Metabolic brain disease最新文献

Cerebral stroke is characterized by high rate of disability and mortality. Emerging evidence indicates a relationship between acute ischemic stroke and alterations in the intestinal microbiota. Herein, the mechanism of Eucommia ulmoides extract (EUE) within ischemic stroke will be investigated from the perspective of intestinal microflora. In the study, EUE significantly reduced the area of cerebral infarction, ameliorated neurological deficits, and reduced neuronal death in mice. EUE reversed intestinal microbiota deregulation by regulating bacterial abundance, including up-regulating the abundance of the beneficial bacteria Dubosiella, Lachnospiraceae_NK4A136_group, and down-regulating the abundance of the deleterious bacteria Helicobacter, Bifidobacterium, Allobaculum, and Ileibacterium abundance. In addition, EUE also upregulated metabolites associated with inflammation and neuroprotection, including LysoPE, octadecyl fumarate, and adrenic acid. In in vitro experiments, the combination of EUE and LysoPE (0:0/20:4) significantly inhibited apoptosis, inflammatory responses, and oxidative stress levels in OGD cells compared to use alone. In conclusion, EUE significantly alleviated symptoms and neurological deficits in MCAO mice, and its mechanism is related to its involvement in remodeling intestinal microbiota and metabolism. EUE and LysoPE (0:0/20:4) are expected to be a potential novel regimen for the clinical treatment of cerebral ischemic stroke.

Neuroinflammation, a pervasive hallmark in many neurological and neuropsychiatric diseases, is largely dictated by the functional phenotypic dynamics of microglia, the immune system of the brain. Recent data illustrate that these phenotypic changes, from neuroprotective scavenging to neurotoxic pro-inflammatory effects, are intrinsically regulated by microglial metabolic repolarization. This review synthesizes understanding of discrete microglial metabolic phenotypes like the glycolytic reliance of pro-inflammatory (M1-like) microglia and the oxidative phosphorylation/fatty acid oxidation bias of anti-inflammatory/resolving (M2-like) microglia. We discuss how central metabolic sensors like AMPK, mTOR, and HIF-1α oversee these metabolic shifts in response to disease-targeted pathologies in Alzheimer's, Parkinson's, Multiple Sclerosis, ischemic stroke, and traumatic brain injury. Moreover, we review innovative therapeutic strategies directed toward microglial metabolism, involving pharmacological modulators (e.g., metformin, rapamycin, and ketone bodies), nutritional interventions (e.g., ketogenic diets), and modulation of gut microbiota. By tightly specific re-tuning of microglial cells' bioenergetics, these approaches enable unprecedented opportunities to counteract neuroinflammation, enhance pathological clearance, and induce neuroprotection, paving the way for a new generation of disease-modifying therapies of neurodegenerative disorders.

Tourette syndrome (TS), predominantly affecting children and adolescents aged 2-15 years, significantly impairs quality of life and social functioning. Shaoma Zhijing granules (SMZJG), a compound traditional Chinese medicine (TCM), has demonstrated comparable efficacy to tiapride (TIA) in alleviating TS symptoms with fewer adverse effects. To elucidate its tmaterial basis and mechanism of action, we employed iminodipropionitrile (IDPN) and 2, 5-dimethoxy-4-iodoarylamine (DOI) to induce a rat model of TS. SMZJG treatment significantly ameliorated IDPN- and DOI-induced stereotyped behavioral impairments and effectively counteracted the reduction in striatum volume. Notably, SMZJG was found to markedly correct neurotransmitter imbalances, suppress M1 microglial activation, and reduce the levels of interleukin-1α (IL-1α), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) in serum. These findings collectively suggest that SMZJG alleviates TS-associated behavioral disorders, potentially through mechanisms such as reducing striatal atrophy, modulating neurotransmitter imbalances, regulating abnormal neurotransmitter receptor expression, and decreasing microglial proliferation as well as levels of pro-inflammatory cytokines and chemokines in serum.

Hua Feng Dan (HFD) has demonstrated definitive efficacy in the treatment of ischemic stroke (IS); however, its active components and underlying mechanisms of action remain unclear. This study employed a rat model of middle cerebral artery occlusion (MACO) to evaluate the neuroprotective effects of HFD against cerebral ischemia. Metabolomics approaches were used to demonstrate the complexity of HFD for the treatment of IS. Liquid chromatography/mass spectrometry (LC/MS) was used to identify the main chemical constituents of HFD. Network pharmacology and molecular docking were employed to predict the targets and mechanisms of HFD for IS. Experimental validation was performed to elucidate the underlying mechanisms. HFD demonstrated the ability to enhance neurological function, decrease the area of cerebral infarction, and improve brain structure in rats subjected to MCAO. Twenty-nine distinct metabolites were identified using non-targeted metabolomics analysis of urine. It was determined that HFD mediated its therapeutic effects on IS via amino sugar, nucleotide sugar metabolism, and glycerophospholipid metabolism. Additionally, a total of fifty-six compounds were identified from the alcoholic extracts of HFD, mainly alkaloids, bile acids, flavonoids, and coumarins. The results of network pharmacology and molecular docking suggest that AKT1, STAT3, EGFR, ERK2, and ERK1 are key therapeutic targets. Additionally, HFD upregulates the levels of AKT1 while downregulating those of ERK1/2. This may represent an intrinsic mechanism underlying its anti-cerebral ischemia effects. This study preliminarily elucidates the mechanism of action of HFD in the treatment of IS, providing guidance for its clinical application in this context.

