Impact of the COVID-19 pandemic on acute stroke care: An analysis of the 24-month data from a comprehensive stroke center in Shanghai, China.

INTRODUCTION: Whether the coronavirus disease-2019 (COVID-19) pandemic is associated with a long-term negative impact on acute stroke care remains uncertain. This study aims to compare the timing of key aspects of stroke codes between patients before and after the COVID-19 pandemic. METHODS: This retrospective cohort study was conducted at an academic hospital in Shanghai, China and included all adult patients with acute ischemic stroke hospitalized via the emergency department (ED) stroke pathway during the 24 months since the COVID-19 outbreak (COVID-19: January 1, 2020-December 31, 2021). The comparison cohort included patients with ED stroke pathway visits and hospitalizations during the same period (pre-COVID-19: January 1, 2018-December 31, 2019). We compared critical time points of prehospital and intrahospital acute stroke care between patients during the COVID-19 era and patients during the pre-COVID-19 era using t test, χ2 , and Mann-Whitney U test where appropriate. RESULTS: A total of 1194 acute ischemic stroke cases were enrolled, including 606 patients in COVID-19 and 588 patients in pre-COVID-19. During the COVID-19 pandemic, the median onset-to-hospital time was about 108 min longer compared with the same period of pre-COVID-19 (300 vs 192 min, p = 0.01). Accordingly, the median onset-to-needle time was 169 min in COVID-19 and 113 min in pre-COVID-19 (p = 0.0001), and the proportion of patients with onset-to-hospital time within 4.5 h was lower (292/606 [48.2%] vs 328/558 [58.8%], p = 0.0003) during the pandemic period. Furthermore, the median door-to-inpatient admission and door-to-inpatient rehabilitation times increased from 28 to 37 h and from 3 to 4 days (p = 0.014 and 0.0001). CONCLUSIONS: During the 24 months of COVID-19, a prolongation of stroke onset to hospital arrival and to intravenous rt-PA administration times were noted. Meanwhile, acute stroke patients needed to stay in the ED for a longer time before hospitalization. Educational system support and process optimization should be pursued in order to acquire timely delivery of stroke care during the pandemic.

Baicalin Represses C/EBPß via Its Antioxidative Effect in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the gradual loss of dopaminergic (DA) neurons in the substantia nigra (SN) and the formation of intracellular Lewy bodies (LB) in the brain, which aggregates α-synuclein (α-Syn) as the main component. The interest of flavonoids as potential neuroprotective agents is increasing due to its high efficiency and low side effects. Baicalin is one of the flavonoid compounds, which is a predominant flavonoid isolated from Scutellaria baicalensis Georgi. However, the key molecular mechanism by which Baicalin can prevent the PD pathogenesis remains unclear. In this study, we used bioinformatic assessment including Gene Ontology (GO) to elucidate the correlation between oxidative stress and PD pathogenesis. RNA-Seq methods were used to examine the global expression profiles of noncoding RNAs and found that C/EBPß expression was upregulated in PD patients compared with healthy controls. Interestingly, Baicalin could protect DA neurons against reactive oxygen species (ROS) and decreased C/EBPß and α-synuclein expression in pLVX-Tet3G-α-synuclein SH-SY5Y cells. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced PD mouse model, the results revealed that treatment with Baicalin improved the PD model's behavioral performance and reduced dopaminergic neuron loss in the substantia nigra, associated with the inactivation of proinflammatory cytokines and oxidative stress. Hence, our study supported that Baicalin repressed C/EBPß via redox homeostasis, which may be an effective potential treatment for PD.

Activation of CB2R with AM1241 ameliorates neurodegeneration via the Xist/miR-133b-3p/Pitx3 axis.

Activation of cannabinoid receptor type II (CB2R) by AM1241 has been demonstrated to protect dopaminergic neurons in Parkinson's disease (PD) animals. However, the specific mechanisms of the action of the CB2R agonist AM1241 for PD treatment have not been characterized. Wild-type (WT), CB1R knockout (CB1-KO), and CB2R knockout (CB2-KO) mice were exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 1 week to obtain a PD mouse model. The therapeutic effects of AM1241 were evaluated in each group. Behavioral tests, analysis of neurotransmitters, and immunofluorescence results demonstrated that AM1241 ameliorated PD in WT animals and CB1-KO animals. However, AM1241 did not ameliorate PD symptoms in CB2-KO mice. RNA-seq analysis identified the lncRNA Xist as an important regulator of the protective actions of AM1241. Specifically, AM1241 allowed WT and CB1-KO animals treated with MPTP to maintain normal expression of Xist, which affected the expression of miR-133b-3p and Pitx3. In vitro, overexpression of Xist or AM1241 protected neuronal cells from death induced by 6-hydroxydopamine and increased Pitx3 expression. The CB2 receptor agonist AM1241 alleviated PD via regulation of the Xist/miR-133b-3p/Pitx3 axis, and revealed a new approach for PD treatment.

MANF protects dopamine neurons and locomotion defects from a human α-synuclein induced Parkinson's disease model in C. elegans by regulating ER stress and autophagy pathways.

Many studies have demonstrated that mesencephalic astrocyte-derived neurotrophic factor (MANF) has been shown protective effects on neurotoxin based models of Parkinson's disease (PD). It still remains unclear whether MANF can rescue dopaminergic (DA) neurons in an α-synuclein model. Glial cell line-derived neurotrophic factor (GDNF) and its related neurturin (NRTN) can protect DA neurons in the neurotoxin but not α-synuclein animal models of PD, it failed in the clinical trials. Since α-synuclein model can better mimic the progression of human PD, in our study we overexpressed MANF specifically in DA neurons by using an α-synuclein Caenorhabditis elegans (C. elegans) model. Our results showed MANF alleviated progressive neuronal degeneration and prevented locomotion defects. Indeed, MANF can protect cilia of DA neurons at an early stage, suggested that MANF participated in the whole process of neuronal degeneration. Furthermore, we found MANF facilitated the removal of misfolded α-synuclein proteins and rescued the function of damaged DA neurons. By using RNAi approach, we inhibited ER stress and autophagy related genes and effects of MANF were decreased, which demonstrated ER stress and autophagy pathways were involved in the MANF-mediated neuroprotection. Our study suggests MANF exhibits potential as a neuroprotective agent for PD therapy.

Nrf2-mediated neuroprotection by MANF against 6-OHDA-induced cell damage via PI3K/AKT/GSK3ß pathway.

Oxidative stress and apoptosis are thought to be broadly involved in the pathogenesis of Parkinson's disease. We previously reported that Mesencephalic astrocyte-derived neurotrophic factor (MANF) possesses anti-oxidation and anti-apoptotic effects against 6-OHDA-induced neurotoxicity, but the specific molecular mechanism remains unclear. In this study, we showed that MANF up-regulates the expression of nuclear factor erythroid 2-related factor (Nrf2) and promotes its translocation into the nucleus. The anti-oxidation and anti-apoptotic effects of MANF could be partially blocked by inhibitor or shRNA-mediated knockdown of Nrf2. Furthermore, MANF activated phospoinositide-3-kinase (PI3K)/Akt signaling and suppressed glycogen synthase kinase (GSK3ß) activation. PI3K inhibitor (LY49002) abolished effects of MANF on AKT phosphorylation, GSK3ß inactivation, Nrf2 nuclear translocation and subsequently abrogated MANF-mediates cytoprotection. Collectively, our findings indicated that MANF-mediated protection against 6-OHDA-induced cytotoxicity by potentiating the Nrf2-related survival mechanism through the PI3K/Akt/GSK3ß pathway.