Neurochemical Research最新文献

In recent years, the role of novel protein acylation modifications in neuroinflammation has gradually become a hot research topic. In this paper, we reviewed the molecular mechanisms of five types of acylation modifications, namely lactylation (Kla), succinylation (Ksucc), crotonylation (Kcr), β-hydroxybutyrylation (Kbhb) and palmitoylation, and their association with neuroinflammation. To clarify the roles of these acylation modifications in neuroinflammation, we summarized the acyl donors, key regulatory enzymes (acyltransferases and deacylases), and dynamic regulatory networks for each modification type. On the one hand, they are directly involved in the inflammatory response by regulating microglial activation and pro-inflammatory factor release; on the other hand, they can indirectly affect the neurodegenerative disease process through metabolic reprogramming. This article also discusses drug development for novel acylases, including strategies based on enzyme activity inhibition or metabolic intervention, and points out the limitations of current studies. Future studies need to explore the spatial and temporal dynamics of acylation modifications, cross-regulatory networks and their functions in the neuroimmune microenvironment to provide new targets for the development of precise anti-neuroinflammatory therapies. The discovery of novel acylation modifications not only expands the theoretical framework of protein post-translational modification (PTM), but also opens up a multi-dimensional intervention pathway for the treatment of neuroinflammation-related diseases.

Schisanhenol (Sal) is a lignan component derived from the traditional Chinese medicine Schisandra rubrifora (Franch.). Pharmacological research has highlighted that Sal exhibits pronounced neuroprotection against oxidative stress-triggered damage. An in vivo mice model of Parkinson’s disease (PD) was developed using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and in vitro studies employed 1-methyl-4-phenylpyridinium (MPP⁺) as a neurotoxin in SH-SY5Y cells. Behavioral tests, immunohistochemistry, biochemical analyses, cell viability assays, and Western blot were applied. Sal (50 mg/kg and 100 mg/kg) markedly alleviates behavioral disorders in mice. The quantity of tyrosine hydroxylase (TH)-positive cells and TH protein levels in the substantia nigra (SN) were significantly augmented, while alpha-Synuclein (α-Syn) declined. Iron content in SN was reduced, thioredoxin reductase (TrxR) activity was enhanced, and protein Nrf2, TrxR1, and GPX4 were upregulated. In vitro findings showed that Sal (25 µM, 50 µM, 100 µM) significantly restored cell viability, ‌replenished GSH/GSSG ratio, and reduced MDA levels. Molecularly, Sal administration upregulated GPX4, HO-1, Nrf2, and TrxR1 expression, as well as enhanced mitochondrial membrane potential. Particularly, Sal treatment heightened Nrf2 protein entry to the nucleus and upregulated TrxR1 expression. The nuclear translocation of Nrf2 was reversed by Nrf2 inhibitor ML385. Meanwhile, The neuroprotective effect of Sal was reversed by ML385 and TrxR1 inhibitor Auranofin. Sal exhibits significant therapeutic potential in mitigating MPTP-induced PD in mice and MPP⁺-induced Dopaminergic (DA) neuron toxicity in SH-SY5Y cells, as it protects DA neurons while inhibiting ferroptosis. These outcomes are likely associated with the Nrf2/TrxR1/GPX4 pathway.

Intracerebral hemorrhage (ICH) has poor clinical outcomes, with microglia-induced neuroinflammation being a key pathological process. This study investigated the therapeutic potential of ectomesenchymal stem cells (EMSCs) from the nasal mucosa in ICH. Using a mouse ICH model, we transplanted EMSCs intracranially. We assessed neurological function, neuronal survival, microglial polarization, and inflammatory responses. In vitro, we co-cultured EMSCs with hemin-stimulated microglia and performed transcriptomic analysis. Key proteins in the NF-κB and MAPK pathways were evaluated in vivo based on in vitro findings. EMSC transplantation significantly improved neurological deficits and reduced neuronal injury. It promoted microglial polarization towards the anti-inflammatory M2 phenotype and increased levels of the anti-inflammatory cytokine IL-10. Mechanistically, EMSCs suppressed the activation of the NF-κB and MAPK signaling pathways in microglia. Our findings demonstrate that EMSCs alleviate neuroinflammation and neural injury after ICH by modulating microglial polarization, potentially via inhibiting the NF-κB and MAPK pathways. This suggests EMSCs as a promising novel therapy for hemorrhagic stroke.

