Major depressive disorder (MDD) is a severe, and often treatment-resistant, psychiatric disorder. Mesenchymal stem cell-derived exosomes have been shown to be neuroprotective. Here we employed adipose-derived mesenchymal stem cell exosomes (ADSC-Exos) as a novel therapeutic approach for depressive-like behavior in mice and explored the underlying mechanisms.

ADSC-Exos were administered intranasally to mice subjected to chronic restraint stress to assess behavioral changes and neuroprotection in terms of apoptosis, AMPK-mTOR signaling, and NLRP3 pathway activation by western blotting, microglial activation by immunofluorescence, and changes in serum inflammatory factors by ELISA. The effects of ADSC-Exos were also studied in vitro in HT22 cells.

ADSC-Exos significantly improved depressive-like behavior, anxiety-like behavior, and cognitive function in mice. ADSC-Exos had significant neuroprotective effects, including reducing neuronal apoptosis and promoting autophagy by activating AMPK-mTOR signaling, ultimately reducing neuroinflammation. In vitro, ADSC-Exos inhibited corticosterone-induced apoptosis, activated autophagy in an AMPK pathway-dependent manner, and inhibited NLRP3 inflammasome activation.

ADSC-Exos may be a potential treatment for MDD by alleviating depressive-like behaviors and protecting against tissue injury, possibly through activation of AMPK-mTOR signaling and inhibition of NLRP3 inflammasome-mediated neuroinflammation.

Alzheimer's disease poses a significant global health challenge owing to the progressive cognitive decline of patients and absence of curative treatments. The current therapeutic strategies, primarily based on cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists, offer limited symptomatic relief without halting disease progression, highlighting an urgent need for novel research directions that address the key mechanisms underlying Alzheimer's disease. Recent studies have provided insights into the critical role of glycolysis, a fundamental energy metabolism pathway in the brain, in the pathogenesis of Alzheimer's disease. Alterations in glycolytic processes within neurons and glial cells, including microglia, astrocytes, and oligodendrocytes, have been identified as significant contributors to the pathological landscape of Alzheimer's disease. Glycolytic changes impact neuronal health and function, thus offering promising targets for therapeutic intervention. The purpose of this review is to consolidate current knowledge on the modifications in glycolysis associated with Alzheimer's disease and explore the mechanisms by which these abnormalities contribute to disease onset and progression. Comprehensive focus on the pathways through which glycolytic dysfunction influences Alzheimer's disease pathology should provide insights into potential therapeutic targets and strategies that pave the way for groundbreaking treatments, emphasizing the importance of understanding metabolic processes in the quest for clarification and management of Alzheimer's disease.

Major depressive disorder (MDD) presents as a multifaceted syndrome with complex pathophysiology and variable treatment responses, posing significant challenges in clinical management. Neuroinflammation is known to play pivotal mechanism in depression, linking immune responses with central nervous system (CNS) dysfunction. This review explores the interplay between peripheral and central inflammatory processes in MDD, emphasizing discrepancies in biomarker validity and specificity. While peripheral markers like cytokines have historically been investigated as proxies for neuroinflammation, their reliability remains contentious due to inconsistent findings, lack of correlation with neuroinflammatory markers, the influence of confounding variables, and the role of regulatory mechanism within the CNS. Additionally, the human brain shows a pattern of regionalized inflammation. Current methodologies for investigating neuroinflammation in humans in vivo, including neural-derived extracellular vesicles (EVs) and positron emission tomography (PET) neuroimaging using translocator protein, offer promising avenues while facing substantial limitations. We propose that future research in MDD may benefit from combined microglia-derived EV-TSPO PET neuroimaging analyses to leverage the strengths and mitigate the limitations of both individual methods.

In the pathogenesis of major depressive disorder, chronic stress-related neuroinflammation hinders favorable prognosis and antidepressant response. Mitochondrial DNA may be an inflammatory trigger, after its release from stress-induced dysfunctional central nervous system mitochondria into peripheral circulation. This evidence supports the potential use of peripheral mitochondrial DNA as a neuroinflammatory biomarker for the diagnosis and treatment of major depressive disorder. Herein, we critically review the neuroinflammation theory in major depressive disorder, providing compelling evidence that mitochondrial DNA release acts as a critical biological substrate, and that it constitutes the neuroinflammatory disease pathway. After its release, mitochondrial DNA can be carried in the exosomes and transported to extracellular spaces in the central nervous system and peripheral circulation. Detectable exosomes render encaged mitochondrial DNA relatively stable. This mitochondrial DNA in peripheral circulation can thus be directly detected in clinical practice. These characteristics illustrate the potential for mitochondrial DNA to serve as an innovative clinical biomarker and molecular treatment target for major depressive disorder. This review also highlights the future potential value of clinical applications combining mitochondrial DNA with a panel of other biomarkers, to improve diagnostic precision in major depressive disorder.

Exosomes are extracellular vesicles that carry biomolecular cargos such as proteins, lipids, RNA, and DNA. These molecules play crucial roles in cell-to-cell communication and are involved in various physiological and pathological processes. Due to their potential as biomarkers for disease diagnosis and prognosis, research has increasingly focused on developing more efficient methods for their isolation and characterization. In this study, blood samples were collected from 30 participants, and serum was subsequently isolated. Serum-derived exosomes (SDEs) were extracted using ultracentrifugation (UC) as well as the Total Exosome Isolation Reagent. Modifications to the UC method were implemented to improve yield and purity, and a detailed description of the method is also provided. The exosomes were characterized by Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM), Dynamic Light Scattering (DLS), and Western Blotting (WB) to evaluate their size, morphology, and protein content. The exosome yields from both isolation methods were evaluated using the BCA assay. Protein estimation suggested that the Total Exosome Isolation Reagent produced exosome concentrations that were 10-fold higher compared to those obtained through ultracentrifugation. Morphological analysis showed that exosomes exhibited circular, spherical, and irregular shapes, with diameters ranging from 30 to 200 nm. Western Blotting confirmed the presence of exosomal markers (TSG101, ALIX, LAMP2, and CD63) in the SDEs. In conclusion, both ultracentrifugation and the Total Exosome Isolation Reagent effectively isolate SDEs. Thus, although both methods are viable, modified ultracentrifugation is the preferred choice for applications due to its cost-effectiveness and suitability for achieving pure protein yields.

