Ubiquitin C-terminal hydrolase-L1 Levels Research Articles

The Importance of Increased Serum GFAP and UCH-L1 Levels in Distinguishing Large Vessel from Small Vessel Occlusion in Acute Ischemic Stroke.

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.

Blood biomarkers of neuronal injury in paediatric cerebral malaria and severe malarial anaemia

Abstract Persistent neurodisability is a known complication in paediatric survivors of cerebral malaria and severe malarial anaemia. Tau, ubiquitin C-terminal hydrolase-L1, neurofilament-light chain, and glial fibrillary acidic protein have proven utility as biomarkers that predict adverse neurologic outcomes in adult and paediatric disorders. In paediatric severe malaria, elevated tau is associated with mortality and neurocognitive complications. We aimed to investigate whether a multi-analyte panel including ubiquitin C-terminal hydrolase-L1, neurofilament-light chain, and glial fibrillary acidic protein can serve as biomarkers of brain injury associated with mortality and neurodisability in cerebral malaria and severe malarial anaemia. In a prospective cohort study of Ugandan children, 18 months to 12 years of age with cerebral malaria (n = 182), severe malarial anaemia (n = 158), and asymptomatic community children (n = 118), we measured admission blood levels of ubiquitin C-terminal hydrolase-L1, neurofilament-light chain, and glial fibrillary acidic protein. We investigated differences in biomarker levels, associations with mortality, blood–brain barrier integrity, neurodeficits and cognitive Z-scores in survivors up to 24-month follow-up. Admission ubiquitin C-terminal hydrolase-L1 levels were elevated &amp;gt;95th percentile of community children in 71 and 51%, and neurofilament-light chain levels were elevated &amp;gt;95th percentile of community children in 40 and 37% of children with cerebral malaria and severe malarial anaemia, respectively. Glial fibrillary acidic protein was not elevated in disease groups compared with controls. In cerebral malaria, elevated neurofilament-light chain was observed in 16 children who died in hospital compared with 166 survivors (P = 0.01); elevations in ubiquitin C-terminal hydrolase-L1 levels were associated with degree of blood–brain barrier disruption (P = 0.01); and the % predictive value for neurodeficits over follow-up (discharge, 6-, 12-, and 24 months) increased for ubiquitin C-terminal hydrolase-L1 (60, 67, 72, and 83), but not neurofilament-light chain (65, 68, 60, and 67). In cerebral malaria, elevated ubiquitin C-terminal hydrolase-L1 was associated with worse memory scores in children &amp;lt;5 years at malaria episode who crossed to over 5 years old during follow-up cognitive testing [β −1.13 (95% confidence interval −2.05, −0.21), P = 0.02], and elevated neurofilament-light chain was associated with worse attention in children ≥5 years at malaria episode and cognitive testing [β −1.08 (95% confidence interval −2.05, −1.05), P = 0.03]. In severe malarial anaemia, elevated ubiquitin C-terminal hydrolase-L1 was associated with worse attention in children &amp;lt;5 years at malaria episode and cognitive testing [β −0.42 (95% confidence interval −0.76, −0.07), P = 0.02]. Ubiquitin C-terminal hydrolase-L1 and neurofilament-light chain levels are elevated in paediatric cerebral malaria and severe malarial anaemia. In cerebral malaria, elevated neurofilament-light chain is associated with mortality whereas elevated ubiquitin C-terminal hydrolase-L1 is associated with blood–brain barrier dysfunction and neurodeficits over follow-up. In cerebral malaria, both markers are associated with worse cognition, while in severe malarial anaemia, only ubiquitin C-terminal hydrolase-L1 is associated with worse cognition.

Elevated cerebrospinal fluid ubiquitin C-terminal hydrolase-L1 levels correlate with phenotypic severity and therapeutic response in Niemann-Pick disease, type C1

