Neurotoxicity Research最新文献

Cerebral ischemia-reperfusion (I/R) injury is the main cause of early complications and adverse outcomes after treatment such as myocardial infarction and acute ischemic stroke. In this study, we aimed to explore the functions of insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) and tripartite motif-containing 45 (TRIM45) in neuron injury after cerebral I/R injury. HMC3 cells were exposed to oxygen-glucose deprivation and reoxygenation (OGD/R) to mimic cerebral I/R injury in vitro. Western blot and qRT-PCR were conducted for gene expression. NLR family pyrin domain containing 3 (NLRP3) inflammasome activity was analyzed by western blot. ELISA kits were utilized to determine the concentrations of inflammatory cytokines. Flow cytometry was used to analyze iNOS⁺ cells, CD206⁺ cells and neuron apoptosis. Methylated RNA Immunoprecipitation (meRIP) assay and RIP assay were adopted to analyze the relation between TRIM45 and IGF2BP1. CCK-8 assay and TUNEL assay were adopted for the viability and death of neurons. Mice model of middle cerebral artery occlusion (MCAO) was used to explore the function of IGF2BP2 in cerebral I/R injury. IGF2BP1 level was upregulated in HMC3 cells. IGF2BP1 overexpression promoted NLRP3 inflammasome activation and pro-inflammatory phenotype in OGD/R-stimulated HMC3 cells. Mechanically, IGF2BP1 modulated TRIM45 expression through m6A methylation modification. IGF2BP1 knockdown inhibited NLRP3 inflammasome activation and pro-inflammatory phenotype in OGD/R-stimulated HMC3 cells by m6A methylation modification of TRIM45. Inhibition of IGF2BP1 improved the viability and suppressed the death and apoptosis of neurons in the co-culture system of microglia-like and neurons by regulating TRIM45 expression. Inhibition of IGF2BP1 improved the neurotoxicity of proinflammatory HMC3 cells in co-cultured neurons via reducing the m6A methylation of TRIM45. However, the number of biological replicate samples was relatively small (n = 3) and the results in this study were preliminary study.

Background: Observational studies have shown that exposure to per- and polyfluoroalkyl substances can lead to neurotoxicity. We focus on whether perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) affect brain morphology and the potential molecular mechanisms of toxicity.

Methods: Causal relationship between exposure to both PFOA and PFOS and brain morphology was explored based on Mendelian randomization (MR), and the toxic molecular mechanism was investigated using network toxicology.

Results: MR analysis indicated PFOA exposure reduced brain volume in left parahippocampal (p = 0.018) and right rostral anterior cingulate (p = 0.007), while PFOS exposure decreased volume in left middle temporal (p = 0.036), paracentral (p = 0.022), postcentral (p = 0.014), posterior cingulate (p = 0.002), rostral middle frontal (p = 0.040), superior frontal (p = 0.027), superior parietal (p = 0.033), and in the right hemisphere: inferior parietal (p = 0.017), superior frontal (p = 0.030), superior parietal (p = 0.025), and caudal middle frontal (p = 0.041). GO/KEGG analyses revealed 161 targets linked to the neurotoxicity of PFOA and PFOS, primarily associated with fatty acid metabolism, GABA signaling, neurotransmitter receptor activity, ferroptosis, and PPAR pathways. Molecular docking verified key targets (PPARG, FASN, SCD, CD36, GOT2) underlying the toxicity mechanism.

Conclusions: Exposure to PFOA and PFOS leads to reduced brain volume - neurotoxicity at the macroscopic level. At the molecular level, we identified PPARG, FASN, SCD, CD36, and GOT2 as key targets implicated in the pathology of brain damage induced by PFOA and PFOS.

Background and objectives: Neurodegenerative diseases are characterized by degeneration or progressive loss/death of neurons in specific areas of the brain, often worsened by cigarette smoke through oxidative stress and inflammation. Cordyceps militaris (C. militaris) exhibits antioxidant and anti-inflammatory properties, suggesting potential neuroprotective effects. This study evaluated the protective role of C. militaris hot water extract (CMWE) against cigarette smoke extract-induced neurodegeneration in zebrafish.

Methods: Neurodegeneration was induced in zebrafish using cigarette smoke extract, and CMWE was administered at 1 mg/L and 4 mg/L. Behavioral performance was assessed using Y-maze, inhibitory avoidance, and novel tank tests. LC-MS was employed to identify CMWE constituents, while antioxidant activity was evaluated by the DPPH assay. Histological analysis of the periventricular grey zone (PGZ) of the optic tectum was performed to assess neuronal integrity.