Oxidative stress and inflammatory responses play crucial roles in the development of secondary brain injury following traumatic brain injury (TBI). Thus, this study aimed to investigate the potential cerebroprotective effects of salvianolic acid B (SalB) in mitigating oxidative stress and inflammatory responses post-TBI through the activation of Nrf2.

This study aims to investigate the potential cerebroprotective effects of SalB in ameliorating oxidative stress and inflammatory responses following TBI by activating Nrf2, thereby laying a foundation for TBI treatment.

Controlled cortical impact and hydrogen peroxide were employed to replicate TBI in animal and cellular models, respectively.Behavioral studies predict neural function, Western Blot (WB) predicts oxidative stress, immunofluorescence and ELISA predict inflammatory response.The Nrf2 inhibitor ML385 was employed to investigate the involvement of the Nrf2 pathway in mediating the protective effects of SalB.

SalB was delivered via intraperitoneal injection 1 h after TBI induction, with its neuroprotective efficacy evaluated across a range of concentrations. In the cellular assay, SalB was used to incubate cells simultaneously with H2O2. WB analysis was employed to quantify protein levels, while malondialdehyde, glutathione, superoxide intensity, and reactive oxygen radical probes were utilized to evaluate oxidative stress. Immunofluorescence and ELISA techniques were used to characterize microglia phenotype and inflammatory response. Behavioral assays were also conducted to evaluate neurological function. The Nrf2 inhibitor ML385 was employed to investigate the involvement of the Nrf2 pathway in mediating the protective effects of SalB.

Animal and cellular experiments indicate that SalB can mitigate oxidative stress through the Nrf2/Peroxiredoxin 2 pathway, and reduce inflammatory response via the Nrf2/Toll-like receptor 4/Myeloid differentiation primary response protein 88 pathway in a dose-dependent manner. Consequently, SalB demonstrates efficacy in enhancing neurological function following TBI. Conversely, the inhibitory effects of ML385 counteract the antioxidant and anti-inflammatory properties of SalB.

SalB exerts its beneficial effects post-TBI through Nrf2-dependent antioxidants and as anti-inflammatory responses.

Exosomes are a class of extracellular vesicles that encompass a diverse array of bioactive molecules, including proteins, lipids, mRNA, and microRNA(miRNA). Virtually all cell types release exosomes under both physiological and pathological conditions. In addition to electrical and chemical signals, exosomes are an alternative route of signaling between cells in the brain. In the brain, they are involved in processes such as synaptic plasticity, neuronal stress response, intercellular communication, and neurogenesis. A number of studies have shown that exosomes regulate the occurrence and development of depression by participating in the regulation of hypothalamic-pituitary-adrenal axis, brain-derived neurotrophic factor, immune inflammatory response and other mechanisms, showing that they may become potential biological agents for the diagnosis and treatment of depression. In addition, exosomes have the ability to easily cross the blood-brain barrier, making them ideal drug or molecular delivery tools for the central nervous system. Engineered exosomes have good brain targeting ability, and their research in central nervous system diseases has begun to emerge. However, the molecular pathways involved in the pathogenesis of depression remain unknown, and further studies are needed to fully understand the role of exosomes in the development or improvement of depression. Therefore, in this review, we mainly focus on the diagnostic performance and therapeutic effect of exosomes in depression, and explore the advantages of exosomes as biomarkers and gene delivery vectors for depression.

Major depressive disorder (MDD) is a major global mental concern that severely affects quality of life, yet current pharmacological treatments remain limited in their effectiveness. Long-term chronic stress has been shown to increase the incidence of depression and anxiety. Micro RNAs (miRNAs) have been revealed to participate in the pathological process of depression and represent promising therapeutic targets. In this study, we found that microRNA-129-5p (miR-129-5p) was significantly decreased in the brains of depressive mice. Overexpression of miR-129-5p in the hippocampus effectively alleviated depressive-like behaviors and reduced the activation of microglial cells and astrocytes. In addition, ATP levels in depressive mice were significantly increased following miR-129-5p overexpression. The antidepressant effects of miR-129-5p were reversed when ATP function was blocked with the non-specific P2 receptor antagonist suramin. In vitro experiments revealed that miR-129-5p overexpression enhanced ATP production in astrocytes. Furthermore, using a dual-luciferase reporter assay, we found that miR-129-5p directly targeted Mysm1. When overexpressed in astrocytes, miR-129-5p significantly suppressed Mysm1 expression, promoted phosphorylation of p53 and AMPK, and enhanced the expression of PGC1α, factors previously associated with ATP production. Our findings highlight the crucial role of miR-129-5p in regulating depression, suggesting that miR-129-5p overexpression may serve as an effective strategy for antidepressant treatment.

The diagnosis and exploration of central nervous system (CNS) diseases remain challenging due to the blood-brain barrier (BBB), complex signaling pathways, and heterogeneous clinical manifestations. Neurons, as the core functional units of the CNS, play a pivotal role in CNS disease progression. Extracellular vesicles (EVs), capable of crossing the BBB, facilitate intercellular and cell-extracellular matrix (ECM) communication, making neuron-derived extracellular vesicles (NDEVs) a focal point of research. Recent studies reveal that NDEVs, carrying various bioactive substances, can exert either pathogenic or protective effects in numerous CNS diseases. Additionally, NDEVs show significant potential as biomarkers for CNS diseases. This review summarizes the emerging roles of NDEVs in CNS diseases, including Alzheimer's disease, depression, traumatic brain injury, schizophrenia, ischemic stroke, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. It aims to provide a novel perspective on developing therapeutic and diagnostic strategies for CNS diseases through the study of NDEVs.

Extracellular vesicles (EVs) are small, membrane-bound particles that are naturally released by nearly all cell types in the body. They serve as molecular biosignatures, reflecting the state of their cells of origin and providing a non-invasive peripheral marker of central nervous system (CNS) activity under physiological and pathological conditions. We conducted a systematic review (ID: CRD42024528824) of studies investigating the use of EVs in mood disorders within clinical populations. We screened articles indexed in PubMed, EMBASE, Scopus, ISI Web of Science, and APA PsycInfo from January 2010 to October 2024. Available research has focused on four key areas: (1) EV cargo as mechanistic and diagnostic biomarkers; (2) EV cargo as predictive or tracking biomarkers for antidepressant response; (3) EV cargo and neuroimaging correlates; and (4) EV physical properties. Most studies examined major depressive disorder (MDD), with others addressing bipolar disorder (BD), adolescent depression, postpartum depression, and late-life depression. Notably, only 35,55 % of the studies utilized brain-derived EVs. Through analyses of EV-derived miRNA, proteins, mtDNA, and metabolites, these studies have explored neural mitochondrial function, brain insulin resistance, neurogenesis, neuroinflammation, and blood-brain barrier permeability in the context of mood disorders. Some EV-derived markers demonstrated diagnostic and predictive potential. This review discusses key findings, limitations of current research, and future directions for leveraging EVs in the study of mood disorders.

