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Kidney renal clear cell carcinoma (KIRC) is one of the most hazardous tumors in the urinary system. The regulation of oxygen consumption in renal clear cell carcinoma is a consequence of adaptive reprogramming of oxidative metabolism in tumor cells. APPL1 is a signaling adaptor involved in cell survival, oxidative stress, inflammation, and energy metabolism. However, the correlation of APPL1 with regulatory T cell (Treg) infiltration and prognostic value in KIRC remain unclear. In this study, we comprehensively predicted the potential function and prognostic value of APPL1 in KIRC. For KIRC patients, relatively low expression of APPL1 was associated with high degree of metastasis, pathological stage, and shorter overall time or poor prognosis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses suggested that low expression of APPL1 may be adapted to the malignant progression of tumors via affecting oxygen-consuming metabolism. In addition, the expression level of APPL1 was negatively correlated with Treg cell infiltration and chemotherapy sensitivity, which indicated that APPL1 may regulate the tumor immune infiltration and chemotherapy resistance by decrease oxygen-consuming metabolic process in KIRC. Therefore, APPL1 may become one of the important prognostic factors, and it may serve as a candidate prognostic biomarker in KIRC.

Objective: The objective of this study is to investigate the relationship between mean platelet volume (MPV)/platelet count (PC) ratio and post-thrombolytic early neurological deterioration (END) in patients with mild and moderate stroke. Methods: Mild and moderate stroke patients treated with intravenous thrombolysis (IVT) at the Affiliated Changsha Central Hospital of the University of South China between January 2016 and March 2022 were prospectively and consecutively enrolled. END was defined as an increase in the total National Institutes of Health Stroke Scale (NIHSS) score of ≥4 points or an increase in the motor items of ≥1 point within 24 hours after IVT treatment. Logistic regression and restricted cubic spline models were used to estimate the relationship between the MPV/PC ratio and postthrombolytic END. Results: Among the 406 patients recruited, 64 (15.8%) patients developed END. Patients in the first quintile of MPV/PC ratio (adjusted OR = 0.27, 95% CI = 0.11-0.66, p = 0.004) and the fifth quintile (adjusted OR = 0.26, 95% CI = 0.10-0.69, p = 0.007) had a significantly lower risk of END compared with those in the third quintile. Restricted cubic spline analysis revealed an inverted U-shaped relationship between the MPV/PC ratio and END (p for nonlinearity = 0.016). MPV/PC ratio cut-off value associated with the highest END risk was 51.0. An MPV/PC ratio ≤ 51.0 was shown to be positively associated with END (adjusted OR = 1.07, 95% CI = 1.02-1.14, p = 0.012), while an MPV/PC ratio >51.0 was negatively associated with END (adjusted OR = 0.94, 95% CI = 0.88-1.00, p = 0.040). A significant interaction existed between the MPV/PC ratio and age in the low MPV/PC ratio group (p = 0.012). MPV/PC ratio was positively associated with END only in patients ≥ 60 years, whereas this association was insignificant in patients < 60 years. Conclusion: An inverted U-shaped relationship between the MPV/PC ratio on admission and postthrombolytic END was identified in patients with mild and moderate stroke, with a threshold MPV/PC ratio of 51.0. The MPV/PC ratio closer to the threshold was associated with a higher risk of post-thrombolytic END.

Blood-brain-barrier (BBB) disruption is an important pathological characteristic of ischemic stroke (IS) and mainly results from dysfunction of brain vascular endothelial cells and tight junctions. Zebularine is a novel inhibitor of DNA methyltransferase (DNMT). Here, we assessed its effects on BBB disruption in IS. Firstly, we reported that Zebularine maintained BBB integrity in middle cerebral artery occlusion (MCAO) mice by increasing the expressions of zona occludens-1 (ZO-1) and vascular endothelial (VE)-cadherin. Importantly, we found that Zebularine reduced the production of pro-inflammatory cytokines, attenuated brain edema, and improved neurological deficits. In in vitro experiments, the bEnd.3 brain endothelial cells were exposed to oxygen and glucose deprivation/reoxygenation (OGD/R), and the protective effects of Zebularine were assessed. Our findings demonstrated that Zebularine prevented OGD/R-induced cytotoxicity by reducing the release of lactate dehydrogenase (LDH). Additionally, Zebularine protected bEnd.3 cells against OGD/R-induced hyper-permeability and reduction of trans-endothelial electrical resistance (TEER). Notably, we found that treatment with Zebularine activated the Adenosine 5ʹ-monophosphate (AMP)-activated protein kinase (AMPK) pathway by increasing the phosphorylation of adenosine monophosphate-activated protein kinase α (AMPKα). Blockage of AMPKα using its specific inhibitor compound C abolished the beneficial effects of Zebularine in mitigating endothelial hyper-permeability by reducing the expressions of ZO-1 and VE-cadherin. These findings suggest that the protective effects of Zebularine against OGD/R-induced endothelial hyper-permeability are mediated by the activation of AMPKα. In conclusion, our study sheds light on the potential application of Zebularine in the treatment of IS.

