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Background: Sleep problem is a common complication of Alzheimer's disease (AD). Extensive preclinical studies have been performed to investigate the AD pathology. However, the pathophysiological consequence of AD complicated by sleep problem remains to be further determined., Purpose: To investigate brain metabolism and perfusion in an AD mouse model complicated by sleep problem, and subsequently identify potential imaging markers to better understand the associated pathophysiology., Methods: We examined the oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen (CMRO 2 ), and cerebral blood flow (CBF) using state-of-the-art MRI techniques in a cohort of 5xFAD model mice. Additionally, neuroinflammation, indicated by activated microglia, was assessed using histology techniques. Sleep fragmentation (SF) was utilized as a representative for sleep problems., Results: SF was associated with significant increases in OEF ( P = 0.023) and CMRO 2 ( P = 0.029), indicating a state of hypermetabolism. CBF showed a significant genotype-by-sleep interaction effect ( P = 0.026), particularly in the deep brain regions such as the hippocampus and thalamus. Neuroinflammation was primarily driven by genotype rather than SF, especially in regions with significant interaction effect in CBF measurements., Conclusion: These results suggest that brain metabolism and perfusion measurements are promising markers for studying the co-pathogenesis of AD and SF., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Han, Liu, Lee, Yang, Wu, Lu and Wei.)

Objective: The objective of this study was to analyze the application of health management and medication self-management education in the control of chronic diseases in the elderly, specifically focusing on patients with diabetes, hypertension, cardiovascular diseases, and chronic obstructive pulmonary disease (COPD). The study aimed to assess the impact of these interventions on patients› self-management abilities, quality of life, medication adherence, intervention satisfaction, and the occurrence of adverse events. The findings aimed to provide a scientific basis for improving elderly chronic disease management and enhancing patients› health and quality of life., Methods: A total of 106 elderly chronic disease patients admitted to our hospital from July 2021 to April 2023 were selected as the research subjects. All patients met the complete inclusion criteria. They were divided into two groups based on the type of health management intervention received. The control group (n=53) received conventional health management intervention. In contrast, the observation group (n=53) received health management from the medical examination center based on the PDCA model and medication self-management education intervention. The self-management ability, quality of life, medication adherence, occurrence of adverse events, and intervention satisfaction of the two groups of patients were compared. The PDCA (Plan-Do-Check-Act) model was chosen as the framework for this study due to its systematic approach to management and its potential to address the specific needs and complexities associated with chronic diseases in the elderly. The PDCA model emphasizes a continuous cycle of improvement, involving planning, implementation, evaluation, and adjustment of interventions., Results: Before the intervention, there was no significant difference in self-concept, self-management responsibility, self-management knowledge, and self-management skills between the two groups (P > .05). After the intervention, the observation group's self-concept, self-management responsibility, self-management knowledge, and self-management skills were significantly higher than those of the control group (P < .05). Before the intervention, there was no significant difference in SF-36 scores between the two groups (P > .05). After the intervention, the SF-36 scores of the observation group were significantly higher than those of the control group (P < .05). The medication adherence score in the control group was (5.73±0.92), and the incidence of adverse events was 32.08%. In the observation group, the medication adherence score was (7.42±0.81), and the incidence of adverse events was 11.32%. The medication adherence score in the observation group was significantly higher than that in the control group, and the incidence of adverse events was significantly lower than that in the control group (P < .05). The intervention satisfaction in the control group was 73.58%. In comparison, the intervention satisfaction in the observation group was 96.23%, indicating that the intervention satisfaction in the observation group was significantly higher than that in the control group (P < .05). These results suggest that the implementation of the PDCA model in health management and medication self-management education can enhance patients' self-management abilities, improve medication adherence, and ultimately lead to better quality of life and reduced risk of adverse events for elderly chronic disease patients., Conclusion: The application of health management and medication self-management education based on the PDCA model in the control of elderly chronic diseases is ideal. Compared to conventional health management interventions, the former can enhance patients' self-management abilities and improve medication adherence, thereby further improving patients' quality of life, satisfaction, and the risk of adverse events. Therefore, this approach is worthy of clinical promotion and application.

Background: This paper explores the widely discussed relationship between electronic media use and sleep quality, indicating negative effects due to various factors. However, existing meta-analyses on the topic have some limitations., Objective: The study aims to analyze and compare the impacts of different digital media types, such as smartphones, online games, and social media, on sleep quality., Methods: Adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the study performed a systematic meta-analysis of literature across multiple databases, including Web of Science, MEDLINE, PsycINFO, PubMed, Science Direct, Scopus, and Google Scholar, from January 2018 to October 2023. Two trained coders coded the study characteristics independently. The effect sizes were calculated using the correlation coefficient as a standardized measure of the relationship between electronic media use and sleep quality across studies. The Comprehensive Meta-Analysis software (version 3.0) was used to perform the meta-analysis. Statistical methods such as funnel plots were used to assess the presence of asymmetry and a p-curve test to test the p-hacking problem, which can indicate publication bias., Results: Following a thorough screening process, the study involved 55 papers (56 items) with 41,716 participants from over 20 countries, classifying electronic media use into "general use" and "problematic use." The meta-analysis revealed that electronic media use was significantly linked with decreased sleep quality and increased sleep problems with varying effect sizes across subgroups. A significant cultural difference was also observed in these effects. General use was associated with a significant decrease in sleep quality (P<.001). The pooled effect size was 0.28 (95% CI 0.21-0.35; k=20). Problematic use was associated with a significant increase in sleep problems (P≤.001). The pooled effect size was 0.33 (95% CI 0.28-0.38; k=36). The subgroup analysis indicated that the effect of general smartphone use and sleep problems was r=0.33 (95% CI 0.27-0.40), which was the highest among the general group. The effect of problematic internet use and sleep problems was r=0.51 (95% CI 0.43-0.59), which was the highest among the problematic groups. There were significant differences among these subgroups (general: Q between =14.46, P=.001; problematic: Q between =27.37, P<.001). The results of the meta-regression analysis using age, gender, and culture as moderators indicated that only cultural difference in the relationship between Eastern and Western culture was significant (Q between =6.69; P=.01). All funnel plots and p-curve analyses showed no evidence of publication and selection bias., Conclusions: Despite some variability, the study overall confirms the correlation between increased electronic media use and poorer sleep outcomes, which is notably more significant in Eastern cultures., (©Xiaoning Han, Enze Zhou, Dong Liu. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 23.04.2024.)