Alzheimer’s disease (AD) is a multifactorial disorder that demands a comprehensive management strategy. Both aerobic exercise training and intermittent fasting (IF) have been shown to ameliorate AD symptoms, yet the impact of exercise in the fasted state remains understudied. This study compared the effects of four weeks of moderate‑intensity treadmill running in either a fasted or a normal fed state on cognitive function and hippocampal BDNF signaling in an amyloid-β (Aβ)_1–42-injected rat model of AD. Twenty‑month‑old male Wistar rats were allocated into five groups (n = 12 each): AD, AD plus IF (ADIF), AD plus exercise training (ADET), AD plus IF plus exercise training (ADIFET), and control. AD was induced by bilateral intra‑hippocampal Aβ_1–42 injection. Exercise interventions (fasted or fed) were conducted 5 days/week for 4 weeks. Aβ injection significantly impaired learning and memory and reduced hippocampal levels of PKA, CREB, and BDNF (p < 0.001). Both fasting and exercise independently elevated plasma and hippocampal β-hydroxybutyrate (βHB) (p < 0.001), with the highest βHB increase observed in the fasted-exercise group (p < 0.01). All intervention groups (ADIF, ADET, and ADIFET) demonstrated significant improvements in cognitive performance and hippocampal levels of PKA, CREB, and BDNF (p < 0.001). The combined fasting plus exercise group produced greater benefits than either IF or exercise alone (p < 0.05), and exercise alone outperformed fasting alone (p < 0.05). These findings indicate that aerobic exercise in the fasted state offers superior neuroprotective and cognitive benefits, likely via upregulation of βHB/PKA/CREB/BDNF signaling, highlighting fasted‑state exercise as a promising therapeutic approach for AD.

Pearls, formed from the nacreous layers of marine mollusks, have long been used in traditional medicine, yet the molecular basis of their bioactivity remains insufficiently characterized. Mitochondrial dysfunction is a central feature of Alzheimer’s disease (AD) pathology and represents a critical therapeutic target. Although nacre extract has been reported to improve cognitive impairment, its effects on mitochondrial function and biogenesis under amyloid-β (Aβ)-induced toxicity remain unclear. In this study, we examined the impact of nacre extract on mitochondrial activity in PC12 cells and in an Aβ-injected mouse model. Treatment with nacre extract significantly alleviated Aβ-induced mitochondrial dysfunction in PC12 cells, restoring membrane potential, ATP production, and the expression of mitochondrial biogenesis–related genes, including PPARγ and Nrf1. MitoBright LT staining demonstrated recovery of mitochondrial mass following extract administration. In vivo, we first isolated and identified a sulfated polysaccharide fraction from nacre extract, which significantly improved Aβ-induced memory impairment. In parallel, this fraction preserved mitochondrial function in the brains of Aβ-injected mice, as evidenced by maintained membrane potential, ATP levels, and hippocampal succinate dehydrogenase expression. Together, these findings demonstrate that nacre extract exerts neuroprotective effects through its sulfated polysaccharide fraction, highlighting its potential as a marine-derived therapeutic resource against AD-related neurodegeneration.

L-gamma-glutamylethylamide (L-theanine, theanine) is an amino acid and an umami component found in green tea. According to previous reports, theanine acts on the central nervous system by alleviating stress and maintaining natural sleep. Furthermore, theanine has been reported to have a mild cancer-suppressing effect. However, the molecular mechanism of theanine’s potential central nervous system (CNS) activity remains unclear. We evaluated the inhibitory effect of theanine on the proliferation of neural cell lines and found that theanine most effectively inhibited the proliferation of NSC-34 mouse motor neuron-like hybrid cells compared to other neural cells. NSC-34 cell proliferation inhibition by theanine was completely alleviated by co-administration of α-(methylamino) isobutyric acid or leucine, a substrate of solute carrier family 38 member 1 (Slc38a1, the glutamine transporter) or Slc7a5 (the glutamine/leucine exchanger) respectively. This suggests that theanine uptake into cells occurs via Slc38a1 and excretion from cells occurs via Slc7a5. However, inhibition was observed even in the absence of glutamine and did not correlate with changes in mammalian target of rapamycin phosphorylation levels. These results suggest that theanine inhibits proliferation in a manner that is still unclear after it is taken up into cells. Based on these findings, we propose that theanine may exert an inhibitory effect on the proliferation of neural cells that have abnormally proliferating Slc38a1, namely neuroblastoma.

