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Aim: To clarify the role of Eomesodermin (EOMES) to serve as a disease‐relevant biomarker and the intracellular molecules underlying the immunophenotype shifting of CD4+T subsets in amyotrophic lateral sclerosis (ALS). Methods: The derivation and validation cohorts included a total of 148 ALS patients and 101 healthy controls (HCs). Clinical data and peripheral blood were collected. T‐cell subsets and the EOMES expression were quantified using multicolor flow cytometry. Serum neurofilament light chain (NFL) was measured. In 1‐year longitudinal follow‐ups, the ALSFRS‐R scores and primary endpoint events were further recorded in the ALS patients of the validation cohort. Results: In the derivation cohort, the CD4+EOMES+T‐cell subsets were significantly increased (p < 0.001). EOMES+ subset was positively correlated with increased serum NFL levels in patients with onset longer than 12 months. In the validation cohort, the elevated CD4+EOMES+T‐cell proportions and their association with NFL levels were also identified. The longitudinal study revealed that ALS patients with higher EOMES expression were associated with higher progression rates (p =.010) and worse prognosis (p =.003). Conclusions: We demonstrated that increased CD4+EOMES+T‐cell subsets in ALS were associated with disease progression and poor prognosis. Identifying these associations may contribute to a better understanding of the immunopathological mechanism of ALS. [ABSTRACT FROM AUTHOR]

Purpose of Review: Parkinson's disease (PD) is a common neurodegenerative disease, which can cause progressive deterioration of motor function causing muscle stiffness, tremor, and bradykinesia. In this review, we hope to describe approaches that can improve the life of PD patients through modifications of energy metabolism. Recent Findings: The main pathological features of PD are the progressive loss of nigrostriatal dopaminergic neurons and the production of Lewy bodies. Abnormal aggregation of α‐synuclein (α‐Syn) leading to the formation of Lewy bodies is closely associated with neuronal dysfunction and degeneration. The main causes of PD are said to be mitochondrial damage, oxidative stress, inflammation, and abnormal protein aggregation. Presence of abnormal energy metabolism is another cause of PD. Many studies have found significant differences between neurodegenerative diseases and metabolic decompensation, which has become a biological hallmark of neurodegenerative diseases. Summary: In this review, we highlight the relationship between abnormal energy metabolism (Glucose metabolism, lipid metabolism, and amino acid metabolism) and PD. Improvement of key molecules in glucose metabolism, fat metabolism, and amino acid metabolism (e.g., glucose‐6‐phosphate dehydrogenase, triglycerides, and levodopa) might be potentially beneficial in PD. Some of these metabolic indicators may serve well during the diagnosis of PD. In addition, modulation of these metabolic pathways may be a potential target for the treatment and prevention of PD. [ABSTRACT FROM AUTHOR]

Background: Diterpene ginkgolides meglumine injection (DGMI) is a platelet‐activating factor receptor (PAFR) antagonist that can be used to treat acute ischemic stroke (AIS). This study evaluated the efficacy and safety of an intensive antiplatelet strategy based on PAFR antagonists and explored the underlying mechanisms of PAFR antagonists in AIS treatment. Methods: This is a retrospective study applying propensity score methods to match AIS patients treated with DGMI to nontreated patients. The primary outcome was functional independence (modified Rankin Scale [mRS] 0–2) at 90 days. The safety outcome was bleeding risk. We used McNemar test to compare the efficacy outcome. Subsequently, the network pharmacology analysis was performed. Results: 161 AIS patients treated with DGMI in the study were matched with 161 untreated patients. Compared with untreated patients, DGMI‐treated patients had a significantly higher rate of mRS ranking 0–2 at 90 days (82.0% vs. 75.8%, p < 0.001), without increased risk of bleeding. The gene enrichment analysis showed that the overlap genes of DGMI targeted and AIS‐related enriched in thrombosis and inflammatory‐related signaling pathways. Conclusions: An intensive antiplatelet strategy of DGMI plus traditional antiplatelet agents is effective in treating AIS and may work by mediating post‐stroke inflammation and thrombosis. [ABSTRACT FROM AUTHOR]