Aim: Magnesium supplementation may extend the life span; however, the biological mechanism is still unknown. Leukocyte telomere length (LTL) is a marker of cell aging and biological health in humans. Data concerning whether magnesium supplementation can maintain telomere length, thus prolonging life are limited. We aimed to investigate the association between dietary magnesium intake and LTL in United States middle-aged and elderly adults., Methods: A total of 4,039 United States adults aged ≥ 45 years from National Health and Nutrition Examination Survey (1999-2002). Dietary magnesium intake was collected by a trained interviewer using 24-h dietary recall method and LTL was obtained using the quantitative polymerase chain reaction method. Multiple linear regression analysis was performed to evaluate the crude and adjusted association of dietary magnesium intake with LTL., Results: The overall mean (SD) of LTL was 5.6 (0.6) kp. After adjusting potential confounders, every 1 mg increase in log-transformed dietary magnesium intake was associated with 0.20 kp (95% confidence intervals: 0.05-0.34) longer LTL. Participants with the highest tertile (≥299 mg) of dietary magnesium intake had statistically significant longer LTL (β = 0.07, P = 0.038) compared with the lowest tertile (<198 mg), with significant linear trends across tertiles. Moreover, the association between dietary magnesium intake and LTL was significantly stronger in participants with higher levels of education (≥high school compared with < high school, P for interaction = 0.002). E -value analysis suggested robustness to unmeasured confounding., Conclusion: Our findings showed that increased dietary magnesium intake was associated with longer LTL, which suggested that magnesium was conducive to a longer life expectancy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hu, Bai, Hu, Zhang, Han and Li.)

Polarization-sensitive photodetection is highly appealing considering its great important applications. However, the inherent in-plane symmetry of a material and the single structure of a detector hinder the further development of polarization detectors with high anisotropic ratios. Herein, we design a p-WSe 2 /TaIrTe 4 /n-MoS 2 (p-Ta-n) heterojunction. As a type-II Weyl semimetal, TaIrTe 4 with an orthorhombic structure has strong in-plane asymmetry, which is confirmed by angle-resolved polarized Raman spectroscopy and second-harmonic generation. Due to the specific structure of the p-Ta-n junction with two vertical built-in electric fields, the device obtains a broadband self-powered photodetection ranging from visible (405 nm) to telecommunication wavelength (1550 nm) regions. Further, an optimized device containing 50-70 nm-thick layered TaIrTe 4 has been realized. What is more, high-resolution imaging of "T" based on the device with clear borders illustrates excellent stability of the device. Significantly, the photocurrent anisotropic ratio of the p-Ta-n detector can reach 9.1 under 635 nm light, which is more than eight times that of the best known TaIrTe 4 -based photodetector reported before. This p-Ta-n junction containing a type-II Weyl fermion semimetal can provide an effective approach toward highly polarization-sensitive and high-performance integrated broadband photodetectors.

Mechanical forces generated by cells and the tension of the extracellular matrix (ECM) play a decisive role in establishment, homeostasis maintenance, and repair of tissue morphology. However, the dynamic change of cell-derived force during large-scale remodeling of soft tissue is still unknown, mainly because the current techniques of force detection usually produce a nonnegligible and interfering feedback force on the cells during measurement. Here, we developed a method to fabricate highly stretchable polymer-based microstrings on which a microtissue of fibroblasts in collagen was cultured and allowed to contract to mimic the densification of soft tissue. Taking advantage of the low-spring constant and large deflection range of the microstrings, we detected a strain-induced contraction force as low as 5.2 µN without disturbing the irreversible densification. Meanwhile, the microtissues displayed extreme sensitivity to the mechanical boundary within a narrow range of tensile stress. More importantly, results indicated that the cell-derived force did not solely increase with increased ECM stiffness as previous studies suggested. Indeed, the cell-derived force and collagen tension exchanged dramatically in dominating the microtissue strain during the densification, and the proportion of cell-derived force decreased linearly as the microtissue densified, with stiffness increasing to ∼500 Pa. Thus, this study provides insights into the biomechanical cross-talk between the cells and ECM of extremely soft tissue during large-extent densification, which may be important to guide the construction of life-like tissue by applying appropriate mechanical boundary conditions., Competing Interests: The authors declare no competing interest.

