Metabolic brain disease最新文献

Brain energy metabolism primarily depends on glucose, which serves as the primary energy source for neuronal activity. Glucose entry into the brain is mediated by glucose transporters, the major isoforms of which are GLUT1 and GLUT3. GLUT1 is responsible for delivering glucose to the brain parenchyma, while GLUT3, with its high affinity for glucose, ensures glucose uptake by neurons. Growing evidence indicates that disturbed glucose metabolism is closely associated with impaired brain function and the progression of neurological diseases, and regulating these transporters may be a potential therapeutic strategy to restore metabolic balance. This review focuses on the current understanding of the functions and regulation of GLUT1 and GLUT3. We first examine their distribution and their distinct contributions to glucose utilization, then summarize how pathological factors such as ischemia, hypoxia, oxidative stress, and neuroinflammation alter the expression and activity of these transporters. At the molecular level, we highlight the multiple signaling pathways involved in the regulation of glucose transporters. The PI3K/Akt, HIF-1α, AMPK, and mTOR pathways, along with microRNA-mediated mechanisms, influence the expression and activity of GLUT1 or GLUT3, respectively, in diverse physiological and pathological contexts. We also discuss evidence for pathway crosstalk, including interactions between PI3K/Akt, mTOR, and HIF-1α, as well as AMPK-mTOR coupling, which may provide additional regulatory insights. In summary, despite significant progress, critical gaps remain in linking upstream signaling to transporter dynamics and therapeutic effects. A deeper understanding of the regulatory networks underlying glucose metabolism will more accurately capture the complexity of disease-related metabolic regulation and may reveal novel therapeutic targets for intervening in glucose metabolism disorders.

A stroke is a sudden neurological impairment caused by damage to the vascular system of the central nervous system. Remote ischemic conditioning (RIC) has emerged as a promising therapeutic strategy, gaining attention for its potential to provide neuroprotection against cerebral strokes in both clinical and preclinical settings. Recent research highlights autophagy as a key element of RIC-induced neuroprotection during cerebral ischemia. Preclinical studies suggest that RIC effectively modulates key signalling pathways, including AKT/GSK-3β, AKT-Bcl-2, Transcription Factor EB (TFEB), PINK1/Parkin, and AMPK. This modulation promotes autophagy and enhances the neuroprotective effects of RIC. Furthermore, evidence from preclinical studies indicates that RIC significantly reduces inflammation, oxidative stress, and infarct size while modulating apoptotic signalling through the activation of autophagy. This article highlights recent research that illustrates the complex interplay between RIC-induced autophagy and neuroprotection, indicating that targeting these pathways may offer innovative therapeutic approaches for treating ischemic stroke.

This research was designed to explore the anti-epileptic action of the ethanolic leaf extract of Lagerstroemia loudonii (LLE) compared to the extract-loaded MβCD-stabilized nanosuspension (MβCD-NS). UPLC-ESI-QTOF -MS/MS analysis of LLE revealed the identification of 57 compounds; phenolics were the major recorded class. Nanosuspensions were prepared and examined; the particle size of the selected physically stable MβCD-NS was 445.8 ± 61.08 nm with a uniform size distribution and an almost spherical outline as shown by TEM. Based on the acute toxicity results, LLE or MβCD-NS was orally gavage at doses of 100 and 200 mg/kg. Convulsions were induced by maximum electric shock (MES, 35 mA, 3 s), and pentylenetetrazole (PTZ, 85 mg/kg i.p) in mice. MβCD-NS (200 mg/kg) demonstrated significant anticonvulsant effects, including complete protection% in MES study and low tonic convulsion score in PTZ-model. PTZ injection instigated locomotor deficits, oxidative and nitrosative insults, neuroinflammation, imbalance in brain neurotransmitters viz. dopamine, serotonin, norepinephrine, GABA, glutamate, and severe structural changes in the brain. However, LLE and MβCD-NS (200 mg/kg) ameliorated all these alterations through preserving antioxidant defense mechanisms by improving GSH content, and Nrf2 immuno-expression, as well as reducing MDA, NO, and GSSG levels in the brain. MβCD-NS restored the brain neurotransmitter levels that involved in the observed improvement in the animals' locomotor activity. The detected low TNF-α immuno-expression of the brain regions of the MβCD-NS group highlighted its anti-inflammatory action. In conclusion, MβCD-NS exhibited superior anti-epileptic potential by counteracting neuronal oxido-inflammatory damage, positioning it as a promising therapeutic strategy for epilepsy.

