Stroke remains a major global health challenge due to its high mortality and significant socioeconomic burden. Despite advances in clinical management, effective diagnostic tools and therapeutic strategies remain limited. This study aimed to identify and expand the repertoire of biomarkers of damage and repair that could serve as potential diagnostic and prognostic tools across post-stroke phases. Twenty-three male wild-type mice were assigned according to three longitudinal time points to control pre-stroke, 24-hour acute, and 35-day chronic post-stroke groups. Ischemic injury was induced via a 30-minute middle cerebral artery occlusion Koizumi method. Magnetic resonance imaging and neurological scoring were used to assess lesion size and functional deficit acutely, as well as structural and functional recovery during the chronic phase. Proteomic profiling of the ipsilateral and contralateral cortices was performed using data-independent acquisition (DIA)-based MS method. Statistical analysis revealed 74 differentially expressed proteins showing significant temporal changes in expression, which were classified into four temporal expression clusters: acutely and chronically upregulated, acutely upregulated and chronically downregulated, acutely downregulated and chronically upregulated, and acutely and chronically downregulated. Gene ontology analysis identified 47 affected biological processes, including synaptic signaling, immune response, cell-cell communication, cytoskeletal organization, and proliferation. Thirteen proteins previously not associated with stroke pathophysiology were identified, including 10 from the ipsilateral cortex (Dbi, Cpne3, Dnm2, Eef1a1, Taldo1, Pgls, Gnb5, Phf24, Ctsz, Capg) and 3 from the contralateral cortex (Agpat3, Cacng8, Endod). The identified biomarkers provide novel molecular insights into post-stroke energy metabolism, neuroinflammation, and cellular remodeling, highlighting potential targets for further intervention.

HIV-1-associated neurocognitive disorders (HAND) are highly prevalent in the era of combination of antiretroviral therapies. Recent studies suggest that damage of blood-brain barrier (BBB) may serve as an early biomarker of cognitive dysfunction in people living with HIV. This is due to the ability of HIV-1, along with infected monocytes and macrophages, to traverse the BBB via either paracellular or transcellular way. HIV-1 viral proteins have been shown to disrupt tight junctions within the BBB, thereby directly compromising its structural and functional integrity. This study determined the effects of the HIV-1 transactivator of transcription (Tat) protein on the morphological profiles and gene expression of mouse prefrontal cortex endothelial cells (ECs) and human brain microvascular endothelial cells (HBMVEC). Both mouse ECs and HBMVEC were exposed in vitro to 12.5 nM recombinant Tat for 48 h. After treatment, cells were immunostained with CD31, DAPI or phalloidin, and harvested for RNA sequencing to access changes in gene expression. Staining results showed a reduction in CD31 expression accompanied by an increase in phalloidin staining intensity in both mouse ECs and HBMVECs after Tat exposure. Moreover, the phalloidin staining revealed disruption of actin cytoskeleton structure in both mouse ECs and HBMVECs after Tat exposure. RNA sequencing analysis of mouse ECs and HBMVECs exposed to Tat displayed strikingly comparable transcriptomic signatures, as confirmed by gene set enrichment analysis (GSEA). In particular, both mouse ECs and HBMVECs showed significant upregulation of hallmark inflammatory response pathways following Tat exposure. These findings provide mechanistic insight into HIV-1 Tat drives endothelial injury, leading to both morphological and transcriptional alterations.

