Single-cell and bulk RNA-seq unveils the immune infiltration landscape associated with cuproptosis in cerebral cavernous malformations.

BACKGROUND: Cerebral cavernous malformations (CCMs) are vascular abnormalities associated with deregulated angiogenesis. Their pathogenesis and optimal treatment remain unclear. This study aims to investigate the molecular signatures of cuproptosis, a newly identified type of cell death, associated with CCMs development. METHODS: Bulk RNA sequencing (RNA-seq) from 15 CCM and 6 control samples were performed with consensus clustering and clustered to two subtypes based on expression levels of cuproptosis-related genes (CRGs). Differentially expressed genes and immune infiltration between subtypes were then identified. Machine learning algorithms including the least absolute shrinkage and selection operator and random forest were employed to screen for hub genes for CCMs associated with cuproptosis. Furthermore, Pathway enrichment and correlation analysis were used to explore the functions of hub genes and their association with immune phenotypes in CCMs. An external dataset was then employed for validation. Finally, employing the Cellchat algorithm on a single-cell RNA-seq dataset, we explored potential mechanisms underlying the participation of these hub genes in cell-cell communication in CCMs. RESULTS: Our study revealed two distinct CCM subtypes with differential pattern of CRG expression and immune infiltration. Three hub genes (BTBD10, PFDN4, and CEMIP) were identified and validated, which may significantly associate with CCM pathogenesis. These genes were found to be significantly upregulated in CCM endothelial cells (ECs) and were validated through immunofluorescence and western blot analysis. Single-cell RNA-seq analysis revealed the cellular co-expression patterns of these hub genes, particularly highlighting the high expression of BTBD10 and PFDN4 in ECs. Additionally, a significant co-localization was also observed between BTBD10 and the pivotal cuproptosis gene FDX1 in Mki67+ tip cells, indicating the crucial role of cuproptosis for angiogenesis in CCMs. The study also explored the cell-cell communication between subcluster of ECs expressing these hub genes and immune cells, particularly M2 macrophages, suggesting a role for these interactions in CCM pathogenesis. CONCLUSION: This study identifies molecular signatures linking cuproptosis to CCMs pathogenesis. Three hub genes-PFDN4, CEMIP, and BTBD10-may influence disease progression by modulating immunity. Further research is needed to understand their precise disease mechanisms and evaluate their potential as biomarkers or therapeutic targets for CCMs.

Propolis Ethanolic Extract Attenuates D-gal-induced C2C12 Cell Injury by Modulating Nrf2/HO-1 and p38/p53 Signaling Pathways.

Previous study has shown that propolis ethanolic extract (PEE) has a protective effect on aging skeletal muscle atrophy. However, the exact molecular mechanism remains unclear. This study aimed to investigate the effect of PEE on D-galactose (D-gal)-induced damage in mouse C2C12 cells. The results revealed that PEE increased the viability of senescent C2C12 cells, decreased the number of senescence-associated ß-galactosidase (SA-ß-Gal)-positive cells and promoted the differentiation of C2C12 cells. PEE resisted oxidative stress caused by D-gal by activating the Nrf2/HO-1 signaling pathway and maintained the differentiation ability of C2C12 cells. PEE inhibited apoptosis by suppressing p38 phosphorylation and reducing p53 expression. In summary, our findings reveal the molecular mechanism by which PEE protects D-gal-induced C2C12 cells, providing a theoretical basis for the development of PEE for the alleviation of muscle atrophy.

Brain perfusion, cognition, and plasma Alzheimer's biomarkers in moyamoya disease.

INTRODUCTION: Because growing interest has been focusing on cerebral blood flow (CBF) to predict, prevent, and treat Alzheimer's disease (AD), it is important to clarify the role of CBF in AD pathology and cognitive decline. METHODS: In a moyamoya disease (MMD) cohort, we examined CBF, specific cognitive domains, and plasma AD biomarkers, as well as correlations among these variables. RESULTS: CBF was significantly reduced in newly diagnosed MMD patients, while plasma phosphorylated tau181 was elevated and positively correlated with hypoperfusion accumulation. MMD patients scored significantly lower than controls in multiple cognitive tests. Revascularization increased CBF to the recipient brain territories as well as cognitive performance but produced no significant change in AD biomarker levels. DISCUSSION: These data suggest a link between accumulated reductions in CBF and cognitive decline, as well as a possible role of AD-like pathological burden. Further studies in MMD will provide opportunities to explore new treatment strategies.

Moyamoya disease: A human model for chronic hypoperfusion and intervention in Alzheimer's disease.