Results: Cigarette smoke exposure led to aimless exploration, impaired memory retention, and increased bottom-dwelling behavior. CMWE improved behavioral outcomes, with 4 mg/L showing greater efficacy than 1 mg/L. LC-MS revealed bioactive compounds including cordycepin, adenosine, ergothioneine, D-mannitol, and vitamins. The DPPH assay confirmed strong antioxidant activity. Histological evaluation showed reduced pyknotic neuronal density in CMWE-treated groups compared with diseased controls, indicating anti-inflammatory effects.

Conclusions: CMWE mitigated cigarette smoke-induced behavioral and histological hallmarks of neurodegeneration in zebrafish, likely via synergistic antioxidant and anti-inflammatory mechanisms. These findings support the potential of C. militaris as a natural product-based therapeutic candidate for neurodegenerative disorders, warranting further studies on its individual constituents and mechanisms of action.

Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and debilitating complication of cancer treatment, characterized by sensory dysfunction, including allodynia and hyperalgesia. Despite its clinical significance, there are no FDA-approved preventive options for CIPN, and current symptom management remains limited in effectiveness. Recent insights into CIPN's underlying mechanisms have highlighted the roles of neuroimmune interactions and ion channel dysfunction, particularly involving nicotinic acetylcholine receptors (nAChRs). Notably, the α7 and α9 nAChR subtypes play a critical role in controlling neuronal excitability and inflammatory responses in both peripheral and central sensory pathways. Conopeptides, a group of disulfide-rich peptides from cone snail venom, have attracted attention as highly selective modulators of ion channels involved in pain pathways. This review highlights α-conotoxins targeting nAChRs, specifically RgIA4 and GeXIVA[1,2], which have dual therapeutic effects by blocking pain signals and reducing neuroinflammation. We explore the structural variety and functional specificity of conopeptides, their mechanisms in CIPN animal models, and their potential as disease-modifying agents. The review also covers recent advances in peptide engineering aimed at improving cross-species compatibility, receptor selectivity, and serum stability of conopeptides in targeting nAChR. The article highlights the potential of nAChR-targeting conopeptides as next-generation treatments for CIPN, outlining key challenges and future directions for clinical development.

The objective of the present review is to discuss the involvement of altered mitochondrial quality control in Mn-induced neurotoxicity. Existing data demonstrate that mitochondrial autophagy (mitophagy) and brain mitochondrial unfolded protein response (mtUPR) are activated in response to Mn exposure to counteract the Mn-induced mitochondrial dysfunction. Both mitophagy and mtUPR have significant overlap and mechanistic intersections with the integrated stress response (ISR). Increased Mn exposures impair mitochondrial dynamics, further aggravating Mn-induced mitochondrial dysfunction. Specifically, Mn suppresses PTEN-induced kinase 1 (PINK1)-Parkin-dependent mitophagy through a variety of mechanisms, including nitric oxide synthase 2 (NOS2)-dependent PINK1 S-nitrosylation, inhibition of transcription factor EB (TFEB) signaling, and mammalian target of rapamycin complex 1 (mTORC1) activation. In addition, Mn promotes mitochondrial fission by up-regulating dynamin-1-like protein (Drp1) expression and phosphorylation via the activation of c-Jun N-terminal kinase (JNK) and inhibition of sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) pathways. Concomitantly, Mn impairs mitochondrial fusion by inhibiting mitofusin (Mfn) 1/2 and dynamin-like 120 kDa protein (Opa1) expression, leading to a reduction in mitochondrial size and disruption of the mitochondrial network. High-dose Mn exposure results in inhibition of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α)/nuclear factor erythroid 2-related factor 2 (NRF2)-dependent mitochondrial biogenesis. The latter may be mediated by inhibition of SIRT1/SIRT3 activity, as well as modulation of PINK1/ zinc finger protein 746 (ZNF746)/PGC-1α axis. Alterations in the mitochondrial quality control system may contribute to Mn-induced neuronal damage and neuroinflammation, indicating that dysregulation of the brain mitochondrial dynamics is an important mechanism by which Mn induces its neurotoxicity.