BackgroundNiemann-Pick disease, type C1 (NPC1) is an ultrarare, recessive disorder due to pathological variants of NPC1. The NPC1 phenotype is characterized by progressive cerebellar ataxia and cognitive impairment. Although classically a childhood/adolescent disease, NPC1 is heterogeneous with respect to the age of onset of neurological signs and symptoms. While miglustat has shown to be clinically effective, there are currently no FDA approved drugs to treat NPC1. Identification and characterization of biomarkers may provide tools to facilitate therapeutic trials. Ubiquitin C-terminal hydrolase-L1 (UCHL1) is a protein which is highly expressed by neurons and is a biomarker of neuronal damage. We thus measured cerebrospinal fluid (CSF) levels of UCHL1 in individuals with NPC1. MethodsCSF levels of UCHL1 were measured using a Quanterix Neuroplex 4 assay in 94 individuals with NPC1 and 35 age-appropriate comparison samples. Cross-sectional and longitudinal CSF UCHL1 levels were then evaluated for correlation with phenotypic measures and treatment status. ResultsCSF UCHL1 levels were markedly elevated (3.3-fold) in individuals with NPC1 relative to comparison samples. The CSF UCHL1 levels showed statistically significant (adj p < 0.0001), moderate, positive correlations with both the 17- and 5-domain NPC Neurological Severity Scores and the Annual Severity Increment Scores. Miglustat treatment significantly decreased (adj p < 0.0001) CSF UCHL1 levels by 30% (95% CI 17–40%). ConclusionsCSF UCHL1 levels are elevated in NPC1, increase with increasing clinical severity and decrease in response to therapy with miglustat. Based on these data, UCHL1 may be a useful biomarker to monitor disease progression and therapeutic response in individuals with NPC1.

Plasma ubiquitin C-terminal hydrolase-L1 (UCH-L1) level as a blood biomarker of neurological damage after allogeneic hematopoietic cell transplantation.

Several biofluid-based biomarkers for traumatic brain injury show promise for use in diagnosis and outcome prediction. In contrast, few studies have investigated biomarkers for non-traumatic brain injury. We focused on ubiquitin C-terminal hydrolase-L1 (UCH-L1), which has been proposed as a screening tool for traumatic brain injury, and investigated whether the plasma UCH-L1 level could also be a useful biomarker in patients with non-traumatic brain injury. We measured UCH-L1 in 25 patients who had experienced neurological complications after allogeneic hematopoietic cell transplantation (HCT) and 22 control patients without any complications or graft-versus-host disease. Although UCH-L1 levels before HCT did not differ significantly (P = 0.053), levels after HCT were higher in patients with neurological complications compared with the control group (P < 0.001). At a UCH-L1 cutoff value of 0.072ng/ml, sensitivity was 68.0% and specificity was 100%. The statistical power of UCH-L1 for neurological complications seemed to be higher than that of CT and comparable to that of MRI. Thus, increased levels of UCH-L1 might reflect the presence of neurological damage even in patients with non-traumatic brain injury. Further large cohort investigations are warranted.

Blood component resuscitative strategies to mitigate endotheliopathy in a murine hemorrhagic shock model.

Resuscitation with plasma components has been shown to improve endotheliopathy induced by hemorrhagic shock, but the optimal resuscitation strategy to preserve the endothelial glycocalyx has yet to be defined. The aim of this study was to determine if resuscitation with lactated ringers (LR), whole blood (WB), packed red blood cells (RBC), platelet rich plasma (PRP), platelet poor plasma (PPP), balanced RBC:PRP (1:1), or day 14 RBC (d14) would best minimize endothelial damage following shock. Male C57BL/6 mice were hemorrhaged to a goal mean arterial pressure (MAP) of 25 mm Hg for one hour. Unshocked sham mice served as controls. Mice were then resuscitated with equal volumes of LR, WB, RBC, PRP, PPP, 1:1, or d14 RBC and then sacrificed at 1-, 4-, or 24-hours (n = 5). Serum was analyzed for syndecan-1, ubiquitin C-terminal hydrolase L1 (UCHL-1), and cytokine concentrations. Lungs underwent syndecan-1 immunostaining and lung injury scores were calculated after H&E stains. Proteolytic cleavage of the endothelial glycocalyx was assessed by serum matrix metalloprotease 9 (MMP-9) levels. Serum syndecan-1 and UCHL-1 levels were significantly increased following resuscitation with d14 RBC compared to other groups. Early elevation in lung syndecan-1 staining was noted in LR treated mice while d14 mice showed decreased staining compared to sham mice following shock. Lung injury scores were significantly elevated 4 hours after resuscitation with LR and d14 RBC compared to WB. Serum MMP-9 levels were significantly increased at 1 and 4-hours in d14 mice compared to sham mice. Systemic inflammation was increased in animals receiving LR, 1:1, or d14 RBC. Resuscitation with WB following hemorrhagic shock reduces endothelial syndecan-1 shedding and mitigates lung injury. Aged RBC and LR fail to attenuate endothelial injury following hemorrhagic shock. Further research will be necessary to determine the effect of each of these resuscitative fluids in a hemorrhagic shock model with the addition of tissue injury.

