Neurochemical Research最新文献

This study investigates the neuroprotective potential of STAT3 inhibition in reducing oxidative stress-induced neuronal damage and apoptosis, a major factor contributing to the onset and progression of neurodegenerative diseases, including Alzheimer’s disease (AD). Our findings demonstrate that STAT3 inhibitors significantly enhance cell survival and reduce apoptosis in SH-SY5Y cells exposed to hydrogen peroxide. These protective effects are mediated through the ERK/CREB signaling pathway rather than direct suppression of STAT3 phosphorylation. Further analysis revealed that the ERK pathway is a critical mediator of CREB activation following STAT3 inhibition. The protective effects of STAT3 inhibitors were significantly reduced in the presence of the ERK inhibitor PD98059, underscoring the importance of the ERK/CREB axis in neuroprotection. We observed that STAT3 inhibitors promote CREB phosphorylation, leading to the upregulation of immediate early genes such as c-Fos, c-Jun, Arc, Egr-1, NR4A1, and Homer1a, as well as BDNF. These genes are crucial for synaptic plasticity and long-term memory formation, suggesting that STAT3 inhibition may ameliorate cognitive impairments in neurodegenerative conditions. Our results highlight the potential of STAT3 inhibitors to counteract oxidative stress and enhance cognitive functions by modulating the ERK/CREB signaling pathway. These findings provide valuable insights into the molecular mechanisms of STAT3 inhibition and support its therapeutic potential for treating neurodegenerative diseases.

This study aimed to assess the potential of multiparametric chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) for MCI detection. Twenty-eight patients with MCI and 31 age- and gender-matched normal controls (NCs) were enrolled. CEST MRI was performed with a gradient and spin-echo sequence on a 3T scanner. Multi-parametric CEST parameters were analyzed, such as amide CEST, amine CEST, amine and amide concentration independent assay (AACID), magnetization transfer ratio yielding rex (MTR_rex-amide), and downfield rNOE suppressed apparent exchange-dependent relaxation amide proton (DNS-AREX-amide). Statistical analyses of CEST parameters were performed to evaluate group differences, their correlations with Montreal cognitive assessment (MoCA) score, and diagnostic performance for MCI. Compared with NC group, amide CEST as well as MTR_rex-amide decreased in the left hippocampus and amine CEST as well as AACID increased in the right hippocampus in the MCI group; In both hippocampi, the DNS-AREX-amide were significantly lower in the MCI group versus the NC group (all P < 0.05). Amine CEST in the right hippocampus was negatively correlated with MoCA score (r = − 0.457, p = 0.017); DNS-AREX-amide in the bilateral hippocampus was positively correlated with MoCA score (left: r = 0.449, P = 0.019; right: AUC = 0.529, P = 0.05). DNS-AREX-amide in the bilateral hippocampus have a good ability to identify MCI (left: AUC = 0.756, P < 0.01; right: AUC = 0.762, P < 0.01). CEST MRI provides a potential imaging diagnostic strategy for MCI, which may promote early detection of MCI and provide novel insights into the pathological progress toward AD.

Cognitive impairment refers to abnormalities in learning, memory and cognitive judgment, mainly manifested as symptoms such as decreased memory, impaired orientation and reduced computational ability. As the fundamental unit of information processing in the brain, neural circuits have recently attracted great attention due to their functions in regulating pain, emotion and behavior. Furthermore, a growing number of studies have suggested that neural circuits play an important role in cognitive impairment. Neural circuits can affect perception, attention and decision-making, they can also regulate language skill, thinking and memory. Pathological conditions crucially affecting the integrity and preservation of neural circuits and their connectivity will heavily impact cognitive abilities. Nowadays, technological developments have led to many novel methods for studying neural circuits, such as brain imaging, optogenetic techniques, and chemical genetics approaches. Therefore, neural circuits show great promise as a potential target in mitigating cognitive impairment. In this review we discuss the pathogenesis of cognitive impairment and the regulation and detection of neural circuits, thus highlighting the role of neural circuits in cognitive impairment. Hence, therapeutic agents against cognitive impairment may be developed that target neural circuits important in cognition.