Melamine, an industrial chemical linked to neurotoxicity, prompted this study investigating taurine's neuroprotective effects in rat brains. The study examined the impact of taurine on brain metabolic enzymes, neurochemicals, autophagy-related proteins, and oxidative-inflammatory pathways. Twenty-eight rats were divided into four groups (seven rats per group): control (saline), taurine (100 mg/kg), melamine (50 mg/kg/day), and melamine plus taurine. Taurine administration (30 min post-melamine) continued daily for 28 days, starting on day 29 to day 56, which allowed for the assessment of its restorative effect against ongoing melamine-induced neurotoxicity. Non-spatial recognition memory was evaluated using the novel-object recognition memory test (NORT). Following this, brain neurochemical status, metabolic enzymes, autophagic proteins, and oxidative-inflammatory markers were assessed postmortem. Results demonstrated that taurine improved cognitive function in melamine-treated rats, as evidenced by increased exploration of novel objects in the NORT. Taurine protected against melamine-induced oxidative stress. Additionally, taurine reduce tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-1β expression, modulated mammalian target of rapamycin (mTOR) and beclin-1, restored brain metabolic enzyme activity, enhanced neurotransmitter levels, and prevented alterations in α-synuclein and paraoxonase 1 (PON1). In conclusion, taurine protects against melamine-induced neurotoxicity in rats by improving autophagic response, downregulating apoptosis and inflammation markers, inhibiting oxidative stress, and potentially restoring brain metabolic enzyme activities and neurotransmitter levels.

Oxaliplatin-induced peripheral neuropathy (OIPN) is a severe, dose-limiting complication that significantly reduces quality of life in cancer patients, with no effective preventive or therapeutic options currently available. There is increasing evidence that neuroinflammation plays a central role in OIPN initiation and progression. This review provides a critical and up-to-date analysis of recent studies on the molecular mechanisms of oxaliplatin-induced neuroinflammation, with a particular focus on the integration of mitochondrial dysfunction, immune-mediated inflammation, glial activation, microRNA dysregulation, and gut-nerve axis disruption. Recent findings demonstrate that oxaliplatin disrupts mitochondrial dynamics, increases oxidative stress, and impairs blood-nerve barrier integrity, triggering neuroinflammatory responses. Neuroinflammation in OIPN is mediated through the activation of several key signaling pathways, including MAPK, NF-κB, Wnt/β-catenin, TLR4, and mTOR, which lead to increased production of pro-inflammatory cytokines and activation of glial cells. Furthermore, emerging evidence has identified dysregulation of the gut-nerve axis and alterations in gut microbiota composition as contributing factors that exacerbate oxaliplatin-induced neuroinflammation and neuropathic pain. Various pharmacological and plant-derived compounds, such as naringin, baicalein, and puerarin, as well as selective inhibitors of inflammatory pathways, have shown promising neuroprotective effects in animal models by attenuating inflammatory responses and alleviating neuropathic symptoms. By synthesizing these converging lines of evidence, this review further outlines potential future directions, including the development of combination therapies targeting multiple inflammatory pathways, microbiome-based interventions, and the translation of preclinical findings into well-designed clinical trials.

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease causing motor neuron loss. 90-95% of ALS cases are sporadic, and the interplay of genetic predispositions and environmental exposures is essential in ALS pathology. Several neurotoxic exposures, such as smoking, pesticides, and organic solvents, have been implicated as affecting the risk of ALS. However, it is unclear how these exposures impact specific cellular mechanisms and influence ALS risk. We investigated the potential mechanisms of toxicity of diesel exhaust, toluene, pesticides, and smoking on ALS pathology through a bioinformatics approach. We retrieved the gene sets targeted by these environmental exposures, and the gene sets involved in ALS-associated biological processes. We performed overlap analysis to assess the statistical significance of the overlap between the gene sets associated with environmental exposures and those linked to ALS. Response to oxidative stress, synaptic signaling, lipid metabolic process, cellular oxidant detoxification, and regulation of gliogenesis significantly overlapped with the gene sets targeted by each of the four environmental exposures. Contrarily, chaperone-mediated autophagy, DNA repair, and regulation of action potential, significantly overlapped only with the gene sets targeted by diesel exhaust, pesticides, and toluene, respectively. Finally, transport across the blood-brain barrier, vesicle-mediated transport, actin filament-based transport, autophagy, transport to the Golgi and subsequent modification of proteins, metabolism of lipids, regulation of neurotransmitter receptor levels, and axon guidance significantly overlapped only with the gene set targeted by tobacco smoke pollution. This study aims to investigate the molecular relationships between neurotoxic exposures and ALS by overlap analysis, providing a framework that can be applied to investigate other exposure-disease interactions.