Search Results (18)

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

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: 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

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

In the post-COVID-19 era, treatment options for potential SARS-CoV-2 outbreaks remain limited. An increased incidence of central nervous system (CNS) disorders has been observed in long-term COVID-19 patients. Understanding the shared molecular mechanisms between these conditions may provide new insights for developing effective therapies. This study developed an integrative drug-repurposing framework for COVID-19, leveraging comorbidity data with CNS disorders, network-based modular analysis, and dynamic perturbation analysis to identify potential drug targets and candidates against SARS-CoV-2. We constructed a comorbidity network based on the literature and data collection, including COVID-19-related proteins and genes associated with Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and autism spectrum disorder. Functional module detection and annotation identified a module primarily involved in protein synthesis as a key target module, utilizing connectivity map drug perturbation data. Through the construction of a weighted drug–target network and dynamic network-based drug-repurposing analysis, ubiquitin–carboxy-terminal hydrolase L1 emerged as a potential drug target. Molecular dynamics simulations suggested pregnenolone and BRD-K87426499 as two drug candidates for COVID-19. This study introduces a dynamic-perturbation-network-based drug-repurposing approach to identify COVID-19 drug targets and candidates by incorporating the comorbidity conditions of CNS disorders. Full article

Background: Accurate diagnosis of Alzheimer’s disease (AD) and frontotemporal dementia (FTD) represents a health issue due to the absence of disease traits. We assessed the performance of a SIMOA panel in cerebrospinal fluid (CSF) from 43 AD and 33 FTD patients with 60 matching Control subjects in combination with demographic–clinical characteristics. Methods: 136 subjects (AD: n = 43, FTD: n = 33, Controls: n = 60) participated. Single-molecule array (SIMOA), glial fibrillary acidic protein (GFAP), neurofilament light (NfL), TAU, and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) in CSF were analyzed with a multiplex neuro 4plex kit. Receiver operating characteristic (ROC) curve analysis compared area under the curve (AUC), while the principal of the sparse partial least squares discriminant analysis (sPLS-DA) was used with the intent to strengthen the identification of confident disease clusters. Results: CSF exhibited increased levels of all SIMOA biomarkers in AD compared to Controls (AUCs: 0.71, 0.86, 0.92, and 0.94, respectively). Similar patterns were observed in FTD with NfL, TAU, and UCH-L1 (AUCs: 0.85, 0.72, and 0.91). sPLS-DA revealed two components explaining 19% and 9% of dataset variation. Conclusions: CSF data provide high diagnostic accuracy among AD, FTD, and Control discrimination. Subgroups of demographic–clinical characteristics and biomarker concentration highlighted the potential of combining different kinds of data for successful and more efficient cohort clustering. Full article

The measurement of blood glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) may assist in the management of mild traumatic brain injury (mTBI). This study aims to compare GFAP and UCH-L1 values measured using a handheld device with those measured using a core laboratory platform. We enrolled 230 mTBI patients at intermediate risk of complications. Following French guidelines, a negative S100B value permits the patient to be discharged without a computed tomography scan. Plasma GFAP and UCH-L1 levels were retrospectively measured using i-STAT^® and Alinity^® i analyzers in patients managed within 12 h post-trauma. Our analysis indicates a strong correlation of biomarker measurements between the two analyzers. Cohen’s kappa coefficients and Lin’s concordance coefficients were both ≥0.7, while Spearman’s correlation coefficient was 0.94 for GFAP and 0.90 for UCH-L1. Additionally, the diagnostic performance in identifying an intracranial lesion was not significantly different between the two analyzers, with a sensitivity of 100% and specificity of approximately 30%. GFAP and UCH-L1 levels measured using Abbott’s i-STAT^® and Alinity^® i platform assays are highly correlated both analytically and clinically in a cohort of 230 patients managed for mTBI according to French guidelines. Full article

A traumatic brain injury (TBI) is a major health issue affecting many people across the world, causing significant morbidity and mortality. TBIs often have long-lasting effects, disrupting daily life and functionality. They cause two types of damage to the brain: primary and secondary. Secondary damage is particularly critical as it involves complex processes unfolding after the initial injury. These processes can lead to cell damage and death in the brain. Understanding how these processes damage the brain is crucial for finding new treatments. This review examines a wide range of literature from 2021 to 2023, focusing on biomarkers and molecular mechanisms in TBIs to pinpoint therapeutic advancements. Baseline levels of biomarkers, including neurofilament light chain (NF-L), ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1), Tau, and glial fibrillary acidic protein (GFAP) in TBI, have demonstrated prognostic value for cognitive outcomes, laying the groundwork for personalized treatment strategies. In terms of pharmacological progress, the most promising approaches currently target neuroinflammation, oxidative stress, and apoptotic mechanisms. Agents that can modulate these pathways offer the potential to reduce a TBI’s impact and aid in neurological rehabilitation. Future research is poised to refine these therapeutic approaches, potentially revolutionizing TBI treatment. Full article