Advanced age correlates with higher morbidity and mortality among patients affected with the novel coronavirus disease 2019 (COVID-19). Because systemic inflammation and neurological symptoms are also common in severe COVID-19 cases, there is concern that COVID-19 may lead to neurodegenerative conditions such as Alzheimer’s disease (AD). In this review, we summarize possible mechanisms by which infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, may cause AD in elderly COVID-19 patients and describe preventive measures to mitigate risk. Potential mechanisms include NLRP3 inflammasome activation and IL-1β release, renin-angiotensin system hyperactivation, innate immune activation, oxidative stress, direct viral infection, and direct cytolytic β-cell damage. Anti-inflammatory therapies, including TNF-α inhibitors and nonsteroidal anti-inflammatory drugs, antioxidants such as the vitamin E family, nutritional intervention, physical activity, blood glucose control, and vaccination are proposed as preventive measures to minimize AD risk in COVID-19 patients. Since several risk factors for AD may converge during severe SARS-CoV-2 infection, neurologists should be alert for potential symptoms of AD and actively implement preventive measures in patients presenting with neuropsychiatric symptoms and in high-risk patients such as the elderly.

Background Plank exercise (PE) is a whole-body isometric muscle training which is beneficial for physical health. However, none of the previous studies investigated the responses within a typical isometric muscle training or PE protocol consisting of multiple sets. The application of PE was restricted for the understudied metabolic and cardiovascular responses, especially for the patients with cardiovascular diseases. This study is to alleviate the safety concerns of PE by investigating the PE-induced metabolic and cardiovascular responses. Methods Eleven male recreational-level college students completed a baseline cardiopulmonary exercise test, continuous PE (CPE) and intermittent PE (IPE). Ratio of maximal oxygen uptake per kilogram of body mass (%VO2max/kg), ratio of maximal heart rate (%HRmax), and respiratory exchange ratio (RER) were continuously measured during PEs and divided into seven equal timepoints. Blood pressure (BP) was measured every minute during, before, and after PEs. A mixed-model repeated measures ANOVA was used to examine the interaction effect of exercise × phase. Results The %VO2max/kg (F6,69=11.25, P max (F6,65=7.74, P 6,69=11.56, P 2,26=8.42, P = 0.002; diastolic BP, F2,24=22.63, P 2max/kg (33.5 [2.2] vs. 27.7 [1.9], P = 0.043) and %HRmax (63.2 [3.9] vs. 53.3 [2.1], P = 0.019) increased more significantly from the 40% duration of CPE. Systolic BP increased by larger magnitudes during CPE than IPE (154.2 [3.8] vs. 142.3 [4.8] mmHg, P = 0.002). RERs were over 1 during PEs without cardiovascular and metabolic variables over the anaerobic threshold. Conclusion Energy was mainly supplied by anaerobic metabolism during PEs. CPE may be preferable for trainees aiming at anaerobic capacity enhancement. IPEs may be preferable to CPEs for youth patients with mild and borderline cardiovascular diseases due to their lower metabolic and cardiovascular responses.

Although many studies have focused on functional impairment after intracerebral hemorrhage, little is known about the relationship between secondary injuries to distal regions and neurological function. Our study aimed to evaluate the secondary injuries after intracerebral hemorrhage and explore their relationship to neurological functional outcome. Twenty-one patients with hemorrhages in supratentorial, deep locations and 10 healthy subjects were recruited. Longitudinal examinations of diffusion tensor imaging, hydrogen proton magnetic resonance spectroscopy imaging and neuropsychological assessment were performed after weeks 1 and 12 to elucidate the relationship between magnetic resonance imaging parameters and neurologic outcomes. By week 12, motor function had significantly improved, but cognitive function had deteriorated compared to week 1. Fractional anisotropy values for the ipsilateral cerebral peduncle correlated with motor function at week 1. No significant correlation between fractional anisotropy for the ipsilateral cerebral peduncle and the Fugl-Meyer Motor Scale was found at week 12. Fractional anisotropy values for the ipsilateral hippocampus were related to the Montreal Cognitive Assessment and Mini-Mental State Examination at weeks 1 and 12. Deep supratentorial hemorrhage may result in injury to distal regions, which correlate with impaired motor and cognitive function.

