Urolithin B Attenuates Cerebral Ischemia-reperfusion Injury by Modulating Nrf2-regulated Anti-oxidation in Rats.

Ischemia-reperfusion (IR) induces a wide range of irreversible injuries. Cerebral IR injury (IRI) refers to additional brain tissue damage that occurs after blood flow is restored following cerebral ischemia. Currently, no established methods exist for treating IRI. Oxidative stress is recognized as a primary mechanism initiating IRI and a crucial focal target for its treatment. Urolithin B, a metabolite derived from ellagitannins, antioxidant polyphenols, has demonstrated protective effects against oxidative stress in various disease conditions. However, the precise mechanism underlying UB's effect on IRI remains unclear. In our current investigation, we assessed UB's ability to mitigate neurological functional impairment induced by IR using a neurological deficit score. Additionally, we examined cerebral infarction following UB administration through TTC staining and neuron Nissl staining. UB's inhibition of neuronal apoptosis was demonstrated through the TUNEL assay and Caspase-3 measurement. Additionally, we examined UB's effect on oxidative stress levels by analyzing malondialdehyde (MDA) concentration, superoxide dismutase (SOD) activity, and immunohistochemistry analysis of inducible nitric oxide synthase (iNOS) and 8-hydroxyl-2'-deoxyguanosine (8-OHdG). Notably, UB demonstrated a reduction in oxidative stress levels. Mechanistically, UB was found to stimulate the Nrf2/HO-1 signaling pathway, as evidenced by the significant reduction in UB's neuroprotective effects upon administration of ATRA, an Nrf2 inhibitor. In summary, UB effectively inhibits oxidative stress induced by IR through the activation of the Nrf2/HO-1 signaling pathway. These findings suggest that UB holds promise as a therapeutic agent for the treatment of IRI.

Utility of serum macrophage migration inhibitory factor as a potential biomarker for detection of cerebrocardiac syndrome following severe traumatic brain injury.

BACKGROUND: Cerebrocardiac syndrome (CCS) is a common complication after severe traumatic brain injury (sTBI) and its occurrence obviously increases the risk of a poor outcome. Macrophage migration inhibitory factor (MIF) acts as an inflammatory cytokine and its circulating concentration are related to acute heart and brain injury. The aim of this study was to examine the association of serum concentration of MIF with posttraumatic CCS. METHODS: From January 2016 to February 2019, 116 sTBI patients and 116 healthy controls with similar age and gender percentage were recruited. Relationship between serum MIF concentration and CCS was assessed using multivariate analysis. RESULTS: Serum MIF concentration of patients were significantly higher than those among controls. Serum MIF concentration were intimately correlated with Glasgow coma scale scores (t = -5.553, P < 0.001) and serum C-reactive protein concentration (t = 5.320, P < 0.001) in a multivariate linear regression model. 61 patients (52.6%) displayed CCS. Under ROC curve analylsis, there was a strong discriminatory ability for CCS regarding serum MIF concentration (area under curve, 0.834; 95% confidence interval, 0.754-0.897). Serum MIF concentration were highly associated with CCS independent of other confounding factors (odds ratio, 5.608; 95% CI: 1.896-16.587). CONCLUSIONS: Increased MIF in serum may be a useful biomarker for early detection of CCS after head trauma.

Serum soluble tumor necrosis factor-like weak inducer of apoptosis is a potential biomarker for outcome prediction of patients with aneurysmal subarachnoid hemorrhage.

BACKGROUND: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) might contribute to brain inflammation after acute brain injury. The current study was designed to investigate whether serum soluble TWEAK (sTWEAK) can serve as a potential biomarker for functional outcome after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: In this single-center prospective, observational study, admission serum sTWEAK concentrations were quantified among 112 aSAH patients. Impact of serum sTWEAK concentrations on a poor outcome (Glasgow outcome scale score 1-3) at 6 months after stroke onset was determined using multivariate analysis. RESULTS: Admission serum sTWEAK concentrations were intimately correlated with serum C-reactive protein concentrations, World Federation of Neurological Surgeons scores and modified Fisher scores. A total of 38 patients (33.9%) had a poor outcome at post-hemorrhagic 6 months. Admission serum sTWEAK concentrations were substantially higher in patients with a poor outcome than in the other remainders. Under receiver operating characteristic curve, serum sTWEAK concentrations significantly distinguished a poor outcome. Serum sTWEAK concentrations > 3.23 ng/ml discriminated the risk of a poor outcome with medium-high sensitivity and specificity and independently predicted a poor outcome. CONCLUSIONS: Serum sTWEAK, in close correlation with inflammation and hemorrhagic severity, might represent a potential biomarker for predicting clinical outcome after aSAH.