Accumulating data suggest that various neurologic manifestations are reported in critically-ill COVID-19 patients. Although low testosterone levels were associated with poor outcomes, the relationship between testosterone levels and indices of brain injury are still poorly understood. Therefore, we aimed to explore whether testosterone levels are associated with glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), biomarkers of brain injury, in patients with a severe form of COVID-19. The present study was conducted on 65 male patients aged 18–65 with severe COVID-19. Blood samples were collected at three time points: upon admission to ICU, 7 days after, and 14 days after. In patients with neurological sequels (n = 20), UCH-L1 serum concentrations at admission were markedly higher than in patients without them (240.0 (155.4–366.4) vs. 146.4 (92.5–243.9) pg/mL, p = 0.022). GFAP concentrations on admission did not differ between the groups (32.2 (24.2–40.1) vs. 29.8 (21.8–39.4) pg/mL, p = 0.372). Unlike GFAP, UCH-L1 serum concentrations exhibited a negative correlation with serum testosterone in all three time points (r = −0.452, p < 0.001; r = −0.430, p < 0.001 and r = −0.476, p = 0.001, respectively). The present study suggests that the traumatic brain injury biomarker UCH-L1 may be associated with neurological impairments seen in severe COVID-19. Moreover, a negative correlation between UCH-L1 and serum testosterone concentrations implies that testosterone may have a role in the development of neurological sequels in critically-ill COVID-19 patients. Full article

The diagnosis of brain gliomas is mainly based on imaging methods. The gold standard in this area is MRI. Recommendations for the prevention, diagnosis, and treatment of gliomas are periodically modified and updated. One of the diagnostic techniques used when a brain glioma is suspected is liquid biopsy. However, this technique requires further development to confirm its effectiveness. This paper presents a proposal of three potential biomarkers of brain gliomas—extracellular matrix metalloproteinase-1 (MMP-1), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and the 20S proteasome—which were quantified in blood plasma using SPRi biosensors. A statistical analysis of the results indicated no significant changes in the concentrations between the control group (K) and grades G1 and G2, and similarly between grades G3 and G4. However, the differences in the concentrations between the groups K/G1/G2 and G3/G4 were statistically significant. A positive average correlation was found between the concentrations of the proteins and the patient’s age. The individual tested proteins were also highly correlated with each other. Our work proposes a new diagnostic technique that may aid in the diagnosis of brain gliomas. Full article

Spermatogonia are stem and progenitor cells responsible for maintaining mammalian spermatogenesis. Preserving the balance between self-renewal of spermatogonial stem cells (SSCs) and differentiation is critical for spermatogenesis and fertility. Ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1) is highly expressed in spermatogonia of many species; however, its functional role has not been identified. Here, we aimed to understand the role of UCH-L1 in murine spermatogonia using a Uch-l1^−/− mouse model. We confirmed that UCH-L1 is expressed in undifferentiated and early-differentiating spermatogonia in the post-natal mammalian testis. The Uch-l1^−/− mice showed reduced testis weight and progressive degeneration of seminiferous tubules. Single-cell transcriptome analysis detected a dysregulated metabolic profile in spermatogonia of Uch-l1^−/− compared to wild-type mice. Furthermore, cultured Uch-l1^−/− SSCs had decreased capacity in regenerating full spermatogenesis after transplantation in vivo and accelerated oxidative phosphorylation (OXPHOS) during maintenance in vitro. Together, these results indicate that the absence of UCH-L1 impacts the maintenance of SSC homeostasis and metabolism and impacts the differentiation competence. Metabolic perturbations associated with loss of UCH-L1 appear to underlie a reduced capacity for supporting spermatogenesis and fertility with age. This work is one step further in understanding the complex regulatory circuits underlying SSC function. Full article

The ubiquitin–proteasome system (UPS) participates in the degradation of proteins which play an important role in regulating the cell cycle, apoptosis, and angiogenesis, as well as in the immune system. These processes are important in carcinogenesis. Transitional cell carcinoma (TCC) is one of the predominant types of bladder cancer. The relationship between the ubiquitin–proteasome system and cancer progression has become a topic of increasing interest among researchers. In this work, we propose an application of surface plasmon resonance imaging (SPRi)-based biosensors for the detection of 20S proteasome and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) in the blood serum and urine of patients with TCC. The aim of the study was to determine 20S proteasome and UCH-L1 concentrations and to correlate the results with clinicopathological parameters. The group of subjects consisted of 82 patients with confirmed TCC, in addition to a control group of 27 healthy volunteers. It was found that 20S proteasome and UCH-L1 concentrations were significantly elevated in both the serum and urine of TCC patients, compared with the healthy subjects. There was a correlation between 20S proteasome concentrations in serum and urine, as well as between serum proteasome and UCH-L1 concentration. The SPRi biosensor sensitive to 20S proteasome using PSI inhibitor as the receptor, and the SPRi biosensor sensitive to the UCH-L1 protein using the protein-specific antibody as the receptor is suitable for the determination of 20S proteasome and UCH-L1 in body fluids and can serve as useful tools in the investigation of cancer biomarkers. Full article