BackgroundCerebral venous disorder may have a harmful effect on ischaemic stroke; however, the underlying mechanism remains to be elucidated. Although Dl-3-n-butylphthalide is a multitarget agent for antiischaemic stroke, its neuroprotective role in brain ischaemia accompanied by brain venous disturbance remains unclear. In this study, we induced cerebral venous disturbance by the occlusion of bilateral external jugular veins (EJVs) to explore the potential mechanism of the adverse effects of cerebrovenous disorders in cerebral infarction and explore the protective effect of Dl-3-n-butylphthalide on cerebral infarction accompanied through cerebral venous disturbance.MethodsCerebral venous disturbance was induced in Sprague-Dawley rats through the permanent occlusion of bilateral EJVs, and cerebral ischaemic stroke was induced through the permanent occlusion of the right cortical branches of the middle cerebral artery. 2,3,5-triphenyltetrazolium chloride staining, MRI, Evans blue extravasation and behavioural test were performed to evaluate infarction volume, cerebral blood flow (CBF), blood–brain barrier (BBB) integrity and neurological function. Immunofluorescence staining and western blot analysis were performed to detect loss of neuron, endothelial cells, pericytes and tight junctions.ResultsBilateral EJVs occlusion did not cause cerebral infarction; however, it increased the infarction volume compared with the simple middle cerebral artery occlusion (MCAO) group, accompanied by severe neuron loss, worse neurological function, lower CBF, increased EJVs pressure, exacerbated Evans blue extravasation and brain oedema, as well as attenuated angiogenesis. Dl-3-n-butylphthalide displayed a neuroprotective effect in rats with MCAO accompanied by EJVs occlusion by reducing neuron loss, accelerating CBF restoration, promoting angiogenesis and relieving BBB damage.ConclusionBilateral EJVs occlusion did not significantly affect normal rats but aggravated brain damage in the case of ischaemic stroke. Dl-3-n-butylphthalide treatment plays a neuroprotective role in rats with MCAO accompanied by EJVs occlusion, mainly due to the promotion of CBF restoration and BBB protection.

Objective: The objective of this study is to determine whether the administration of intravenous alteplase would be beneficial or futile to patients with acute ischemic stroke caused by large vessel occlusion (LVO) before endovascular treatment (EVT) and determine the relationship between Hounsfield units (HU) in non-contrast computed tomography (NCCT) and recanalization by alteplase. Methods: We performed a retrospective analysis of patients with acute ischemic stroke caused by LVO who received intravenous thrombolysis (IVT) or followed by EVT at our center during November 2016 and October 2020. The clinical characteristics and imaging features of patients who achieved recanalization after IVT, and those who did not, were compared. Results: Forty-three eligible patients were enrolled; 12 achieved recanalization by IVT. Baseline clinical characteristics did not differ between patients of the recanalization and non-recanalization groups. HU in the NCCT were estimated and statistically significant maximum and mean values of the ipsilateral middle cerebral artery (MCA) were found between the groups (P< 0.05). The results hint that patients in the non-recanalization group have a higher rHU and δHU value of the ipsilateral MCA compared with recanalization group (P< 0.05). With regards to the receiver operator characteristic (ROC) curve, we demonstrated that a high HU value of the ipsilateral MCA could be a predictor for non-recanalization by IVT. Conclusion: Patients suffering LVO stroke are less likely to obtain recanalization by IVT with a high HU value of the ipsilateral MCA. It is feasible to screen patients with LVO using HU for direct EVT.

Purpose The recommendation strength of the guidelines for mechanical thrombectomy among patients with large pre-treatment core infarct is weak. We evaluated the safety and outcome of endovascular treatment for acute ischemic stroke with diffusion-weighted imaging-Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECTS) ≤ 5. Methods Data on acute ischemic stroke patients with DWI-ASPECTS ≤ 5 who underwent endovascular treatment within 6 h, or presented an arterial spin labeling-DWI (ASL-DWI) mismatch within 12 h, at our center were retrospectively collected. We report the clinical characteristics and outcome of every patient, and review the relevant literature. Results Among the 19 patients who were enrolled, all experienced successful reperfusion, and 10 achieved a favorable outcome (modified Rankin scale (mRS) ≤ 2). Two patients presented with symptomatic intracranial hemorrhage (sICH); both of them had a poor outcome (mRS > 2). Conclusion Acute ischemic stroke patients with large DWI lesions caused by large vessel occlusion can achieve a favorable clinical outcome with endovascular treatment if recanalization is performed within 6 h, or after 6 h in case of an ASL-DWI mismatch. Electronic supplementary material The online version of this article (10.1007/s00234-019-02177-1) contains supplementary material, which is available to authorized users.

