Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a systemic autoimmune disease characterized by significant renal involvement, yet identifying novel biomarkers for renal complications remains a clinical priority. Metrnl is a recently identified immunomodulatory cytokine implicated in inflammation, but its specific role in AAV has historically been unknown. To address this, this study investigated serum Metrnl levels via ELISA in 37 patients with microscopic polyangiitis (MPA), 17 with granulomatosis with polyangiitis (GPA), and 30 healthy controls (HCs), analysing correlations with clinical parameters such as the Birmingham Vasculitis Activity Score (BVAS) and renal function indicators under false discovery rate (FDR) correction. The results demonstrated that serum Metrnl levels were significantly elevated in both MPA and GPA patients compared to HCs and exhibited a strong positive correlation with BVAS in both subgroups. Crucially, following FDR adjustment, Metrnl levels showed significant correlations with key markers of renal impairment, including creatinine, cystatin C, and estimated glomerular filtration rate (eGFR). Stratification of MPA patients based on renal function (eGFR cut-off: 60 ml/min/1.73 m²) further revealed substantially higher Metrnl levels in those with impaired renal function. Receiver operating characteristic curve analysis indicated superior diagnostic efficacy for Metrnl in identifying AAV with renal involvement [area under the curve (AUC) = 0.8150] compared to diagnosing AAV overall (AUC = 0.7214). Collectively, these findings provide the first evidence that serum Metrnl is elevated in AAV and associated with disease activity and renal dysfunction, suggesting that Metrnl warrants further investigation as a potential biomarker for renal involvement in AAV.

ABSTRACT The axon initial segment (AIS) is a specialized neuronal microdomain that serves as a physical diffusion barrier, separating the axon from somatodendritic compartments. As a highly plastic structure, the AIS dynamically regulates neuronal excitability and contributes to circuit homeostasis. Recent advances in super‐resolution imaging and disease modeling have expanded our understanding of its role in neurodevelopment and neurodegenerative disorders. This review first systematically outlines the molecular architecture of the AIS, including its cytoskeletal scaffolds and ion‐channel complexes. Then, we discuss AIS plasticity, ranging from activity‐dependent alterations to the molecular mechanisms that regulate it, and to its key biological functions, such as its role in action potential initiation, neuronal polarization, subcellular organelle sorting, and neural circuit excitability. We further highlight emerging evidence that AIS disruption represents an early pathological event in neurodegenerative and neuropsychiatric disorders. By integrating physiological and pathological perspectives, and by evaluating emerging biomarker strategies and therapeutic interventions, this review outlines directions and challenges for future AIS‐targeted therapies. Meanwhile, it summarizes key experimental and potential clinical tools for future AIS research. Overall, elucidating the molecular mechanism of the AIS in both health and disease provides a deeper understanding for advancing the diagnosis and treatment of neurological diseases.

Background: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that primarily affects the motor neurons. T cell intracellular antigen 1 (TIA1) is a risk gene for ALS pathogenesis. To elucidate TIA1-mediated disease mechanisms, a mouse model recapitulating clinical and pathological features of ALS is needed. TIA1 mutations are rare in human ALS, and mutations are heterozygous, while this study uses a homozygous TIA1 mutant mouse model to amplify pathogenic effects for experimental tractability. Methods: To explore the mechanisms by which mutant TIA1 causes ALS neurodegeneration, we generated a TIA1 mutant mouse by introducing ALS-causing mutations into the endogenous animal via cytosine base editors. Next, behavioral experiments (open-field and rotarod tests) assessed motor function and analyzed pathologies using morphological assessments. Results: Our TIA1Δ mouse model phenocopies select pivotal features of ALS, including TAR DNA-binding protein 43 (TDP-43) accumulation, motor neuron loss, neuroinflammation in the lumbar spinal cord, and muscle atrophy. Notably, this homozygous mutation design with reduced TIA1 expression differs from human heterozygous TIA1 mutations. Conclusions: This work provides a foundation for understanding the TIA1-ALS relationship and for developing strategies to treat this intractable neurodegenerative disorder. Caution is warranted extrapolating findings to human ALS pathogenesis due to model design differences.