Endogenous neurogenesis could promote stroke recovery. Furthermore, anti-inflammatory phenotypical microglia (M2-microglia) could facilitate Neural Stem Cell (NSC)-mediated neurogenesis following Ischemic Stroke (IS). Nonetheless, the mechanisms through which M2 microglia influence NSC-mediated neurogenesis post-IS remain unclear. On the other hand, M2 microglia-derived small Extracellular Vesicles (M2-sEVs) could exert phenomenal biological effects and play significant roles in cell-to-cell interactions, highlighting their potential involvement in NSC-mediated neurogenesis post-IS, forming the basis of this study.

M2-sEVs were first isolated from IL-4-stimulated microglia. For in vivo tests, M2-sEVs were intravenously injected into mice every day for 14 days after transient Middle Cerebral Artery Occlusion (tMCAO). Following that, the infarct volume and neurological function, as well as NSC proliferation in the Subventricular Zone and dentate gyrus, migration, and differentiation in the infarct area, were examined. For in vitro tests, M2-sEVs were administered to NSC subjected to Oxygen-Glucose Deprivation (OGD) and then reoxygenation, after which NSC proliferation and differentiation were assessed. Finally, M2-sEVs were subjected to microRNA sequencing to explore the regulatory mechanisms.

Our findings revealed that M2-sEVs reduced the infarct volume and increased the neurological score in mice post-tMCAO. Furthermore, M2-sEV treatment promoted NSC proliferation and neuronal differentiation both in vivo and in vitro. Additionally, microRNA sequencing revealed miR-93-5p and miR-25-3p enrichment in M2-sEVs. Inhibitors of these miRNAs prevented TGFBR, PTEN, and FOXO3 downregulation in NSC, reversing M2-sEVs' beneficial effects on neurogenesis and sensorimotor recovery.

M2-sEVs increased NSC proliferation and neuronal differentiation, and protected against IS, at least partially, via delivering miR-25-3p and miR-93-5p to downregulate TGFBR, PTEN, and FOXO3 expression in NSC.

It has been reported that L1 cell adhesion molecule (L1CAM) antibody can capture neuron-derived extracellular vesicles (NDEVs) derived from peripheral blood. This antibody is significantly associated with occurrence of adult psychiatric disorders. However, the role and mechanism of L1CAM+ EVs (L1+ EVs) in adolescent with major depressive disorder (AMDD) is not well understood. This research aimed to explore the function and potential mechanism of L1+ EVs and miRNAs genes in AMDD.

L1+ EVs derived from the serum of AMDD and healthy controls (HC) were transplanted into adolescent mice via tail vein. Their effects were explored using behavioral tests, hippocampal Nissl staining, and whole genome mRNA sequencing. MiRNAs expression in L1+ EVs was evaluated by whole-genome sequencing and qRT-PCR. Bioinformatics analysis was employed to explore the possible pathogenic molecular mechanisms of these miRNAs in AMDD.

Transplantation of L1+ EVs from AMDD induced depression-like behavior and hippocampal neuronal damage in adolescent mice and aberrant expression of 298 mRNA genes. The molecular signals related to MDD were enriched in the top pathways of the differentially expressed genes. Compared with HC, miR-375-3p and miR-200a-3p were upregulated in L1+ EVs from AMDD, miR-375-3p was also increased in the hippocampus of AMDD serum L1+ EVs-recipient mice. Bioinformatics analysis revealed that miR-375-3p might modulate the network of molecules associated with the MAPK pathway via protein interaction involving hippocampal differential genes Cadm2, Cacna2d1, and Casz1.

MiR-375-3p might contribute to L1+ EVs-induced AMDD. L1+ EVs miR-375-3p and miR-200a-3p could potentially serve as potential biomarkers for AMDD.

Mental disorders are complex conditions that encompass various symptoms and types, affecting approximately 1 in 8 people globally. They place a significant burden on both families and society as a whole. So far, the etiology of mental disorders remains poorly understood, making diagnosis and treatment particularly challenging. Extracellular vesicles (EVs) are nanoscale particles produced by cells and released into the extracellular space. They contain bioactive molecules including nucleotides, proteins, lipids, and metabolites, which can mediate intercellular communication and are involved in various physiological and pathological processes. Recent studies have shown that EVs are closely linked to mental disorders like schizophrenia, major depressive disorder, and bipolar disorder, playing a key role in their development, diagnosis, prognosis, and treatment. Therefore, based on recent research findings, this paper aims to describe the roles of EVs in mental disorders and summarize their potential applications in diagnosis and treatment, providing new ideas for the future clinical transformation and application of EVs.

Liver hepatocellular carcinoma (LIHC) is a highly aggressive cancer with poor prognosis due to its complex tumor microenvironment (TME) and immune evasion. Regulatory T cells (Tregs) play a critical role in tumor progression. Suppressor of cytokine signaling 2 (SOCS2), a key immune regulator, may modulate Treg activity and impact LIHC growth and metastasis.

To explore how the SOCS2 affects Treg activity in LIHC and its impact on tumor growth and metastasis.

LIHC transcriptome data from The Cancer Genome Atlas database were analyzed using Gene Set Enrichment Analysis, Estimation of Stromal and Immune Cells in Malignant Tumors Using Expression Data, and Cell-Type Identification by Estimating Relative Subsets of RNA Transcripts to evaluate immune pathways and Treg infiltration. Key prognostic genes were identified using Weighted Gene Co-expression Network Analysis and machine learning. In vitro, co-culture experiments, migration assays, apoptosis detection, and enzyme-linked immunosorbent assay were conducted. In vivo, tumor growth, metastasis, and apoptosis were assessed using subcutaneous and lung metastasis mouse models with hematoxylin and eosin staining, Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling, and immunohistochemistry analyses.

