Molecular Neurobiology最新文献

Cerebral ischemia/reperfusion injury (CIRI) commonly occurs during the treatment of ischemic stroke and leads to severe consequences, including neuronal death and permanent loss of motor function. Accurate differentiation between the ischemic penumbra (IP) and the ischemic core area is crucial for timely intervention. Multimodal MRI plays a crucial role in the early diagnosis and treatment evaluation of acute ischemic stroke. PANoptosis is a recently discovered form of programmed cell death including apoptosis, necroptosis, and pyroptosis. It has been implicated in neuronal loss during CIRI, especially through absent in melanoma 2 (AIM2). Melatonin (Mel) exerts neuroprotective effects; however, whether PANoptosis is the main cause of neuronal death in CIRI and whether Mel exerts anti-PANoptotic effects to rescue CIRI remain unclear. This study aimed to examine the effects of Mel on PANoptosis in the IP of rats with CIRI and to systematically investigate the underlying mechanisms using multimodal MRI combined with histopathologic techniques. A rat CIRI model comprising 42 healthy male Sprague-Dawley rats, weighing 240-270 g, was established using the modified Zea-Longa wire bolus method. Multimodal MRI, including T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI)-MRI, and chemical exchange saturation transfer (CEST), was performed to evaluate the ischemic lesions and identify IP. T2WI, DWI-MRI, and tissue staining demonstrated that Mel significantly reduced infarct volume, improved neuron morphology, and decreased the proportion of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells. The IP was identified as the mismatch region between CEST and DWI-MRI, which was expanded by Mel treatment. In addition, Mel inhibited the expression of PANoptotic key proteins, as well as AIM2 expression, in IP neurons. In summary, multimodal MRI enables dynamic monitoring of IP after CIRI in vivo and effectively evaluates the neuroprotective effects of Mel on IP. Mel broadens the time window for CIRI rescue and exerts a neuroprotective effect by downregulating AIM2 expression in neurons, thereby suppressing PANoptotic neuronal death in the IP areas and alleviating brain injury in rats with CIRI.

Oxidative stress (OS) is a hallmark of secondary brain damage after intracerebral hemorrhage (ICH), contributing to the progression of neurological damage and poor clinical outcomes. While mesenchymal stem cell-derived exosomes (MSC-Exo) demonstrate antioxidative potential, the specific mechanisms underlying their protective effects, particularly concerning mitochondrial dynamics, remain unclear. This study identifies OPA1-mediated mitochondrial fusion as a novel mechanism through which MSC-Exo alleviates oxidative stress and brain injury after ICH. In vivo fluorescence imaging and immunofluorescence assay revealed that intravenously injected MSC-Exo could be effectively internalized by neuronal cells in ICH mice. MRI assay indicated that although MSC-Exo had little effect on the volume of hematoma, it significantly relieved brain edema and improved the neurological outcomes. MSC-Exo effectively reduced oxidative stress and neuronal apoptosis in the peri-hematoma tissues. Notably, both in vivo and in vitro studies showed that MSC-Exo significantly alleviated mitochondrial morphological damage following ICH. MSC-Exo substantially reversed the downregulation of OPA1 after ICH but showed no significant impact on other proteins associated with mitochondrial dynamics. Neuron-specific knockout of OPA1 (Opa1^cko) aggravated the impairment of mitochondrial morphology, the accumulation of superoxide production, and the deficits of mitochondrial respiratory capacities following ICH. Moreover, MSC-Exo failed to restore mitochondrial morphology and functionality, alleviate oxidative stress-induced damage, enhance neuronal viability, and facilitate functional recovery subsequent to ICH in Opa1^cko mice models.