Gut microbiota (GM) plays a significant role in the pathophysiology of neuropsychiatric diseases like depression. A complex two-way system between gut and brain termed as gut-brain axis (GBA) dependent on intestinal GM and central nervous system (CNS). Alterations in the GM can affect behavior and brain neurochemistry including tryptophan metabolism through immune mediated pathways. Researchers focused to understand immune challenges involving kynurenine action via indoleamine-2,3-dioxygenase (IDO) induces depressive like "sickness behavior". This study examined the role of Lactobacillus fermentum (LF) and 1-methyl-D-tryptophan (1-MT) on IDO regulation, proinflammatory cytokine responses, and gut microbial diversity in chronic unpredictable mild stress (CUMS) depression model. LF (oral administration, 1 × 10⁸ CFU/day/mouse for 28 days) and 1-MT (intraperitoneal, 15 mg/KgBW/day for 21 days) supplementation decreases the expression of cytokines and IDO in cortex, hippocampus, and medulla. Likewise, the mRNA and protein level of cytokines and IDO were modulated after LF and 1-MT administration. Additionally, 16 S rRNA gene sequencing showed that Lactobacillus fermentum restored gut microbial β-diversity and increased overall community richness, indicating a shift toward a balanced microbiome. These results suggest that LF alleviates stress-induced neuroinflammatory and immune changes by modulating IDO activity in the tryptophan pathway. The findings highlight the therapeutic potential of LF as a microbiota-based intervention for regulating neuroinflammation and mood disorders such as depression.

Modified Xiaoyao San (MXYS) is a well-established clinical prescription for the treatment of depression in China. While MXYS shows considerable promise for the development of new antidepressants, its pharmacological mechanisms remain poorly understood. This study aims to investigate the antidepressant potential and underlying mechanisms of MXYS in lipopolysaccharide (LPS)-induced depression-like behaviors in mice. Behavioral assessments (sucrose preference test, tail suspension test, open field test) demonstrated that MXYS significantly ameliorated LPS-induced anhedonia and behavioral despair. Histopathological and molecular analyses revealed that MXYS mitigated LPS-induced neuronal damage in the prefrontal cortex (PFC), restored dendritic spine density, and rebalanced neuroinflammatory cytokines by reducing the pro-inflammatory IL-1β and elevating the anti-inflammatory IL-10. Moreover, MXYS promoted microglial polarization toward the anti-inflammatory M2 phenotype (CD206⁺) while suppressing the pro-inflammatory M1 phenotype (CD68⁺). Mechanistically, MXYS inhibited NLRP3 inflammasome activation and pyroptosis through the upregulation of the E3 ubiquitin ligase TRIM31, which facilitated NLRP3 degradation. Transmission electron microscopy confirmed that MXYS inhibited LPS-induced microglial pyroptosis, as evidenced by reduced Gasdermin D (GSDMD) expression and preserved cellular ultrastructure. In vitro validation using LPS-stimulated BV2 microglia further corroborated the MXYS-mediated suppression of NLRP3 inflammasome activity, pyroptosis, and inflammatory cytokine dysregulation, alongside enhanced TRIM31 expression. Collectively, these findings demonstrate that MXYS exerts antidepressant effects by modulating neuroinflammation through TRIM31-dependent NLRP3 ubiquitination, microglial phenotype switching, and the inhibition of pyroptosis, providing novel insights into its therapeutic potential for the treatment of depression.

Intracerebral hemorrhage (ICH) is a severe subtype of stroke associated with high mortality and disability. With the global population aging, the incidence of ICH is increasing, highlighting the importance of understanding endogenous protective mechanisms. Activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway mitigates oxidative stress and inflammatory injury after ICH, but the influence of hemorrhage volume on this response remains unclear. Here, we established rat ICH models with varying hemorrhage volumes (25, 50, 75, and 100 µL) and assessed Nrf2/ARE pathway activation using histopathology, immunohistochemistry, immunofluorescence, Western blotting, and RT-qPCR. Oxidative stress markers and antioxidant enzyme activities were also evaluated. Bioinformatic analysis of public datasets identified NQO-1 as a key differentially expressed gene after ICH. Among all groups, the 50 µL model showed the strongest Nrf2 nuclear translocation, highest NQO-1 and HO-1 expression, reduced oxidative damage, and attenuated inflammatory responses. These findings suggest that moderate hemorrhage volume elicits optimal endogenous Nrf2/ARE activation, offering maximal neuroprotection. Clinically, this supports a stratified treatment approach: enhancing Nrf2/ARE signaling in moderate-volume ICH and considering surgical reduction of hematoma burden in large-volume cases before pharmacological activation. This study provides an experimental basis for integrating molecular pathway modulation into individualized ICH management.

