Enriched environment priors to TET1 hippocampal administration for regulating psychiatric behaviors via glial reactivity in chronic cerebral hypoperfusion models.

BACKGROUND: Chronic cerebral hypoperfusion (CCH) has been gradually regarded as a common etiologic mechanism for cognitive and psychiatric disturbances. Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) played an important role in adult hippocampal neurogenesis (AHN), neuronal circuits formation, cognition and psychiatric disorders. Enriched environment (EE) showed a beneficial effect on cognition and depression via effectively regulating AHN and glial reactivity. This study aimed to assess which strategy was feasible to improve cognition and psychiatric disturbances by comparing the TET1 hippocampal microinjection and EE in CCH models and to investigate the possible mechanisms. METHOD: CCH rats were established via permanent bilateral common carotid artery occlusion (2-VO). Rats were stereotaxically injected with the human catalytic domain of TET1 (hTET1) to overexpress the hTET1 in the hippocampus 10 days before 2-VO. 3 days after 2-VO, rats were subjected to standard environment or EE with free access to food and water. Behavioral tests were used to appraise depression and cognition before sacrifice. Epigenetic molecules, adult neurogenesis, synaptic proteins expression, and glial activation were analyzed using immunofluorescent staining, qRT-PCR and western blot. RESULTS: In the present study, we found both EE and genetical treatment with overexpressing hTET1 were sufficient for stimulating AHN. However, promoting ANH could not deal with the cognitive dysfunction and depressive-like behaviors in CCH rats. Notably, a healthy local brain environment with elevated BDNF and astrocytes was conducive to improving cognitive dysfunction. Meanwhile, astrocytes were involved in the cognitive regulating process of neurons, presynaptic function and microglia. In general, we held that depressive disturbances were determined by BDNF levels, neuronal and presynaptic function, as well as glial activation containing astrocytes and microglia. To further support this point, we investigated severe depressive symptoms that were strongly correlated with the activation of astroglia and microglia. Importantly, causal mediation analysis showed significant mediation by the presence of reactive glial cells in the relation between neural plasticity and depressive symptoms. Finally, we showed EE performed better than hTET1 treatment for cognitive deficits and depression. EE with less glial reactivity was much more resistant to depression, while hTET1 with more glial activation was more vulnerable to depressive disorders. CONCLUSIONS: EE was likely to be superior to TET1 hippocampal administration for cognition and psychiatric behaviors in CCH rats. Furthermore, a healthy local brain environment with elevated BDNF and astrocytes was conducive to improving cognitive dysfunction. More glial activation, and more vulnerable to depressive disorders. These results were important for our understanding of disease mechanisms and provided valuable tools for the overall management of CCH patients.

Dimethyl fumarate improves cognitive deficits in chronic cerebral hypoperfusion rats by alleviating inflammation, oxidative stress, and ferroptosis via NRF2/ARE/NF-κB signal pathway.

Cerebrovascular disease and its risk factors cause persistent decrease of cerebral blood flow, chronic cerebral hypoperfusion (CCH) is the major foundation of vascular cognitive impairment (VCI). The hippocampus is extremely vulnerable to cerebral ischemia and hypoxia. Oxidative stress and neuroinflammation injury are important pathophysiological mechanisms of this process, which is closely related to hippocampal neurons damage and loss. Dimethyl fumarate (DMF), an FDA-approved therapeutic for multiple sclerosis (MS), plays a protective role in multiple neurological disorders. Studies have shown that DMF exerts anti-inflammatory and antioxidant effects via the NRF2/ARE/NF-κB signaling pathway. Thus, this study aimed to evaluate the neuroprotective effect of DMF in the CCH rat model. Ferroptosis, a novel defined iron-dependent cell death form, were found to be strongly associated with the pathophysiology of CCH. Emerging evidences have shown that inhibition of ferroptosis by targeting NRF2 exerted neuroprotective effect in neurodegeneration diseases. We also investigated whether DMF can alleviate cognitive deficits through inhibition of ferroptosis by the NRF2 signaling pathway in this study. DMF was intragastric for consecutive five weeks (100 mg/kg/day). Then behavior test and histological, molecular, and biochemical analysis were performed. We found that DMF treatment significantly improved cognitive deficits and partially reversed hippocampus neuronal damage and loss caused by CCH. And DMF treatment decreased hippocampus IL-1ß, TNF-α, and IL-6 pro-inflammatory cytokines concentration, and mediated the NF-κB signaling pathway. And DMF also alleviated hippocampus oxidative stress through reducing MDA, and increasing GSH and SOD levels, which are also closely associated with ferroptosis. Besides, DMF treatment reduced the expression of PTGS2, and increased the expression of FTH1 and xCT, and the iron content is also reduced, which were the important features related to ferroptosis. Furthermore, DMF activated the NRF2/ARE signaling pathway and upregulated the expression of HO-1, NQO1 and GPX4. These outcomes indicated that DMF can improve cognitive impairment in rats with CCH, possibly through alleviating neuroinflammation, oxidative stress damage and inhibiting ferroptosis of hippocampal neurons. Overall, our results provide new evidence for the neuroprotective role of DMF.

