Cerebral ischemia-reperfusion injury (IRI) potentiates existing brain damage and increases mortality and morbidity via poorly understood mechanisms. The aim of our study is to investigate the role of Sirtuin 3 (Sirt3) in the development and progression of cerebral ischemia-reperfusion injury with a focus on mitochondrial fission and the Wnt/β-catenin pathway. Our data indicated that Sirt3 was downregulated in response to cerebral IRI. However, the overexpression of Sirt3 reduced the brain infarction area and repressed IRI-mediated neuron apoptosis. Functional assays demonstrated that IRI augmented mitochondrial fission, which induced ROS overproduction, redox imbalance, mitochondrial pro-apoptotic protein leakage, and caspase-9-dependent cell death pathway activation. However, the overexpression of Sirt3 blocked mitochondrial fission and induced pro-survival signals in neurons subjected to IRI. At the molecular level, our data further illustrated that the Wnt/β-catenin pathway is required for the neuroprotection exerted by Sirt3 overexpression. Wnt/β-catenin pathway activation via inhibiting β-catenin phosphorylation attenuates mitochondrial fission and mitochondrial apoptosis. Collectively, our data show that cerebral IRI is associated with Sirt3 downregulation, Wnt/β-catenin pathway phosphorylated inactivation, and mitochondrial fission initiation, causing neurons to undergo caspase-9-dependent cell death. Based on this, strategies for enhancing Sirt3 activity and activating the Wnt/β-catenin pathway could be therapeutic targets for treating cerebral ischemia-reperfusion injury.
Induced neural stem cells (iNSCs) can be directly transdifferentiated from somatic cells. One potential clinical application of the iNSCs is for nerve regeneration. However, it is unknown whether iNSCs function in disease models. We produced transdifferentiated iNSCs by conditional overexpressing Oct4, Sox2, Klf4, c-Mycin mouse embryonic fibroblasts. They expanded readily in vitro and expressed NSC mRNA profile and protein markers. These iNSCs differentiated into mature astrocytes, neurons and oligodendrocytes in vitro. Importantly, they reduced lesion size, promoted the recovery of motor and sensory function as well as metabolism status in middle cerebral artery stroke rats. These iNSCs secreted nerve growth factors, which was associated with observed protection of neurons from apoptosis. Furthermore, iNSCs migrated to and passed through the lesion in the cerebral cortex, where Tuj1+ neurons were detected. These findings have revealed the function of transdifferentiated iNSCs in vivo, and thus provide experimental evidence to support the development of personalized regenerative therapy for CNS diseases by using genetically engineered autologous somatic cells.
Ginkgo biloba extract EGb761 is widely used to treat patients with learning and memory impairment in Alzheimer's disease and Parkinson's disease in China. However, it is not yet clear whether the analog of EGb761 (EGb) has a protective effect on the learning and memory damage induced by chronic fluorosis. In this study, 30 Wistar rats were randomly divided into three groups: a control group, a sodium fluoride (NaF) + EGb group, and a NaF group. The rats were administered 0.5 ml water containing NaF (100 mg/l) and EGb (120 mg/kg) per day via gavage. After 3 months, the rats' capacity for learning and memory was tested using a Y-maze. Damage to hippocampal neurons was evaluated by histological examination of the CA3 area. Superoxide dismutase (SOD) activity and the levels of glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) were measured. Furthermore, the expression levels of Bcl-2 and Bax and the levels of cleaved Caspase3 in the hippocampus were evaluated by RT-PCR and Western blotting. The results showed that EGb could improve learning and memory abilities, enhance the activities of SOD and GSH-Px, attenuate the level of MDA, upregulate the ratio of Bcl-2/Bax, and downregulate the level of cleaved Caspase3.
Background
To compare the clinicopathologic parameters and oncologic outcomes between type 1 and type 2 papillary renal cell carcinoma (PRCC).
Methods
This study was approved by the review board (NO.XYFY2019-KL032–01). Between 2007 and 2018, 52 consecutive patients who underwent surgery at a single tertiary referral hospital were included. Clinicopathologic and survival data were collected and entered into a database. The Kaplan-Meier method, and univariate and multivariate Cox proportional hazard regression analyses were performed to estimate progression-free survival (PFS) and cancer-specific survival (CSS).
Results
Of the 52 patients, 24 (46.2%) were diagnosed with type 1 PRCC, and 28 (53.8%) had type 2 PRCC. The mean tumor size was 4.8 ± 2.5 cm. The two subtypes displayed different morphological features: foamy macrophages were more common in type 1 PRCC, while eosinophils and microvascular angiolymphatic invasion were more frequent in type 2 PRCC. Type 2 cases showed higher tumor stage and World Health Organization/International Society of Urological Pathology (WHO/ISUP) grade than type 1 cases (T3-T4: 43% vs 17%, P = 0.041; G3-G4: 43% vs 8%, P = 0.005). In univariate analysis, type 2 PRCC had a lower probability for PFS and CSS than patients with type 1 PRCC (P = 0.016, P = 0.049, log-rank test, respectively). In multivariate analysis, only WHO/ISUP grade (HR 11.289, 95% CI 2.303–55.329, P = 0.003) and tumor size (HR 1.244, 95% CI 1.034–1.496, P = 0.021) were significantly associated with PFS.
Conclusions
PRCC subtype displayed different morphological features: foamy macrophages, eosinophils and microvascular angiolymphatic invasion are pathologic features that may aid in the distinction of the two subtypes. Histologic subtype of PRCC is not an independent prognostic factor and only WHO/ISUP grade and tumor size were independent predictors for PFS.
Objective: To determine the effect of the serum albumin level on admission in patients with spontaneous subarachnoid hemorrhage (SAH).Methods: A total of 229 patients with SAH were divided into control and hypoalbuminemia groups. The serum albumin levels were measured. The data, including age, gender, co-existing medical conditions, risk factors, Hunt-Hess (H-H) grade on admission, Glasgow coma score (GCS) on admission, complications during hospitalizations, length of hospital stay, length of intensive care unit (ICU) stay, in-hospital mortality, survival rate, outcome at discharge, and the 6-month follow-up outcome, were compared between the two groups.Results: Older age, an increased number of patients who consumed an excess of alcohol, and a lower GCS on admission were findings in the hypoalbuminemia group compared to the control group (p < 0.001). The ratio of patients with H-H grade I on admission in the hypoalbuminemia group was decreased compared to the control group (p < 0.05). Patients with hypoalbuminemia were more likely to be intubated, and have pneumonia and cerebral vasospasm than patients with a normal albumin level on admission (p < 0.001). Furthermore, the length of hospital and ICU stays were longer in the hypoalbuminemia group than the control group (p < 0.001). Hypoalbuminemia on admission significantly increased poor outcomes at discharge (p < 0.001). The number of patients with severe disability was increased and the recovery rate was decreased with respect to in-hospital outcomes in the hypoalbuminemia group than the control group (p < 0.001).Conclusion: Hypoalbuminemia was shown to be associated with a poor prognosis in patients with SAH.
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