The relationship between cerebral glucose metabolism and glucose transporter expression after intracerebral hemorrhage (ICH) is unclear. Few studies have used positron emission tomography (PET) to explore cerebral glucose metabolism after ICH in rodents. In this study, we produced ICH in mice with an intrastriatal injection of collagenase to investigate whether glucose metabolic changes in 18 F-fluoro-2-deoxy-D-glucose (FDG)-PET images are associated with expression of glucose transporters (GLUTs) over time. On days 1 and 3 after ICH, the ipsilateral striatum exhibited significant hypometabolism. However, by days 7 and 14, glucose metabolism was significantly higher in the ipsilateral striatum than in the contralateral striatum. The contralateral hemisphere did not show hypermetabolism at any time after ICH. Qualitative immunofluorescence and Western blotting indicated that the expression of GLUT1 in ipsilateral striatum decreased on days 1 and 3 after ICH and gradually returned to baseline by day 21. The 18 F-FDG uptake after ICH was associated with expression of GLUT1 but not GLUT3 or GLUT5. Our data suggest that ipsilateral cerebral glucose metabolism decreases in the early stage after ICH and increases progressively in the late stage. Changes in 18 F-FDG uptake on PET imaging are associated with the expression of GLUT1 in the ipsilateral striatum.

Hematoma size after intracerebral hemorrhage (ICH) significantly affects patient outcome. However, our knowledge of endogenous mechanisms that underlie hematoma clearance and the potential role of the anti-inflammatory cytokine interleukin-10 (IL-10) is limited. Using organotypic hippocampal slice cultures and a collagenase-induced ICH mouse model, we investigated the role of microglial IL-10 in phagocytosis ex vivo and hematoma clearance in vivo. In slice culture, exposure to hemoglobin induced IL-10 expression in microglia and enhanced phagocytosis that depended on IL-10-regulated expression of CD36. Following ICH, IL-10-deficient mice had more severe neuroinflammation, brain edema, iron deposition, and neurologic deficits associated with delayed hematoma clearance. Intranasal administration of recombinant IL-10 accelerated hematoma clearance and improved neurologic function. Additionally, IL-10-deficient mice had weakened in vivo phagocytic ability owing to decreased expression of microglial CD36. Moreover, loss of IL-10 significantly increased monocyte-derived macrophage infiltration and enhanced brain inflammation in vivo. These results indicate that IL-10 regulates microglial phagocytosis and monocyte-derived macrophage infiltration after ICH and that CD36 is a key phagocytosis effector regulated by IL-10. Leveraging the innate immune response to ICH by augmenting IL-10 signaling may provide a useful strategy for accelerating hematoma clearance and improving neurologic outcome in clinical translation studies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Sepsis is a common and lethal syndrome. Long non-coding RNA (lncRNA) transcript predicting survival in AKI (TapSAKI) has recently been found to serve as an important regulator in sepsis. However, the underlying mechanism of TapSAKI in sepsis pathogenesis remains largely unknown. Our data demonstrated that lipopolysaccharide (LPS)-induced HK-2 cell injury by weakening cell viability and enhancing cell apoptosis and inflammation. TapSAKI was upregulated and miR-205 was downregulated in LPS-induced HK-2 cells. TapSAKI knockdown or miR-205 overexpression alleviated LPS-induced cytotoxicity in HK-2 cells. TapSAKI sequestered miR-205 via acting as a miR-205 sponge. Moreover, the mitigating effect of TapSAKI silencing on LPS-induced HK-2 cell injury was mediated by miR-205. Additionally, the interferon regulatory factor 3 (IRF3) signaling was involved in the regulation of the TapSAKI/miR-205 axis on LPS-induced HK-2 cell damage. Our current study suggested that TapSAKI silencing relieved LPS-induced injury in HK-2 cells at least in part by sponging miR-205 and regulating the IRF3 signaling pathway, highlighting a novel understanding for sepsis pathogenesis and a promising target for this disease treatment., Competing Interests: Conflict of interest: The authors declare that they have no financial conflicts of interest., (© 2021 Xiaoning Han et al., published by De Gruyter.)

Both carotid intima-media thickness (cIMT) and carotid plaque (CP) quantified by B-mode ultrasound have been proposed as surrogate imaging biomarkers of subclinical atherosclerosis, while the relationship between cIMT and CP, whether cIMT evaluation in a given patient might allow for predicting the development of a carotid plaque, is still discussed controversially. We investigated the cross-sectional relationship between cIMT and CP, and the predictive value of cIMT for incident CP formation in 1078 subjects with mean age of 52 ± 5 years in a community based atherosclerosis cohort in Beijing. Participants underwent ultrasonography of bilateral carotid arteries and received vascular risk factor assessment at baseline and after a mean of 2.35 years follow-up. The prevalence of plaque was increased by 3.75-fold for upper quartile cIMT compare with the lower quartile even after adjustments for traditional risk factors at baseline. Among the 746 plaque-free subjects at baseline, 230 (31.0%) developed new CP. After adjusted for demographics and vascular risk factors, neither baseline cIMT nor the cIMT change from baseline to follow-up predicted incident CP. In conclusion, although cIMT associates with CP cross-sectionally, increased cIMT dose not independently predict future plaque development. Our data suggest that paying attention to the traditional risk factors might prevent subjects from developing carotid plaques regardless from IMT changes.

