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 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.

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.

The prognostic value of plasma soluble CD40 ligand levels following aneurysmal subarachnoid hemorrhage.

BACKGROUND: Increased circulating soluble CD40 ligand (sCD40L) levels have been reported to be associated with severity and mortality of severe traumatic brain injury. The current study tested the hypothesis that elevated plasma sCD40L levels are predictive of clinical outcomes of aneurysmal subarachnoid hemorrhage (aSAH). METHODS: Plasma sCD40L concentrations of 120 aSAH patients and 120 healthy volunteers were measured using enzyme-linked immunosorbent assay. An unfavorable outcome was defined as Glasgow Outcome Scale score of 1-3. RESULTS: Plasma sCD40L levels were significantly elevated in aSAH patients compared with healthy controls; plasma sCD40L levels were highly associated with clinical severity reflected by World Federation of Neurological Surgeons (WFNS) score and Fisher score; sCD40L emerged as an independent predictor of 6-month mortality and unfavorable outcome and 6-month overall survival; although a combined logistic-regression model did not demonstrate the additive benefit of sCD40L to WFNS score and Fisher score, sCD40L possessed similar predictive value to WFNS score and Fisher score based on receiver operating characteristic curves. CONCLUSIONS: Higher plasma sCD40L levels on presentation are associated with clinical severity and have potential to be a good prognostic biomarker of aSAH.

Identification of plasma adrenomedullin as a possible prognostic biomarker for aneurysmal subarachnoid hemorrhage.

Increased plasma adrenomedullin levels have been reported in critically ill patients. This study tested the hypothesis that plasma adrenomedullin levels are significantly increased in patients with acute spontaneous aneurysmal subarachnoid hemorrhage, and are predictive of clinical outcomes. Plasma adrenomedullin levels from 120 adult patients with spontaneous aneurysmal subarachnoid hemorrhage and 120 healthy volunteers during the study period were evaluated. Mortality and poor long-term outcome (Glasgow Outcome Scale score of 1-3) at 6 months were recorded. Data showed that circulating plasma adrenomedullin levels significantly increased in patients on admission compared with the volunteers. In patients who died or had poor outcome at 6 months, plasma adrenomedullin levels were significantly higher compared with survivors and patients with good outcome. Plasma adrenomedullin levels on presentation were highly associated with clinical severity assessed using World Federation of Neurological Surgeons score and Fisher score, emerged as the independent risk factor of 6-month mortality and poor outcome, and possessed similar predictive value to World Federation of Neurological Surgeons score and Fisher score based on receiver operating characteristic curves. A combined logistic-regression model did not demonstrate the additive benefit of adrenomedullin to World Federation of Neurological Surgeons score and Fisher score. Thus, higher plasma adrenomedullin levels on presentation are associated with clinical severity and worse outcomes in patients with acute spontaneous aneurysmal subarachnoid hemorrhage.

Predictive value of phosphorylated axonal neurofilament subunit H for clinical outcome in patients with acute intracerebral hemorrhage.

BACKGROUND: Phosphorylated axonal neurofilament subunit H (pNF-H) is a biomarker of axonal injury. We investigated whether plasma pNF-H concentrations were associated with 6-month clinical outcomes and early neurological deterioration (END) of patients with acute intracerebral hemorrhage. METHODS: Plasma pNF-H concentrations of 112 patients and 112 healthy individuals were quantified by ELISA. Unfavorable outcome was defined as modified Rankin Scale score >2. Associations of plasma pNF-H concentrations with END, 6-month mortality and unfavorable outcome were evaluated. RESULTS: Plasma pNF-H concentrations were increased in patients than in healthy individuals [700.2 (430.8) pg/ml vs. 25.5 (32.4) pg/ml, P<0.001]. A logistic regression analysis selected plasma pNF-H concentration as an independent predictor for 6-month mortality [OR: 1.287, 95% CI: 1.140-1.524, P<0.001], 6-month unfavorable outcome (OR 1.265, 95% CI 1.121-1.517, P<0.001) and END (OR 1.246, 95% CI 1.109-1.498, P<0.001). A receiver operating characteristic curve analysis showed that plasma pNF-H concentration predicted 6-month clinical outcomes and END with high area under curves (all P<0.001). The predictive value of pNF-H was similar to that of the National Institutes of Health Stroke Scale score (all P>0.05). In a combined logistic-regression model, pNF-H did not improve the predictive value of National Institutes of Health Stroke Scale score (all P>0.05). CONCLUSIONS: Increased plasma pNF-H concentration was highly associated with 6-month clinical outcomes and END of patients with intracerebral hemorrhage.