Osteogenesis-angiogenesis coupling plays an important role during the occurrence of glucocorticoid-induced osteoporosis (GIOP), while the detailed pathophysiology is complex and yet to be elucidated. In this study, we investigated the role of Angiogenin (Ang), a pro-angiogenic ribonuclease secreted by mesenchymal stem cells, and its upstream regulation in GIOP. In vitro, we assessed the effects of Ang modulation on the viability, commitment, and pro-angiogenic capacity of dexamethasone (DEX)-treated bone marrow mesenchymal stem cells (BMSCs). In vivo, a mouse model of GIOP was constructed and Ang expression was modulated via tail-vein injection. Bone loss, trabecular structure, and type H vessels (CD31-high, endomucin-high; CD31hiEMCNhi) and their surrounding osteoblasts in the distal femur were evaluated using micro-computed tomography and histological staining. Furthermore, we explored the mechanistic role of ERK5 in regulating Ang expression. Results showed that Ang played an important role in regulating BMSC osteogenic commitment, viability and pro-angiogenic potential. DEX exposure compromised these effects by downregulating Ang and Ang overexpression effectively rescued DEX-induced BMSC dysfunction in vitro. Furthermore, Ang overexpression rescued DEX-induced bone loss and attenuated the impairment of osteogenesis-angiogenesis coupling in the distal femur by DEX. Mechanistically, ERK5 was capable of regulating the expression of Ang; ERK5 inhibition suppressed Ang expression, while ERK5 activation restored it. In conclusion, Glucocorticoids induce osteoporosis via inhibiting the ERK5/Ang signaling axis, thereby disrupting osteogenesis-angiogenesis coupling. Targeting this pathway via Ang overexpression offers a promising strategy to mitigate glucocorticoid-induced bone loss.

From a neuroscience perspective, cancer neuroscience has emerged as a subfield of cancer research. Presumable mechanisms underlying cancer-related neuronal activity (termed neurosciences) include the induction and modulation of signaling pathways that govern cell fate determination and emotional responses (anxiety and stress), such as structural molecules (synaptic structures and current transduction) and secretory substances (neurotransmitters, cytokines, hormones and neuropeptides). In the past 3 years, these neuronal activities, which can either promote cancer growth or be hijacked by cancer cells to support tumor survival and invasion, have been widely demonstrated to be closely related to cancer progression. The molecular mechanisms are also being refined. Despite their great promise, translating neuroscientific discoveries into clinically actionable strategies for cancer diagnosis, prognosis, and treatment remains a formidable task. In this comprehensive review, we attempt to provide a full account of the intersection between neuroscience and cancer research. From the perspective of cancer neuroscience, we fully discuss the potential signaling molecules and their regulatory mechanisms, as well as targets and emerging therapeutic strategies that control tumor progression via multiomics approaches. Overall, cancer neuroscience may have unprecedented potential for understanding neuronal functions and cancer development, ultimately offering the significantly improved cancer treatment.

There is a complex pathological association between neurodegenerative diseases and cancer. The epidemiological negative correlation between Parkinson's disease (PD) and brain tumor is particularly noteworthy. PD is characterized by the loss of dopaminergic neurons and the formation of Lewy bodies, while glioma, the representative of brain tumors, originates from the malignant transformation of glial cells. The molecular interaction network between these two diseases is elusive, limiting the development of cross-disease treatment strategies. This review systematically summarizes the associations between PD and glioma in genetic predispositions, epigenetic modifications, alterations in subcellular compartments, and cellular mechanisms concerning neurons, glial cells, and stem cells. Additional links arise from circadian rhythm regulation, oxidative stress, and gut microbiota, underscoring the importance of systemic pathways that connect neurodegeneration and tumorigenesis. Within this context, cancer neuroscience emerges as a critical framework, demonstrating how neuronal activity drives cancer progression by shaping the tumor microenvironment. Therapeutic opportunities build upon these mechanistic insights, including engineering neuron types to suppress cancer growth, modulating synaptic genes, inducing neuronal cell death cascades, and controlling inflammation to disrupt tumor-nerve crosstalk. Emerging neuroscience-inspired technologies may drastically expand the treatment landscape. This review tries to unveil a potential theoretical paradigm for developing precise therapies with both neuroprotection and antitumor effects.