Inhibitory interneurons are critical for maintaining the excitatory/inhibitory balance. During the development cortical interneurons originate from the ganglionic eminence and arrive at the dorsal cortex through two tangential migration routes. However, the mechanisms underlying the development of cortical interneurons remain unclear. 3-Phosphoinositide-dependent protein kinase-1 (PDK1) has been shown to be involved in a variety of biological processes, including cell proliferation and migration, and plays an important role in the neurogenesis of cortical excitatory neurons. However, the function of PDK1 in interneurons is still unclear. Here, we reported that the disruption of Pdk1 in the subpallium achieved by crossing the Dlx5/6-Cre-IRES-EGFP line with Pdk1 fl/fl mice led to the severely increased apoptosis of immature interneurons, subsequently resulting in a remarkable reduction in cortical interneurons. However, the tangential migration, progenitor pools and cell proliferation were not affected by the disruption of Pdk1. We further found the activity of AKT-GSK3β signaling pathway was decreased after Pdk1 deletion, suggesting it might be involved in the regulation of the survival of cortical interneurons. These results provide new insights into the function of PDK1 in the development of the telencephalon.

Background: The aim of this prospective randomized crossover study was to compare the short-term effects of high-flow nasal cannula (HFNC) therapy and a 45° head-up tilt to the short-term effects of conventional oxygen (O 2 ) therapy in post-abdominal surgery patients., Methods: A total of 18 subjects who were successfully weaned from ventilator support after abdominal surgery were included in the study. The subjects were randomly assigned to 2 groups: conventional O 2 was applied in group A for 15 min, and HFNC (60 L/min) was applied in group B for 15 min. A 15-min washout period with conventional O 2 was performed before the interventions were switched in both groups. Heart rate, blood pressure, breathing frequency, ratio of arterial partial pressure of oxygen to the fraction of inspired oxygen (P aO 2 /F IO 2 ), and subject-reported comfort scores were recorded. Changes in end-expiratory lung impedance (EELI) were calculated with electrical impedance tomography., Results: Results are presented as the percent change in lung volume compared to baseline during volume-controlled continuous mandatory ventilation before extubation. HFNC improved EELI in both the ventral (conventional O 2 vs HFNC, -48.2% ± 41.0 vs -30.0% ± 40.3, P < .001) and the dorsal (conventional O 2 vs HFNC, -37.0% ± 75.9 vs -26.5% ± 68.4, P = .02) regions of the lungs. Subjective subject-reported scores indicated that HFNC was more comfortable than conventional O 2 (conventional O 2 vs HFNC, 5.8 ± 1.5 vs 6.9 ± 1.9, P = .02). No differences were found in the other examined parameters. A head-up tilt position with conventional O 2 improved EELI in the dorsal regions (55.9% ± 100.1, P < .001) but not in the ventral regions (-37.9% ± 43.1%, P = .38) of the lungs compared to HFNC or conventional O 2 alone., Conclusions: In post-abdominal surgery subjects who had been extubated, HFNC improved lung volume and patient comfort. A head-up tilt position introduced a heterogeneous increase in EELI in the dorsal regions of the lungs. HFNC therapy may be beneficial in this patient group. (ChiCTR1900020886, http://chictr.org.cn)., (Copyright © 2020 by Daedalus Enterprises.)

Background: Gynostemma pentaphyllum is an important perennial medicinal herb belonging to the family Cucurbitaceae. Aerial stem-to-rhizome transition before entering the winter is an adaptive regenerative strategy in G. pentaphyllum that enables it to survive during winter. However, the molecular regulation of aerial stem-to-rhizome transition is unknown in plants. Here, integrated transcriptome and miRNA analysis was conducted to investigate the regulatory network of stem-to-rhizome transition., Results: Nine transcriptome libraries prepared from stem/rhizome samples collected at three stages of developmental stem-to-rhizome transition were sequenced and a total of 5428 differentially expressed genes (DEGs) were identified. DEGs associated with gravitropism, cell wall biosynthesis, photoperiod, hormone signaling, and carbohydrate metabolism were found to regulate stem-to-rhizome transition. Nine small RNA libraries were parallelly sequenced, and seven significantly differentially expressed miRNAs (DEMs) were identified, including four known and three novel miRNAs. The seven DEMs targeted 123 mRNAs, and six pairs of miRNA-target showed significantly opposite expression trends. The GpmiR166b-GpECH2 module involved in stem-to-rhizome transition probably promotes cell expansion by IBA-to-IAA conversion, and the GpmiR166e-GpSGT-like module probably protects IAA from degradation, thereby promoting rhizome formation. GpmiR156a was found to be involved in stem-to-rhizome transition by inhibiting the expression of GpSPL13A/GpSPL6, which are believed to negatively regulate vegetative phase transition. GpmiR156a and a novel miRNA Co.47071 co-repressed the expression of growth inhibitor GpRAV-like during stem-to-rhizome transition. These miRNAs and their targets were first reported to be involved in the formation of rhizomes. In this study, the expression patterns of DEGs, DEMs and their targets were further validated by quantitative real-time PCR, supporting the reliability of sequencing data., Conclusions: Our study revealed a comprehensive molecular network regulating the transition of aerial stem to rhizome in G. pentaphyllum. These results broaden our understanding of developmental phase transitions in plants.