SOCS2 overexpression inhibited Treg cell activity, reducing LIHC cell migration and invasion while increasing apoptosis. In vivo, SOCS2 suppressed tumor growth and metastasis, confirming its therapeutic potential.

SOCS2 modulates CD4+ T function in the TME, contributing to LIHC progression. Targeting SOCS2 presents a potential therapeutic strategy for treating LIHC.

Implant-related infections (IRIs) present a significant challenge in clinical treatment because of the formation of biofilms. The complex architecture of biofilms not only impedes antibiotic penetration, fostering the evolution of multidrug resistance in bacteria under minimal selective pressure but also suppresses the antimicrobial activity of macrophages and induces their pyroptosis in large quantities. This excessive pyroptosis impairs the collective immune function of macrophages, enabling pathogens to evade immune system clearance and rendering infection difficult to eradicate. Existing treatment strategies often necessitate extensive surgical debridement, which not only causes significant harm to patients' physiological health and quality of life but also results in limited therapeutic outcomes. To address these challenges, this study developed a mesoporous silica nanoparticle system (MRL) modified with the RGD (Arginine-Glycine-Aspartic acid) tripeptide and loaded with the antimicrobial peptide LL-37. The LL-37 released from MRL can not only directly disrupt bacterial cell membranes, preventing bacteria from developing resistance through conventional mutation mechanisms, but also enhance antimicrobial activity by modulating macrophage polarization toward the M1 phenotype. However, LL-37 may induce and exacerbate macrophage pyroptosis within biofilms. Therefore, we modified the nanoparticles with RGD to increase macrophage viability and reduce their number of deaths, thereby alleviating the immunosuppression caused by excessive macrophage pyroptosis. In vitro and in vivo experiments demonstrated that MRL, while preserving the antimicrobial activity and immunomodulatory function of LL-37, significantly reduced macrophage pyroptosis and protected the collective immune activity of macrophages. Thus, the fine-tuned regulation of immune response was achieved, providing new insights and strategies for the treatment of IRIs.

The presence of a neurogenic bladder is a severe but common complication of spinal cord injury (SCI). Multiple pathological factors, such as hypoxia, ischemia, and oxidative stress caused by SCI, promote M1 microglial polarization and the release of proinflammatory factors to amplify inflammation. An excessive inflammatory response stimulates the generation of reactive oxygen species (ROS) and induces oxidative stress to promote neuronal ferroptosis, thus leading to bladder dysfunction after SCI. Therefore, promoting the recovery of neural function by regulating the interaction between microglia and neurons is important. For this purpose, we developed an engineered immunoregulatory cyanobacterial capsule named siRNA@Cyanzyme, which consists of MnO2@zeolitic-imidazolate framework@cyanobacteria (Cyanzyme) and a small-interfering RNA targeting ACSL4 (siRNA-ACSL4). Cyanzyme reversed M1 microglial polarization via photosynthetic oxygen to promote anti-inflammatory factor release. MnO2 nanoenzymes grown on the surface of ZIF-8 eliminated excessive ROS to reduce oxidative stress. Moreover, Cyanzyme increased the delivery efficiency of siRNA-ACSL4, which is a key regulator of ferroptosis. Both treatments alleviated GABAergic neuron damage to mitigate bladder dysfunction. Our data demonstrated that siRNA@Cyanzyme effectively reversed M1 microglial polarization, reduced neuronal ferroptosis, and ultimately restored neurogenic bladder function.

Non-coding RNAs (ncRNAs) have gained significant attention in recent years due to advancements in biotechnology, particularly high-throughput total RNA sequencing. These developments have led to new understandings of non-coding biology, revealing that approximately 80% of non-coding regions in the genome possesses biochemical functionality. Among ncRNAs, circular RNAs (circRNAs), first identified in 1976, have emerged as a prominent research field. CircRNAs are abundant in most human cell types, evolutionary conserved, highly stable, and formed by back-splicing events which generate covalently closed ends. Notably, circRNAs exhibit high expression levels in neural tissue and perform diverse biochemical functions, including acting as molecular sponges for microRNAs, interacting with RNA-binding proteins to regulate their availability and activity, modulating transcription and splicing, and even translating into functional peptides in some cases. Recent advancements in computational and experimental methods have enhanced our ability to identify and validate circRNAs, providing valuable insights into their biological roles. This review focuses on recent developments in circRNA research as they related to neuropsychiatric and neurodegenerative conditions. We also explore their potential applications in clinical diagnostics, therapeutics, and future research directions. CircRNAs remain a relatively underexplored area of non-coding biology, particularly in the context of neurological disorders. However, emerging evidence supports their role as critical players in the etiology and molecular mechanisms of conditions such as schizophrenia, bipolar disorder, major depressive disorder, Alzheimer's disease, and Parkinson's disease. These findings suggest that circRNAs may provide a novel framework contributing to the molecular dysfunctions underpinning these complex neurological conditions.