Serum ubiquitin C-terminal hydrolase-L1, glial fibrillary acidic protein, and neurofilament light chain are good entry points and biomarker candidates for neurosyphilis diagnosis among patients without HIV to avoid lumbar puncture.

Laboratory tests to diagnose neurosyphilis using cerebrospinal fluid (CSF) are currently disadvantageous as a lumbar puncture is required, which may result in patients with neurosyphilis missing an opportunity for early diagnosis. Thus, blood biomarker candidates that are more convenient and minimally invasive to collect for diagnosing neurosyphilis is urgently needed. This observational study aimed to analyze serum ubiquitin C-terminal hydrolase-L1 (UCH-L1), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NF-L) levels in 153 patients without HIV and to evaluate their diagnostic performance in neurosyphilis compared with CSF. Serum UCH-L1, GFAP, and NF-L levels were significantly higher in patients with neurosyphilis compared with patients with uncomplicated syphilis or non-syphilis. For the diagnosis of neurosyphilis, serum UCH-L1, GFAP, and NF-L revealed sensitivities of 90.20%, 80.40%, and 88.24%, and specificities of 92.16%, 78.43%, and 80.39%, respectively, at cut-off levels of 814.50 pg/mL, 442.70 pg/mL, and 45.19 pg/mL, respectively. In patients with syphilis, serum UCH-L1, GFAP, and NF-L levels correlated strongly or moderately with those in the CSF, with similar or better diagnostic performance than those in the CSF. The testing algorithms' sensitivity and specificity increased to 98.04% and 96.08%, respectively, when subjected to parallel and combination testing, respectively. To avoid lumbar puncture, each serum UCH-L1, GFAP, and NF-L is a good entry point and biomarker candidate for the diagnosis of neurosyphilis among patients without HIV. These proteins used in concerto can further improve the diagnostic sensitivity and specificity.

Serum assessment of traumatic axonal injury: the correlation of GFAP, t-Tau, UCH-L1, and NfL levels with diffusion tensor imaging metrics and its prognosis utility.

Diagnosis of traumatic axonal injury (TAI) is challenging because of its underestimation by conventional MRI and the technical requirements associated with the processing of diffusion tensor imaging (DTI). Serum biomarkers seem to be able to identify patients with abnormal CT scanning findings, but their potential role to assess TAI has seldomly been explored. Patients with all severities of traumatic brain injury (TBI) were prospectively included in this study between 2016 and 2021. They underwent blood extraction within 24 hours after injury and imaging assessment, including DTI. Serum concentrations of glial fibrillary acidic protein, total microtubule-associated protein (t-Tau), ubiquitin C-terminal hydrolase L1 (UCH-L1), and neurofilament light chain (NfL) were measured using an ultrasensitive Simoa multiplex assay panel, a digital form of enzyme-linked immunosorbent assay. The Glasgow Outcome Scale-Extended score was determined at 6 months after TBI. The relationships between biomarker concentrations, volumetric analysis of corpus callosum (CC) lesions, and fractional anisotropy (FA) were analyzed by nonparametric tests. The prognostic utility of the biomarker was determined by calculating the C-statistic and an ordinal regression analysis. A total of 87 patients were included. Concentrations of all biomarkers were significantly higher for patients compared with controls. Although the concentration of the biomarkers was affected by the presence of mass lesions, FA of the CC was an independent factor influencing levels of UCH-L1 and NfL, which positioned these two biomarkers as better surrogates of TAI. Biomarkers also performed well in determining patients who would have had unfavorable outcome. NfL and the FA of the CC are independent complementary factors related to outcome. UCH-L1 and NfL seem to be the biomarkers more specific to detect TAI. The concentration of NfL combined with the FA of the CC might help predict long-term outcome.

Evaluation of cerebrospinal fluid ubiquitin C-terminal hydrolase-L1, glial fibrillary acidic protein, and neurofilament light protein as novel markers for the diagnosis of neurosyphilis among HIV-negative patients