Investigators are increasingly interested in using microglial depletion to study the role of microglia under pathologic conditions. Liposome-encapsulated clodronate is commonly used to eliminate macrophage populations because it causes functionally irreversible inhibition and apoptosis once phagocytized by macrophages. Recent studies have shown that microglia can be depleted in disease models by injecting clodronate liposomes into the brain parenchyma. However, it is unclear whether intracerebral administration of clodronate liposomes is a practical method of eliminating microglia under physiologic conditions or whether microglial depletion induces damage to other brain cells. In this study, injecting 1 μL of clodronate liposomes (7 μg/μL) into the striatum of mice caused ablation of microglia at 1 day that persisted for 3 days. Microglia reappeared in the boundary regions of microglia elimination after 5 days. Importantly, we observed an increase in proinflammatory cytokine levels and an increase in neural/glial antigen 2 and glial fibrillary acidic protein expression in the perilesional region. In contrast, expression levels of myelin basic protein, microtubule-associated protein 2, and postsynaptic protein-95 decreased in the periphery of regions where microglia were depleted. Moreover, clodronate liposome administration decreased the density and integrity of blood vessels in the perilesional regions. In cultured primary neurons, clodronate liposome exposure also attenuated ATP synthesis. Together, these findings suggest that intracerebral administration of clodronate liposomes into brain parenchyma can deplete microglia, but can also damage other brain cells and blood vessel integrity.

20-HETE, an arachidonic acid metabolite synthesized by cytochrome P450 4A, plays an important role in acute brain damage from ischemic stroke or subarachnoid hemorrhage. We tested the hypothesis that 20-HETE inhibition has a protective effect after intracerebral hemorrhage (ICH) and then investigated its effect on angiogenesis. We exposed hippocampal slice cultures to hemoglobin and induced ICH in mouse brains by intrastriatal collagenase injection to investigate the protective effect of 20-HETE synthesis inhibitor N-hydroxy-N'-(4- n -butyl-2-methylphenyl)-formamidine (HET0016). Hemoglobin-induced neuronal death was assessed by propidium iodide after 18 h in vitro. Lesion volume, neurologic deficits, cell death, reactive oxygen species (ROS), neuroinflammation, and angiogenesis were evaluated at different time points after ICH. In cultured mouse hippocampal slices, HET0016 attenuated hemoglobin-induced neuronal death and decreased levels of proinflammatory cytokines and ROS. In vivo, HET0016 reduced brain lesion volume and neurologic deficits, and decreased neuronal death, ROS production, gelatinolytic activity, and the inflammatory response at three days after ICH. However, HET0016 did not inhibit angiogenesis, as levels of CD31, VEGF, and VEGFR2 were unchanged on day 28. We conclude that 20-HETE is involved in ICH-induced brain damage. Inhibition of 20-HETE synthesis may provide a viable means to mitigate ICH injury without inhibition of angiogenesis.

Ferroptosis is a recently identified, iron-regulated, non-apoptotic form of cell death. It is characterized by cellular accumulation of lipid reactive oxygen species that ultimately leads to oxidative stress and cell death. Although first identified in cancer cells, ferroptosis has been shown to have significant implications in several neurologic diseases, such as ischemic and hemorrhagic stroke, Alzheimer's disease, and Parkinson's disease. This review summarizes current research on ferroptosis, its underlying mechanisms, and its role in the progression of different neurologic diseases. Understanding the role of ferroptosis could provide valuable information regarding treatment and prevention of these devastating diseases.

This study aimed to investigate the predictive values of central systolic blood pressure (cSBP) and peripheral systolic blood pressure (pSBP) for the progression of carotid intima-media thickness (cIMT). A total of 953 Chinese participants from an atherosclerosis cohort with complete information, including baseline cSBP, questionnaire information, biochemical examination, baseline, and follow-up carotid ultrasonography quantitative data, were included in this study. A multilinear regression model, adjusted for possible covariates, was used to investigate the predictive values of cSBP and pSBP for rate of cIMT change. The average age of all participants was (52.11 ± 4.74 years). The baseline levels of cSBP, pSBP, max cIMT, and mean cIMT were (132.55 ± 18.18)mmHg, (130.76 ± 15.40)mmHg, (813.52 ± 118.49)µm and (681.11 ± 99.90)µm, respectively Those with hypertension, diabetes and dyslipidemia accounted for 40.71% (388), 18.05% (172), and 70.41% (671), respectively. After 2.3 years of follow-up, the average rates of max and mean cIMT change were 8.70 (-0.49-19.43)% and 2.59 (-4.72-10.81)%, respectively. Per standard deviation increase of cSBP, but not pSBP, was associated with increases of max (for cSBP, β 1.07, 95%CI 0.18-1.96, p = 0.018; for pSBP, β 0.48, 95%CI -0.45-1.41, p = 0.315) and mean (for cSBP, β 0.84%, 95%CI 0.10-1.58, p = 0.027; for pSBP, β 0.59%, 95%CI -0.18-1.37, p = 0.135) cIMT change rate after adjusting for possible covariates. In conclusion, cSBP, but not pSBP, is independently associated with cIMT progression in our community-based Chinese population. cSBP should be considered for the purpose of CVD primary prevention.

Activation and polarization of microglia and macrophages are critical events in neuroinflammation and hematoma resolution after intracerebral hemorrhage (ICH). However, distinguishing microglia and monocyte-derived macrophages histologically can be difficult. Although they share most cell surface markers, evidence indicates that the gene regulation and function of these two cell types might be different. Flow cytometry is the gold standard for discriminating between the two cell populations, but it is rarely used in the ICH research field. We developed a flow cytometry protocol to identify and sort microglia and monocyte-derived macrophages from mice that have undergone well-established ICH models induced by collagenase or blood injection. In addition, we combined a recently established magnetic-activated cell separation system that allows eight tissue samples to be assessed together. This protocol can be completed within 5-8 h. Sorted cells are fully preserved and maintain expression of microglia-specific ( Tmem119/Sall1 ) and macrophage-specific ( Ccr2/CD69 ) markers. They retain phagocytic ability, respond to lipopolysaccharide stimulation, and engulf fluorescent latex beads. Thus, this protocol represents a very important tool for researching microglial and monocyte-derived macrophage biologic function after ICH and other brain diseases.

