Metabolic brain disease最新文献

Glioblastoma (GBM) is a common primary central nervous system tumor. Although the multimodal integrated treatment for GBM has made great progress in recent years, the overall survival time of GBM is still short. Thus, novel treatments for GBM are worth further investigation and exploration. This study aimed to investigate the effects of etomidate on GBM tumor growth and the underlying mechanism. A xenograft tumor model was established and treated with etomidate to assess tumor growth. Immunohistochemistry (IHC) assay evaluated the positive rate of Ki67 cells in tumor tissues. Cell counting kit (CCK)-8 and EdU assays accessed the cell viability and proliferation. Immunofluorescence (IF) staining detected the distribution of macrophage markers in tumor tissues. The percentages of M1- and M2-like macrophages in tumor-associated macrophages (TAMs) and co-culture system (macrophages and GBM cells) were detected using flow cytometry. Macrophage polarization-related genes were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Etomidate treatment inhibited the tumor growth, and increased the CD86⁺ cells but decreased the CD206⁺ cells in TAMs. The gene expression of M1 markers was increased in TAMs of etomidate-treated mice, whereas that of M2 markers was decreased. Moreover, etomidate treatment increased the number of CD86⁺ M1-like macrophages co-cultured with tumor cells but decreased that of CD206⁺ M2-like macrophages, with the upregulation of M1 markers and downregulation of M2 markers. Etomidate inhibited GBM tumor growth by promoting M1 macrophage polarization, suggesting a new insight into the clinical treatment of GBM.

Obesity results from an energy imbalance and has been considered an epidemic due to its increasing rates worldwide. It is classified as a low-grade chronic inflammatory disease and has associated comorbidities. Different nutritional strategies are used for the purpose of weight loss, highlighting low-carbohydrate (LC) diets, ketogenic diets, and intermittent fasting (IF). These strategies can lead to metabolic and behavioral changes as they stimulate different biochemical pathways. Therefore, this study evaluated memory, energy metabolism, neuroinflammation, oxidative stress, and antioxidant defense parameters in mice subjected to an LC diet, ketogenic diet (KD), or IF. Eighty male Swiss mice, 60 days old, were divided into 4 groups: control, LC, KD, or IF. Body weight was measured weekly, and food intake every 48 h. After 15 days of nutritional interventions, the animals were subjected to the behavioral object recognition test and subsequently euthanized. Then, visceral fat was removed and weighed, and the brain was isolated for inflammatory and biochemical analysis. We concluded from this study that the LC and KD strategies could damage memory, IF improves the production of adenosine triphosphate (ATP), and the LC, KD, and IF strategies do not lead to neuroinflammatory damage but present damage at the level of oxidative stress.

Autism spectrum disorders (ASD) are a family of complex neurodevelopmental disorders, characterized mainly through deficits in social behavior and communication. While the causes giving rise to autistic symptoms are numerous and varied, the treatment options and therapeutic avenues are still severely limited. Nevertheless, a number of signalling pathways have been implicated in the pathogenesis of the disease, and targeting these pathways might provide insight into potential treatments and future strategies. Importantly, alterations in inflammation, oxidative stress, and mitochondrial dysfunction have been noted in the brains of ASD patients, and among the pathways involved in these processes is the Nrf2 cascade. This particular pathway has been hypothesized to be involved in inducing both, inflammatory and anti-inflammatory/neuroprotective effects in the brain, sparking an interest in its use in ASD. Sulforaphane, a sulfur-containing phytochemical present mainly in cruciferous plants like broccoli and cabbage, has shown efficacy in activating the Nrf2 signaling pathway, which in turn brings about a protective effect on neuronal cells, especially against mitochondrial dysfunction. Its efficacy against ASD has not yet been evaluated, and in this paper, we attempt to discuss the therapeutic potential of this agent in the therapy of autism, with special emphasis on the role of the Nrf2 pathway in the disorder.

Traumatic brain injury (TBI), as a serious central nervous system disease, can result in severe neurological dysfunction or even disability and death of patients. The early and effective intervention of secondary brain injury can improve the prognosis of TBI. Endoplasmic reticulum (ER) stress is one of the main reasons to recover TBI. ER stress inhibition may be beneficial in treating TBI. Sestrin2 is a crucial regulator of ER stress, and its activation can significantly improve TBI. In this paper, we analyze the biological function of sestrin2, the latest findings on ER stress, and the relationship between ER stress and TBI. We elucidate the relationship of sestrin2 inhibiting ER stress via activating the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin complex 1 (MTORC1) signaling. Finally, we elaborate on the possible role of sestrin2 in TBI and explain how its activation potentially improves TBI.