Hypertension-related Depression (HD) is a complex mental disorder that exerts a significant negative impact on patients' quality of life. Previous studies have demonstrated that damages to vascular endothelial and hippocampus are the primary pathological features in HD rats. Under hypertensive conditions, inflammatory cytokines in peripheral blood vessels can induce central nervous system inflammation through penetration of a damaged blood-brain barrier, peripheral immune cells, and neural pathways, damaging the brain and triggering HD. Therefore, interactions between vascular endothelial cells, neurons, and glial cells are critical for the understanding of HD. However, in vivo animal models are often limited by the complexity of intrinsic systems, high inter-individual variability, and stringent ethical regulations. A reliable model that could be easily manipulated is needed for investigating the mechanisms involved in communication between vascular endothelial cells, neurons, and glial cells in HD. We therefore aimed to create a composite tri-culture model consisting of rat aortic endothelial cells (RAECs), neurons, and microglia to study HD. First, RAECs were stimulated with lipopolysaccharide to mimic endothelial injury under hypertensive conditions. Vascular endothelial function and inflammatory levels were assessed using fluorescent probes and enzyme-linked immunosorbent assays. RAECs treated with 1 μg/ml LPS for 24 h had reduced levels of nitric oxide, increased levels of endothelin-1 and inflammatory mediators. These findings are consistent with the endothelial dysfunction and inflammatory responses observed in spontaneously hypertensive rats, which suggests that the lipopolysaccharide-induced RAECs model effectively mimics key pathological features of hypertension-related endothelial injury. Subsequently, the supernatants from lipopolysaccharide-induced RAECs were combined with 200 μM corticosterone and transferred to neuron-microglia co-cultures to simulate damages to hippocampal neuron under HD conditions. To evaluate the features of cells, neuronal viability was measured by CCK-8 and live-dead assays. Nissl staining was used to assess neuronal Nissl bodies, while the levels of inflammatory factors and monoamine neurotransmitters in the culture supernatants were evaluated by enzyme-linked immunosorbent assays. Reactive oxygen species in neurons were visualized by a fluorescent probe, apoptosis was detected using TUNEL assays, and immunofluorescence was used to assess microglial phenotypes and the levels of TLR4 and NF-κB. It was found that neurons in the tri-culture model had reduced viability, higher levels of apoptosis, fewer Nissl bodies, increased inflammation, and reduced levels of monoamine neurotransmitters. Additionally, the number of M1 microglia was increased, along with elevated levels of TLR4 and NF-κB proteins. These findings were similar to damages of hippocampal neuron, abnormal levels of monoamine neurotransmitters, microglia polarization, and hippocampal inflammatory response observed in the HD rat model. In conclusion, our findings indicate that the tri-culture model can effectively simulate the pathological characteristics of HD, especially in vascular endothelial damage, neuroinflammation, monoamine neurotransmitters disorders. Therefore, the tri-culture model would provides a reliable and invaluable experimental tool for further research on the pathogenesis and treatment of HD.

Acute brain injuries (ABI) caused by various emergencies can lead to structural and functional damage to brain tissue. Common causes include traumatic brain injury, cerebral hemorrhage, ischemic stroke, and heat stroke. Globally, ABI represent a significant portion of neurosurgical cases. Previous studies have emphasized the significant therapeutic potential of stem cell-derived extracellular vesicles (EVs). Recent research indicates that EVs extracted from resident cells in the central nervous system (CNS) also show therapeutic potential following brain injury. Microglia, as innate immune cells of the CNS, respond to changes in the internal environment by altering their phenotype and secreting EVs that impact various CNS cells, including neurons, astrocytes, oligodendrocytes, endothelial cells, neural stem cells (NSCs), and microglia themselves. Notably, under different external stimuli, microglia can either promote neuronal survival, angiogenesis, and myelin regeneration while reducing glial scarring and inflammation, or they can exert opposite effects. This review summarizes and evaluates the current research findings on how microglia-derived EVs influence various CNS cells after ABI under different external stimuli. It analyzes the interaction mechanisms between EVs and resident CNS cells and discusses potential future research directions and clinical applications.

Depression is a prevalent mental disorder that affects numerous individuals, manifesting as persistent anhedonia, sadness, and hopelessness. Despite extensive research, the exact causes and optimal treatment approaches for depression remain unclear. Extracellular vesicles (EVs), which carry biological molecules such as proteins, lipids, nucleic acids, and metabolites, have emerged as crucial players in both pathological and physiological processes. EVs derived from various sources exert distinct effects on depression. Specifically, EVs released by neurons, astrocytes, microglia, oligodendrocytes, immune cells, stem cells, and even bacteria contribute to the pathogenesis of depression. Moreover, there is growing interest in potential of EVs as diagnostic and therapeutic tools for depression. This review provides a comprehensive overview of recent research on EVs from different sources, their roles in depression, and their potential clinical applications.

Cerebrovascular disease (CVD) is a significant neurological condition resulting from pathological changes in the brain's blood supply and is currently the leading cause of death and disability worldwide. The progression of CVD is closely associated with endothelial damage, plaque formation, and thrombosis, driven by long-term alterations in vascular endothelial cells, smooth muscle cells, microglia, and other immune-inflammatory cells. Among the key molecular pathways involved, the Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling pathway plays a central role. Dysregulation of the JAK-STAT pathway is implicated in the pathogenesis of CVD by influencing the aforementioned cell types and associated pathological processes. Importantly, the role of the JAK-STAT pathway varies across different types of CVD and throughout different stages of disease progression (e.g., pre-morbid, acute, and chronic phases). This review examines the composition, activation, and regulation of the JAK-STAT pathway and summarizes recent findings on its involvement in CVD. We discuss the distinct roles of JAK-STAT signaling in various CVD conditions, the potential reasons for these differences, and explore the clinical translational prospects and technical challenges of targeting the JAK-STAT pathway for therapeutic intervention in CVD.

Current treatments for ischemic stroke aim to achieve rapid reperfusion with intravenous thrombolysis and/or endovascular thrombectomy, which have proven to attenuate disability. Despite the significant progress in reperfusion therapies, functional recovery remains inconsistent, primarily due to ongoing neuronal excitotoxicity and neuroinflammation. In this study we investigated the relationship between neuronal activity and neuroinflammation in an ischemic mouse model using chemogenetic techniques. MCAO cerebral ischemia model was established in mice; in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) was established in PC12 neurons. By measuring c-Fos expression, we showed that MCAO caused the activation of both excitatory and inhibitory neurons within the M1 primary motor cortex, which subsequently induced reactive activation of local microglia through the secretion of unique neuronal extracellular vesicles (EVs). Chemogenetic inhibition of abnormal neuronal activity in stroke-affected cortical neurons reversed microglia activation and reduced neuronal apoptosis. By analyzing the miRNAs in EVs from the ischemic M1 cortex, we found that miR-128-3p was significantly downregulated in ischemia-challenged neurons and their EVs, leading to neuronal injury and proinflammatory polarization of microglia. Intravenous injection of miR-128-3p mimics significantly improved neuronal survival, reduced neuroinflammation accompanied by better functional recovery after ischemic stroke. In summary, stroke-induced abnormal neuronal activity reduces miR-128-3p levels in ischemic neurons and EVs, leading to increased microglia activation and neuronal injury after a stroke. The study highlights that inhibiting abnormal neuronal activity or delivering miR-128-3p-enriched EVs as novel methods for stroke treatment.