To evaluate the possibility of using cerebrospinal fluid (CSF) ubiquitin C-terminal hydrolase L1 (UCH-L1), glial fibrillary acidic protein (GFAP), and neurofilament light protein (NF-L) for the diagnosis of neurosyphilis (NS). A cross-sectional study of 576 subjects was conducted at Zhongshan Hospital from January 2021 to August 2022 to evaluate the diagnostic accuracy of CSF UCH-L1, GFAP, and NF-L for NS and analyze their correlations with CSF rapid plasma reagin (RPR), white blood cells (WBCs), and protein. Patients with NS had higher CSF UCH-L1, GFAP, and NF-L levels than patients with syphilis/non-NS and nonsyphilis. Using a cut-off point of 652.25 pg/ml, 548.89 pg/ml, and 48.38 pg/ml, CSF UCH-L1, GFAP, and NF-L had a sensitivity of 85.11%, 76.60%, and 82.98%, with a specificity of 92.22%, 85.56%, and 91.11%, respectively, for NS diagnosis. Moreover, parallel and serial testing algorithms improved their sensitivity and specificity to 93.62% and 98.89%, respectively. Interestingly, levels between patients with NS who are CSF RPR-positive and -negative did not differ and showed a weak or moderate correlation with WBC and CSF protein in patients with syphilis. CSF UCH-L1, GFAP, and NF-L can be used as novel markers for the diagnosis of NS, independent of CSF RPR, WBC, and proteins.

FDG-PET/CT Assessment of the Cerebral Protective Effects of Hydrogen in Rabbits with Cardiac Arrest.

Anatomical imaging methods and histological examinations have limited clinical value for early monitoring of brain function damage after cardiac arrest (CA) in vivo. We aimed to assess the cerebral protective effects of hydrogen in rabbits with CA by using fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT). Male rabbits were divided into the hydrogen-treated (n=6), control (n=6), and sham (n=3) groups. Maximum standardized uptake values (SUVmax) were measured by FDG-PET/CT at baseline and post-resuscitation. Blood Ubiquitin C-terminal hydrolase-L1 (UCH-L1) and neuron-specific enolase (NSE) were measured before and after the operation. After surgical euthanasia, brain tissues were extracted for Nissl staining. SUVmax values first decreased at 2 and 24 h after resuscitation before rising in the hydrogentreated and control groups. SUVmax values in the frontal, occipital, and left temporal lobes and in the whole brain were significantly different between the hydrogen and control groups at 2 and 24 h postresuscitation (P<0.05). The neurological deficit scores at 24 and 48 h were lower in the hydrogentreated group (P<0.05). At 24 h, the serum UCH-L1 and NSE levels were increased in the hydrogen and control groups (P<0.05), but not in the sham group. At 48 and 72 h post-CA, the plasma UCH-L1 and NSE levels in the hydrogen and control groups gradually decreased. Neuronal damage was smaller in the hydrogen group compared to the control group at 72 h. FDG-PET/CT could be used to monitor early cerebral damage, indicating a novel method for evaluating the protective effects of hydrogen on the brain after CA.

Association between Blood and Computed Tomographic Imaging Biomarkers in a Cohort of Mild Traumatic Brain Injury Patients.

The objective of this work was to analyze the relationships between traumatic brain injury (TBI) on computed tomographic (CT) imaging and blood concentration of glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), and S100B. This prospective cohort study involved 644 TBI patients referred to Stanford Hospital's Emergency Department between November 2015 and April 2017. Plasma and serum samples of 462 patients were analyzed for levels of GFAP, UCH-L1, and S100B. Glial neuronal ratio (GNR) was calculated as the ratio between GFAP and UCH-L1 concentrations. Admission head CT scans were reviewed for TBI imaging common data elements, and performance of biomarkers for identifying TBI was assessed via area under the receiver operating characteristic curve (ROC). We also dichotomized biomarkers at established thresholds and estimated standard measures of classification accuracy. We assessed the ability of GFAP, UCH-L1, and GNR to discriminate small and large/diffuse lesions based on CT imaging using an ROC analysis. In our cohort of mostly mild TBI patients, GFAP was significantly more accurate in detecting all types of acute brain injuries than UCH-L1 in terms of area under the curve (AUC) values (p < 0.001), and also compared with S100B (p < 0.001). UCH-L1 and S100B had similar performance (comparable AUC values, p = 0.342). Sensitivity exceeded 0.8 for each biomarker across all different types of TBI injuries, and no significant differences were observed by type of injury. There was a significant difference between GFAP and GNR in distinguishing between small lesions and large/diffuse lesions in all injuries (p = 0.004, p = 0.007). In conclusion, GFAP, UCH-L1, and S100B show high sensitivity and negative predictive values for all types of TBI lesions on head CT. A combination of negative blood biomarkers (GFAP and UCH-L1) in a patient suspected of TBI may be used to safely obviate the need for a head CT scan. GFAP is a promising indicator to discriminate between small and large/diffuse TBI lesions.