Serum soluble lectin-like oxidized low-density lipoprotein receptor-1 as a biomarker of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Delayed cerebral ischemia (DCI) greatly contributes to the high morbidity and mortality of aneurysmal subarachnoid hemorrhage (aSAH) patients. Expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) was substantially raised in the basilar arterial wall of SAH rabbits. We attempted to ascertain the relationship between serum soluble LOX-1 (sLOX-1) levels and the occurrence of DCI after aSAH. MATERIALS AND METHODS: We enrolled 125 aSAH patients and 125 healthy controls. Serum sLOX-1 levels were quantified using commercial enzyme-linked immunosorbent assay kit. The relationship between sLOX-1 levels and DCI was analyzed utilizing the multivariate logistic regression analysis. RESULTS: Serum sLOX-1 levels were significantly higher in stroke patients than in controls (median: 1,450.2 vs. 445.7 pg/ml, p < .001). Serum sLOX-1 levels were highly correlated with World Federation of Neurological Surgeons (WFNS) scores, Hunt-Hess scores, and modified Fisher scores (r = .574, .625, and .569, respectively). Forty-two patients (33.6%) experienced DCI. Serum sLOX-1 > 1,450.2 pg/ml, WFNS scores and modified Fisher scores were the independent predictors of DCI. Under receiver operating characteristic curve, serum sLOX-1 levels exhibited a significant discriminatory capability (area under curve 0.825, 95% confidence interval 0.747-0.887). The predictive power of serum sLOX-1 levels was similar to those of WFNS scores and modified Fisher grade (both p > .05). Moreover, serum sLOX-1 levels significantly improved their predictive capability (both p < .05). CONCLUSIONS: Serum soluble LOX-1, in positive association with hemorrhagic severity, appears to have the potential to become a promising predictor of DCI after aSAH.

Serum soluble lectin-like oxidized low-density lipoprotein receptor-1 concentrations and prognosis of aneurysmal subarachnoid hemorrhage.

BACKGROUND: Oxidized low-density lipoprotein (ox-LDL) and its receptor, lectin-like ox-LDL receptor-1 (LOX-1) are involved in the pathogenesis of atherosclerosis. Expression of LOX-1 was substantially raised in the basilar arterial wall of subarachnoid hemorrhage (SAH) rabbits. We ascertained the relationship between serum soluble LOX-1 concentrations and functional outcome after human aneurysmal SAH. METHODS: We enrolled 94 aneurysmal SAH patients and 94 healthy controls. Serum soluble TOX-1 concentrations were quantified using commercial enzyme-linked immunosorbent assay kit. A poor outcome was defined as Glasgow outcome scale score of 1-3. RESULTS: Median values of serum soluble LOX-1 in stroke patients were significantly higher than those in controls (1.5 vs. 0.4 ng/ml, P < 0.001). Thirty patients (31.9%) had a poor outcome at 6 months after stroke. Serum soluble LOX-1 was a strong predictor of poor outcome (OR 5.20, 95% CI 1.25-22.04). Serum soluble LOX-1 concentrations exhibited a significant discriminatory capability (area under curve 0.811, 95% confidence interval 0.717-0.884). The predictive powers of World Federation of Neurological Surgeons grade, Hunt-Hess grade, modified Fisher grade, and serum soluble LOX-1 concentrations were comparable (all P > 0.05). CONCLUSIONS: Serum soluble LOX-1 appears to have the potential to become a promising prognostic predictor after human aneurysmal SAH.

Macrophage migration inhibitory factor levels in serum from patients with acute intracerebral hemorrhage: Potential contribution to prognosis.