A simple-to-use web-based calculator for survival prediction in Parkinson's disease.

BACKGROUND: To establish and validate a nomogram and corresponding web-based calculator to predict the survival of patients with Parkinson's disease (PD). METHODS: In this cohort study, we retrospectively evaluated patients (n=497) with PD using a two-stage design, from March 2004 to November 2007 and from July 2005 to July 2015. Predictive variables included in the model were identified by univariate and multiple Cox proportional hazard analyses in the training set. RESULTS: Independent prognostic factors including age, PD duration, and Hoehn and Yahr stage were determined and included in the model. The model showed good discrimination power with the area under the curve (AUC) values generated to predict 4-, 6-, and 8-year survival in the training set being 0.716, 0.783, and 0.814, respectively. In the validation set, the AUCs of 4- and 6-year survival predictions were 0.85 and 0.924, respectively. Calibration plots and decision curve analysis showed good model performance both in the training and validation sets. For convenient application, we established a web-based calculator (https://tangyl.shinyapps.io/PDprognosis/). CONCLUSIONS: We developed a satisfactory, simple-to-use nomogram and corresponding web-based calculator based on three relevant factors to predict prognosis and survival of patients with PD. This model can aid personalized treatment and clinical decision-making.

Neurological Implications of Non-critically Ill Patients With Coronavirus Disease 2019 in a Fangcang Shelter Hospital in Wuhan, China.

Background: Coronavirus disease 2019 (COVID-19) is a new viral respiratory disease and has become a pandemic. Fever, weakness, and dry cough are the main clinical manifestations. However, little is known about neurological symptoms of non-critically ill COVID-19 patients. Objective: To investigate the neurological symptoms and implications of patients with non-critically ill COVID-19 patients. Materials and Methods: This retrospective cohort study investigated all COVID-19 patients admitted to Wuhan East-West Lake Fangcang shelter hospital. Demographic data, clinical manifestations, comorbidities, radiological data, the result of nucleic acid test, and treatments were collected and analyzed. Results: Among 1,682 patients with confirmed non-critically ill COVID-19, 509 patients (30.3%) had neurological symptoms, including myalgia (311, 18.5%), headache (216, 12.8%), fatigue (83, 4.9%), and dizziness (15, 0.9%). One hundred and fourteen patients (6.8%) were the expansion of pulmonary infection according to their chest CT images and medical history. Compared with patients without neurological symptoms, patients with neurological symptoms had a significantly longer length of hospital stay, time of nucleic acid turning negative, and the mean time from onset of symptom to hospital admission (p < 0.05). Patients with neurological symptoms were more likely to occur the expansion of pulmonary infection compared with the patients without neurological symptoms (46/509 [9.0%] vs. 68/1,173 [5.8%]). Conclusions: Non-critically ill COVID-19 patients commonly have neurological symptoms. Neurological symptoms are significantly associated with the processes of COVID-19. Early identification and aggressive treatment are particularly important for COVID-19 patients with neurological symptoms.

Medium Term Follow-Up of 337 Patients With Coronavirus Disease 2019 (COVID-19) in a Fangcang Shelter Hospital in Wuhan, China.