In an attempt to identify markers that better characterize microglial states and to search for potential therapeutic targets, we performed a study using the IMG cell line as an in vitro microglial model. Specifically, we tested its response to several pro-inflammatory stimuli (lipopolysaccharide, interferon gamma, and tumor necrosis factor) and an anti-inflammatory stimulus (Interleukin-4) after 12 and 24 h of incubation. We performed RNA sequencing to identify genes modified at both incubation times (i.e., genes with sustained changes in the window between 12 and 24 h) that could reflect sustained microglial transcriptional responses. We also used Gene Ontology (GO) analysis to identify the most relevant pathways modified by these stimuli. RNA sequencing revealed four gene sets: (1) common genes that respond similarly to IL-4 and LPS, (2) specific LPS responders, (3) specific IL-4 responders, and (4) genes that exhibit LPS-induced upregulation and IL-4-induced downregulation, and vice versa (opposite responders). We hypothesize that the common gene set represents a general microglia response to pathological conditions, while the LPS- and IL-4-responder gene sets define specific microglial states under pro- and anti-inflammatory stimuli, respectively. We further propose that opposite responder genes act as metabolic switches between certain microglial states. The GO analysis indicated that LPS strongly upregulates biological processes related to the innate immune response, while IL-4 upregulates pathways related to repair, metabolic reprogramming, and cellular cooperation. Finally, the transcriptional response of IMG cells closely mirrored that of primary microglia, revealing highly similar gene expression and GO term profiles under LPS stimulation.

Folic acid (FA), a vital water-soluble B vitamin, is indispensable for the development and maintenance of the nervous system. By modulating one-carbon metabolism, FA critically influences DNA and RNA synthesis, methylation reactions, and cell division, thereby profoundly affecting neurogenesis. Neurogenesis, encompassing the proliferation, differentiation, and maturation of neural stem cells, is tightly regulated by FA through its role in DNA synthesis and methylation. Impaired neurogenesis is implicated in various neurological disorders, highlighting its critical role in cognitive function, brain homeostasis, and neural repair. Recent advances have elucidated the intricate link between FA metabolism and neurogenesis, revealing potential therapeutic targets. Here, we provide a comprehensive review of the molecular mechanisms underlying FA's regulation of neurogenesis, focusing on its impact on epigenetic regulation and signaling pathways. We also discuss the interplay between folate metabolism, neurogenesis, and systemic diseases, emphasizing the translational potential of targeting FA metabolism in neurological disorders. Understanding these mechanisms is crucial for advancing fundamental neuroscience and developing novel therapeutic strategies for neurodevelopmental and neurodegenerative diseases. Future research should focus on elucidating the specific molecular pathways and potential therapeutic applications of FA in neurogenesis.