Analysis of Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase L1 in Postmortem Serum and Cerebrospinal Fluid in Traumatic Cerebral Deaths

Objective: There is a growing body of research aimed at identifying biological markers that could indicate traumatic cerebral deaths such as traumatic brain damage in the postmortem period. In the event of astrocytic and neuronal injury, glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) are released into cerebrospinal fluid and blood. In the postmortem identification of traumatic brain injury, the present research explores the ability of GFAP and UCH-L1.&#x0D; Methods: Cerebrospinal fluid and blood samples were obtained from medicolegal autopsies, 17 cases with severe head trauma, 9 cases with the non-lethal head trauma group and 18 control cases. UCH-L1 and GFAP levels in postmortem cerebrospinal fluid and serum were determined&#x0D; from an enzyme-linked immunosorbent assay (ELISA).&#x0D; Results: GFAP level in cerebrospinal fluid and serum was 2.68±0.67 ng/ml and 0.79±0.92 ng/ml in the lethal head trauma group, 2.74±0.64 ng/ml and 1.05±0.68 ng/ml the non-lethal head trauma group and 2.49±0.55 ng/ml and 1.05±0.89 ng/ml in the control group, respectively.&#x0D; UCH-L1 level in cerebrospinal fluid and serum was 3.02±0.68 ng/ml and 2.69±0.77 ng/ml in the lethal head trauma group, 3.34±0.70 ng/ml and 2.59±0.65 ng/ml the non-lethal head trauma group and 3.28±0.33 ng/ml and 2.74±0.34 ng/ml in the control group, respectively. Elevated cerebrospinal fluid and serum UCH-L1 and GFAP levels were observed in all cases, although absence of statistically significant difference between the trauma and control groups (p&gt;0.05).&#x0D; Conclusion: Further studies are needed to assess whether postmortem serum and CSF GFAP and UCH-L1 concentrations increase regardless of the cause of death.

Predicting Clinical Outcomes 7-10 Years after Severe Traumatic Brain Injury: Exploring the Prognostic Utility of the IMPACT Lab Model and Cerebrospinal Fluid UCH-L1 and MAP-2.

Severe traumatic brain injury (TBI) is a major contributor to disability and mortality in the industrialized world. Outcomes of severe TBI are profoundly heterogeneous, complicating outcome prognostication. Several prognostic models have been validated for acute prediction of 6-month global outcomes following TBI (e.g., morbidity/mortality). In this preliminary observational prognostic study, we assess the utility of the International Mission on Prognosis and Analysis of Clinical Trials in TBI (IMPACT) Lab model in predicting longer term global and cognitive outcomes (7-10years post injury) and the extent to which cerebrospinal fluid (CSF) biomarkers enhance outcome prediction. Very long-term global outcome was assessed in a total of 59 participants (41 of whom did not survive their injuries) using the Glasgow Outcome Scale-Extended and Disability Rating Scale. More detailed outcome information regarding cognitive functioning in daily life was collected from 18 participants surviving to 7-10years post injury using the Cognitive Subscale of the Functional Independence Measure. A subset (n = 10) of these participants also completed performance-based cognitive testing (Digit Span Test) by telephone. The IMPACT lab model was applied to determine its prognostic value in relation to very long-term outcomes as well as the additive effects of acute CSF ubiquitin C-terminal hydrolase-L1 (UCH-L1) and microtubule associated protein 2 (MAP-2) concentrations. The IMPACT lab model discriminated favorable versus unfavorable 7- to 10-year outcome with an area under the receiver operating characteristic curve of 0.80. Higher IMPACT lab model risk scores predicted greater extent of very long-term morbidity (β = 0.488 p = 0.000) as well as reduced cognitive independence (β = - 0.515, p = 0.034). Acute elevations in UCH-L1 levels were also predictive of lesser independence in cognitive activities in daily life at very long-term follow-up (β = 0.286, p = 0.048). Addition of two CSF biomarkers significantly improved prediction of very long-term neuropsychological performance among survivors, with the overall model (including IMPACT lab score, UCH-L1, and MAP-2) explaining 89.6% of variance in cognitive performance 7-10years post injury (p = 0.008). Higher acute UCH-L1 concentrations were predictive of poorer cognitive performance (β = - 0.496, p = 0.029), whereas higher acute MAP-2 concentrations demonstrated a strong cognitive protective effect (β = 0.679, p = 0.010). Although preliminary, results suggest that existing prognostic models, including models with incorporation of CSF markers, may be applied to predict outcome of severe TBI years after injury. Continued research is needed examining early predictors of longer-term outcomes following TBI to identify potential targets for clinical trials that could impact long-ranging functional and cognitive outcomes.