Alzheimer’s disease (AD) is characterized by the accumulation of tau protein tangles and amyloid-β (Aβ) plaques in the central nervous system (CNS), leading to progressive neurodegeneration. Hence, the discovery of disease-modifying agents capable of delaying the progression is essential for effective management. Aminonaphthoquinone (ANQ) is an attractive pharmacophore with various biological effects. This study explores the neuroprotective potentials of ANQ derivatives (1–18) using in vitro models of AD pathology (i.e., Aβ₄₂-induced SH-SY5Y cells). Findings demonstrated that all compounds mitigated Aβ₄₂-induced cellular damage by preserving cell viability and morphology. Among all, four compounds (10, 12, 16, and 18) showed potent antioxidant activities as well as abilities to minimize AD-related damages (i.e. decreasing intracellular reactive oxygen species (ROS) production, preserving mitochondrial membrane potential (MMP), protecting membrane damage, and modulating beta-secretase 1 (BACE1) activity) with comparable protective effects to the well-known neuroprotectant, resveratrol (RSV). A molecular docking study indicated these compounds could suitably bind to sirtuin 1 (SIRT1) protein with preferable affinity. Key amino acid residues and key functional groups essential for binding interactions were revealed. Target prediction identified a list of possible AD-related targets of these compounds offering insights into their mechanisms of action and suggesting their multifunctional potentials. Additionally, in silico predictions revealed that these candidates showed favorable drug-like properties. Overall, this study highlighted the therapeutic potential of ANQ derivatives in AD treatment, emphasizing the need for further experimental validation and comprehensive investigations to fully realize their therapeutic benefits.

Traumatic brain injury (TBI) is a common cause of morbidity and death in all age groups, with an estimated 50 million people having brain injury due to trauma each year. Accurate blood-based biomarkers are needed to assist with diagnosis of patients across the spectrum of time and severity. Our objectives were to explore the diagnostic precision of time- and severity- related four blood-based biomarkers: AKT3, GSK-3β, hsa-miR-16-5p, and MALAT-1 for TBI for the purpose of diagnosis, prognosis, and follow-up. 40 samples were recruited as the following: 30 TBI patients and 10 healthy volunteers as controls with matched age and sex. They were divided according to the Glasgow Coma Scale into mild (mTBI), moderate (modTBI), and severe(sTBI) TBI. Blood samples were withdrawn at entry, and after 5 and 30 days, RT-PCR was used for measuring the expression level. The results showed upregulated expression levels of AKT3, hsa-miR-16-5p and significantly downregulated expression levels of GSK-3β in TBI patients compared to controls at all timings measured. mTBI patients showed a higher expression level of hsa-miR-16-5p compared with modTBI, and sTBI patients. MALAT-1 level showed a significant increase in severe cases only. We concluded that AKT3, hsa-miR-16-5p, and GSK-3β are excellent diagnostic biomarkers in TBI patients at initial assessment, as well as at 5 and 30 days following the injury. Moreover, MALAT-1 had good diagnostic value in sTBI patients, and its prognostic value extends to 30 days. GSK-3β was an excellent biomarker for detecting mTBI.

The goal of this study is to explore the role of the LMNB1 gene in glioma. A cohort of 160 patients who underwent glioma surgery were randomly selected of this study. The LMNB1 expression was assessed employing immunohistochemical and real-time quantitative polymerase chain reaction methods. Initially, RNA interference technology was applied to suppress gene expression, followed by the evaluation of tumor cell proliferation, apoptosis, cell cycle dynamics, and migration. The underlying molecular mechanisms of LMNB1 function were examined by a human phospho-kinase array and immunoblotting. And we established the xenograft models to determine the effect of tumor growth as well as the degree of invasion in shLMNB1 mice. Elevated LMNB1 expression correlated with unfavorable overall survival and disease-free survival. A substantial inhibition in cell growth was observed subsequent to LMNB1 knockdown in SHG-44 and U251 glioma cells. SHG-44-shLMNB1 cells exhibited a reduction in the S phase population, along with an increase in cells in G1 and G2 phases. Similarly, shLMNB1 U251 cells showed fewer cells in the S phase and an elevation in cells in G1 phase. Notably, increased apoptosis was observed in U251-shLMNB1 cells and SHG-44-shLMNB1 cells. Wound healing and Transwell migration assays demonstrated a significant decrease in the migration rate of both SHG-44-shLMNB1 and U251-shLMNB1 cells. The phosphorylation levels of Akt1/2/3, as well as the expressions of PI3K, AKT, and p-AKT proteins, were reduced in the shLMNB1 group. Downregulation of LMNB1 repressed tumor progress in vivo. The silencing of LMNB1 was found to significantly reduce the proliferation of human glioma cells, induce apoptosis in tumor cells, impede the progression of the cell cycle, and inhibit the migration of tumor cells. Consequently, we hypothesize that LMNB1 promotes glioma cell proliferation through mechanisms involving the inhibition of tumor cell apoptosis, acceleration of the cell cycle, and enhancement of tumor cell migration. We found that LMNB1 exert critical roles in glioma progression may via regulation of PI3K/Akt signaling pathway. These observations suggest that LMNB1 holds clinical potential for diagnostic and prognostic applications in glioma, presenting novel targets for drug development.

