NeuroMolecular Medicine最新文献

Microglia-mediated neuroinflammation plays an important role in the pathogenesis of Parkinson's disease (PD). Studies have shown that butylphthalide (3-n-butylphthalide or NBP) can play an anti-inflammatory role in other diseases by regulating the activation of microglia. This study investigates the neuroprotective and anti-inflammatory effects of NBP in a mouse model of Parkinson's disease (PD) induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The primary aim was to determine whether NBP can improve symptoms of PD by modulating microglial activation and to explore the underlying mechanisms involved. Motor function (assessed via Open Field and Pole Climbing tests), dopaminergic neuronal loss, and activation of different microglial subtypes were assessed in control, MPTP-treated, and NBP + MPTP-treated mice. A p38 phosphorylation inhibitor + MPTP group was also established to investigate potential mechanisms of NBP action. Mice treated with NBP exhibited significantly improved motor function and reduced dopaminergic neuronal loss compared to MPTP-treated mice. In PD mice, pro-inflammatory factor expression was elevated, anti-inflammatory factor expression was reduced, and the expression of arginase-1 (arg-1), a marker for M2 microglia, was decreased. NBP treatment resulted in reduced levels of pro-inflammatory factors, increased levels of anti-inflammatory factors, and elevated arg-1 expression. Additionally, inhibition of p38 phosphorylation further decreased pro-inflammatory factor expression while increasing both anti-inflammatory factor levels and arg-1 expression. The findings indicate that NBP regulates neuroinflammation and improves symptoms of PD by promoting the transformation of microglia to the M2 phenotype, likely mediated through the p38 phosphorylation pathway.

A significant increase of neurodevelopment disorders (NDDs) among children presents growing healthcare challenge worldwide. Owing to heterogenic, multifactorial nature of NDDs, understanding pathophysiology of disease, finding effective methods for the early detection and intervention of NDDs has become extremely complex. This study aims to investigate the molecular mechanisms of NDDs, focusing on the associations between hyperphosphatasia (HPP) and hyperlipidemia (HLD) in patients with intellectual disability (ID). Blood samples from 800 study participants (ID patients and healthy individuals, HC) were analyzed for the biochemical differences. Among them, 105 ID patients with uniquely altered biochemical profiles (ID-HPP, n = 28; ID-HLD, n = 77) and 65 HC samples were further investigated for nLC-MS/MS-based proteomic analysis. A total of 354 proteins were identified in label-free quantitative proteomic analysis of the all groups (ID-HPP, ID-HLD, and HC). The ID-HPP and ID-HLD groups each had distinct protein profiles compared to HC, with 28 and 85 differentially expressed proteins, respectively. The ID-HLD group had 66 unique proteins, whereas ID-HPP had 9 unique proteins, with 19 proteins common among the subgroups of ID. Pathway analysis of common proteins revealed shared pathways as the complement system and lipoprotein metabolism disruptions, but distinct pathway disturbances: toll-like receptor and integrin signaling in ID-HPP, and hemostatic pathway dysregulation in ID-HLD. These findings elucidate systemic pathway abnormalities in NDDs, including ID.

Alzheimer's disease (AD) remains one of the most debilitating neurodegenerative disorders, with its pathological hallmark being progressive cognitive decline and memory loss. Recent research has illuminated the crucial role of the brain-derived neurotrophic factor (BDNF) in the central nervous system (CNS), highlighting its impact on neurogenesis, synaptic plasticity, and neuronal survival. Dysregulation of the BDNF signaling axis, particularly the imbalance between its precursor form and mature BDNF, is strongly implicated in the pathophysiology of AD. This review explores the molecular mechanisms through which BDNF modulates AD neuropathology and presents novel therapeutic strategies to activate BDNF signaling. We focus on the potential of BDNF activators, such as TrkB agonists and mimetic molecules, to restore synaptic function and ameliorate cognitive deficits in AD. Furthermore, we examine the challenges in translating these findings into clinical practice, including issues with blood-brain barrier penetration and the need for precise receptor targeting. The review emphasizes the therapeutic potential of repurposed drugs, including statins and metformin, in enhancing BDNF signaling and offers new insights into the future of AD treatment. Ultimately, this work provides a compelling argument for BDNF-based therapies as a promising avenue for mitigating the cognitive decline associated with Alzheimer's disease, signaling a hopeful direction for future research and clinical trials.