The interaction between lipid droplet (LD) metabolism and immune polarisation of microglia after stroke plays a key role in the regulation of neuroinflammation and tissue repair. This review analysed the molecular mechanism, spatiotemporal specificity, and the dual role of the LD metabolism-immune axis in microglia after stroke. Microglial LDs can dynamically store neutral lipids and regulate the metabolite-immune network, playing a protective role in the early stage of stroke by isolating pro-inflammatory precursors, inhibiting oxidative stress and iron death, and maintaining energy buffer. Spatiotemporal analysis revealed significant heterogeneity in the distribution and function of LDs across different stages of stroke and in distinct brain areas (infarct core, peri-infarct region, and non-infarct area), directly correlating with the pro-inflammatory/anti-inflammatory phenotypic transformation of microglia. The development of LD-related biomarkers (such as near-infrared imaging), the repurpose of peroxisome proliferator-activated receptor γ agonists (rosiglitazone) and HDAC inhibitors (volinostat), as well as the design of novel drugs (such as Triggering Receptor Expressed on Myeloid Cells 2 agonists and perilipin 2 small interfering RNA) are expected to improve stroke outcomes by transforming metabolic homeostasis and immune balance. Multi-omics technology and intelligent delivery system should be combined to overcome the limitations of the blood-brain barrier, promote the clinical transformation of the "metabolism-immunity" collaborative intervention strategy, and provide a new paradigm for precision treatment of stroke.

Perineuronal nets (PNNs) are key regulators of neuronal excitability, yet whether they are altered during neurogenic hypertension is unknown. Here, we mapped the developmental trajectory of PNNs in the paraventricular nucleus of the hypothalamus (PVN), a crucial nucleus involved in blood pressure (BP) regulation, and examined their modulation in neurogenic hypertension. We show that PNNs in the PVN follow a developmental pattern similar to other brain regions. The most prevalent neuron subtype enwrapped by PNNs was neuronal nitric oxide synthase (nNOS)-expressing neurons in both sexes, and sex differences were observed only in oxytocin (OXT)-enwrapped neurons. In the DOCA-salt mouse model of neurogenic hypertension, males, but not females, exhibit an increased number and area of PNNs in the PVN with increased excitatory/inhibitory (E/I) ratio. Given that PNNs modulate neuronal activity, our findings may implicate recruitment of previously "silent" neurons as potential contributors of PVN hyperactivity in hypertension. These results demonstrate that PNN remodeling is associated with neurogenic hypertension in male mice.

Stroke is a health problem all over the world. It is a primary cause of disability and ranked number two death cause. In kingdom of Saudi Arabia KSA, the prevalence of stroke in the KSA estimated to be more than 40 per 100 thousand in 2021. The incidence of stroke is increasing in KSA. The risk factors for stroke are grouped into modifiable and nonmodifiable. The modifiable risk factors include diabetes, hyperlipidemia physical inactivity, and diet, whereas the nonmodifiable include sex, age, and race/ethnicity. Decreasing the modifiable risk factors reduces the burden of stroke in population. The long noncoding RNAs (LncRNAs) ANRIL is suggested as a biomarker and treatment target for stroke. The Transcription factor 7-like 2 (TCF7L2) has crucial roles in biological and pathological processes such as inflammation, metabolism, and atherosclerosis. In this study, we examined the associations of ANRIL rs1333045 C>T, CYP2C19*17 (C806T, rs12248560C>T, and TCF7L2 rs12255372 G>T with stroke in 100 stroke cases and 100 matched healthy controls from Tabuk population using the amplification refractory mutation system PCR (ARMS-PCR). Results indicated that the T allele of the ANRIL rs1333048 C>T was associated with stroke with Odd ratio (OR) = 1.73, P value-0.0067. Likewise, the GT genotype and the T allele of the TCF7L2 rs12255372 G>T were associated with stroke with OR = 2.14, P value = 0.01, and 1.9, P value = 0.004, respectively. In addition, the CT genotype and T allele of the CYP2C19*17 (rs12248560) C>T were also associated stroke with OR = 2, P value = 0.02 and OR = 2.3, P value = 0.002, respectively. We conclude that ANRIL rs1333045 C>T, CYP2C19*17 (C806T, rs12248560C>T, and TCF7L2 rs12255372 G>T are potential loci for susceptibility to stroke. This will assist in treatment and/or prevention of cerebrovascular disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder. Recent studies have demonstrated that the dysregulated metabolism of metal ions, particularly copper and iron imbalance in the brains of AD patients,  is closely associated with the pathogenesis of Alzheimer's disease. Based on GEO database and GeneCards database, this study screened and identified 1191 AD-related differentially expressed genes (DEGs), as well as 671 and 682 genes highly associated with copper and iron metabolism. The intersection analysis yielded 26 differentially expressed copper- and iron-related genes (DECIGs). GO and KEGG enrichment analysis indicated that most of them were involved in cellular energy metabolism. PPI network analysis identified 12 hub genes, five of which had AUC values greater than 0.8, indicating strong diagnostic potential. qRT-PCR validation revealed that three hub genes (GOT1, LDHA, and UQCRFS1) showed significant differences in the expression levels between the AD and the control group. The multigene diagnostic model based on the three genes exhibited considerable diagnostic value.