Inflammatory responses occur rapidly after intracerebral hemorrhage and participate in both short-term toxicity and long-term recovery. Microglia/macrophages react to hemorrhagic injury and exhibit dynamic phenotypes and phagocytic capability. Astrocytes secrete cytokines, chemokines, and gliotransmitters that can regulate neuroinflammation. In addition, infiltrating neutrophils and T-lymphocytes modulate immunoreactions, which further cross-talk with microglia/macrophages. Thus, the search for effective immunotherapy to target specific cell type-mediated inflammation might represent a new direction for intracerebral hemorrhage treatment, separate from traditional anti-inflammatory drug discovery.

Intracerebral hemorrhage (ICH) is a detrimental type of stroke. Mouse models of ICH, induced by collagenase or blood infusion, commonly target striatum, but not other brain sites such as ventricular system, cortex, and hippocampus. Few studies have systemically investigated brain damage and neurobehavioral deficits that develop in animal models of ICH in these areas of the right hemisphere. Therefore, we evaluated the brain damage and neurobehavioral dysfunction associated with right hemispheric ICH in ventricle, cortex, hippocampus, and striatum. The ICH model was induced by autologous whole blood or collagenase VII-S (0.075 units in 0.5 µl saline) injection. At different time points after ICH induction, mice were assessed for brain tissue damage and neurobehavioral deficits. Sham control mice were used for comparison. We found that ICH location influenced features of brain damage, microglia/macrophage activation, and behavioral deficits. Furthermore, the 24-point neurologic deficit scoring system was most sensitive for evaluating locomotor abnormalities in all four models, especially on days 1, 3, and 7 post-ICH. The wire-hanging test was useful for evaluating locomotor abnormalities in models of striatal, intraventricular, and cortical ICH. The cylinder test identified locomotor abnormalities only in the striatal ICH model. The novel object recognition test was effective for evaluating recognition memory dysfunction in all models except for striatal ICH. The tail suspension test, forced swim test, and sucrose preference test were effective for evaluating emotional abnormality in all four models but did not correlate with severity of brain damage. These results will help to inform future preclinical studies of ICH outcomes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

(-)-Epicatechin is a brain-permeable, natural product found at high concentrations in green tea and cocoa. Our previous research has shown that (-)-epicatechin treatment reduces hemorrhagic stroke injury via nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in vivo. However, the mechanism of action of this compound in modulation of oxidant stress and in protection against hemoglobin-induced astrocyte injury is unclear. Therefore, we explored the cellular and molecular mechanisms that underlie these protective effects in vitro. Mouse primary astrocytes isolated from wild-type mice and Nrf2 knockout (KO) mice were preconditioned with hemoglobin to simulate intracerebral hemorrhage (ICH) in vitro. Effects of (-)-epicatechin were measured by Western blotting, immunostaining, MTT assay, and reactive oxidant stress (ROS) assay. (-)-Epicatechin increased Nrf2 nuclear accumulation and cytoplasmic levels of superoxide dismutase 1 (SOD1) in wild-type astrocytes but did not increase SOD1 expression in Nrf2 knockout (KO) astrocytes. Furthermore, (-)-epicatechin treatment did not alter heme oxygenase 1 (HO1) expression in wild-type astrocytes after hemoglobin exposure, but it did decrease HO1 expression in similarly treated Nrf2 KO astrocytes. In both wild-type and Nrf2 KO astrocytes, (-)-epicatechin suppressed phosphorylated JNK and nuclear expression of JNK, c-jun, and c-fos, indicating that inhibition of activator protein-1 (AP-1) activity by (-)-epicatechin is Nrf2-independent. These novel findings indicate that (-)-epicatechin protects astrocytes against hemoglobin toxicity through upregulation of Nrf2 and inhibition of AP-1 activity. These cellular and molecular effects may partially explain the cerebroprotection as we previously observed for (-)-epicatechin in animal models of ICH.