Aims: The ubiquilin‐like protein ubiquilin 2 (UBQLN2) is associated with amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD). The biological function of UBQLN2 has previously been shown to be related to stress granules (SGs). In this study, we aimed to clarify the regulatory relationship between UBQLN2 and SGs. Methods: In this study, we transfected UBQLN2‐WT or UBQLN2‐P497H plasmids into cell lines (HEK293T, HeLa), and observed the process of SG dynamics by immunofluorescence. Meanwhile, immunoblot analyses the protein changes of stress granules related components. Results: We observed that ubiquilin 2 colocalizes with the SG component proteins G3BP1, TIA‐1, ATXN2, and PABPC1. In cells expressing WT UBQLN2 or P497H mutants, in the early stages of SG formation under oxidative stress, the percentage of cells with SGs and the number of SGs per cell decreased to varying degrees. Between WT and mutant, there was no significant difference in eIF2α activity after stress treatment. Interestingly, the UBQLN2 P497H mutant downregulates the level of TIA‐1. In addition, the overexpression of the UBQLN2 P497H mutant inhibited the phosphorylation of 4E‐BP1 and affected the nucleoplasmic distribution of TDP‐43. Conclusions: Ubiquilin 2 colocalizes with the SG component proteins G3BP1, TIA‐1, ATXN2, and PABPC1. It participates in regulating SG dynamics. And UBQLN2 mutation affects the assembly of stress granules by regulating TIA‐1. In addition, the overexpression of the UBQLN2 P497H mutant inhibited the phosphorylation of 4E‐BP1 and affected the nuclear and cytoplasmic distribution of TDP‐43. These provide new insights into the role of UBQLN2 in oxidative stress and the pathogenesis of ALS. [ABSTRACT FROM AUTHOR]

Aims: As a normal physiological process, sleep has recently been shown to facilitate clearance of macromolecular metabolic wastes from the brain via the glymphatic system. The aim of the present study was to investigate pathophysiological roles of astroglial aquaporin 4 (AQP4), a functional regulator of glymphatic clearance, in a mouse model of chronic sleep disruption (SD). Methods: Adult AQP4 null mice and wild‐type (WT) mice were given 7 days of SD using the improved rotating rod method, and then received behavioral, neuropathological, and neurochemical analyses. Results: Aquaporin 4 deletion resulted in an impairment of glymphatic transport and accumulation of β‐amyloid and Tau proteins in the brain following SD. AQP4 null SD mice exhibited severe activation of microglia, neuroinflammation, and synaptic protein loss in the hippocampus, as well as decreased working memory, compared with WT‐SD mice. Conclusion: These results demonstrate that AQP4‐mediated glymphatic clearance ameliorates brain impairments caused by abnormal accumulation of metabolic wastes following chronic SD, thus serving as a potential target for sleep‐related disorders. [ABSTRACT FROM AUTHOR]