Glioblastoma (GB) is among the most aggressive and treatment-resistant brain tumors, largely due to its heterogeneous tumor microenvironment (TME) and the protective nature of the blood-brain barrier (BBB). Recent advances have highlighted the therapeutic potential of neural stem cells (NSCs), which possess tumor-homing capabilities that enable them to selectively migrate toward and infiltrate GB sites. Engineered NSCs can deliver therapeutic agents, including oncolytic viruses, prodrug-converting enzymes, and genetic materials, offering targeted treatment while minimizing systemic toxicity. Preclinical studies have demonstrated NSCs' promise in enhancing drug delivery, modulating the TME, and promoting anti-tumor immune responses. However, translational hurdles persist, including tumor heterogeneity, species-specific immune responses, and challenges in ensuring long-term safety. Emerging strategies-such as genetic modification to improve tumor targeting and the incorporation of biomaterials to enhance retention-are under investigation. Integrating personalized medicine approaches may further optimize NSC-based therapies by tailoring treatment to individual patient profiles. While significant barriers remain, ongoing research may ultimately establish NSCs as a viable and effective platform for GB therapy.

Lead (Pb) is a hazardous heavy metal frequently used because it is readily available and inexpensive. Due to contaminated soil, dust, and items like paints and batteries, lead exposure is still an issue of concern in many nations. There is no known safe threshold of exposure, and it can have serious adverse effects on human health. Exposure to lead has been linked to detrimental effects on the developing nervous system of both children and adults. Alzheimer's disease (AD) is the most prevalent type of dementia affecting adults over the age of 65, resulting in a decrease in memory and thinking skills. In this review, we describe the role of lead in exacerbating the build-up of hyperphosphorylated tau proteins and formation of amyloid-β (Aβ) plaques, major neurotoxicants which can impair neuronal function leading to AD. We highlight the effect of developmental and lifelong lead exposure on various gene expression changes resulting in the formation of the neurotoxicants responsible to AD. Understanding the mechanisms related to Aβ plaques and neurofibrillary tangles (NFTs) formation serves as a novel approach to identify biomarkers for lead-induced AD and developing therapeutic interventions. Lead exposure has been related to adverse effects on the developing neurological systems of both adults and children.

Alzheimer's disease (AD) leads to a progressive loss of cognitive abilities and memory. A critical factor now recognized as driving AD pathology is neuroinflammation-inflammation occurring in the nervous system, which contributes to neuronal harm and communication breakdowns. our research investigated the specific effects of neuroinflammation on neuronal signaling pathways. In this study, we primarily employed the SH-SY5Y neuroblastoma cell line as an in vitro neuronal model to investigate inflammatory responses relevant to AD etiology, alongside supplementary observations in primary neurons and 3D spheroids for comparative analysis. Our analysis focused on modifications of key molecules, including the neuroprotective protein Brain-Derived Neurotrophic Factor (BDNF), pro-inflammatory cytokines such as IL-6 and TNF-α, and crucial regulatory kinases. Our results demonstrated that LPS treatment dramatically lowered the vitality and decreased BDNF levels in the SH-SY5Y cells. Furthermore, we observed a considerable elevation in the pro-inflammatory cytokines IL-6 and TNF-α, coupled with elevated levels of COX-2 and iNOS. Gene expression data validated that LPS treatment altered the expression of essential signaling kinases (Protein Kinase A (PKA), Protein Kinase B (AKT), and Mitogen-Activated Protein Kinase (MAPK)). Our first comparative analysis revealed that 3D spheroid cultures may elicit more pronounced inflammatory responses than standard 2D cultures; nevertheless, our detailed investigation primarily focused on the SH-SY5Y model. This study revealed that LPS-induced neuroinflammation affects neuronal signaling in vitro, thereby revealing a relationship between inflammation and neuronal dysfunction in cellular models of neuroinflammation. These findings highlight pathways that may be relevant to AD pathophysiology; however, further in vivo studies are necessary to demonstrate their translational relevance to humans.