Controlled Decompression Alleviates Brain Injury via Attenuating Oxidative Damage and Neuroinflammation in Acute Intracranial Hypertension.

Background The benefits of controlled decompression (CDC) for patients with acute intracranial hypertension especially in terms of alleviating the complications caused by rapid decompression (RDC) have been confirmed by clinical studies. This study is aimed at evaluating the therapeutic potency of CDC with ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) by investigating the potential molecular mechanism in the acute intracranial hypertension (AICH) rabbit model. Methods Male New Zealand white rabbits were randomly subdivided into the sham-operated (SH) group, CDC group, and RDC group. Blood plasma samples and brain tissue were collected 2 days before operation (baseline) and at 3, 6, 24, and 72 hours after operation to measure the levels of UCH-L1, GFAP, oxidative stress indicators, and inflammatory cytokines by performing ELISA or Western blot. The neurological score of the rabbits and brain water content was graded 24 h after surgery. qPCR, immunofluorescence, and FJ-C staining were conducted. Results CDC improved neurological function, lowered brain water content, ameliorated neuronal degeneration, attenuated oxidative damage, and inflammatory responses to a greater extent than RDC. Plasma UCH-L1 level was significantly lower in the CDC group at 3 h postoperatively than in the RDC group. CDC reduced plasma GFAP levels to various degrees at 3 h, 6 h, and 24 h postoperatively compared with RDC. Immunofluorescence confirmed that the expression of UCH-L1 and GFAP in the cortex of the CDC group was lower than that of the RDC group. Conclusions Our data collectively demonstrate that CDC could attenuate oxidative damage and inflammatory responses, downregulate UCH-L1 and GFAP levels, and contribute to an improved neuroprotective effect compared with RDC.

Changes in Serum LncRNA MEG3/miR-181b and UCH-L1 Levels in Patients with Moderate and Severe Intracerebral Hemorrhage.

To study on the association of lnc-MEG3/miR-181b and UCH-L1 in the progression of cerebral hemorrhage. Further facilitation the development of novel strategies that use their potential as a therapeutic targets. In this study, we studied the lncRNA MEG3 and miR-181b expression in 30 patients with ICH who were admitted to the General Hospital of Xinjiang Military Command from January 2021 to May 2021 by quantitative polymerase chain reaction. Serum levels of UCH-L1 were detected by enzyme-linked immune sorbent assay, and disease severity was evaluated using the Glasgow Coma Scale. We also recorded ICH-related deaths in hospital. We found that lnc-MEG3 and UCH-L1 levels increased and miR-181b levels decreased in the serum of patients with ICH. lnc-MEG3, miR-181b, and UCH-L1 levels were also associated with the severity of the condition. Our data indicated that lnc-MEG3, miR-181b, and UCH-L1 are likely involved in the pathophysiology of ICH, and could form the basis of future studies on potential targets for the treatment of traumatic CNS injuries. UCH-L1 could also find application in ICH management. Further studies on the plasma lncRNA-MEG3, miR-181b, and UCH-L1 levels in patients with ICH could yield novel biological targets for the prediction and treatment of ICH.

Evaluation of Acute Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase-L1 Plasma Levels in Traumatic Brain Injury Patients with and without Intracranial Lesions.

This pilot study aimed to evaluate the association of plasma ubiquitin C-terminal hydrolase-L1 (UCH-L1), glial fibrillary acidic protein (GFAP), and S100 calcium-binding protein B (S100B) with intracranial abnormalities visible on a computed tomography (CT) scan (CT positive) and injury severity in acute traumatic brain injury (TBI). For these purposes, a cohort of 109 adult TBI patients was recruited within 6 h from the injury event. A hyperacute subcohort of 20 patients who had their blood collected within 2 h from injury was analyzed separately for early acute biomarker levels. Levels of GFAP and UCH-L1 were analyzed using the prototype Abbott i-STAT™ TBI Plasma Test (Abbott Laboratories, Abbot Park, IL), alongside S100B measurement (Elecsys; Roche Diagnostics, Penzberg, Germany). In the hyperacute subcohort, GFAP and UCH-L1, but not S100B, levels were significantly higher in the CT-positive group compared to CT-negative patients. AUC values for differentiation between CT-positive and CT-negative patients were 0.97 for GFAP, 0.87 for UCH-L1, and 0.60 for S100B. Severity discrimination, defined by Glasgow Coma Scale (GCS) score, was then analyzed in the total patient cohort. Levels of all three biomarkers were significantly different between mild (GCS, 13–15) and moderate/severe (GCS, 3–12) injury groups. UCH-L1 showed the highest area under the curve value for severity discrimination (0.94), followed by GFAP (0.91) and S100B (0.83). These results support the clinical utility of GFAP and UCH-L1 as TBI biomarkers able to rule out CT-positive injury in acute TBI. Moreover, excellent differentiation of GFAP and UCH-L1 between mild and moderate/severe TBI groups affirms their close association with the underlying pathology.