Objective: Chronic cerebral hypoperfusion (CCH) is a common consequence of various cerebral vascular disorders, hemodynamics and blood composition changes, which can lead to neurodegenerative injury and cognitive dysfunction. Therefore, it is important to take measures to prevent or reverse its development. Methods: Eighty Sprague-Dawley rats were randomly divided into five groups: Sham group, Vehicle groups (2-week group and 4-week group), Rosuvastatin-treated groups (2-week group and 4-week group). Both vehicle and treated group rats were treated with bilateral common carotid artery occlusion (BCCAO). Then rats in the treated group were intravenously injection with rosuvastatin (0.2 mg/kg/day) daily for 14 days beginning 24 hours after BCCAO. The vehicle groups were given the same amount of saline. The MRI ASL technique was used to scan cerebral blood flow (CBF) at pre-occlusion, BCCAO, 1, 2, 3, and 4 weeks after operation. Morris water maze test detected spatial memory abilities of the treated and vehicle rats after BCCAO. Immunofluorescence staining was used to detect the expression of CD34, GFAP, NeuN and Caspase-3 positive cells in hippocampus. Results: CBF decreased significantly after BCCAO in both rosuvastatin-treated and vehicle groups and then increased gradually. The CBF of the treated group was basically recovered to baseline levels at 1 or 2 weeks after BCCAO. But it took the vehicle group 4 weeks to restore to baseline. The vertebral artery (VA) diameter of the treated group was greater than that of the vehicle group (p+ and NeuN + cells in the hippocampus of the treated group was more than that in the vehicle group (p+ and Caspase-3 + cells was less than in the vehicle group (p Conclusion: Rosuvastatin can accelerate the recovery of cerebral blood flow in CCH rats, which may be related to the dilation of VAs and angiogenesis; and its effects on reducing astrocyte activation and neuroprotection may help to ameliorate cognitive dysfunction in CCH rats.

Previous findings have demonstrated, in a rat model, that chronic cerebral hypoperfusion (CCH) decreases cortical cerebral blood flow (CBF) while Dl-3-n-Butylphthalide (DNB) accelerates the timely recovery of CBF. However, potential biomarkers, therapeutic targets, and underlying mechanisms for these processes are unclear. In this study, a solid-phase antibody microarray for simultaneously detecting multiple proteins was used to search cortex biotargets in CCH compared to a sham control group, and these results were further examined by biological functional analysis. After DNB treatment, western blot and immunostaining were used to verify candidate protein expression. Importantly, we identified seven proteins that may serve as novel biotargets contributing to CCH. The levels of Tie-2, CNTFRα, IL-4, IL-10, ITGAM, MDC, and TROY were uniquely altered in the CCH. The Tie-2 level was significantly decreased and identified in CCH 2 week (W), CCH 4 W and CCH 8 W. In addition, Ang-1 level and Ang-1/Ang-2 ratio were significantly decreased in CCH 2 W and CCH 4 W while Ang-2 level was increased in the CCH, whereas DNB treatment created the inverse effect to some extent. Moreover, the expression of VEGF and CD34 in the earlier stage of CCH and the diameters of bilateral vertebral arteries (VAs), were significantly enlarged by DNB treatment. Together, we found that the Ang-1/Ang-2/Tie-2 signaling axis was altered in the CCH rat cortex, and DNB treatment could timely regulate this angiopoietin/Tie signaling axis to promote neovascularization in early stages.

Background: Bilirubin is the metabolic end-product of heme degradation by heme oxy-genase (HO), which has recently been shown to act as an antioxidant which can protect against atherosclerosis. This study explored the relationship between serum bilirubin levels and different degrees of atherosclerotic stenosis in intracranial or extracranial arteries. Methods: The study included 189 patients undergoing digital subtraction angiography (DSA) diagnosed as being normal or having been confirmed as atherosc lerotic stenosis in the intracranial or extracranial arteries. The patients were allocated to normal, mild (Results: Indirect bilirubin (Ibil) concentrations increased in parallel with the increasing severity of atherosclerotic stenosis in the intracranial or extracranial arteries, but decreased in patients with occluded cranial vessels. Multivariate analysis showed that Ibil levels were significantly higher in patients with severe stenosis group than in those with mild stenosis (OR, 1.464; 95% CI, 1.050 - 2.042; P = 0.024). However, Ibil levels were significantly lower in patients with occlusion than in those with severe stenosis (OR, 0.790; 95% CI, 0.684 - 0.913; P = 0.001). Conclusions: Ibil appears to have a protective effect against the development of atherosclerotic stenosis in intracranial or extracranial arteries. The biosynthesis of Ibil increases with stenosis progresses but decreases once occlusion occurs.