Stroke is a neurological condition caused by an acute focal injury to the central nervous system, typically resulting from vascular events such as cerebral infarction, intracerebral hemorrhage, or subarachnoid hemorrhage. It is associated with high rates of incidence, disability, recurrence, and mortality. To reduce stroke-related mortality, researchers worldwide have developed various in vitro and in vivo models to study molecular mechanisms at different levels, including genes, microRNAs, and proteins, to identify biomarkers for improved diagnosis, treatment, and prognosis. Metabolomics, an emerging field derived from genomics and proteomics, plays a crucial role in understanding stroke pathophysiology. Changes in the metabolome can reflect the body's physiological state following a stroke. Numerous studies have identified biomarkers that aid in stroke diagnosis and treatment by analyzing metabolic alterations in vivo or in vitro stroke models. This article reviews the causes, diagnosis, and treatment of stroke, the role of metabolomics in stroke research, and the clinical significance of some biomarkers discovered by metabolomics for clinical work.

Ischemic stroke (IS), also known as ischemic cerebrovascular accident, is a serious consequence of cerebral ischemia characterized by high morbidity, disability, and mortality. The primary causes of IS include atherosclerosis, cardiogenic embolism, large artery occlusion, and small artery disease. The occurrence of IS involves multiple cellular death mechanisms such as vascular obstruction, inflammatory response, excitotoxicity, oxidative stress, as well as neuronal apoptosis, necroptosis, and pyroptosis. Despite the application of current drugs and therapeutic strategies in the treatment of IS, their efficacy remains limited, and they are often accompanied by adverse effects. Therefore, identifying novel and more effective treatment strategies is of critical importance. In recent years, oxytocin (OT) has attracted widespread attention due to its multiple biological effects in the central nervous system, especially its neuroprotective effects. OT can reduce ischemic damage by stabilizing the blood-brain barrier (BBB), inhibiting neuroinflammation, alleviating oxidative stress, regulating excitotoxicity, and calcium overload. Additionally, OT promotes neurovascular remodeling via the VEGF/BDNF axis and modulates Na⁺/K⁺-ATPase activity, GABA signaling pathways, and DNA methylation, thereby contributing to recovery after stroke. However, the pharmacokinetic characteristics of OT, limitations in delivery methods, and the challenges of individualized treatment restrict its clinical application. This review will summarize the mechanisms of OT in IS, discuss the challenges and limitations in its clinical application, and explore future development directions, including optimization of nasal delivery systems, development of nanodrug carriers, use of perfusion-weighted imaging to determine the therapeutic window, and personalized treatment strategies based on genetic profiling. The aim is to provide theoretical support and guidance for further research on OT and its clinical application.

Background: The role of RE1-Silencing Transcription Factor (REST) in human neurogenesis remains unexplored. This study aims to investigate the expression patterns and possible targets of REST during the early stages of human neurogenesis. Methods: Human neural stem cells and neurons from human induced pluripotent stem cells (hiPSCs) were generated through established protocols. hiPSCs and derived neurons were characterized by immunocytochemistry (SOX2, OCT4, TUJ-1) and qPCR for pluripotency and neuronal marker expression. REST expression and the effect of REST inhibition using X5050 at different stages of development were evaluated using immunostaining. Further, proteomic analysis was performed to identify the key molecules and signalling pathways impacted by the inhibition of REST during neurogenesis. Western blotting and quantitative PCR were used to validate the key molecule targeted by REST inhibition. Results: Immunocytochemistry and qPCR examinations have affirmed the promising expression of pluripotency markers (SOX2, OCT4, Nanog) in hiPSCs and the neuronal marker TUJ-1 in differentiated neurons. REST expression is seen in hiPSCs, immature neurons, and mature neurons derived from hiPSCs. In immature neurons, REST proteins are seen in the soma and axons, while in mature neurons, REST is seen in the soma and is absent in the axons. The inhibition of REST in hiPSCs, NSCs and neuronal precursor cells with X5050 significantly reduced REST levels. Reduced REST levels in NSCs led to significant downregulation of essential proteins involved in neurogenesis, including SOX2, a key regulator of neural stem cell proliferation. REST inhibition by X5050 disrupted pivotal neurogenic signaling axis, including MAPK and WNT pathways, and reduced the mRNA expression of NESTIN, β-catenin (CTNNB1), and MAPK3, indicating perturbation of neural stem cell identity and key regulatory mechanisms. Conclusion: REST is a crucial regulator of human neurogenesis. REST is essential to drive neurogenesis as it controls the SOX2 levels during this stage. The role of REST in regulating neurogenic pathways offers novel perspectives on its potential as a target for therapy of neurodevelopmental diseases. Graphical abstract.