As a major neonatal brain disorder, hypoxic-ischemic encephalopathy(HIE) presents with elevated risks of long-term disability and neonatal death. Ferroptosis is a distinct mode of regulated cell death marked by excess intracellular iron, oxidative lipid injury, and suppressed GPX4 activity, and has gained attention as a pivotal mechanism in the development of HIE. Signaling pathways such as Nrf2, TLR4/NF-κB, and endoplasmic reticulum stress(ERS) play critical roles.Vitamin D (VD) and its receptor (VDR), beyond their classical roles in calcium-phosphate homeostasis, as neuroprotective modulators of ferroptosis. VD/VDR signaling promotes antioxidant defenses (e.g., via the Nrf2/HO-1 pathway), restores GPX4 activity, regulates iron and lipid metabolism, and mitigates neuroinflammation.These insights provide a rationale for exploring VD/VDR-based interventions as adjunctive strategies to therapeutic hypothermia, which could potentially be explored to improve neurodevelopmental outcomes in affected neonates.

The role of Toll-like receptor 2 (TLR2) in the central nervous system (CNS) is critical in several conditions including neurological disorders such as pain, and neurodegenerative disorders such as Parkinson's disease. Therefore, understanding TLR2 function in the CNS is of considerable importance. In this study, we investigated neuronal responses to individual TLR2 ligands. The expression levels of cytokines increased in the culture in the presence of TLR2 ligands. Additionally, increased lactate dehydrogenase (LDH) was noted during lipoteichoic acid (LTA) stimulation. During LTA stimulation, a decrease in the peak amplitude of Ca oscillations was observed. MnTBAP, which is a reactive oxygen species (ROS) blocker, inhibited the LTA-induced cell death but had no effect on the peak amplitude of the Ca spike. Conversely, Pam3CSK4 (P3C) stimulation increased the number of Ca peaks, which was inhibited by a tumor necrosis factor alpha (TNFα) signaling inhibitor. Our study revealed that several TLR2 ligands, each with different specificities, elicited diverse responses in primary cortical cells. In conclusion, TLR1-TLR2 and TLR2-TLR6 signaling reduces the peak amplitude and induces cell death, and TLR1-TLR2 signaling enhances Ca dynamics via a TNFα pathway.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a strong genetic basis. There is increasing evidence that long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) play key roles in ASD pathophysiology. This review examines current findings regarding these non-coding RNAs, including genetic studies that have identified ASD-associated variants in non-coding regions; expression analyses that have revealed their dysregulation in brain tissue and peripheral blood; and mechanistic investigations that have demonstrated their involvement in neuronal differentiation, synaptic function, and gene regulatory networks. Despite substantial progress, the precise contributions of lncRNAs and circRNAs to ASD have not been fully characterized. Further research is required to elucidate their complex regulatory interactions, which may ultimately facilitate the development of novel diagnostic biomarkers and targeted therapeutic strategies for ASD.

