: Kaplan–Meier analysis and gastric cancer patient tissues were used to assess UCHL1 expression. Cell viability assay, colony-forming assay, and transwell migration and invasion assay were performed to evaluate cell growth. Immunoprecipitation and Western blotting analyzed protein expression and interactions. Results: This study demonstrates that UCHL1 expression is markedly upregulated in gastric cancer tissues compared to normal tissues. Elevated UCHL1 expression is associated with poor patient prognosis, supporting its potential role as an oncogenic factor. Reduced UCHL1 expression suppressed cell proliferation, migration, and invasion in gastric cancer cell lines. As the underlying mechanism, we identified CIP2A, a known oncogenic regulator of c-Myc, as a downstream effector of UCHL1. UCHL1 knockdown reduced CIP2A protein levels via deubiquitination, attenuated c-Myc signaling, and decreased expression of key cell cycle regulators. Furthermore, UCHL1 knockdown significantly downregulated cyclin D1 expression, arresting the cell cycle in the G1 phase and inhibiting cell proliferation. Conclusions: Collectively, our findings reveal that UCHL1 promotes gastric cancer progression, highlighting it as a potential therapeutic target. Full article

Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is a critical deubiquitinating enzyme that is highly expressed in the central nervous system, where it participates in protein degradation and turnover as part of the ubiquitin–proteasome system (UPS). Convincing evidence supports the role of UCH-L1 dysfunction in several neurodegenerative disorders, given its unique position at the crossroad of several aetiopathogenic pathways, including those implicated in Alzheimer’s disease (AD) onset. Indeed, UCH-L1 depletion correlates with decreased levels of triggering receptor expressed on myeloid cells 2 (TREM2), with consequent effects on neuroinflammation. Notably, UCH-L1 can affect the level of phosphorylated tau protein, thus contributing to the formation of neurofibrillary tangles (NFTs). In addition, UCH-L1 influences β-Secretase 1 (BACE1) expression, resulting in the abnormal accumulation of amyloid-β plaques in brain parenchyma. These findings underline UCH-L1’s centrality in maintaining the homeostasis of protein folding and aggregation, which are significantly impaired in AD and AD-related dementias. Given these assumptions, UCH-L1 is recognized as a potential biomarker for AD, highlighting its relevance in governing the fate of crucial pathological mediators of cognitive impairment and neurodegeneration. Herein, we contextualize the involvement of UCH-L1 in different dementia-associated pathways and summarize the state of the art of UCH-L1 as a biomarker for AD diagnosis. Full article

Mild traumatic brain injury (mTBI) remains a clinical challenge, particularly in cases with normal computed tomography (CT) findings but persistent or evolving symptoms. Conventional diagnostic approaches relying solely on clinical criteria and neuroimaging often lack adequate sensitivity and may lead to unnecessary radiation exposure. Recent advances in biomarker research have identified several blood-based proteins such as glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), S100 calcium-binding protein B (S100B), Tau protein, neuron-specific enolase (NSE), and neurofilament light chain (NFL) as potential tools for improving diagnostic precision and guiding clinical decisions. In this study, we synthesize current evidence evaluating the diagnostic and prognostic utility of these biomarkers using sensitivity, specificity, negative predictive value (NPV), and area under the receiver operating characteristic curve (AUC). GFAP and UCH-L1 have shown high sensitivity in detecting intracranial lesions and are now FDA-cleared for emergency department triage within 12 h of injury. While S100B remains widely investigated, its low specificity limits its application beyond select clinical scenarios (i.e., in patients without polytrauma). Additionally, Tau, NSE, and NFL are emerging as prognostic markers, with studies suggesting associations with persistent symptoms and long-term neurocognitive outcomes. Overall, the integration of biomarker-based data into clinical workflows may enhance early mTBI diagnosis, reduce reliance on imaging, and enable individualized follow-up and prognostic stratification. Future research should refine optimal sampling windows and explore multimarker panels to maximize diagnostic and prognostic performance. Full article

Background/Objectives: Traumatic brain injury (TBI), especially mild TBI (mTBI), is frequently caused by traffic accidents, falls, or sports injuries. Although computed tomography (CT) is the gold standard for diagnosis, overuse can lead to unnecessary radiation exposure, increased healthcare costs, and emergency department saturation. Blood-based biomarkers have emerged as potential tools to optimize CT scan use. This systematic review aims to evaluate recent evidence on the role of specific blood biomarkers in guiding CT decisions in patients with mTBI. Methods: A systematic search was conducted in the PubMed, Cochrane, and CINAHL databases for studies published between 2020 and 2024. Inclusion criteria focused on adult patients with mTBI evaluated using both CT imaging and at least one of the following biomarkers: glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and S100 calcium-binding protein B (S100B). After screening, six studies were included in the final review. Results: All included studies reported high sensitivity and negative predictive value for the selected biomarkers in detecting clinically relevant intracranial lesions. GFAP and UCH-L1, particularly in combination, consistently identified low-risk patients who could potentially forgo CT scans. While S100B also showed high sensitivity, discrepancies in cutoff values across studies highlighted the need for harmonization. Conclusions: Blood biomarkers such as GFAP, UCH-L1, and S100B demonstrate strong potential to reduce unnecessary CT imaging in mTBI by identifying patients at low risk of significant brain injury. Future research should focus on standardizing biomarker thresholds and validating protocols to support their integration into clinical practice guidelines. Full article