Aims: Leonurine has been shown to trigger antioxidant responses during ischemic stroke, and nuclear factor erythroid 2‐related factor 2 (Nrf‐2) imparts protective effects against oxidative injury. The present study has determined that leonurine prevents ischemic injury of brain tissues via Nrf‐2 pathway activation. Methods: Male ICR mice and Nrf‐2−/− mice were subjected to permanent middle cerebral artery occlusion (pMCAO) and received leonurine treatment at 2 hours after pMCAO by intraperitoneal injection. Neurological deficit scores as well as infarct volume were assessed to determine the neuroprotective role of leonurine. Nrf‐2 was investigated using Western blotting and real‐time polymerase chain reaction (RT‐PCR) analysis to elucidate the neuroprotective mechanism of leonurine. Commercial kits were employed to determine reactive oxygen species (ROS), superoxide (SOD), catalase (CAT), glutathione peroxidase (GSH‐Px), malonaldehyde (MDA), and glutathione (GSH). Vascular endothelial growth factor (VEGF) was evaluated by Western blotting and RT‐PCR analysis, and VEGF was localized using immunofluorescence. Results: The application of leonurine on ICR mice resulted in an improvement in neurological deficit scores and a reduction in infarct volume. Leonurine upregulated nuclear Nrf‐2 protein and increased total Nrf‐2 protein expression and mRNA levels. Leonurine regulated SOD, MDA, CAT, GSH, and GSH‐Px, and it significantly inhibited ROS production in ICR mice. Leonurine improved VEGF expression and increased VEGF expression in neurons, astrocytes, and endothelial cells. However, leonurine had no obvious beneficial effects on Nrf‐2−/− mice. Conclusions: Leonurine exerted neuroprotective effects, promoted antioxidant responses, and upregulated VEGF expression by activating the Nrf‐2 pathway. [ABSTRACT FROM AUTHOR]

Aims This study explored sFasL expression in neurons and the potential role of neuronal sFasL in modulating the microglial phenotypes. Methods In vivo, middle cerebral artery occlusion ( MCAO) was induced in both FasL-mutant ( gld) and wild-type (wt) mice. In vitro, primary cortical neuron or microglia or coculture from wt/ gld mice was subjected to oxygen glucose deprivation ( OGD). sFasL level in the supernatant was evaluated by ELISA. Neuronal-conditioned medium (NCM) or exogenous sFasL was applied to primary microglia with or without FasL neutralizing antibody. Protein expression of JAK2/ STAT3 and NF-κB pathways were determined by Western blot. The effect of microglia phenotype from wt/ gld mice on the fate of ischemic neurons was further elucidated. Results In vivo, compared with wild-type mice, M1 markers ( CD16, CD32 and iNOS) were attenuated in gld mice after MCAO. In vitro, post- OGD neuron released more sFasL. Both post- OGD NCM and exogenous sFasL could trigger M1-microglial polarization. However, this M1 phenotype shift was partially blocked by utilization of FasL neutralizing antibody or gld NCM. Consistently, JAK2/ STAT3 and NF-κB signal pathways were both activated in microglia after exogenous sFasL treatment. Compared with wild-type mice, M1-conditioned medium prepared from gld mice protected neuron against OGD injury. Conclusions Ischemic neurons release sFasL, which contributes to M1-microglial polarization. The underlying mechanisms may involve the activation of JAK2/ STAT3 and NF-κB signaling pathways. [ABSTRACT FROM AUTHOR]

Background The angiotensin (Ang) converting enzyme 2 ( ACE2)/Ang-(1-7)/Mas receptor pathway is an important component of the renin-angiotensin system and has been suggested to exert beneficial effects in ischemic stroke. Aims This study explored whether the ACE2/Ang-(1-7)/Mas pathway has a protective effect on cerebral ischemic injury and whether this effect is affected by age. Methods We used three-month and eight-month transgenic mice with neural over-expression of ACE2 ( SA) and their age-matched nontransgenic ( NT) controls. Neurological deficits and ischemic stroke volume were determined following middle cerebral artery occlusion (MCAO). In oxygen and glucose deprivation ( OGD) experiments on brain slices, the effects of the Mas receptor agonist (Ang1-7) or antagonist (A779) on tissue swelling, Nox2/Nox4 expression reactive oxygen species ( ROS) production and cell death were measured. Results (1) Middle cerebral artery occlusion -induced ischemic injury and neurological deficit were reduced in SA mice, especially in eight-month animals; (2) OGD-induced tissue swelling and cell death were decreased in SA mice with a greater reduction seen in eight-month mice; (3) Ang-(1-7) and A779 had opposite effects on OGD-induced responses, which correlated with changes in Nox2/Nox4 expression and ROS production. Conclusions Angiotensin converting enzyme 2/Ang-(1-7)/Mas axis protects brain from ischemic injury via the Nox/ ROS signaling pathway, with a greater effect in older animals. [ABSTRACT FROM AUTHOR]