Neuroinflammation is a major contributor to intracerebral hemorrhage (ICH) progression, but no drug is currently available to reduce this response and protect against ICH-induced injury. Recently, the natural product pinocembrin has been shown to ameliorate neuroinflammation and is undergoing a phase II clinical trial for ischemic stroke treatment. In this study, we examined the efficacy of pinocembrin in an ICH model, and further examined its effect on microglial activation and polarization. In vivo, pinocembrin dose-dependently reduced lesion volume by ∼47.5% and reduced neurologic deficits of mice at 72h after collagenase-induced ICH. The optimal dose of pinocembrin (5mg/kg) suppressed microglial activation as evidenced by decreases in CD68-positive microglia and reduced proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. Pinocembrin also reduced the number of classically activated M1-like microglia without affecting M2-like microglia in the perilesional region. Additionally, pinocembrin decreased the expression of toll-like receptor (TLR)4 and its downstream target proteins TRIF and MyD88. The protection by pinocembrin was lost in microglia-depleted mice and in TLR4 lps-del mice, and pinocembrin failed to decrease the number of M1-like microglia in TLR4 lps-del mice. In lipopolysaccharide-stimulated BV-2 cells or primary microglia, pinocembrin decreased M1-related cytokines and markers (IL-1β, IL-6, TNF-α, and iNOS), NF-κB activation, and TLR4 expression, but it did not interfere with TLR4/MyD88 and TLR4/TRIF interactions or affect microglial phagocytosis of red blood cells. Inhibition of the TLR4 signaling pathway and reduction in M1-like microglial polarization might be the major mechanism by which pinocembrin protects hemorrhagic brain. With anti-inflammatory properties, pinocembrin could be a promising new drug candidate for treating ICH and other acute brain injuries., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Organotypic hippocampal slice cultures (OHSCs) have been used as a powerful ex vivo model for decades. They have been used successfully in studies of neuronal death, microglial activation, mossy fiber regeneration, neurogenesis, and drug screening. As a pre-animal experimental phase for physiologic and pathologic brain research, OHSCs offer outcomes that are relatively closer to those of whole-animal studies than outcomes obtained from cell culture in vitro. At the same time, mechanisms can be studied more precisely in OHSCs than they can be in vivo. Here, we summarize stroke and traumatic brain injury research that has been carried out in OHSCs and review classic experimental applications of OHSCs and its limitations.

Inflammatory mechanisms mediated by prostaglandins may contribute to the progression of intracerebral hemorrhage (ICH)-induced brain injury, but they are not fully understood. In this study, we examined the effect of prostaglandin E2 receptor EP1 (EP1R) activation and inhibition on brain injury in mouse models of ICH and investigated the underlying mechanism of action. ICH was induced by injecting collagenase, autologous blood, or thrombin into the striatum of middle-aged male and female mice and aged male mice. Effects of selective EP1R agonist ONO-DI-004, antagonist SC51089, and nonspecific Src family kinase inhibitor PP2 were evaluated by a combination of histologic, magnetic resonance imaging (MRI), immunofluorescence, molecular, cellular, and behavioral assessments. EP1R was expressed primarily in neurons and axons but not in astrocytes or microglia after ICH induced by collagenase. In middle-aged male mice subjected to collagenase-induced ICH, EP1R inhibition mitigated brain injury, brain edema, cell death, neuronal degeneration, neuroinflammation, and neurobehavioral deficits, whereas its activation exacerbated these outcomes. EP1R inhibition also was protective in middle-aged female mice and aged male mice after collagenase-induced ICH and in middle-aged male mice after blood- or thrombin-induced ICH. EP1R inhibition also reduced oxidative stress, white matter injury, and brain atrophy and improved functional outcomes. Histologic results were confirmed by MRI. Src kinase phosphorylation and matrix metalloproteinase-9 activity were increased by EP1R activation and decreased by EP1R inhibition. EP1R regulated matrix metalloproteinase-9 activity through Src kinase signaling, which mediated EP1R toxicity after collagenase-induced ICH. We conclude that prostaglandin E2 EP1R activation plays a toxic role after ICH through mechanisms that involve the Src kinases and the matrix metalloproteinase-9 signaling pathway. EP1R inhibition could be a novel therapeutic strategy to improve outcomes after ICH., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Interkinetic nuclear migration (INM) is a key feature of cortical neurogenesis. INM functions to maximize the output of the neuroepithelium, and more importantly, balance the self-renewal and differentiation of the progenitors. Although INM has been reported to be highly correlated with the cell cycle, little is known about the effects of cell cycle regulators on INM. In this study, by crossing Foxm1(fl/fl) mice with Emx1-Cre line, we report that a conditional disruption of forkhead transcription factor M1 (Foxm1) in dorsal telencephalon results in abnormal cell cycle progression, leading to impaired INM through the downregulation of Cyclin b1 and Cdc25b. The impairment of INM disturbs the synchronization of apical progenitors (APs) and promotes the transition from APs to basal progenitors (BPs) in a cell-autonomous fashion. Moreover, ablation of Foxm1 causes anxiety-related behaviors in adulthood. Thus, this study provides evidence of linkages among the cell cycle regulator Foxm1, INM, and adult behavior.

A flurry of studies over the past decade has shown that astrocytes play a more active role in neural function than previously recognized. Hippocampal slices prepared from young rodent pups have served as a popular model for studying the pathways by which astrocytes participate in synaptic transmission. It is, however, not known how well astrocytes tolerate traumatic injury and hypoxia, which are unavoidable when preparing acute slices. We here showed that astrocytes exhibit striking changes in expression of several receptors and structural proteins, including re-expression of the developmental marker nestin within 90 min following preparation of live vibratome slices. Moreover, immunoelectron microscopy showed a 2.7-fold loss of astrocytic processes in acute hippocampal slices prepared from glial fibrillary acidic protein-green fluorescent protein reporter mice. A sharp decrease in the number of mitochondria was also noted in acute slices, concurrently with an increase in mitochondrial size. Glycogen content decreased 3-fold upon slice preparation and did not recover despite stable recordings of field excitatory postsynaptic current. Analysis of Ca(2+) signaling showed that astrocytic responses to purine receptor and mGluR5 agonists differed in slice versus in vivo. These observations suggest that the functional properties and the fine structure of astrocytes in slices may be reflective of early stages of reactive gliosis and should be confirmed in vivo when possible., (Copyright © 2013 Wiley Periodicals, Inc.)