Background/Objectives: This study aimed to investigate the optimal sound presentation level for sound localization testing to assess the effect of hearing interventions in individuals with unilateral conductive hearing loss (UCHL). Methods: Nine participants with normal hearing were tested, and simulated two-stage UCHL was created using earmuffs and earplugs. We created two types of masking conditions: (1) only an earplug inserted, and (2) an earplug inserted with an earmuff worn. A sound localization test was performed for each condition. The sound presentation levels were 40, 45, 50, 55, 60, 65, and 70 dB SPL, and the results were evaluated using root mean square and d-values. Results: Both values showed little difference in masking Condition 2, regardless of the sound presentation level, whereas in masking Condition 1, the values were at their minimum at 55 dB SPL. In addition, comparing the differences between masking Conditions 1 and 2 for each sound presentation level, the greatest difference was observed at 55 dB SPL for both values. Conclusions: The optimal sound presentation level for sound localization testing to assess hearing intervention effects in UCHL was 55 dB. This result may be attributed to the effect of input from the non-masked ear, accounting for interaural attenuation; the effect was considered minimal at 55 dB SPL. Full article

Traumatic brain injury (TBI) initiates a complex cascade of pathophysiological events that have far-reaching consequences beyond the initial injury. This review examines the current state of the literature on the mechanisms underlying neurotrauma and neuroinflammation, with particular emphasis on the molecular cross-talk between these disparate pathways that ultimately precipitates the development of chronic traumatic encephalopathy (CTE). We integrate this mechanistic knowledge with potential diagnostic biomarkers, such as glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and advances in neuroimaging and machine learning-based predictive tools. Finally, we discuss the current therapeutic approaches under investigation, and highlight which molecular targets have yet to be explored for potential therapeutic development. 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

Background: Mild traumatic brain injury (mTBI), commonly known as concussion, is a major public health issue characterized by subtle neuronal damage that traditional imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) often fail to detect. Fluid biomarkers have emerged as promising diagnostic and prognostic tools for mTBI. Objectives: This umbrella meta-analysis aims to evaluate the diagnostic accuracy and clinical utility of the key fluid biomarkers, S100B, glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1, neurofilament light chain (NfL)) and tau protein, in detecting mTBI and to clarify their roles as screening, confirmatory, and complementary indicators. Methods: A systematic review was performed using PubMed, Web of Science, Scopus, and Cochrane to identify the published meta-analyses that assessed the biomarkers in mTBI. Sensitivity, specificity, and diagnostic odds ratios were then calculated using random-effects models. Heterogeneity was evaluated with the I² statistic, and publication bias was assessed via funnel plots. The results of S100B demonstrated high sensitivity (91.6%) but low specificity (42.4%), making it an effective rule-out biomarker to minimize unnecessary CT scans. In contrast, GFAP exhibited moderate sensitivity (84.5%) with improved specificity (61.0%), supporting its role in confirming mTBI diagnoses. UCH-L1 revealed a sensitivity of 86.7% alongside low specificity (37.3%), indicating its potential as a complementary marker. Additionally, the NfL levels were notably elevated in sports-related concussions, while the diagnostic utility of tau protein remains inconclusive due to limited available data. Conclusions: The findings underscore the clinical promise of fluid biomarkers in the management of mTBI. S100B and GFAP are particularly valuable as screening and confirmatory markers, respectively. Nonetheless, further standardization of biomarker thresholds and additional longitudinal studies are necessary to validate the roles of UCH-L1, NfL, and Tau protein. The integration of these biomarkers into a multimodal diagnostic panel may enhance mTBI detection accuracy and facilitate improved patient stratification and management. Full article

Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy characterized by rapid progression, high metastatic potential, and limited therapeutic options. Lysine-specific demethylase 1 (LSD1) has been identified as a promising epigenetic target in SCLC. RG6016 (ORY-1001) is a selective LSD1 inhibitor currently under clinical investigation for its antitumor activity. In this study, publicly available RNA-Seq datasets from SCLC patient-derived xenograft (PDX) models treated with RG6016 were reanalyzed using bioinformatic approaches. Differential gene expression analysis was conducted to identify genes responsive to LSD1 inhibition. Candidate genes showing significant downregulation were further evaluated by molecular docking to assess their potential interaction with RG6016. The analysis identified a set of differentially expressed genes following RG6016 treatment, including notable downregulation of MYC, UCHL1, and TSPAN8. In silico molecular docking revealed favorable docking poses between RG6016 and the proteins encoded by these genes, suggesting potential direct or indirect targeting. These findings support a broader mechanism of action for RG6016 beyond its known interaction with LSD1. This study demonstrates that RG6016 may exert its antitumor effects through the modulation of additional molecular targets such as MYC, UCHL1, and TSPAN8 in SCLC. The combined bioinformatic and molecular docking analyses provide new insights into the potential multi-target profile of RG6016 and indicate the need for further experimental validation. Full article