The endocannabinoid system (ECS) is a lipid-derived signaling network composed of cannabinoid receptors, endogenous ligands, and metabolic enzymes. Through its widespread neuromodulatory functions, the ECS regulates dopaminergic, noradrenergic, and glutamatergic pathways that are critical for attention and behavioral control. Emerging evidence indicates that dysregulation of ECS components may contribute to the pathophysiology of attention deficit hyperactivity disorder (ADHD). This review synthesizes current biochemical evidence on ECS involvement in ADHD pathophysiology, with a focus on receptor signaling, ligand levels, and enzyme activity. By evaluating emerging molecular targets and highlighting gaps in mechanistic knowledge, it aims to guide future studies toward novel therapeutic strategies. A total of 11 preclinical and 2 clinical studies evaluating ECS-related biochemical alterations in ADHD were included. Preclinical research demonstrates alterations in ECS components linked to hyperactivity and impaired cognitive regulation. Although clinical research in this area remains limited, preliminary results are promising, supporting ECS-targeted approaches as novel therapeutic strategies for ADHD. Overall, current evidence suggests that dysregulation of the endocannabinoid system contributes to ADHD pathophysiology. Clarifying ECS-related biochemical mechanisms in ADHD may identify novel molecular targets, while advancing translational efforts toward ECS-based therapeutic strategies.

Ischemic stroke (IS) is a leading cause of death and permanent disability worldwide. Diabetes is a major risk factor for IS and independently increases mortality. This study investigated the neuroprotective effects of Myrtenal (Myrt) in a rat model of IS under both diabetic and non-diabetic conditions. Sprague Dawley rats received Myrt (40 mg/kg, intraperitoneally) for 28 days before undergoing 60-minute middle cerebral artery occlusion followed by 24 h of reperfusion. Neurological outcomes were assessed using behavioral tests, infarct volume was measured by TTC staining, and biochemical analyses evaluated oxidative stress (MDA, SOD, CAT, GSH-Px) and inflammatory markers (NLRP3, TNF-α, IL-6, IL-1β). Western blotting was performed to examine BDNF/TrkB, p-PI3K/p-Akt signaling, and apoptosis-related proteins (Caspase-3, Bcl-2, Bax). IS impaired neurological function and increased infarct size, apoptosis, inflammation, and lipid peroxidation, while reducing antioxidant enzymes and BDNF/TrkB and p-PI3K/p-Akt levels (p < 0.05). These pathological changes were more severe in diabetic rats. Pretreatment with Myrt significantly ameliorated these effects in both diabetic and non-diabetic groups (p < 0.05). These findings suggest that Myrt exerts neuroprotective effects against IS by suppressing inflammation, oxidative stress, and apoptosis, possibly through modulation of BDNF/TrkB and p-PI3K/p-Akt pathways. These findings indicate that Myrt may possess neuroprotective potential in IS under both hyperglycemic and normoglycemic conditions.

Post-stroke cognitive impairment (PSCI) is a prevalent cerebrovascular condition resulting from ischemic stroke. This study aimed to determine the expression levels of NEXN-AS1 in PSCI, evaluate its clinical significance, and further uncover the molecular mechanisms through which it contributes to the initiation and progression of PSCI. The quantification of NEXN-AS1, miR-92a-3p, and NRF1 expression was performed using qRT-PCR. The diagnostic utility of serum NEXN-AS1 was assessed through ROC analysis. Risk factors associated with cognitive impairment following stroke were identified using both univariate and multivariate logistic regression. A cellular model of cognitive dysfunction was established via oxygen-glucose deprivation/reperfusion (OGD/R). The PSCI animal model was established through the Middle cerebral artery occlusion (MCAO) surgery. Inflammatory status was determined by measuring cytokine levels, including IL-6, IL-1β, and IL-10, while oxidative stress was evaluated by quantifying ROS, MDA, and CAT. In stroke patients, NEXN-AS1 expression was notably downregulated and further decreased in cases with PSCI. It served as a reliable biomarker for distinguishing stroke patients from healthy individuals and PSCI from post-stroke cognitive normality (PSCN) groups. Upregulation of NEXN-AS1 in BV2 cells following OGD/R stimulation led to increased proliferation, decreased inflammatory response, and reduced oxidative stress. Moreover, miR-92a-3p expression reversed the protective effects of NEXN-AS1 under OGD/R conditions. Overexpression of NEXN-AS1 alleviated cognitive dysfunction, inflammatory response and oxidative stress in PSCI rats, while overexpression of miR-92a-3p counteracted the protective effect of NEXN-AS1 on PSCI rats. Further analysis identified NRF1 as a downstream target of miR-92a-3p. NEXN-AS1 exerts protective effect against ischemic brain injury in both in vitro and in vivo models by regulating miR-92a-3p. Therefore, NEXN-AS1 may predict the occurrence of PSCI, and NEXN-AS1 may contribute to PSCI pathogenesis via regulation of the miR-92a-3p/NRF1 axis.