Ischemic stroke often results in severe injury to white matter structures including the axons, oligodendroglia, and other glial cells. Immature stages of oligodendroglia, such as oligodendrocyte precursor cells (OPCs) and premature oligodendroglia, are more vulnerable to ischemia than mature oligodendroglia. Extensive studies have been performed on the necroptosis of neurons following cerebral ischemia. The present study aimed to investigate the effect of necrostatin-1 (Nec-1), a necroptosis inhibitor, on the survival of OPCs and long-term functional recovery following transient cerebral ischemia. Male adult ICR mice (25–30 g) were subjected to 60-min middle cerebral artery occlusion (MCAO) and 24 h of reperfusion. Nec-1 (0.04 mg/kg) was injected intracerebroventricularly 1 h before the onset of MCAO. Cognitive functions were evaluated ≤30 days after MCAO. Necroptosis-related proteins, receptor-interacting protein kinase 1 (RIPK1), RIPK3, MLKL, and P-MLKL, were assessed by western blot analyses. The cultured primary mouse OPCs were used to confirm the effects of Nec-1 on the viability of OPCs following oxygen-glucose deprivation (OGD). This study demonstrated that pretreatment with Nec-1 significantly promoted OPCs survival, alleviated white matter injury, and improved cognitive function after transient cerebral ischemia. Nec-1 also inhibited the activation of RIPK1, RIPK3, MLKL, and P-MLKL in the subventricular zone (SVZ) and corpus callosum regions after MCAO. OPCs’ culture experiments confirmed that Nec-1 significantly reduced the necroptosis of OPCs, perhaps by inhibiting the expression of RIPK1, RIPK3, MLKL, and P-MLKL. Nec-1, an inhibitor of RIPK1, may reduce ischemic white matter damage and improve recovery of long-term neurological function following cerebral ischemia.

To investigate the differentiation potential of purified CD90+ cells sorted from adipose-derived stem cells (ADSCs), CD90+ cells were sorted from rabbit ADSCs using flow cytometry. Then, cell expansion of CD90+ cells and unsorted ADSCs was observed using an inverted microscope. Furthermore, cell surface markers including CD40, CD105, and CD90 on CD90+ cells and unsorted ADSCs were quantified using flow cytometry. Additionally, multi-lineage differentiation ability between CD90+ cells and unsorted ADSCs was compared, and expression of adipocyte-related genes PPAR-r and CEBPA as well as stem cell-related gene SOX2 in CD90+ cells and unsorted ADSCs was determined using real-time quantitative PCR. We found that CD90+ cells had a stronger cell proliferation ability than unsorted ADSCs. CD90+ cells showed a stronger ability of osteoblast and chondrocyte differentiation than unsorted ADSCs and CD90- cells, whereas the adipose differentiation ability of CD90+ cells was similar to that of ADSCs and CD90- cells. CD14, CD105, and CD90 on CD90+ cells were expressed more highly than those on ADSCs. Additionally, the mRNA expression level of SOX2 in CD90+ cells was significantly higher than that in ADSCs, whereas the expression of PPAR-r and CEBPA was markedly lower than that in ADSCs. These results suggested that the purified CD90+ cells sorted from ADSCs exhibit a stronger differentiation potential than the unsorted ADSCs.

Proprotein convertase subtilisin/kexin 9 (PCSK9) is the ninth member of the proprotein convertase family. It is an important regulator of cholesterol metabolism. PCSK9 can bind to low-density lipoprotein receptors (LDLRs) and induce the degradation of these receptors through the endosome/lysosome pathway, thus decreasing the LDLR levels on the cell surface of hepatocytes, resulting in increased serum low-density lipoprotein cholesterol (LDL-C) concentrations. Recent studies have found that gene polymorphisms of PCSK9 are associated with hypercholesterolemia, risk of atherosclerosis, and ischemic stroke. Furthermore, monoclonal antibodies, peptide mimetics, small molecule inhibitors and gene silencing agents that are associated with PCSK9 are some of the newer pharmaceutical therapeutic strategies and approaches for lowering serum LDL-C levels. In this review, we will discuss recent advances in PCSK9 research, which show that PCSK9 is correlated with lipid metabolism, atherosclerosis, and, in particular, ischemic stroke. We will also discuss the current state of PCSK9 therapeutics and their potential in modulating these diseases.