Plasma neurofilament light chain level predicts outcomes in stroke patients receiving endovascular thrombectomy

BackgroundTimely endovascular thrombectomy (EVT) significantly improves outcomes in patients with acute ischemic stroke (AIS) with large vessel occlusion type. However, whether certain central nervous system-specific plasma biomarkers correlate with the outcomes is unknown. We evaluated the temporal changes and prognostic roles of the levels of these biomarkers in patients with AIS undergoing EVT.MethodsWe enrolled 60 patients who received EVT for AIS and 14 controls. The levels of plasma biomarkers, namely neurofilament light chain (NfL), glial fibrillary astrocytic protein (GFAP), tau, and ubiquitin C-terminal hydrolase L1 (UCHL1), were measured with an ultrasensitive single molecule array before, immediately after, and 24 h after EVT (T1, T2, and T3, respectively). The outcomes of interest were death or disability at 90 days (defined as a modified Rankin Scale score of 3–6) and types of hemorrhagic transformation (hemorrhagic infarction or parenchymal hemorrhage).ResultsOf the 180 blood samples from the 60 patients who received EVT, the plasma NfL, GFAP, and UCHL1 levels at T1 were significantly higher than those of the controls, and the levels of all four biomarkers were significantly higher at T3. Patients with parenchymal hemorrhage had a significantly higher rate of increase in GFAP (Pinteraction = 0.005) and UCHL1 (Pinteraction = 0.007) levels compared with those without parenchymal hemorrhage. In a multivariable analysis with adjustment for age, sex, National Institute of Health Stroke Scale score, history of atrial fibrillation, and recanalization status, higher NfL levels at T1 (odds ratio [OR] 2.05; 95% confidence interval [CI], 1.03–4.08), T2 (OR, 2.08; 95% CI, 1.05–4.01), and T3 (OR, 3.94; 95% CI, 1.44–10.79) were independent predictors of death or disability at 90 days.ConclusionAmong patients with AIS who received EVT, those with hemorrhagic transformation exhibited significant increase in plasma GFAP and UCHL1 levels over time. Higher plasma NfL were predictive of unfavorable functional outcomes.

Long-term inhibition of UCHL1 decreases hypertension and retinopathy in spontaneously hypertensive rats.

ObjectiveTo investigate the role of the deubiquitinase ubiquitin C-terminal hydrolase L1 (UCHL1) in hypertension and retinopathy in the spontaneously hypertensive rat (SHR).MethodsWistar–Kyoto (WKY) rats and SHRs were administered the UCHL1 inhibitor LDN57444 (20 μg/kg/day) for 4 months. Pathological changes were detected with hematoxylin and eosin, immunofluorescence, and dihydroethidium staining. The mRNA and protein expression of UCHL1 were examined by real-time PCR and immunoblotting analysis.ResultsAt 6 months of age, SHRs showed significantly increased mRNA and protein levels of UCHL1 in the retina compared with WKY rats. Moreover, SHRs exhibited significantly increased central retinal thickness, inflammation, and reactive oxygen species production compared with WKY rats, and these effects were markedly attenuated by systemic administration of the UCHL1 inhibitor LDN57444. The beneficial effects of LDN57444 were possibly associated with reduced blood pressure and the inactivation of several signaling pathways.ConclusionUCHL1 is involved in hypertension and retinopathy in SHRs, suggesting that UCHL1 may be used as a potential therapeutic target for treating hypertensive retinopathy.

Characterization of Cerebrospinal Fluid Ubiquitin C-Terminal Hydrolase L1 as a Biomarker of Human Acute Traumatic Spinal Cord Injury.