Stress granules (SGs) are membraneless organelles formed in the cellular cytoplasm under stressful conditions through liquid–liquid phase separation (LLPS). SG assembly can be both dependent and independent of the eIF2α pathway, whereas cellular protein quality control systems mediate SG disassembly. Chaperones and specific domains of RNA-binding proteins strongly contribute to the regulation SG dynamics. Chronic stress, arising in association with aging, may promote persistent SGs that are difficult to disassemble, thereby acting as a potential pathological nidus for protein aggregation in neurodegenerative diseases (NDDs). In this review, we discuss the dynamics of SGs and the factors involved with SG assembly and disassembly. We also highlight the relationship among LLPS, SGs, and the pathogenesis of different NDDs. More importantly, we summarize SG assembly-disassembly, which may be a double-edged sword in the pathophysiology of NDDs. This review aims to provide new insights into the biology and pathology of LLPS, SGs, and NDDs.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is primarily known as a respiratory disease. The continued study of the disease has shown that long-term COVID-19 symptoms include persisting effects of the virus on the brain when the infection is over, possibly even leading to neurodegeneration. However, the exact mechanisms of nervous system damage induced by SARS-CoV-2 are still unclear. In this study, we focused on two possibly shared pathways of SARS-CoV-2-induced neural dysfunction and neurodegeneration: protein aggregation, which is associated with impaired protein clearance, and inflammatory responses, which involve a hyper-active immune status. We observed distinct expression and distribution patterns of ten SARS-CoV-2 proteins in the two cell lines, meanwhile forming aggregation puncta and inducing pro-inflammatory responses. We found that the ER stress was induced and that the autophagy-lysosome pathway was inhibited upon viral protein expression. Boosting autophagy function attenuated protein aggregation, suggesting that modulation of autophagy might be a valid strategy for inhibiting cytotoxic effects of SARS-CoV- 2 proteins. Our study provides potential explanations of SARS-CoV-2-induced cell damage, based on shared cellular mechanisms and furthermore, suggests that modulation of proteostasis may serve as therapeutic strategies for preventing long-lasting SARS-CoV-2 cytotoxic effects.

ABSTRACT Parkinson's disease (PD) is a progressive neurodegenerative disorder with a growing global burden. Current pharmacological therapies remain limited to symptomatic management, owning to an incomplete understanding of the mechanisms driving α‑synuclein aggregation and disease progression. This review provides an integrated overview of PD across epidemiological, etiological, pathophysiological, and clinical dimensions. It emphasizes established and emerging risk factors, including environmental toxins, lifestyle variables, and gut microbiota dysbiosis and delineates how peripheral–central pathways such as the gut–brain, erythrocyte–brain, and kidney–brain axes contribute to PD pathogenesis. At the molecular level, we explore key disruptions including proteostatic failure, aberrant phase separation, oxidative stress, neuroinflammation, synaptic dysfunction, iron dyshomeostasis, and impaired cholesterol metabolism. These encompass microbiome‑targeted interventions and blood‐based approaches. We further evaluate a spectrum of management strategies ranging from primary prevention and biomarker‑guided early detection to innovative experimental treatments such as cellular therapies, transfusion‑based modalities, and microbial modulation. By integrating recent advances in systemic pathophysiology with translational perspectives, this review highlights how molecular and cellular dysregulations underlie clinical phenotypes. Finally, we discuss promising biomarkers derived from microbial, inflammatory, and erythrocyte pathways that may facilitate early diagnosis and the development of disease‑modifying therapies.

Parkinson's disease (PD) is a neurodegenerative disorder in which the clinical manifestations include resting tremor, bradykinesia, akinesia, rigidity, and postural instability. The disease can be accompanied by non-motor symptoms such as depression and insomnia. The leading factors in the initiation of this disease include genetic alteration, exposure to toxins, and age. However, the exact mechanisms underlying the pathogenesis of PD remain elusive. Animal models play a critical role in the research on the pathogenesis and treatment of PD. Non-human primates share similar characteristics with humans, particularly in motor and cognitive abilities and the complexity of the neural structure. Non-human primate models for PD can be roughly classified into spontaneous, neurotoxin-based, and gene-editing models. Although having several current limitations, non-human primate models can play an increasingly important role in the research on PD, especially given the rapid development of novel methods in neuroscience.