Long-term hyperglycemia may lead to diabetic microvascular and macrovascular complications that can affect the peripheral vascular system, particularly in wound healing capacity. Impaired angiogenesis and delayed wound healing are significant clinically. Luteolin (3′, 4′, 5, 7-tetrahydroxyflavone) is a naturally occurring flavonoid that is ubiquitously found in plants. Recent evidence has shown that luteolin is an anti-inflammatory and anti-oxidative agent. However, the effect of systemic luteolin administration on diabetic wound restoration remains unclear. Herein, we explored the effectiveness of luteolin for improving delayed and impaired healing of skin wound and further clarified the underlying mechanisms. The results indicated that luteolin significantly attenuates blood glucose concentration, improves impaired healing and accelerates re-epithelization of skin wound in streptozotocin (STZ)-induced diabetic rats. Histopathological staining and immunoblotting revealed an inhibitory effect of luteolin on inflammatory cell and cytokine production. We also observed remarkable decreases in protein expressions of inflammatory factors including matrix metalloproteinase (MMP)-9, tumor necrosis factor (TNF)-α, interleukin (IL-6), and IL1-β and downregulation of nuclear factor (NF)-κB, as well as increases in anti-oxidative enzymes such as superoxide dismutase 1 (SOD1) and glutathione peroxidase (GSH-Px) induced by nuclear factor erythroid 2-related factor (Nrf)-2 following luteolin supplementation. Furthermore, luteolin decreased the expression of vascular endothelial growth factor (VEGF) and increased the expression of ubiquitin carboxy-terminal hydrolase (UCH)-L1, as evidenced by angiogenesis and neuronal regeneration in completely healed wound. In conclusion, systemic administration of luteolin promotes wound restoration by ameliorating inflammation and oxidative stress through the inactivation of NF-κB and upregulation of Nrf2 in STZ-induced diabetic rats. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes the papain-like protease (PLpro). The protein not only plays an essential role in viral replication but also cleaves ubiquitin and ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from host proteins, making it an important target for developing new antiviral drugs. In this study, we searched for novel, noncovalent potential PLpro inhibitors by employing a multistep in silico screening of a 15 million compound library. The selectivity of the best-scored compounds was evaluated by checking their binding affinity to the human ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), which, as a deubiquitylating enzyme, exhibits structural and functional similarities to the PLpro. As a result, we identified 387 potential, selective PLpro inhibitors, from which we retrieved the 20 best compounds according to their IC₅₀ values toward PLpro estimated by a multiple linear regression model. The selected candidates display potential activity against the protein with IC₅₀ values in the nanomolar range from approximately 159 to 505 nM and mostly adopt a similar binding mode to the known, noncovalent SARS-CoV-2 PLpro inhibitors. We further propose the six most promising compounds for future in vitro evaluation. The results for the top potential PLpro inhibitors are deposited in the database prepared to facilitate research on anti-SARS-CoV-2 drugs. Full article

The pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious global health threat. Since no specific therapeutics are available, researchers around the world screened compounds to inhibit various molecular targets of SARS-CoV-2 including its main protease (M^pro) essential for viral replication. Due to the high urgency of these discovery efforts, off-target binding, which is one of the major reasons for drug-induced toxicity and safety-related drug attrition, was neglected. Here, we used molecular docking, toxicity profiling, and multiple molecular dynamics (MD) protocols to assess the selectivity of 33 reported non-covalent inhibitors of SARS-CoV-2 M^pro against eight proteases and 16 anti-targets. The panel of proteases included SARS-CoV M^pro, cathepsin G, caspase-3, ubiquitin carboxy-terminal hydrolase L1 (UCHL1), thrombin, factor Xa, chymase, and prostasin. Several of the assessed compounds presented considerable off-target binding towards the panel of proteases, as well as the selected anti-targets. Our results further suggest a high risk of off-target binding to chymase and cathepsin G. Thus, in future discovery projects, experimental selectivity assessment should be directed toward these proteases. A systematic selectivity assessment of SARS-CoV-2 M^pro inhibitors, as we report it, was not previously conducted. Full article