Aim Dysregulation of the activity of the disintegrin/metalloproteinase ADAM10 could contribute to the development of atherosclerosis. Although a number of genetic studies have focused on the association of ADAM10 gene polymorphisms with susceptibility to diseases, no genetic association studies of ADAM10 gene variability with atherosclerotic cerebral infarction ( ACI) have been conducted. The aim of this study was to analyze the potential association between ADAM10 promoter polymorphisms and ACI. Methods The associations between rs653765 and rs514049 polymorphisms of the ADAM10 promoter and the possible risk of ACI were assessed among 347 patients with ACI and 299 matched healthy individuals in a case-control study. Results Overall, there was a significant difference in the genotypes frequencies of rs653765 ( P = 0.04) between the ACI and control subjects. In addition, the rs653765 mutated allele of ADAM10 was significantly associated with increased ADAM10 expression in patients with ACI ( P = 0.032). In contrast, the allele frequency of rs514049 was not statistically associated with ACI, and the rs514049 variant A > C did not affect the expression of ADAM10 either. Conclusion Our findings indicate a positive association between the rs653765 polymorphism of ADAM10 and ACI, as well as a negative result for rs514049. In addition, a significant increase in ADAM10 expression was observed in patients with ACI carrying the rs653765 C > T mutation. This new knowledge about ADAM10 might be clinically important and confirm a role for ADAM10 in the pathophysiology of ACI, with potentially important therapeutic implications. [ABSTRACT FROM AUTHOR]

Endothelial progenitor cells ( EPCs), which can be cultured in vitro from mononuclear cells in peripheral blood or bone marrow, express both hematopoietic stem cell and endothelial cell markers on their surface. They are believed to participate in endothelial repair and postnatal angiogenesis due to their abilities of differentiating into endothelial cells and secreting protective cytokines and growth factors. Mounting evidence suggests that circulating EPCs are reduced and dysfunctional in various diseases including hypertension, diabetes, coronary heart disease, and ischemic stroke. Therefore, EPCs have been documented to be a potential biomarker for vascular diseases and a hopeful candidate for regenerative medicine. Ischemic stroke, as the major cause of disability and death, still has limited therapeutics based on the approaches of vascular recanalization or neuronal protection. Emerging evidence indicates that transplantation of EPCs is beneficial for the recovery of ischemic cerebral injury. EPC-based therapy could open a new avenue for ischemic cerebrovascular disease. Currently, clinical trials for evaluating EPC transfusion in treating ischemic stroke are underway. In this review, we summarize the general conceptions and the characteristics of EPCs, and highlight the recent research developments on EPCs. More importantly, the rationale, perspectives, and strategies for using them to treat ischemic stroke will be discussed. [ABSTRACT FROM AUTHOR]

Aims To examine whether transplantation of adipose-derived stem cells ( ADSCs) induces neural differentiation and improves neural function in a rat intracerebral hemorrhage ( ICH) model. Methods Adipose-derived stem cells cells were isolated from inguinal fat pad of rat. ICH was induced by injection of collagenase type IV into the right basal ganglia of rat. Forty-eight hours after ICH, ADSCs cells (10 μL of 2-4 × 107 cells/ mL) were injected into the right lateral cerebral ventricle. The differentiation of ADSCs was detected in vitro and in vivo. The neural function was evaluated with Zea Longa 5-grade scale at day 1, 3, 7, 14, or 28. Results Our data demonstrated that ADSCs differentiated into cells that shared the similarities of neurons or astrocytes in vitro. Transplantation of ADSCs decreased cell apoptosis and the transplanted ADSCs were able to differentiate into neuron-like and astrocyte-like cells around the hematoma, accompanied with upregulation of vascular endothelial growth factor expression and improvement of neural function. Conclusions Our data suggest that transplantation of ADSCs could be a therapeutic approach for ICH stroke. [ABSTRACT FROM AUTHOR]