Early-life exposure to light at night can disrupt the maturation of the circadian system and lead to long-lasting behavioural and molecular alterations. We exposed rat pups to constant light (LL; 16 lx) from birth (P0) to postnatal day 20, followed by a standard light-dark cycle (LD 12:12). At postnatal day 60, anxiety-like behaviour was assessed using the open field, elevated zero maze, and light/dark box. In parallel, we analysed circadian gene expression rhythms in the hippocampus, parietal cortex, frontal cortex, and olfactory bulbs, and examined A-to-I RNA editing and splicing in the hippocampus at P30. LL exposure increased body weight in males and tended to enhance anxiety-like behaviour, particularly in females. Locomotor activity during behavioural testing was reduced in both sexes, whereas circadian rhythms in constant darkness remained intact. At the molecular level, LL disrupted circadian gene expression in a brain region- and sex-specific manner. The hippocampus in males showed widespread loss of rhythmicity, while the parietal cortex was more affected in females. LL also reduced Adar2 expression rhythmicity and editing efficiency at functionally relevant sites in Gria2 and Htr2c, suggesting altered coupling between R/G editing and alternative splicing in Gria2. These findings demonstrate that low-intensity LL during a critical postnatal window can induce long-lasting, sex-specific alterations in behaviour and gene regulation. Our data provide the first mechanistic insight into how early environmental light exposure may shape long-term emotional and neurobiological outcomes.

Alzheimer's disease (AD) still lacks a conclusive treatment, largely due to an incomplete understanding of the molecular mechanisms involved. To enhance our knowledge of AD pathogenesis and identify potential therapeutic targets, this study integrates differential gene expression analysis, pathway enrichment, hub gene discovery, protein-protein interaction (PPI) clustering, and transcription factor/protein kinase regulation into a single, cohesive pipeline. This comprehensive systems-level approach moves beyond single-gene analyses to offer a broader, mechanistically focused insight into AD biology. Using RNA-seq data from the CA1 region of the hippocampus-a subregion selectively affected in early AD-we identified 1,104 differentially expressed genes (DEGs). Among the enriched pathways, "7-alpha-hydroxycholesterol" was upregulated, while "vacuolar organization" was downregulated in AD samples. Furthermore, five novel hub genes (MRPS7, RPL5, GFM1, RAD51, and ASPM) were identified within the PPI network. The first three-MRPS7, RPL5, and GFM1-along with ACO2 and MT-ATP6, are potentially linked to hereditary forms of AD due to their roles in mitochondrial function. We also discovered four collaborative clusters within the network that notably associated with the "inflammatory response", "7-alpha-hydroxycholesterol", "Mitochondrial dysfunction" and "Oxidative phosphorylation" pathways, making them promising candidates for therapeutic and diagnostic investigation due their behavioral information members. Additionally, we identified ten transcription factors (GATA2, CHD1, THRA, IRF7, ZBTB48, POLE4, ZNF219, SLC2A4RG, NR1D1, and RXRA) and one protein kinase (PRKCZ) as potential regulatory elements in AD. This study broadens our understanding of Alzheimer's disease by identifying five candidate hub genes, two functional PPI clusters, two signaling pathways, and eleven regulatory proteins, thereby laying the groundwork for future therapeutic and diagnostic developments in molecular AD research.

The SH-SY5Y cell line is a triple-cloned subline of SK-N-SH cells originally isolated in the early 1970s from a bone marrow biopsy of a four-year-old female patient suffering from neuroblastoma. Since then, this cell line has been used as one of the major cell culture models in neuroscience and to study neurodegeneration, as it comprises many of the biochemical and functional properties of neural precursor cells. Differentiation of neuronal precursor cells into a more mature phenotype represents one of the key steps and directed differentiation utilising various reagents is thought to provoke a defined neuronal subtype. Unfortunately, until now there is no consensus, which protocol shall be utilised to reach a specific neuronal subtype. Thus, the aim of the present work was to evaluate four common standard protocols for the differentiation of SH-SY5Y cells and to investigate the respective influences of varying parameters of these differentiation strategies. For this purpose, morphological analyses, mass spectrometry-based quantification of specific marker proteins, time-course protein expression profiling and global proteomics were conducted. On the level of morphology a low serum concentration favoured the abundance of mature neuronal cells containing long and branched neurites. Further low serum levels favoured the expression of dopaminergic marker proteins, in particular DDC, especially when utilising retinoic acid as differentiation agent. Our study clearly shows that an a priori characterisation of SH-SY5Y cells is indispensable to assess the abundance of neuronal subtypes and by that to ensure that the utilised differentiation approach is appropriately aligned with the specific research question.

Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by degeneration of nigrostriatal dopaminergic neurons together with α-synuclein (α-syn) aggregation, neuroinflammation, and oxidative stress. Although intravenous immunoglobulin (IVIG) contains naturally occurring antibodies against α-syn oligomers, it has failed to demonstrate therapeutic efficacy in PD models, likely due to limited delivery across the blood-brain barrier (BBB). Enhancing BBB penetration of IVIG could therefore substantially improve its therapeutic potential in PD. Here, we developed a brain-targeted IVIG formulation (IVIGᴬ) by site-specifically conjugating Angiopep-2 (Ang-2) to the Fc glycan site (Asn297) of IVIG, enabling receptor-mediated transcytosis across the BBB via low-density lipoprotein receptor-related protein-1 (LRP1). Compared with unmodified IVIG, IVIGᴬ exhibited significantly enhanced brain accumulation. Moreover, systemic administration of IVIGᴬ markedly improved motor and cognitive performance in A53T α-syn transgenic mice by reducing phosphorylated α-syn aggregates, preserving dopaminergic neurons and synaptic integrity, and attenuating neuroinflammation, oxidative stress, and complement activation. These findings suggest that IVIGᴬ represents a promising immunotherapeutic agent with translational potential for the treatment of PD and other neurodegenerative disorders.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation of α-synuclein. Non-coding RNAs (ncRNAs)-including microRNAs, long non-coding RNAs, and circular RNAs-have emerged as critical regulators in PD pathogenesis by modulating pathways such as neuroinflammation, mitochondrial function, and protein clearance. Furthermore, exosomal ncRNAs facilitate intercellular communication, propagating pathological signals but also offering therapeutic potential. This review synthesizes the current understanding of ncRNA involvement in PD, structuring the analysis around key pathogenic mechanisms. We provide a critical perspective on the strengths and weaknesses of the current evidence, evaluate the major challenges facing the field-including biomarker validation and therapeutic delivery-and propose a path forward for future research. A deeper, more integrated understanding of these ncRNA networks is essential for developing novel diagnostics and treatments to halt the progression of PD.

Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) pose serious threats to human health, and their pathogenesis is closely related to mitochondrial damage. Mitochondrial dysfunction includes abnormal energy metabolism, oxidative stress imbalance, disturbed calcium homeostasis and altered mitochondrial dynamics, which in turn trigger neuronal apoptosis and neuroinflammation. Mitochondrial dysfunction is a hallmark of many NDs. In addition to their multi-lineage differentiation potential, ability to promote neuronal repair, and capacity to modulate the neuroimmune microenvironment, Mesenchymal stem cells (MSCs) also hold potential for restoring mitochondrial dysfunction. MSCs have important therapeutic potential and mechanistic research value in the context of neurodegenerative disorders through the modulation of mitochondrial homeostasis and its transcellular transfer process. In this paper, we systematically summarize the mechanisms, technological advances, and translational challenges associated with mitochondrial damage in NDs and the role of MSCs in NDs through the modulation of mitochondrial damage and discuss their potential and limitations as a general therapeutic strategy.