Spinal cord injury (SCI) is often complicated by secondary injury as a result of the innate inflammatory response to tissue trauma and swelling. Previous studies have shown that excessive ATP release from peritraumatic regions contributes to the inflammatory response to SCI by activation of low-affinity P2X7 receptors. Because connexin hemichannels constitute an important route for astrocytic ATP release, we here evaluated the impact on post-traumatic ATP release of deletion of connexins (Cx30/Cx43) in astrocytes. In vivo bioluminescence imaging showed a significant reduction in ATP release after weight-drop injury in mice with deletion of Cx43 compared with Cx43-expressing littermates, both on a Cx30 knockout background. Moreover, astrogliosis and microglia activation were reduced in peritraumatic areas of those mice lacking Cx43; motor recovery was also significantly improved, and the traumatic lesion was smaller. Combined, these observations are consistent with a contribution by astrocytic hemichannels to post-traumatic ATP release that aggravates secondary injury and restrains functional recovery after experimental spinal cord injury. Connexins may thereby constitute a new therapeutic target in spinal cord injury.

Defining the microanatomic differences between the human brain and that of other mammals is key to understanding its unique computational power. Although much effort has been devoted to comparative studies of neurons, astrocytes have received far less attention. We report here that protoplasmic astrocytes in human neocortex are 2.6-fold larger in diameter and extend 10-fold more GFAP (glial fibrillary acidic protein)-positive primary processes than their rodent counterparts. In cortical slices prepared from acutely resected surgical tissue, protoplasmic astrocytes propagate Ca(2+) waves with a speed of 36 microm/s, approximately fourfold faster than rodent. Human astrocytes also transiently increase cystosolic Ca(2+) in response to glutamatergic and purinergic receptor agonists. The human neocortex also harbors several anatomically defined subclasses of astrocytes not represented in rodents. These include a population of astrocytes that reside in layers 5-6 and extend long fibers characterized by regularly spaced varicosities. Another specialized type of astrocyte, the interlaminar astrocyte, abundantly populates the superficial cortical layers and extends long processes without varicosities to cortical layers 3 and 4. Human fibrous astrocytes resemble their rodent counterpart but are larger in diameter. Thus, human cortical astrocytes are both larger, and structurally both more complex and more diverse, than those of rodents. On this basis, we posit that this astrocytic complexity has permitted the increased functional competence of the adult human brain.

Preconditioning is an endogenous mechanism in which a nonlethal exposure increases cellular resistance to subsequent additional severe injury. Here we show that connexin 43 (Cx43) plays a key role in protection afforded by preconditioning. Cx43 null mice were insensitive to hypoxic preconditioning, whereas wild-type littermate mice exhibited a significant reduction in infarct volume after occlusion of the middle cerebral artery. In cultures, Cx43-deficient cells responded to preconditioning only after exogenous expression of Cx43, and protection was attenuated by small interference RNA or by channel blockers. Our observations indicate that preconditioning reduced degradation of Cx43, resulting in a marked increase in the number of plasma membrane Cx43 hemichannels. Consequently, efflux of ATP through hemichannels led to accumulation of its catabolic product adenosine, a potent neuroprotective agent. Thus, adaptive modulation of Cx43 can offset environmental stress by adenosine-mediated elevation of cellular resistance.

Protoplasmic astrocytes are critically important to energy metabolism in the CNS. Our current understanding of the metabolic interactions between neurons and glia is based on studies using cultured cells, from which mainly inferential conclusions have been drawn as to the relative roles of neurons and glia in brain metabolism. In this study, we used functional genomics to establish the relative compartmentalization of neuronal and astrocytic metabolic pathways in the adult brain. To this end, fluorescence-activated cell sorting was used to directly isolate neurons and protoplasmic astrocytes from the cortex of adult mice. Microarray analysis showed that astrocytes and neurons each express transcripts predicting individual self-sufficiency in both glycolysis and oxidative metabolism. Surprisingly, most enzymes in the tricarboxylic acid (TCA) cycle were expressed at higher relative levels in astrocytes than in neurons. Mass spectrometric analysis of the TCA cycle intermediates confirmed that freshly isolated adult astrocytes maintained an active TCA cycle, whereas immuno-electron microscopy revealed that fine astrocytic processes encompassing synapses contained a higher density of mitochondria than surrounding cells. These observations indicate that astrocytes exhibit robust oxidative metabolism in the intact adult brain and suggest a prominent contribution of astrocytic metabolism to functional brain imaging, including BOLD (blood-oxygen level-dependent) functional magnetic resonance imaging signals.

Local increase in blood flow during neural activity forms the basis for functional brain imaging, but its mechanism remains poorly defined. Here we show that cortical astrocytes in vivo possess a powerful mechanism for rapid vasodilation. We imaged the activity of astrocytes labeled with the calcium (Ca(2+))-sensitive indicator rhod-2 in somatosensory cortex of adult mice. Photolysis of caged Ca(2+) in astrocytic endfeet ensheathing the vessel wall was associated with an 18% increase in arterial cross-section area that corresponded to a 37% increase in blood flow. Vasodilation occurred with a latency of only 1-2 s, and both indomethacin and the cyclooxygenase-1 inhibitor SC-560 blocked the photolysis-induced hyperemia. These observations implicate astrocytes in the control of local microcirculation and suggest that one of their physiological roles is to mediate vasodilation in response to increased neural activity.