Porphyromonas gingivalis (P. gingivalis) is a gram-negative bacterium and the main causative agent of periodontitis, a disease closely associated with the development of periodontal disease. The progression of periodontitis, a chronic infectious disease, is intricately linked to the inflammatory immune response. Inflammatory cytokines act on periodontal tissues via immunomodulation, resulting in the destruction of the periodontal tissue. Recent studies have established connections between periodontitis and various systemic diseases, including cardiovascular diseases, tumors, and neurodegenerative diseases. Neurodegenerative diseases are neurological disorders caused by immune system dysfunction, including Alzheimer’s and Parkinson’s diseases. One of the main characteristics of neurodegenerative diseases is an impaired inflammatory response, which mediates neuroinflammation through microglial activation. Some studies have shown an association between periodontitis and neurodegenerative diseases, with P. gingivalis as the primary culprit. P. gingivalis can cross the blood-brain barrier (BBB) or mediate neuroinflammation and injury through a variety of pathways, including the gut-brain axis, thereby affecting neuronal growth and survival and participating in the onset and progression of neurodegenerative diseases. However, comprehensive and systematic summaries of studies on the infectious origin of neurodegenerative diseases are lacking. This article reviews and summarizes the relationship between P. gingivalis and neurodegenerative diseases and its possible regulatory mechanisms. This review offers new perspectives into the understanding of neurodegenerative disease development and highlights innovative approaches for investigating and developing tailored medications for treating neurodegenerative conditions, particularly from the viewpoint of their association with P. gingivalis.

Procaine (PCA), a local anesthetic commonly used in stomatology, exhibits antitumor activity in some human malignancies. However, the precise mechanism underlying PCA activity remains unknown, and its antitumor effect in human tongue squamous carcinoma cells has not been reported. Flow cytometry and western blotting were used to assess the effects of PCA on mitochondrial membrane potential (Delta Psi m), intracellular reactive oxygen species (ROS) production, cell cycle and apoptosis. The results suggested that PCA inhibits CAL27 and SCC-15 cell proliferation, and clone formation in a dose-dependent manner. CAL27 cells were more sensitive to PCA than SCC-15 cells. PCA also significantly inhibited cell migration, induced mitochondrial damage, reduced Delta Psi m and increased intracellular ROS production. PCA causes G2/M cycle arrest and induces apoptosis. The possible mechanism for the inhibition of human tongue squamous carcinoma cell proliferation is through the regulation of ERK phosphorylation and PI3K/AKT-mediated signaling pathways. The results further suggested that autophagy occurs during PCA-induced apoptosis in CAL27 cells, and the addition of the autophagy inhibitor hydroxychloroquine sulfate further enhanced the sensitivity of PCA to inhibit cell proliferation, indicating that autophagy plays an important role in protecting cancer cells from apoptosis. PCA shows potential as an anticancer drug and its combination with autophagy inhibitors enhances its sensitivity.

N-1-methyladenine (m1A), a modification of transcripts, regulates mRNA structure and translation efficiency. In a recent issue of Nature, Sun et al. reported that m(1)A in CAG repeat RNA contributes to CAG repeat expansion-induced neurodegeneration in Caenorhabditis elegans and Drosophila through enhancing the ability of endogenous TDP-43 to partition into stress granules mediated by m(1)A. The study is especially important for revealing the pathological function of m(1)A in RNA and the pathological mechanisms of CAG repeat expansion -related neurodegenerative diseases.