A major obstacle for translational research in acute spinal cord injury (SCI) is the lack of biomarkers that can objectively stratify injury severity and predict outcome. Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a neuron-specific enzyme that shows promise as a diagnostic biomarker in traumatic brain injury (TBI), but has not been studied in SCI. In this study, cerebrospinal fluid (CSF) and serum samples were collected over the first 72-96 h post-injury from 32 acute SCI patients who were followed prospectively to determine neurological outcomes at 6 months post-injury. UCH-L1 concentration was measured using the Quanterix Simoa platform (Quanterix, Billerica, MA) and correlated to injury severity, time, and neurological recovery. We found that CSF UCH-L1 was significantly elevated by 10- to 100-fold over laminectomy controls in an injury severity- and time-dependent manner. Twenty-four-hour post-injury CSF UCH-L1 concentrations distinguished between American Spinal Injury Association Impairment Scale (AIS) A and AIS B, and AIS A and AIS C patients in the acute setting, and predicted who would remain "motor complete" (AIS A/B) at 6 months with a sensitivity of 100% and a specificity of 86%. AIS A patients who did not improve their AIS grade at 6 months post-injury were characterized by sustained elevations in CSF UCH-L1 up to 96 h. Similarly, the failure to gain >8 points on the total motor score at 6 months post-injury was associated with higher 24-h CSF UCH-L1. Unfortunately, serum UCH-L1 levels were not informative about injury severity or outcome. In conclusion, CSF UCH-L1 in acute SCI shows promise as a biomarker to reflect injury severity and predict outcome.

The Deubiquitinating Enzyme UCHL1 Induces Resistance to Doxorubicin in HER2+ Breast Cancer by Promoting Free Fatty Acid Synthesis.

Ubiquitin C-terminal hydrolase L1 (UCHL1), which is a deubiquitinating enzyme, is known to play a role in chemoresistance in cancers. However, its potential roles and mechanisms in the chemoresistance of breast cancer (BC) remain unclear. In this study, we examined its expression in patients with BC and employed Kaplan–Meier analysis and the log-rank test for survival analyses. It was found that up-regulated UCHL1 expression was positively associated with both chemoresistance and poor prognosis, especially in patients with HER2+ BC. Moreover, UCHL1 expression was elevated in HER2+ BC cells (SK-BR-3 and BT474). Similarly, doxorubicin (DOX)-resistant BC cells (MCF-7/DOX) had higher UCHL1 levels than MCF-7 cells. CCK-8 assay showed that BC cells with higher UCHL1 levels were more resistant to DOX. Furthermore, by inhibiting UCHL1 in BC cells with elevated UCHL1 expression, we demonstrated that UCHL1 promoted DOX-resistance in BC. Mechanistically, UCHL1 probably promoted DOX-resistance of BC by up-regulating free fatty acid (FFA) synthesis, as exhibited by reduced FFA synthase expression and resurrected DOX-sensitivity upon UCHL1 inhibition. Overall, UCHL1 up-regulation is associated with DOX-resistance and poor prognosis in patients with HER2+ BC. UCHL1 induces DOX-resistance by up-regulating FFA synthesis in HER2+ BC cells. Thus, UCHL1 might be a potential clinical target for overcoming DOX resistance in patients with HER2+ BC.

Traumatic Optic Nerve Injury Elevates Plasma Biomarkers of Traumatic Brain Injury in a Porcine Model.

A diagnosis of traumatic brain injury (TBI) is typically based on patient medical history, a clinical examination, and imaging tests. Elevated plasma levels of glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase L1 (UCH-L1), and neurofilament light chain (NFL) have been observed in numerous studies of TBI patients. It is reasonable to view traumatic optic neuropathy (TON) as a focal form of TBI. The purpose of this study was to assess if circulating GFAP, UCH-L1, and NFL are also elevated in a porcine model of TON. Serum levels of GFAP, UCH-L1, and NFL were measured immediately before optic nerve crush and 1 h post-injury in 10 Yucatan minipigs. Severity of optic nerve crush was confirmed by visual inspection of the optic nerve at time of injury, loss of visual function as measured by flash visual evoked potential (fVEP) at 7 and 14 days, and histological analysis of axonal transport of cholera toxin-β (CT-β) within the optic nerve. Post-crush concentrations of GFAP, UCH-L1, and NFL were all significantly elevated compared with pre-crush concentrations (p < 0.01, p = 0.01, and p < 0.01, respectively). The largest increase was observed for GFAP with the post-injury median concentration increasing nearly sevenfold. The use of these TBI biomarkers for diagnosing and managing TON may be helpful for non-ophthalmologists in particular in diagnosing this condition. In addition, the potential utility of these biomarkers for diagnosing other optic nerve and/or retinal pathologies should be evaluated.