Amoxicillin is a widely used antibiotic globally, and its pervasive environmental presence poses significant risks to human health and ecosystems. Notably, prenatal amoxicillin exposure (PAmE) may have long-term neurodevelopmental toxicity for offspring. In this study, we investigated the lasting effects of PAmE on depressive-like behaviors in offspring rats, emphasizing the biological mechanisms mediated by changes in gut microbiota and its metabolite, myristic acid. Our results showed that PAmE significantly disrupted the gut microbiota composition in offspring, particularly through the reduction of Lachnospiraceae, leading to decreased levels of myristic acid. This disruption hindered the N-myristoylation of ADP-ribosylation factor 1 (ARF1), impaired the normal degradation of the stimulator of interferon genes protein, inhibited autophagic processes, and promoted M1 polarization of microglia, ultimately leading to depressive-like behaviors in the offspring. Remarkably, supplementation with Lachnospira or myristic acid effectively reversed the PAmE-induced neurodevelopmental and behavioral abnormalities, alleviating depressive-like symptoms. This study reveals how PAmE affects offspring neurodevelopment and behavior through gut microbiota and myristic acid, highlighting the crucial role of the gut-brain axis in the modulation of depressive symptoms. Supplementing Lachnospira or myristic acid could represent a novel strategy to mitigate PAmE-induced fetal-originated depression, providing new biological evidence and potential therapeutic avenues.

Bipolar disorder (BD) is psychiatric disorder of not fully acknowledged pathophysiology. Studies show the involvement of innate-immune system activation and inflammation in BD course and treatment efficiency. Microglia are crucial players in the inflammatory response possibly responsible for BD innate-immune activity. Lithium is a mood stabilizer used in treatment for 75 years. Immunomodulation was previously described as one of the potential modes of its action. We hypothesized that lithium might modulate the microglia response to innate-immune-associated cytokines (10 ng/mL TNF-α, 50 ng/mL IL-1β, 20 ng/mL IFN-γ). We aimed to investigate whether lithium treatment and pretreatment of microglia modify the expression of genes associated with NLRP3 inflammasome. We also aimed to verify lithium treatment effect on caspase activity and extracellular IL-1β concentration. For the first time, our study used human microglial cell line - HMC3, the cytokine stimuli and lithium in concentration corresponding to that in the brains of patients. To analyze lithium mode of action, we analyzed the short- and long-term treatment and pretreatment. To assess the influence on microglia responding to innate-immune cytokines, we analyzed the expression of genes involved in innate-immune and inflammasome (TSPO, TLR4, NFKB1, CASP1, CASP4, NLRP3, IL-1β, IL-6), caspase activity, extracellular IL-1β concentration, phospho-GSK-3β(Ser9) expression and lactate concentration. We found that lithium treatment significantly reduced NLRP3 inflammasome-related genes expression. We observed that lithium treatment reduces inflammasome activity, which may attenuate the inflammatory state. Interestingly, the lithium pretreatment resulted in significantly elevated inflammasome activity, suggesting that lithium does not impair the immune response to additional stimuli.

Major depressive disorder (MDD) is usually considered associate with immune inflammation and synaptic injury within specific brain regions. However, the molecular mechanisms underlying the neural deterioration resulting in depression remain unclear. Here, it is found that miR-204-5p is markedly downregulated in the ventromedial prefrontal cortex (vmPFC) in a chronic unpredictable mild stress (CUMS) induce rat model of depression. Knockdown of miR-204-5p in the vmPFC of normal rats results in depression and anxiety-like behaviors accompanied with the activation of microglia, elevated levels of pro-inflammatory cytokines, and increased numbers of neural apoptotic cells, effects which appear to be mediated by activation of the JAK2/STAT3 signaling pathway. Electrophysiological recordings further demonstrate that knockdown of miR-204-5p induces abnormal excitability of pyramidal neurons. In contrast, upregulation of miR-204-5p in the vmPFC of CUMS rats significantly causes inhibition of JAK2/STAT3 signaling pathway, improvements in neuronal impairments, and an abolition of the depression and anxiety-like behaviors. Moreover, pharmacological blocking of the JAK2/STAT3 signaling pathway significantly ameliorates abnormal behaviors resulting from miR-204-5p deficiency within the vmPFC. Collectively, these results provide robust evidence that the miR-204-5p/JAK2/STAT3 pathway may critically involve in the pathogenesis of depression, which may serve as potentially critical therapeutic target in the treatment of MDD.

Major depressive disorder (MDD) is considered a psychiatric disorder and have a relationship with stressful events. Although the common therapeutic approaches against MDD are diverse, a large number of patients do not present an adequate response to antidepressant treatments. On the other hand, effective non-pharmacological treatments for MDD and their tolerability are addressed. Several affective treatments for MDD are used but non-pharmacological strategies for decreasing the common depression-related drugs side effects have been focused recently. However, the potential of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs), microRNAs (miRNAs) as cell-based therapeutic paradigms, besides other non-pharmacological strategies including mitochondrial transfer, plasma, transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS), and exercise therapy needs to further study. This review explores the therapeutic potential of cell-based therapeutic non-pharmacological paradigms for MDD treatment. In addition, plasma therapy, mitotherapy, and exercise therapy in several in vitro and in vivo conditions in experimental disease models along with tDCS and TMS will be discussed as novel non-pharmacological promising therapeutic approaches.

Exosomes, which are small extracellular vesicles (sEVs), serve as versatile regulators of intercellular communication in the progression of various diseases, including neurological disorders. Among the diverse array of cargo they carry, non-coding RNAs (ncRNAs) play key regulatory roles in various pathophysiological processes. Exosomal ncRNAs derived from distinct cells modulate their reciprocal crosstalk locally or remotely, thereby mediating neurological diseases. Nevertheless, the emerging role of exosomal ncRNAsin microglia-mediated phenotypes remains largely unexplored. This review aims to summarise the biological functions of exosomal ncRNAs and the molecular mechanisms that underlie their impact on microglia-mediated intercellular communication, modulating neuroinflammation and synaptic functions within the landscape of neurological disorders. Furthermore, this review comprehensively described the potential applications of exosomal ncRNAs as diagnostic and prognostic biomarkers, as well as innovative therapeutic targets for the treatment of neurological diseases.