This study aimed to explore the effects of AS-252424, a selective acyl-CoA synthetase long-chain family member 4 (ACSL4) inhibitor, against retinal ischemia-reperfusion (IR) injury and to elucidate the underlying mechanisms. A mouse model of retinal IR was established, and AS-252424 was administered intravitreally to assess its neuroprotective effect. Retinal ganglion cell (RGC) survival was evaluated by immunofluorescence. Retinal morphology and function were assessed by hematoxylin and eosin staining and electroretinography. Inner retinal neurons were analyzed for morphology and density by immunofluorescence. Expression, localization, and enzymatic activity of ACSL4 were measured by Western blot, immunofluorescence, and ELISA. Ferroptotic lipid peroxidation and oxidative stress were evaluated using malondialdehyde assay, 4-hydroxynonenal immunolabeling, C11-BODIPY 581/591, dihydroethidium probes, and glutathione quantification. Our results confirmed the localization of ACSL4 in human glaucomatous RGCs, with a similar localization pattern observed in mouse retinas. Furthermore, we demonstrated that ACSL4 expression reached its peak on day 1 after IR in mouse retinas. AS-252424 treatment significantly reduced RGC loss after IR. Importantly, AS-252424 achieved comparable RGC protection to Fer-1 at a lower concentration. We also found that AS-252424 preserved inner retinal structural integrity and alleviated edema after IR, as evidenced by quantitative analysis of individual retinal layer thickness. Functionally, AS-252424 significantly restored the amplitudes of the a-wave, b-wave, oscillatory potentials, and photopic negative response. Mechanistically, AS-252424 lowered arachidonic acid-CoA levels and inhibited lipid peroxidation in retinal RGCs after IR, thereby mitigating ferroptotic cell death. AS-252424 can significantly protect retinal structure and function after IR. The underlying mechanism involves the inhibition of ACSL4-mediated ferroptosis. Targeting ACSL4 represents a promising neuroprotective strategy to preserve visual function in ischemic retinopathy.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by motor neuron loss driven by oxidative stress, neuroinflammation, and dysregulated survival signaling. The objective of this study was to evaluate the neuroprotective efficacy and safety of sulforaphane (SUFP) in a methylmercury (MMHg⁺)-induced preclinical rat model of ALS, with comparison to omaveloxolone (OVX) and dimethyl fumarate (DIMT). SUFP treatment, particularly at 4 mg/kg, significantly restored antioxidant defense mechanisms through upregulation of Nrf2, HO-1, and SIRT1 while suppressing pro-inflammatory cytokines (IL-1β, TNF-α), apoptotic markers (Bax, caspase-3), and stress-related signaling pathways including p75NTR, PI3K/Akt, and MAPKs. These molecular effects translated into meaningful functional recovery, as evidenced by improvements in grip strength, locomotor performance, spatial memory, and depressive-like behavior. Histopathological evaluation demonstrated attenuation of demyelination and preservation of neuronal architecture in cortical, hippocampal, and cerebellar regions. Beyond central neuroprotection, SUFP exerted systemic benefits by normalizing hepatic enzymes, improving skeletal muscle integrity, restoring redox balance, stabilizing neurofilament and myelin-associated proteins, and correcting hematological alterations. Comparative analysis revealed that SUFP conferred superior neuroprotection with a favorable safety profile relative to OVX and, although slightly less efficacious than DIMT, exhibited reduced systemic toxicity. Molecular docking further supported SUFP's interaction with Nrf2-Keap1 targets, reinforcing its antioxidant and anti-inflammatory mechanisms. Collectively, these findings identify SUFP as a multifaceted and well-tolerated therapeutic candidate for ALS, supporting its further translational and clinical evaluation.

Background: The mammalian target of rapamycin (mTOR) plays a pivotal role in regulating neuronal survival and synaptic plasticity, both of which are crucial for the progression of Alzheimer's disease (AD). This study aims to delineate the research trends concerning mTOR and AD through bibliometric analysis.

Methods: A systematic search was conducted in the Web of Science Core Collection database to retrieve publications relevant to mTOR and AD from 2003 to 2025. Subsequently, bibliometric analysis and visualization were performed utilizing VOSviewer, CiteSpace, and the R package "Bibliometrix."

Results: A total of 1,025 articles were included in the analysis. The annual publication growth rate reached 21.22%, peaking in 2022. The three most cited articles addressed topics such as autophagy induction and clearance in neurons related to AD pathology, mTOR in microglial metabolic fitness, and mTOR inhibition against cognitive deficits. China led in publication volume, followed by the USA. The University of Texas System, Egyptian Knowledge Bank, and University of Texas Health Science Center at San Antonio emerged as the top 3 institutions. Oddo Salvatore ranked as the top author by H-index. Keyword analysis revealed four prominent clusters: cellular signaling and neuroplasticity, molecular mechanisms, neuroprotective effects of mTOR inhibition, and roles of mTOR in AD pathogenesis. Burst analysis identified "target," "neuroinflammation," "stress," "kinase," and "clearance" as the latest hotspots in the field.

Conclusion: This bibliometric analysis provides a comprehensive overview of publication trends related to mTOR and AD. Future research is anticipated to focus on refining mTOR inhibitors as a therapeutic strategy and further exploring the underlying mechanisms of AD.