To date, treatment of Central Nervous System (CNS) pathology has largely focused on neuronal structure and function. Yet, revived attention towards fluid circulation within the CNS has exposed the need to further explore the role of glial cells in maintaining homeostasis within neural networks. In the past decade, discovery of the neural glymphatic network has revolutionized traditional understanding of fluid dynamics within the CNS. Advancements in neuroimaging have revealed alternative pathways of cerebrospinal fluid (CSF) generation and efflux. Here, we discuss emerging perspectives on the role of astrocytes in CSF hydrodynamics, with particular focus on the contribution of aquaporin-4 channels to the glymphatic network. Astrocytic structural features and expression patterns are detailed in relation to their function in maintaining integrity of the Blood Brain Barrier (BBB) as part of the neurovascular unit (NVU). This narrative also highlights the potential role of glial dysfunction in pathogenesis of neurodegenerative disease, hydrocephalus, intracranial hemorrhage, ischemic stroke, and traumatic brain injury. The purpose of this literature summary is to provide an update on the changing landscape of scientific theory surrounding production, flow, and absorption of cerebrospinal fluid. The overarching aim of this narrative review is to advance the conception of basic, translational, and clinical research endeavors investigating glia as therapeutic targets for neurological disease.

Brain edema is considered as a common feature associated with hepatic encephalopathy (HE). However, its central role as cause or consequence of HE and its implication in the development of the neurological alterations linked to HE are still under debate. It is now well accepted that type A and type C HE are biologically and clinically different, leading to different manifestations of brain edema. As a result, the findings on brain edema/swelling in type C HE are variable and sometimes controversial. In the light of the changing natural history of liver disease, better description of the clinical trajectory of cirrhosis and understanding of molecular mechanisms of HE, and the role of brain edema as a central component in the pathogenesis of HE is revisited in the current review. Furthermore, this review highlights the main techniques to measure brain edema and their advantages/disadvantages together with an in-depth description of the main ex-vivo/in-vivo findings using cell cultures, animal models and humans with HE. These findings are instrumental in elucidating the role of brain edema in HE and also in designing new multimodal studies by performing in-vivo combined with ex-vivo experiments for a better characterization of brain edema longitudinally and of its role in HE, especially in type C HE where water content changes are small.

Autism Spectrum Disorders (ASD) are a complex set of neurodevelopmental manifestations which present in the form of social and communication deficits. Affecting a growing proportion of children worldwide, the exact pathogenesis of this disorder is not very well understood, and multiple signaling pathways have been implicated. Among them, the ERK/MAPK pathway is critical in a number of cellular processes, and the normal functioning of neuronal cells also depends on this cascade. As such, recent studies have increasingly focused on the impact this pathway has on the development of autistic symptoms. Improper ERK signaling is suspected to be involved in neurotoxicity, and the same might be implicated in autism spectrum disorders (ASD), through a variety of effects including mitochondrial dysfunction and oxidative stress. Niclosamide, an antihelminthic and anti-inflammatory agent, has shown potential in inhibiting this pathway, and countering the effects shown by its overactivity in inflammation. While it has previously been evaluated in other neurological disorders like Alzheimer's Disease and Parkinson's Disease, as well as various cancers by targeting ERK/MAPK, it's efficacy in autism has not yet been evaluated. In this article, we attempt to discuss the potential role of the ERK/MAPK pathway in the pathogenesis of ASD, specifically through mitochondrial damage, before moving to the therapeutic potential of niclosamide in the disorder, mediated by the inhibition of this pathway and its detrimental effects of neuronal development.

Atypical parkinsonism (AP) is a group of complex neurodegenerative disorders with marked clinical and pathophysiological heterogeneity. The use of systems biology tools may contribute to the characterization of hub-bottleneck genes, and the identification of its biological pathways to broaden the understanding of the bases of these disorders. A systematic search was performed on the DisGeNET database, which integrates data from expert curated repositories, GWAS catalogues, animal models and the scientific literature. The tools STRING 11.0 and Cytoscape 3.8.2 were used for analysis of protein-protein interaction (PPI) network. The PPI network topography analyses were performed using the CytoHubba 0.1 plugin for Cytoscape. The hub and bottleneck genes were inserted into 4 different sets on the InteractiveVenn. Additional functional enrichment analyses were performed to identify Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and gene ontology for a described set of genes. The systematic search in the DisGeNET database identified 485 genes involved with Atypical Parkinsonism. Superimposing these genes, we detected a total of 31 hub-bottleneck genes. Moreover, our functional enrichment analyses demonstrated the involvement of these hub-bottleneck genes in 3 major KEGG pathways. We identified 31 highly interconnected hub-bottleneck genes through a systems biology approach, which may play a key role in the pathogenesis of atypical parkinsonism. The functional enrichment analyses showed that these genes are involved in several biological processes and pathways, such as the glial cell development, glial cell activation and cognition, pathways were related to Alzheimer disease and Parkinson disease. As a hypothesis, we highlight as possible key genes for AP the MAPT (microtubule associated protein tau), APOE (apolipoprotein E), SNCA (synuclein alpha) and APP (amyloid beta precursor protein) genes.