The relationship between neuroinflammation and depression is a complex area of research that has garnered significant attention in recent years. Neuroinflammation, characterized by the activation of glial cells and the release of pro-inflammatory cytokines, has been implicated in the pathophysiology of depression. The relationship between neuroinflammation and depression is bidirectional; not only can inflammation contribute to the onset of depressive symptoms, but depression itself can also exacerbate inflammatory responses, creating a vicious cycle that complicates treatment and recovery. The present comprehensive review aimed to explore the current findings on the interplay between neuroinflammation and depression, as well as the mechanisms, risk factors, and therapeutic implications. The mechanisms by which neuroinflammation induces depressive-like behaviors are diverse. Neuroinflammation can increase pro-inflammatory cytokines, activate the hypothalamus-pituitary-adrenal (HPA) axis, and impair serotonin synthesis, all of which contribute to depressive symptoms. Furthermore, the activation of microglia has been linked to the release of inflammatory mediators that can disrupt neuronal function and contribute to mood disorders. Stress-induced neuroinflammatory responses can lead to the release of pro-inflammatory cytokines that not only affect brain function but also influence behavior and mood. Understanding these mechanisms is crucial for developing targeted therapies that can mitigate the effects of neuroinflammation on mood disorders.

Glial cell polarization plays a pivotal role in various neurological disorders. In response to distinct stimuli, glial cells undergo polarization to either mitigate neurotoxicity or facilitate neural repair following injury, underscoring the importance of glial phenotypic polarization in modulating central nervous system function. This review presents an overview of glial cell polarization, focusing on astrocytes and microglia. It explores the involvement of glial polarization in neurological diseases such as Alzheimer's disease, Parkinson's disease, stroke, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis and meningoencephalitis. Specifically, it emphasizes the role of glial cell polarization in disease pathogenesis through mechanisms including neuroinflammation, neurodegeneration, calcium signaling dysregulation, synaptic dysfunction and immune response. Additionally, it summarizes various therapeutic strategies including pharmacological treatments, dietary supplements and cell-based therapies, aimed at modulating glial cell polarization to ameliorate brain dysfunction. Future research focused on the spatio-temporal manipulation of glial polarization holds promise for advancing precision diagnosis and treatment of neurological diseases.

Vascular dementia (VaD) includes a group of brain disorders that are characterized by cerebrovascular pathology.Neuroinflammation, disruption of the blood-brain barrier (BBB) permeability, white matter lesions, and neuronal loss are all significant pathological manifestations of VaD and play a key role in disease progression. Necroptosis, also known asprogrammed necrosis, is a mode of programmed cell death distinct from apoptosis and is closely associated with ischemic injury and neurodegenerative diseases. Recent studies have shown that necroptosis in VaD exacerbates BBB destruction, activates neuroinflammation, promotes neuronal loss, and severely affects VaD prognosis.

In this review, we outline the significant roles of necroptosis and its molecular mechanisms in the pathological process of VaD, with a particular focus on the role of necroptosis in modulating neuroinflammation and exacerbating the disruption of BBB permeability in VaD, and elaborate on the molecular regulatory mechanisms and the centrally involved cells of necroptosis mediated by tumor necrosis factor-α in neuroinflammation in VaD. We also analyze the possibility and specific strategy that targeting necroptosis would help inhibit neuroinflammation and BBB destruction in VaD. With a focus on necroptosis, this study delved into its impact on the pathological changes and prognosis of VaD to provide new treatment ideas.

Major depressive disorder (MDD), as a multimodal neuropsychiatric and neurodegenerative illness with high prevalence and disability rates, has become a burden to world health and the economy that affects millions of individuals worldwide. Neuroinflammation, an atypical immune response occurring in the brain, is currently gaining more attention due to its association with MDD. Microglia, as immune sentinels, have a vital function in regulating neuroinflammatory reactions in the immune system of the central nervous system. From the perspective of steady-state branching states, they can transition phenotypes between two extremes, namely, M1 and M2 phenotypes are pro-inflammatory and anti-inflammatory, respectively. It has an intermediate transition state characterized by different transcriptional features and the release of inflammatory mediators. The timing regulation of inflammatory cytokine release is crucial for damage control and guiding microglia back to a steady state. The dysregulation can lead to exorbitant tissue injury and neuronal mortality, and targeting the cellular signaling pathway that serves as the regulatory basis for microglia is considered an essential pathway for treating MDD. However, the specific intervention targets and mechanisms of microglial activation pathways in neuroinflammation are still unclear. Therefore, the present review summarized and discussed various signaling pathways and effective intervention targets that trigger the activation of microglia from its branching state and emphasizes the mechanism of microglia-mediated neuroinflammation associated with MDD.

Sepsis is a severe, potentially fatal condition defined by organ dysfunction due to excessive inflammation. Its complex pathogenesis and poor therapeutic outcomes pose significant challenges in treatment. Macrophages, with their high heterogeneity and plasticity, play crucial roles in both the innate and adaptive immune systems. They can polarize into M1-like macrophages, which promote pro-inflammatory responses, or M2-like macrophages, which mediate anti-inflammatory responses, positioning them as critical mediators in the immune response during sepsis.Macrophages are the main regulators of inflammatory responses, and their polarization is also regulated by inflammatory signaling pathways. This review highlights recent advances in the inflammatory signaling pathways involved in sepsis, mechanism of macrophage polarization mediated by inflammation-related signaling pathways in sepsis, and the role of signaling pathway mediated macrophage polarization in organ dysfunction involved in sepsis. We also explore the therapeutic potential of targeting macrophage polarization for immunotherapy, offering new perspectives on macrophage-targeted treatments for sepsis.

Phosphoinositide 3-kinase γ (PI3Kγ) is a signaling protein that is constitutively expressed in immune competent cells and plays a crucial role in cell proliferation, apoptosis, migration, deformation, and immunology. Several studies have shown that high expression of PI3Kγ can inhibit the occurrence of inflammation in microglia while also regulating the polarization of microglia to inhibit inflammation and enhance microglial migration and phagocytosis. It is well known that the regulation of microglial polarization, migration, and phagocytosis is key to the treatment of most neurodegenerative diseases. Therefore, in this article, we review the important regulatory role of PI3Kγ in microglia to provide a basis for the treatment of neurodegenerative diseases.