Autism spectrum disorders (ASDs) are increasingly prevalent neurodevelopmental disorders characterized by deficits in social skills, abnormal sensory responses and a loss of neuronal cells. A key factor in these differences is thought to be an imbalance between excitation and inhibition. The aim of this study was to measure the levels of γ-aminobutyric acid (GABA), glutamate (GLU) and serotonin (5-HT) in the thalamus of a rat valproic acid (VPA)-induced ASD model and to correlate these levels with the number of thalamic cells. Ten pregnant Wistar rats were injected with 600 mg/kg VPA on Day 12.5 of gestation, whereas five control rats received saline. After the behavioral tests, the male pups were divided into ASD and control groups with ten animals each. At 55 days of age, pups underwent microdialysis under anesthesia, and thalamic samples were analyzed for GABA, GLU and 5-HT levels by ultrahigh-performance liquid chromatography (UHPLC). After microdialysis, the brain sections were stained, and the volumes of the thalamus and hemispheres were calculated using the Cavalieri method, with the number of neurons and glia determined using the optical fractionator method. Compared with the control group, the ASD group presented increased 5-HT levels, an increased hemispheric volume, a decreased thalamic volume and decreased numbers of thalamic neurons and glia. A negative correlation was observed between the GLU content and glial number in the control group but not in the ASD group. These results indicate a disturbed thalamic neurotransmitter balance. We suggest that the increased thalamic 5-HT levels in ASD rats indicates that 5-HT reuptake is inhibited by the GLU content, which remains unchanged, despite the reduced cell number.

The function and mechanism of Cyclophilin A (CypA) in modulating gene expression associated with Alzheimer’s disease (AD) remain unclear. This multifunctional protein is found to be elevated in the cerebrospinal fluid (CSF) of individuals at risk for AD. The cytotoxic effects of CypA, including both wild-type and the mutant R55A, were assessed using the MTT assay. Prior to this evaluation, the purified recombinant protein was validated through enzymatic activity assays and western blot analysis. Following treatment with CypA and transient transfection using the CypA construct, real-time PCR (qRT-PCR) and western blotting were conducted to analyze the expression of factors involved in various signaling pathways, with an emphasis on inflammation, cell death, and intercellular communication. The findings indicate that CypA has a significant impact on the gene expression of factors associated with inflammation and the progression of AD in SH-SY5Y cells. It can be concluded that CypA is capable of regulating gene expression in SH-SY5Y cells, either in a manner dependent on or independent of its enzymatic activity. Additionally, the influence of this multifunctional protein on gene expression is contingent upon the specific site of action, as well as the dosage and duration of exposure to the cells.

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Neurotrophic factors are endogenous proteins that promote the survival of various neuronal cells. Increasing evidence has suggested a key role for brain-derived neurotrophic factor (BDNF) in the dopaminergic neurotoxicity associated with Parkinson’s Disease (PD). This study explores the therapeutic potential of filbertone, a bioactive compound found in hazelnuts, in neurodegeneration, focusing on its effects on neurotrophic factors and the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. In our study, filbertone markedly elevated the expression of neurotrophic factors, including BDNF, Glial cell line-Derived Neurotrophic Factor (GDNF), and Nerve Growth Factor (NGF), in human neuroblastoma SH-SY5Y cells, mouse astrocyte C8-D1A cells, and mouse hypothalamus mHypoE-N1 cells. Moreover, filbertone effectively countered neuroinflammation and reversed the decline in neurotrophic factors and Nrf2 activation induced by a high-fat diet (HFD) in neurodegeneration models. The neuroprotective effects of filbertone were further validated in models of neurotoxicity induced by palmitic acid (PA) and the neurotoxin MPTP/MPP⁺, where it was observed to counteract PA and MPTP/MPP⁺-induced decreases in cell viability and neuroinflammation, primarily through the activation of Nrf2 and the subsequent upregulation of BDNF and heme oxygenase-1 expression. Nrf2 deficiency negated the neuroprotective effects of filbertone in MPTP-treated mice. Consequently, our finding suggests that filbertone is a novel therapeutic agent for neurodegenerative diseases, enhancing neuronal resilience through the Nrf2 signaling pathway and upregulation of neurotrophic factors.

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