Farrerol, a bioactive compound found in Folium Rhododendri daurici, demonstrates various biological and pharmacological effects. Nevertheless, the stereoselectivity of in vivo processes and bioactivity between its enantiomers have not been thoroughly investigated. This study aimed to explore the stereoselectivity and pharmacological activity variations in farrerol enantiomers, focusing on stereoselective pharmacokinetics, tissue distribution, in vitro metabolism using liver microsomes, in vivo intestinal absorption, molecular simulations of binding affinity with antiproliferative target, and cell viability assessed through the CCK-8 assay. The findings indicated that the pharmacokinetic characteristics of farrerol in rats’ plasma, liver, and kidney tissues displayed enantioselectivity after intragastric administration. Then, no chiral transformation between farrerol enantiomers was observed in the rat plasma when (+)-farrerol and (−)-farrerol were orally administered. Additionally, there are notable stereoselective differences in the inhibition of CYP 1A2, CYP 2C9, CYP 2C19, and CYP 3A4/5 enzymes by (+)-farrerol and (−)-farrerol (p < 0.01). These differences may contribute to the stereoselectivity observed in the hepatic metabolism of the two enantiomers of farrerol. In addition, there were selective differences in the binding of farrerol enantiomers to anti-proliferative targets, including UCHL3, STAT3β, PTP1B, and GSK3β. Farrerol enantiomers exhibited similar growth inhibitory effects in HT-29 cell. Overall, our work will provide a solid theoretical basis and experimental reference for the further development and utilization of farrerol enantiomers. Full article

Objectives: To establish age-adjusted cut-off values for glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and assess their impact on the diagnostic performance of the mild traumatic brain injury (mTBI) assay. Methods: The study included 175 adult mTBI patients presenting at the emergency department (ED) within 12 h from head trauma in whom head CT scan was performed. GFAP and UCH-L1 were measured using chemiluminescence immunoassays on an Abbott analyzer (Abbott Laboratories, USA). Results: Using manufacturer’s defined cut-offs (GFAP < 35 ng/L, UCH-L1 < 400 ng/L), the mTBI assay exhibited diagnostic sensitivity (Se) of 93.1%, specificity (Sp) of 28.8%, negative predictive value (NPV) of 95.5% and a positive predictive value (PPV) of 20.6%. In the subgroup of patients aged under 50, Se and NPV were below 100% (i.e., 75.0% and 92.3%), due to two false negative mTBI results. Age-adjusted cut-offs were defined for three patient groups, ≤49 years, 50–69 years and ≥70 years, and were set to 22.4, 37.0 and 62.3 ng/L for GFAP, and 349.3, 351.6 and 369.0 ng/L for UCH-L1. Using these cut-offs, in all patient groups Se and NPV were 100%, while increased Sp was obtained in patients older than 50 years. Conclusions: Diagnostic Se and NPV can be improved by the use of age-adjusted cut-offs. In this way, the triage protocol for mTBI and head CT scan can be refined, further contributing to the optimization of the diagnostic management of mTBI patients at the ED. 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: Recent studies have shed light on the association between genetic factors and diabetic retinopathy (DR) onset and progression. The purpose of our study was to investigate the association between rs4885322 single-nucleotide polymorphism (SNP) of the UCHL3 gene and rs11558538 SNP of the HNMT gene with the risk of DR in Greek patients with type 2 diabetes mellitus (T2DM). Materials and Methods: In our case–control study, we included 85 T2DM patients with DR and 71 T2DM patients without DR (NDR), matched by ethnicity and gender. Demographic and clinical data of all patients were collected, and then patients went through a complete ophthalmological examination and were genotyped for rs4885322 SNP of UCHL3 gene and for the rs11558538 SNP of HNMT gene. Statistical analysis was implemented by STATA v.16.1. Results: No significant differences in demographic and clinical data were observed between the DR and the NDR group (p-value ≥ 0.05), except for the lower mean of age, longer duration of DM, more frequent use of insulin therapy, and higher levels of hemoglobin A1c (HbA1c) in the DR group. The allelic effect of rs488532 increases the risk of DR by 2.04 times, and in the dominant genetic model, the risk of DR is elevated by 123%, while both associations are statistically significant (p-value < 0.05). Moreover, the allelic effect of rs11558538 is associated with a 3.27 times increased DR risk and, in the dominant genetic model, reveals an augmented risk of DR by 231%, while both associations are also statistically significant (p-value < 0.05). Conclusions: The rs4885322 SNP of the UCHL3 gene and the rs11558538 SNP of the HNMT gene are associated with DR risk in Greek patients with T2DM. However, further studies with larger samples and different ethnicities should be implemented to clarify the exact association of these SNPs and DR onset. Full article