Major depressive disorder (MDD) is a prevalent mental illness and showed a strong link with inflammation. Microglia, as the main resident immune cells, play an important role in the occurrence and development of depression. Circular RNA PTP4A2 (circPTP4A2) was highly expressed in microglia inflammation induced by oxygen glucose deprivation/reperfusion. However, whether circPTP4A2 involves in microglia inflammation in MDD is not clear. Here, chronic unpredictable stress (CUS) induced depressive behaviors and microglia activation in mouse hippocampus, accompanied by the elevated expression of circPTP4A2. Knockdown circPTP4A2 in mouse hippocampus ameliorated depressive-like behaviors and microglia activation. Moreover, CUS promoted phosphorylation of ERK, JNK and P38 in mouse hippocampus as same as LPS-exposed BV2 microglia. Only P38 phosphorylation was inhibited by circPTP4A2 knockdown in the hippocampus. P38 inhibitor, sb203580, repressed circPTP4A2 overexpression-induced inflammatory reaction in BV2 cells. These findings suggest that circPTP4A2 promotes depressive-like behaviors and microglia activation via P38 phosphorylation.

Extracellular vesicles (EVs) are lipid bilayer nanoparticles released from all known cells and are involved in cell-to-cell communication via their molecular content. EVs have been found in all tissues and body fluids, carrying a variety of biomolecules, including DNA, RNA, proteins, metabolites, and lipids, offering insights into cellular and pathophysiological conditions. Despite the emergence of EVs and their molecular contents as important biological indicators, it remains difficult to explore EV-mediated biological processes due to their small size and heterogeneity and the technical challenges in characterizing their molecular content. EV-associated small RNAs, especially microRNAs, have been extensively studied. However, other less characterized RNAs, including protein-coding mRNAs, long noncoding RNAs, circular RNAs, and tRNAs, have also been found in EVs. Furthermore, the EV-associated proteins can be used to distinguish different types of EVs. The spectrum of EV-associated RNAs, as well as proteins, may be associated with different pathophysiological conditions. Therefore, the ability to comprehensively characterize EVs' molecular content is critical for understanding their biological function and potential applications in disease diagnosis. Here, we set out to provide an overview of EV-associated RNAs and proteins as well as approaches currently being used to characterize them.

Triolein, a symmetric triglyceride exhibiting anti-inflammatory and antioxidant properties, has demonstrated potential in mitigating cellular damage. However, its therapeutic efficacy in ischemic stroke (IS) and underlying molecular mechanisms remain elusive. Given the critical roles of inflammation and autophagy in IS pathogenesis, this study aimed to elucidate the effects of triolein in IS and investigate its mechanism of action.

We evaluated the impact of triolein using both in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) and in vivo middle cerebral artery occlusion (MCAO/R) models. Neurological function and cerebral infarct volume were assessed 72 h post-reperfusion. Autophagy was quantified through monodansyl cadaverine (MDC) labeling of autophagic vesicles and Western blot analysis of autophagy-related proteins. Microglial activation was visualized via immunofluorescence, while inflammatory cytokine expression was quantified using RT-qPCR. The cytoprotective effect of triolein on OGD/R-induced HT22 cells was evaluated using Cell Counting Kit-8 and lactate dehydrogenase release assays. The involvement of the Protein kinase B/Mechanistic target of rapamycin kinase (AKT/mTOR) pathway was assessed through Western blot analysis.

Triolein administration significantly reduced infarct volume, enhanced neurological recovery, and attenuated M1 microglial activation and inflammation in MCAO/R-induced mice. Western blot analysis and MDC labeling revealed that triolein exerted an inhibitory effect on post-IS autophagy. Notably, in the BV2-induced OGD/R model, triolein demonstrated an autophagy-dependent suppression of the inflammatory response. Furthermore, triolein inhibited the activation of the AKT/mTOR signaling pathway, consequently attenuating autophagy and mitigating the post-IS inflammatory response.

This study provides novel evidence that triolein exerts neuroprotective effects by inhibiting post-stroke inflammation through an autophagy-dependent mechanism. Moreover, the modulation of the AKT/mTOR signaling pathway appears to be integral to the neuroprotective efficacy of triolein. These findings elucidate potential therapeutic strategies for IS management and warrant further investigation.

The incessant communication that takes place between microglia and neurons is essential the development, maintenance, and pathogenesis of the central nervous system (CNS). As mobile phagocytic cells, microglia serve a critical role in surveilling and scavenging the neuronal milieu to uphold homeostasis.

This review aims to discuss the various mechanisms that govern the interaction between microglia and neurons, from the molecular to the organ system level, and to highlight the importance of these interactions in the development, maintenance, and pathogenesis of the CNS.

Recent research has revealed that microglia-neuron interaction is vital for regulating fundamental neuronal functions, such as synaptic pruning, axonal remodeling, and neurogenesis. The review will elucidate the intricate signaling pathways involved in these interactions, both direct and indirect, to provide a better understanding of the fundamental mechanisms of brain function. Furthermore, gaining insights into these signals could lead to the development of innovative therapies for neural disorders.

The objective of this study is to investigate the impact of ferroptosis on depression and elucidate the molecular mechanism underlying melatonin's inhibitory effect on ferroptosis in the treatment of depression.

In this study, a depression-like behavior model was induced in mice using LPS, and the effect of melatonin on depression-like behavior was evaluated through behavioral experiments (such as forced swimming test (FST) and sucrose preference test (SPT)). Additionally, molecular biological techniques (including real-time fluorescence quantitative PCR, Western blotting, immunoprecipitation) were employed to detect the expression levels and interactions of METTL3, SIRT6 and ferroptosis-related genes in mouse brain tissue. Furthermore, both in vitro and in vivo experiments were conducted to verify the regulatory effect of melatonin on Nrf2/HO-1 pathway and explore its potential molecular mechanism for regulating ferroptosis.

Melatonin was found to significantly ameliorate depression-like behavior in mice, as evidenced by reduced immobility time in the forced swimming test and increased sucrose intake in the sucrose preference test. Subsequent investigations revealed that melatonin modulated SIRT6 stability through METTL3-mediated ubiquitination of SIRT6, leading to its degradation. As a deacetylase, SIRT6 plays a pivotal role in cellular metabolism regulation and antioxidative stress response. This study elucidated potential signaling pathways involving Nrf2/HO-1 through which SIRT6 may exert its effects.

The findings suggest that melatonin can improve depressive behavior by suppressing ferroptosis and protecting neurons through its antioxidant properties. Additionally, targeting the Nrf2/HO-1 pathway via METTL3 and NEDD4 regulation may be a potential therapeutic approach for depression.