Post-stroke insomnia (PSI) is a common complication following stroke, which seriously affects patients' life quality. Electro-acupuncture (EA) is an innovative form of traditional Chinese acupuncture that combines electricity with needles to achieve the prevention and treatment of diseases. However, there is limited understanding regarding the treatment mechanism of EA in PSI. In our study, we aimed to investigate the role of EA on PSI development. Our study findings indicated that the quality of sleep, levels of neurotransmitters 5-hydroxytryptamine (5-HT) and gamma-aminobutyric acid (γ-GABA), and antioxidant levels showed significant improvement following EA treatment in PSI clinical samples and rat models, while the levels of pro-inflammatory factor interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), and astrocyte damage were notably reduced. Furthermore, it was discovered that the levels of sirtuin 1 (Sirt1) were reduced in PSI, a condition that was significantly ameliorated by EA treatment. Additionally, the inhibition of Sirt1 caused a marked elevation in astrocyte apoptosis, inflammatory response, and oxidative stress. Besides, the nuclear factor E2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway was deactivated in the PSI rat model and Sirt1-silenced cells. However, the suppressive impact was successfully counteracted by EA or estazolam (ES), and the overexpression of Nrf2 partially alleviated the increase in apoptosis, inflammation, and oxidative stress caused by Sirt1 knockdown. Taken together, these findings indicated that EA improved sleep quality and silenced Sirt1-induced apoptosis, inflammation, and oxidative stress in PSI by activating the Nrf2-ARE pathway.

Alzheimer's disease (AD)is an age-related neurodegenerative disease characterized by memory decline and cognitive impairment .AD is common in people aged > 65 years, though most of AD cases are sporadic, which accounts for 95%, and 1-5% of AD is caused by familial causes . The causes of AD are aging, environmental toxins, and cardiometabolic factors that induce the degeneration of cholinergic neurons. It has been shown that the metabolic syndrome which is a clustering of dissimilar constituents including insulin resistance (IR), glucose intolerance, visceral obesity, hypertension, and dyslipidemia is implicated in the pathogenesis of AD. Metabolic syndrome disapprovingly affects cognitive function and the development in AD by inducing the development of oxidative stress, neuroinflammation, and brain IR. These changes, together with brain IR, impair cerebrovascular reactivity causing cognitive impairment and dementia. Nevertheless, the fundamental mechanism by which metabolic syndrome persuades AD risk is not entirely explicated. Accordingly, this review aims to discuss the connotation between metabolic syndrome and AD. In conclusion, metabolic syndrome is regarded as a possible risk factor for the initiation of AD neuropathology by diverse signaling pathways such as brain IR, activation of inflammatory signaling pathways, neuroinflammation, defective proteostasis, and dysregulation of lipid mediators.

Alzheimer's disease (AD) is the primary cause of dementia in the elderly. However, effective therapies that modify the disease process in AD remain elusive. Far-infrared radiation (FIR) is commonly utilized as a complementary treatment a range of disease, for example insomnia and rheumatoid arthritis. In this research, we explored how FIR light impacts the cognitive functions of TgCRND8 AD mice and elucidated its underlying molecular mechanism. The cognitive capabilities of TgCRND8 mice assessed by employing the Morris water maze. The concentrations of IL-1β, TNF-α, IL-4, Aβ40, and Aβ42 protein were assessed by enzyme-linked immunosorbent assay. Immunostaining was conducted to assess the Aβ deposits and microglial presence in the brains of TgCRND8 mice. Western blot was applied to detect the protein expressions of tau phosphorylation, amyloid-β (Aβ) production, Jak-2/Stat3, and Nrf-2/HO-1 pathways. The results indicated that FIR light notably ameliorated the cognitive impairments of the AD mice, reduced both Aβ deposition and tau protein hyperphosphorylation at sites of Thr205, Ser369, Ser404, and Thr181, suppressed the release of TNF-α and IL-1β, attenuated the ratios of p-Jak-2/Jak-2 and p-Stat3/Stat3, while increased the protein levels of IL-4, Nrf-2, and HO-1 in the brains of TgCRND8 mice. These findings amply demonstrated that FIR light ameliorated cognitive deficits of TgCRND8 mice via reducing both Aβ burden and tau protein hyperphosphorylation, suppressing the neuroinflammation, and restoring the levels of the oxidative-related proteins through modulating Jak-2/Stat3 and Nrf-2/HO-1 pathways. These experimental findings indicate that FIR light treatment is a promising treatment approach for AD.

Embryonic cerebrospinal fluid (E-CSF) has an important role in neurological development. Due to limited availability, the composition and properties of E-CSF are not known to the present. Our review aims to offer a comprehensive perspective over the studies published to date regarding the composition and effects of E-CSF. We performed a systematic search of four databases for studies regarding normal E-CSF, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We screened 725 records for eligibility criteria, resulting in 44 studies included in the narrative synthesis. Of these, four compared E-CSF with postnatal CSF, and three studies used human E-CSF for composition description. The most comprehensive set of molecular analyses was performed via mass spectrometry, in four studies. We observed a decrease in the number of published studies in the last 5 years. All included studies showed better results when cells were cultured in E-CSF than basal medium. Research on E-CSF remains sparse, particularly concerning its role in human developmental neurobiology. The heterogeneous nature of the study designs and experimental approaches showcase the need for standardized methodologies to better understand the unique properties and potential clinical applications of E-CSF.