Background: With the adoption of powerful preventive and therapeutic measures, a large number of patients with COVID-19 have recovered and been discharged from hospitals in Wuhan, China. Prevention of epidemic rebound is a top priority of current works. However, information regarding post-discharge quarantine and surveillance of recovered patients with COVID-19 is scarce. Methods: This study followed up 337 patients with COVID-19 in a Wuhan East-West Lake Fangcang shelter hospital during the post-discharge quarantine. Demographic, clinical characteristics, comorbidities, and chest computed tomography (CT) image, mental state, medication status, and nucleic acid test data were summarized and analyzed. Results: 21/337 (6.2%) patients were SARS-CoV-2 nucleic acid re-positive, and 4 /337(1.2%) patients were suspected positive. The median day interval between the discharge to nucleic acid re-positivity was 7.5 days (IQR, 6-13), ranging from 6 to 13 days. Cough/expectoration are the most common symptoms, followed by chest congestion/dyspnea during the 2 weeks post-discharge quarantine. Risk factors of nucleic acid re-positivity including the number of lobes infiltration (odds ratio[OR], 1.14; 95% CI, 1.09-1.19), distribution (OR, 0.16; 95% CI, 0.13-0.19), CT imaging feature of patchy shadowing accompanying with consolidation (OR, 9.36; 95% CI, 7.84-11.17), respiratory symptoms of cough accompanying with expectoration (OR, 1.39; 95% CI, 1.28-1.52), and chest congestion accompanying by dyspnea (OR, 1.42; 95% CI, 1.28-1.57). Conclusion: The 2 weeks post-discharge quarantine may be an effective measure to prevent the outbreak from rebounding from the recovered patients. The second week is a critical period during post-discharge quarantine. Special attention should be paid to cough, expectoration, chest congestion, and dyspnea in recovered COVID-19 patients. A few recovered patients may prolong the quarantine based on clinical symptoms and signs and nucleic acid results in the 2 weeks of medical observation.

The Emerging Roles of Ferroptosis in Vascular Cognitive Impairment.

Vascular cognitive impairment (VCI) is a clinical syndrome that encompasses all forms of cognitive deficits caused by cerebrovascular disease, from mild cognitive impairment to dementia. Vascular dementia, the second most common type of dementia after Alzheimer's disease (AD), accounts for approximately 20% of dementia patients. Ferroptosis is a recently defined iron-dependent form of cell death, which is distinct from apoptosis, necrosis, autophagy, and other forms of cell death. Emerging evidence suggests that ferroptosis has significant implications in neurological diseases such as stroke, traumatic brain injury, and AD. Additionally, ferroptosis inhibition has an obvious neuroprotective effect and ameliorates cognitive impairment in various animal models. Here, we summarize the underlying mechanisms of ferroptosis and review the close relationship between ferroptosis and VCI.

Iron Metabolism, Ferroptosis, and the Links With Alzheimer's Disease.

Iron is an essential transition metal for numerous biologic processes in mammals. Iron metabolism is regulated via several coordination mechanisms including absorption, utilization, recycling, and storage. Iron dyshomeostasis can result in intracellular iron retention, thereby damaging cells, tissues, and organs through free oxygen radical generation. Numerous studies have shown that brain iron overload is involved in the pathological mechanism of neurodegenerative disease including Alzheimer's disease (AD). However, the underlying mechanisms have not been fully elucidated. Ferroptosis, a newly defined iron-dependent form of cell death, which is distinct from apoptosis, necrosis, autophagy, and other forms of cell death, may provide us a new viewpoint. Here, we set out to summarize the current knowledge of iron metabolism and ferroptosis, and review the contributions of iron and ferroptosis to AD.

Promotion of anoxia-reoxygenation-induced inflammation and permeability enhancement by nicotinamide phosphoribosyltransferase-activated MAPK signaling in human umbilical vein endothelial cells.

Previous studies have demonstrated that nicotinamide phosphoribosyltransferase (NAMPT) promoted inflammation and permeability of vascular endothelial cells following cardiopulmonary bypass (CPB). In addition, mitogen-activated protein kinase (MAPK) signaling was activated and contributed to these cell responses. However, the mechanism by which NAMPT regulates cellular inflammation and permeability remains unknown, and whether NAMPT regulates MAPK signaling during this process is also not clear. The present study established an anoxia-reoxygenation (A-R) model using human umbilical vein endothelial cells (HUVECs) and investigated the regulation of MAPK signaling by NAMPT by using small RNA transfection, ELISA and western blot analysis. The results demonstrated that A-R significantly induced the expression levels of NAMPT and cellular permeability-associated proteins, and the release of several inflammatory factors. Furthermore, calcium and MAPK signaling were evidently increased. When the A-R cells were transfected with NAMPT small interfering RNA, the expression of cellular permeability-associated proteins was downregulated, the release of inflammatory factors was decreased, and calcium and MAPK signaling was blocked. These data suggest that NAMPT may activate MAPK signaling to promote A-R-induced inflammation and permeability enhancement of HUVECs. Therefore, the current study indicates that NAMPT may be a potential drug target for A-R-induced endothelial cell injury subsequent to CPB.