Coffee is one of the most frequently consumed beverages worldwide and contains the bioactive constituent caffeine, which is the most commonly consumed psychostimulant. There have been mixed reports of coffee/caffeine's effects on mood disorders including anxiety and depression. The aim of this study was to evaluate correlations between coffee/caffeine consumption and salivary and plasma biomarkers associated with anxiety and depression in a healthy population. A cross-sectional study design was employed with participants completing a coffee and caffeine consumption questionnaire and providing either morning (n = 55) and/or afternoon (n = 54) saliva samples and/or a plasma sample (n = 39). Biological samples were examined for numerous biomarkers including amylase, prolactin, cortisol (all saliva), caffeine, TBX B₂, PGE_2, tryptophan and the kynurenine pathway catabolites (all plasma). Weak to moderate inverse or positive correlations between caffeinated coffee consumption and cortisol (R² = -0.3220; P < 0.05; n = 55), kynurenine (R² = 0.3878; P < 0.05; n = 39), and kynurenine-to-tryptophan ratio x 100 (R² = 0.4092; P < 0.05; n = 39), respectively, were identified. Furthermore, positive correlations were identified between caffeine consumption and kynurenine (R² = 0.3148; P < 0.05; n = 39), kynurenine-to-tryptophan ratio x 100 (R² = 0.4023; P < 0.05; n = 39), and cortisol (R² = - 0.2972; P < 0.05; n = 55); and plasma caffeine and kynurenine-to-tryptophan ratio x100 (R² = 0.4297; P < 0.050; n = 39). The current study provides insights into changes associated with biomarkers induced by the consumption of caffeinated coffee and/or caffeine. Weak to moderate correlations were observed between caffeinated coffee consumption and cortisol, kynurenine, and kynurenine-to-tryptophan ratio. Additionally, weak to moderate correlations we also seen between caffeine and the plasma biomarkers, kynurenine and kynurenine-to-tryptophan ratio.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and neuronal degeneration. Current treatments offer limited efficacy. Elaeocarpus angustifolius Blume (Rudraksha), used traditionally in Ayurveda for neurological disorders, has shown potential for cognitive health, warranting investigation in AD models. This study aimed to evaluate the neuroprotective efficacy of an alkaloid-rich fraction of E. angustifolius (EAF) in an AlCl₃-induced rat model of AD. AD-like symptoms were induced by oral administration of AlCl₃ (100 mg/kg) for 60 days, followed by a 30-day oral treatment with EAF (200 and 400 mg/kg). Cognitive performance was assessed using the Morris water maze, elevated plus maze, novel object recognition, and locomotor activity tests. Biochemical and molecular markers were analysed, and hippocampal histopathology was conducted. AlCl₃ exposure caused significant cognitive and motor deficits, elevated Aβ_1-42 and phosphorylated tau, decreased acetylcholine and dopamine, increased glutamate and NF-κB, and reduced NRF-2 expression, indicating oxidative stress and neuroinflammation. EAF treatment significantly improved behavioral outcomes, reduced Aβ_1-42 and tau levels, restored neurotransmitter balance, enhanced antioxidant markers (GSH, SOD, CAT), and reduced MDA. It suppressed NF-κB and upregulated NRF-2, suggesting antioxidant and anti-inflammatory effects. Histopathological analysis confirmed hippocampal neuroprotection. EAF exhibited significant neuroprotective effects by mitigating oxidative stress, neuroinflammation, and AD-related pathologies, including amyloid accumulation and cholinergic dysfunction. These findings support the potential of EAF as a therapeutic candidate for AD prevention and management.

Myasthenia gravis (MG) represents the commonest autoimmune disorder affecting the neuromuscular junction (NMJ). The pathophysiology of MG is mainly linked to the formation of IgG autoantibodies directed against acetylcholine receptors (AChRs) in the NMJ. Besides, type 2 diabetes (T2D) is observed as a conceivable risk factor for the development and progression of MG. Also, T2D is further related with late-onset MG than early-onset MG. Nevertheless, there are no differences in the levels of autoantibodies in T2D patients with MG compared to T2D patients without MG. It has been proposed that increasing the production of advanced glycation end-products (AGEs) proteins and the expression of receptor glycation end-products (RAGE) in early T2D provokes the autoimmunity in MG. Additionally; AGE/RAGE signaling is augmented and contributes in the progression of autoimmunity in MG. Nonetheless, the fundamental association between MG and T2D is not totally elucidated. Therefore, this review aims to discuss and explain the link between T2D and MG. Findings of the present review highlighted that metformin mitigates the pathogenesis of both T2D and MG by regulating of PI3K/AKT/mTOR/AMPK axis and enhancing autophagy.

Chronic psychosocial stress is heterogeneously related to serum cholesterol and glucocorticoids in epidemiologic studies. Moreover, we have found that adiponectin receptor 2 (AdipoR2) signaling pathway plays a role in mediating the effect of glucocorticoids on hepatic cholesterol metabolism. The present study aims to further investigate the role of AdipoR2 in the relationship between glucocorticoid and serum cholesterol under experiencing a same catastrophic earthquake as a stress in students. A total of 722 students who experienced the same earthquake were included in this study. Serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured by routine methods, and serum cortisol by enzyme-linked immunosorbent assays. Genotyping of AdipoR2 rs12342 was performed by polymerase chain reaction-restriction fragment length polymorphism analyses and verified by DNA sequencing. Here we show that not all individuals exhibit an increase in serum cortisol in response to stress. Furthermore, female subjects displayed higher levels of both serum cortisol and cholesterol compared to males following exposure to stress. The genotype of AdipoR2 rs12342 was found to be associated with serum TC and LDL-C levels only in male subjects under increased cortisol. Meanwhile, cortisol was associated with TC in all GG homozygotes, while its association with serum LDL-C was specific to male GG homozygotes only. These results indicate that the impact of stress on serum cholesterol levels is mediated by serum cortisol and AdipoR2 rs12342 in a gender-specific manner, which may provide novel insights into the heterogeneous relationship between stress and serum cholesterol.