BACKGROUND: Intracerebral hemorrhage (ICH) pathophysiology involves inflammation. Macrophage migration inhibition factor (MIF), a pro-inflammatory cytokine, is related to prognosis of ischemic stroke. The aim of this study was to investigate whether serum MIF levels are associated with severity and outcomes in patients with acute ICH. METHODS: We enrolled a total of 120 consecutive ICH patients and 120 healthy controls and sampled blood on admission and at study entry respectively. Enzyme-linked immunosorbent assay was used to quantify serum MIF levels. RESULTS: Serum MIF levels were higher in patients compared with controls and correlated with hematoma volume, National Institutes of Health Stroke Scale (NIHSS) scores and plasma C-reactive protein levels. After adjusting for other significant outcome predictors, MIF in serum was an independent predictor of 6-month overall survival and unfavorable outcome (modified Rankin Scale score >2). Areas under receiver-operating characteristic curve (ROC) of serum MIF levels, hematoma volume and NIHSS scores were similar for 6-month unfavorable outcome. Moreover, serum MIF levels significantly improved areas under ROC of hematoma volume and NIHSS scores. CONCLUSIONS: MIF in serum might be a potential biomarker for reflecting inflammation, severity and prognosis of ICH patients.

Diagnostic and prognostic value of serum vitronectin levels in human glioma.

OBJECTIVE: Vitronectin is an extracellular matrix protein, the synthesis of which by glioma cells correlates with tumor grade. The current study was designed to investigate the relationship between serum vitronectin levels and clinicopathological characteristics, diagnosis and prognosis in glioma patients. METHODS: In a prospective observatory study, a total of 98 glioma patients, 98 healthy controls, 98 other non-glioma brain tumors, and 98 other non-tumor neurological diseases were recruited. Following univariate analyses, multivariate analyses were performed to explore the associations of serum vitronectin levels with survival and clinicopathological parameters. Receiver operating characteristic curve analysis was done to assess its diagnostic and prognostic predictive value. RESULTS: Serum vitronectin levels were significantly elevated in glioma patients as compared with other groups. High Wealth Health Organization grade was independently associated with high vitronectin levels. Serum vitronectin levels could significantly distinguish glioma patients from other groups and discriminate high-grade glioma from low-grade glioma. Vitronectin levels markedly predicted 5-year progression and 5-year mortality. Moreover, serum vitronectin was identified as an independent predictor for 5-year overall survival and 5-year progression-free survival as well as 5-year mortality and 5-year progression. CONCLUSION: Serum vitronectin may be a promising diagnostic and prognostic biomarker that can be detected in the peripheral blood of patients with glioma.

Thioredoxin as a marker for severity and prognosis of aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Circulating levels of thioredoxin (Trx), a potent anti-oxidant that modulates inflammation, cell growth and apoptosis, are increased in various critical care conditions. The purpose of this study was to establish the relationship between serum Trx levels and prognosis of aneurysmal subarachnoid hemorrhage (aSAH). METHODS: An enzyme-linked immunosorbent assay measurement of Trx was performed in serum from 132 patients and 132 healthy volunteers. Clinical outcomes included 6-month mortality and unfavorable outcome (Glasgow outcome scale score of 1-3). RESULTS: The serum Trx levels were significantly higher in patients than in controls (23.4±12.2 ng/mL vs.8.5±4.0 ng/mL, P<0.001) and had close relation to the World Federation of Neurological Surgeons (WFNS) scores (r=0.461, P<0.001) and modified Fisher scores (r=0.459, P<0.001). Trx was an independent predictor for 6-month mortality (Odds ratio, 1.386; 95% confidence interval, 1.015-2.161; P<0.001) and 6-month unfavorable outcome (Odds ratio, 1.297; 95% confidence interval, 1.012-2.002; P<0.001). Based on receiver operating characteristic curve, TRX had similar prognostic value compared with WFNS scores and modified Fisher scores and also significantly improved their prognostic value for 6-month unfavorable outcome, but not for 6-month mortality. CONCLUSIONS: Elevated plasma Trx levels are correlated with the severity and poor prognosis, substantializing Trx as a potential prognostic predictive biomarker following aSAH.