Introduction: Chronic cerebral hypoperfusion has been considered the etiology for sporadic Alzheimer's disease (AD). However, no valid clinical evidence exists due to the similar risk factors between cerebrovascular disease and AD. Methods: We used moyamoya disease (MMD) as a model of chronic hypoperfusion and cognitive impairment, without other etiology interference. Results: Based on the previous reports and preliminary findings, we hypothesized that chronic cerebral hypoperfusion could be an independent upstream crucial variable, resulting in AD, and induce pathological hallmarks such as amyloid beta peptide and hyperphosphorylated tau accumulation. Discussion: Timely intervention with revascularisation would help reverse the brain damage with AD hallmarks and lead to cognitive improvement.

A functional assembly framework based on implementable neurobionic material.

Neurobionic material is an emerging field in material and translational science. For material design, much focus has already been transferred from von Neumann architecture to the neuromorphic framework. As it is impractical to reconstruct the real neural tissue solely from materials, it is necessary to develop a feasible neurobionics framework to realize advanced brain function. In this study, we proposed a mathematical neurobionic material model, and attempted to explore advanced function only by simple and feasible structures. Here an equivalent simplified framework was used to describe the dynamics expressed in an equation set, while in vivo study was performed to verify simulation results. In neural tissue, the output of neurobionic material was characterized by spike frequency, and the stability is based on the excitatory/inhibitory proportion. Spike frequency in mathematical neurobionic material model can spontaneously meet the solution of a nonlinear equation set. Assembly can also evolve into a certain distribution under different stimulations, closely related to decision making. Short-term memory can be formed by coupling neurobionic material assemblies. In vivo experiments further confirmed predictions in our mathematical neurobionic material model. The property of this neural biomimetic material model demonstrates its intrinsic neuromorphic computational ability, which should offer promises for implementable neurobionic device design.

Physiological significance of R-fMRI indices: Can functional metrics differentiate structural lesions (brain tumors)?

Resting-state functional MRI (R-fMRI) research has recently entered the era of "big data", however, few studies have provided a rigorous validation of the physiological underpinnings of R-fMRI indices. Although studies have reported that various neuropsychiatric disorders exhibit abnormalities in R-fMRI measures, these "biomarkers" have not been validated in differentiating structural lesions (brain tumors) as a concept proof. We enrolled 60 patients with intracranial tumors located in the unilateral cranialcavity and 60 matched normal controls to test whether R-fMRI indices can differentiate tumors, which represents a prerequisite for adapting such indices as biomarkers for neuropsychiatric disorders. Common R-fMRI indices of tumors and their counterpart control regions, which were defined as the contralateral normal areas (for amplitude of low frequency fluctuations (ALFF), fractional ALFF (fALFF), regional homogeneity (ReHo) and degree centrality (DC)) and ipsilateral regions surrounding the tumors (for voxel-mirrored homotopic connectivity (VMHC)), were comprehensively assessed. According to robust paired t-tests with a Bonferroni correction, only VMHC (Fisher's r-to-z transformed) could successfully differentiate substantial tumors from their counterpart normal regions in patients. Furthermore, ALFF and DC were not able to differentiate tumor from normal unless Z-standardization was employed. To validate the lower power of the between-subject design compared to the within-subject design, each metric was calculated in a matched control group, and robust two-sample t-tests were used to compare the patient tumors and the normal controls at the same place. Similarly, only VMHC succeeded in differentiating significant differences between tumors and the sham tumor areas of normal controls. This study tested the premise of R-fMRI biomarkers for differentiating lesions, and brings a new understanding to physical significance of the Z-standardization.

The correlation between accumulation of amyloid beta with enhanced neuroinflammation and cognitive impairment after intraventricular hemorrhage.

OBJECTIVE: Intraventricular hemorrhage (IVH) is found in approximately 40% of intracerebral hemorrhages and is associated with increased mortality and poor functional outcome. Cognitive impairment is one of the complications and occurs due to various pathological changes. Amyloid beta (Aß) accumulation and neuroinflammation, and the Alzheimer disease-like pathology, may contribute to cognitive impairment. Iron, the degradation product of hemoglobin, correlates with Aß. In this study, the authors investigated the correlation between Aß accumulation with enhanced neuroinflammation and cognitive impairment in a rat model of IVH. METHODS: Nine male Sprague-Dawley rats underwent an intraventricular injection of autologous blood. Another 9 rats served as controls. Cognitive function was assessed by the Morris water maze and T-maze rewarded alternation tests. Biomarkers of Aß accumulation, neuroinflammation, and c-Jun N-terminal kinase (JNK) activation were examined. RESULTS: Cognitive function was impaired in the autologous blood injection group compared with the control group. In the blood injection group, Aß accumulation was observed, with a co-located correlation between iron storage protein ferritin and Aß. Beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) activity was elevated. Microgliosis and astrogliosis were observed in hippocampal CA1, CA2, CA3, and dentate gyrus areas, with elevated proinflammatory cytokines tumor necrosis factor-α and interleukin-1. Protein levels of phosphorylated JNK were increased after blood injection. CONCLUSIONS: Aß accumulation and enhanced neuroinflammation have a role in cognitive impairment after IVH. A potential therapeutic method requires further investigation.