Tau is a microtubule-associated protein encoded by the MAPT gene and is mainly expressed in neurons. Alternative splicing generates preferentially six isoforms differing in N-terminal inserts (0, 1, or 2N) and microtubule-binding repeats (3R or 4R). Isoform expression varies by cell type, developmental stage, and neuronal maturation. Structurally, 4R isoforms bind and stabilize microtubules more effectively than 3R isoforms, while 3R variants are more prone to oligomerization. Differences among isoforms also affect aggregation and post-translational modification patterns, yet their specific roles in tauopathies remain unclear. Beyond its role in microtubule stabilization, tau is increasingly recognized for its functions in other cellular compartments, particularly mitochondria, where it may contribute to mitochondrial dysfunction in neurodegenerative diseases. Its intrinsically disordered conformation and extensive post-translational modifications enable interactions with multiple mitochondrial components, linking tau biology to broader aspects of neuronal health and pathology. The main focus of this review is to analyze how tau protein interacts with mitochondria and disrupts their function. Literature evidence indicates that tau localizes to the outer mitochondrial membrane, intermembrane space, and matrix, where it interferes with key processes. These include disruption of electron transport chain activity, inhibition of ATP synthase, and reduced ATP production, ultimately compromising neuronal energy supply. In parallel, tau destabilizes microtubule-based trafficking, impairing axonal transport and mitochondrial distribution, while also disrupting fission and fusion dynamics that shape mitochondrial morphology. Quality control pathways are affected as well, with tau altering mitophagy and mitochondria-nucleus signaling. Moreover, tau dysregulates calcium buffering and increases reactive oxygen species production, thereby promoting synaptic dysfunction, oxidative stress, and mitochondrial damage. Collectively, these facts establish tau as a central mediator of mitochondrial impairment and neuronal vulnerability. Elucidating the mechanisms by which tau affects mitochondrial physiology underscores its importance as a therapeutic target, with strategies aimed at preserving mitochondrial integrity offering promising avenues to slow neurodegenerative progression. In the last section, we include examples of clinical applications currently in various phases of testing, some of which show promising potential for implementation.

Glioblastoma multiforme (GBM) is a complex and aggressive central nervous system (CNS) tumor that has a poor prognosis, and restricted therapeutic options are available despite the increasing research conducted. Moreover, the cells in our body package microRNAs, ubiquitous modulators of numerous biological processes, into exosomes for cell-to-cell signaling. Indeed, exosomal miRNAs contribute to several aspects of glioma, such as development, occurrence, metastasis, and immune evasion. Additionally, exosomal miRNAs play a key role in cellular functions and glioma pathogenesis by regulating numerous pathways, including the Wnt/β-catenin, PTEN/PI3K/Akt, EGFR/MAPK, notch signaling, and NF-κB. Notably, exosomal miRNAs are recognized to have promising potential in clinical applications; in fact, exosomal miRNAs are emerging biomarkers for glioma diagnosis and prognosis and are additionally considered as putative therapeutic candidates by inhibiting tumor progression, occurrence, and metastasis. This review presents the current knowledge regarding clinical potential and application of exosomal miRNAs in glioma, as well as the miRNA-mediated regulatory network underlying glioma immunopathogenesis.

Noise-induced hearing loss (NIHL) is a primary contributor to tinnitus, involving mechanisms such as inflammatory damage, central sensitization, and auditory cortex remodeling. However, not all cases of tinnitus are accompanied by NIHL, and the precise relationship between the two remains incompletely understood. Phosphorylation/dephosphorylation, as a core mechanism for fine cellular regulation, influences neuronal excitability, immune responses, and disease development by modulating protein activity, signal transduction, and gene expression. We hypothesized that aberrant phosphorylation levels may alter auditory cortex neuron function, leading to pathological changes at the protein level. Leveraging auditory cortex tissue from a noise-induced tinnitus model, we systematically investigated the pathogenesis of tinnitus and its distinction from NIHL through integrated proteomic and phosphoproteomic analyses. Compared to animals with NIHL alone, the tinnitus model exhibited enhanced neuronal excitability, synaptic dysfunction, hyperactive energy metabolism, and weakened neuroprotection, with disordered membrane receptor function playing a critical role. Multi-omics analysis further revealed that tinnitus development primarily depends on phosphorylation-mediated post-translational modifications reshaping cellular function, rather than changes in protein abundance caused by alterations in gene transcription levels. Collectively, this study elucidates the physiological and cellular structural alterations in noise-induced tinnitus from the dimensions of protein expression and phosphorylation modification. It confirms that tinnitus leads to neural dysfunction through abnormal membrane receptor activity, and the characteristic proteins and phosphorylation sites identified offer novel therapeutic targets for modulating central hyperexcitability in tinnitus.