Liquid-liquid phase separation (LLPS), an emerging biophysical phenomenon, can sequester molecules to implement physiological and pathological functions. LLPS implements the assembly of numerous membraneless chambers, including stress granules and P-bodies, containing RNA and protein. RNA-RNA and RNA-protein interactions play a critical role in LLPS. Scaffolding proteins, through multivalent interactions and external factors, support protein-RNA interaction networks to form condensates involved in a variety of diseases, particularly neurodegenerative diseases and cancer. Modulating LLPS phenomenon in multiple pathogenic proteins for the treatment of neurodegenerative diseases and cancer could present a promising direction, though recent advances in this area are limited. Here, we summarize in detail the complexity of LLPS in constructing signaling pathways and highlight the role of LLPS in neurodegenerative diseases and cancers. We also explore RNA modifications on LLPS to alter diseases progression because these modifications can influence LLPS of certain proteins or the formation of stress granules, and discuss the possibility of proper manipulation of LLPS process to restore cellular homeostasis or develop therapeutic drugs for the eradication of diseases. This review attempts to discuss potential therapeutic opportunities by elaborating on the connection between LLPS, RNA modification, and their roles in diseases. Liquid-liquid phase separation (LLPS) as a rising molecular entity in the cytoplasm regulates diseases progression via a variety of ways. For example, the relationship between LLPS and cancer can be summarized into six aspects: gene fusions/mutations, heterochromatin formation, transcriptional machinery, cellular homeostasis, microenvironment, and RNA modification. In particular, the behavior and mechanism of LLPS in RNA modification may point to new directions for diagnostics and therapy for some of the most dangerous and hard-to-treat tumors. image

Neurodegenerative diseases usually present as progressive impairment of the motor or mental functions of the central or peripheral nervous system, which is often linked to genetic and biochemical factors. The main features include synaptic and neuronal deficits, abnormal protein homeostasis, DNA and RNA defects, inflammation, and pathological protein aggregation. Clinical evidence suggests that circadian rhythms affect different neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, through oxidative stress, neuroinflammation, and other mechanisms. Disruptions in circadian rhythms, which are often linked to alterations in RNA modifications, contribute to disease progression. This review provides an overview of current research progress on neurodegenerative diseases and outlines their relationship in terms of aberrant circadian rhythm, highlights the role of RNA modifications in circadian rhythm-regulated neurodegenerative diseases, and presents the potential applications of RNA-based drugs for treating neurodegenerative diseases.

Parkinson's disease (PD) is a common neurodegenerative disease characterized pathologically by dopaminergic neuron loss and the formation of Lewy bodies, which are enriched with aggregated α-synuclein (α-syn). PD currently has no cure, but therapeutic strategies are available to alleviate symptoms. Early diagnosis can greatly improve therapeutic interventions, but the clinical diagnosis of PD remains challenging and depends mainly on clinical features and imaging tests. Efficient and specific biomarkers are crucial for the diagnosis, monitoring, and evaluation of PD. Here, we reviewed the biomarkers of PD in different tissues and biofluids, along with the current clinical biochemical detection methods. We found that the sensitivity and specificity of single biomarkers are limited, and selecting appropriate indicators for combined detection can improve the diagnostic accuracy of PD.

Parkinson's disease (PD) is an age‐related chronic neurological disorder, mainly characterized by the pathological feature of α‐synuclein (α‐syn) aggregation, with the exact disease pathogenesis unclear. During the onset and progression of PD, synaptic dysfunction, including dysregulation of axonal transport, impaired exocytosis, and endocytosis are identified as crucial events of PD pathogenesis. It has been reported that over‐expression of α‐syn impairs clathrin‐mediated endocytosis (CME) in the synapses. However, the underlying mechanisms still needs to be explored. In this study, we investigated the molecular events underlying the synaptic dysfunction caused by over‐expression of wild‐type human α‐syn and its mutant form, involving series of proteins participating in CME. We found that excessive human α‐syn causes impaired fission and uncoating of clathrin‐coated vesicles during synaptic vesicle recycling, leading to reduced clustering of synaptic vesicles near the active zone and increased size of plasma membrane and number of endocytic intermediates. Furthermore, over‐expressed human α‐syn induced changes of CME‐associated proteins, among which synaptojanin1 (SYNJ1) showed significant reduction in various brain regions. Over‐expression of SYNJ1 in primary hippocampal neurons from α‐syn transgenic mice recovered the synaptic vesicle density, clustering and endocytosis. Using fluorescence‐conjugated transferrin, we demonstrated that SYNJ1 re‐boosted the CME activity by restoring the phosphatidylinositol‐4,5‐bisphosphate homeostasis. Our data suggested that over‐expression of α‐syn disrupts synaptic function through interfering with vesicle recycling, which could be alleviated by re‐availing of SYNJ1. Our study unrevealed a molecular mechanism of the synaptic dysfunction in PD pathogenesis and provided a potential therapeutic target for treating PD.