Insulin receptor substrate 1 (IRS-1) is a key mediator of insulin signaling linked to focal cortical dysplasia. While previous studies have primarily focused on IRS-1 in peripheral tissues, its function in the central nervous system has remained largely unexplored. This study aimed to investigate the spatiotemporal expression patterns of IRS-1 protein in mouse cerebral cortex and human brain organoids, along with its role in neural development. In mice, Irs-1 expression was consistent throughout brain development, with notable localization in the ventricular/subventricular zone during early gestation and later in the outer cerebral cortex. In human brain organoids, IRS-1 was primarily found in rosette structures initially, shifting to the outer cortical layer as they matured. Knockdown of Irs-1 at embryonic day 14.5 via in-utero electroporation impaired neuronal migration, resulting in more neurons remaining in the intermediate zone compared to controls. Moreover, SH-SY5Y cells treated with isotretinoin exhibited a significant decrease in IRS-1 protein expression during maturation. RNA sequencing indicates an upregulation of neurodevelopment-related genes alongside a downregulation of the IRS-1. These findings underscore the significance of IRS-1 in brain development, particularly regarding neuronal migration and differentiation.

The cognitive impairment resulting from stroke is purported to be associated with impaired neuronal structure and function. Transcranial Magnetic Stimulation (TMS) modulates neuronal or cortical excitability and inhibits cellular apoptosis, thereby enhancing spatial learning and memory in middle cerebral artery occlusion/reperfusion (MCAO/R) rats. In this study, we aimed to investigate whether Sterile alpha and Toll/interleukin receptor motif-containing protein 1 (SARM1), a pivotal Toll-like receptor adaptor molecule and its related mechanisms are involved in the ameliorating effect of TMS on cognitive function post-cerebral ischemia. We evaluated hippocampal injury in MCAO/R rats after one week of treatment with 10-Hz TMS at an early stage. The effect of SARM1 was more effectively assessed through lentivirus-mediated SARM1 overexpression. Various techniques, including FJB staining, HE staining, western blot, immunofluorescence, imunohistochemistry, and transmission electron microscopy, were employed to investigate the molecular biological and morphological alterations of axons, myelin sheaths and apoptosis in the hippocampus. Ultimately, Morris Water Maze was employed to evaluate the spatial learning and memory capabilities of the rats. We observed that TMS significantly reduced the levels of SARM1, NF-κB, and Bax following MCAO/R, while elevating the levels of HSP70, Bcl-2, GAP-43, NF-200, BDNF, and MBP. Overexpression of SARM1 not only reversed the neuroprotective effects induced by TMS but also exacerbated spatial learning and memory impairments in rats. Our results demonstrate that TMS mitigates hippocampal cell apoptosis via the SARM1/HSP70/NF-κB signaling pathway, thus fostering the regeneration of hippocampal axons and myelin sheaths, as well as the improvement of spatial learning and memory.

Deregulated reactive oxygen species (ROS) levels trigger oxidative stress (OS) injury that is closely associated with the pathophysiology of various neurological disorders. Therefore, therapeutic efforts at oxidative events in the pathway of neuronal degeneration would be promisingly helpful for intervention and treatment of related diseases. Here, we report that gastrodin, the main bioactive constituent of Rhizoma Gastrodiae, protects the mouse hippocampal HT22 cells from OS caused by hydrogen peroxide (H₂O₂), including the increased cell viability, elevated Glutathione (GSH) levels, decreased Malondialdehyde (MDA) activity, and down-regulated ROS levels with restored cell morphology. Through RNA-sequencing (RNA-Seq) and multiple experiments, we screened the gene Mamdc2 that could be a potential regulating target of gastrodin. Mechanistically, gastrodin exerts its protective effects on neuronal cells from oxidative injury by suppressing miRNA-125b-5p, which increases its target Mamdc2 expression. Overexpression of miR-125b-5p mimics significantly attenuates the gastrodin-triggered protective effects against H₂O₂ in HT22 cells, including the decreased cell viability, down-regulated GSH activity, increased MDA activity, and up-regulated ROS production, compared to the gastrodin-administration with control miRNA group. However, these results could be effectively restored by the ectopic expression of Mamdc2, leading to the opposite outcomes to those of miR-125b-5p mimics-overexpression. Thus, the current study provides evidence that gastrodin has the potential for intervention and therapy of OS injury-associated neurological diseases in future.