Frontiers in Molecular Neuroscience最新文献

Background: Insomnia (ISM) is one of the non-traditional drivers of atherosclerosis (AS) and an important risk factor for AS-related cardiovascular disease. Our study aimed to explore the shared pathways and diagnostic biomarkers of ISM-related AS using integrated bioinformatics analysis.

Methods: We download the datasets from the Gene Expression Omnibus database and the GeneCards database. Weighted gene co-expression network analysis and gene differential expression analysis were applied to screen the AS-related gene set. The shared genes of ISM and AS were obtained by intersecting with ISM-related genes. Subsequently, candidate diagnostic biomarkers were identified by constructing protein-protein interaction networks and machine learning algorithms, and a nomogram was constructed. Moreover, to explore potential mechanisms, a comprehensive analysis of shared genes was carried out, including enrichment analysis, protein interactions, immune cell infiltration, and single-cell sequencing analysis.

Results: We successfully screened 61 genes shared by ISM and AS, of which 3 genes (IL10RA, CCR1, and SPI1) were identified as diagnostic biomarkers. A nomogram with excellent predictive value was constructed (the area under curve of the model constructed by the biomarkers was 0.931, and the validation set was 0.745). In addition, the shared genes were mainly enriched in immune and inflammatory response regulation pathways. The biomarkers were associated with a variety of immune cells, especially myeloid immune cells.

Conclusion: We constructed a diagnostic nomogram based on IL10RA, CCR1, and SPI1 and explored the inflammatory-immune mechanisms, which indicated new insights for early diagnosis and treatment of ISM-related AS.

Mechanical stimuli, such as stretch, shear stress, or compression, activate a range of biomolecular responses through cellular mechanotransduction. In the nervous system, studies on mechanical stress have highlighted key pathophysiological mechanisms underlying traumatic injury and neurodegenerative diseases. However, the biomolecular pathways triggered by mechanical stimuli in the nervous system has not been fully explored, especially compared to other body systems. This gap in knowledge may be due to the wide variety of methods and definitions used in research. Additionally, as mechanical stimulation techniques such as ultrasound and electromagnetic stimulation are increasingly utilized in psychological and neurorehabilitation treatments, it is vital to understand the underlying biological mechanisms in order to develop accurate pathophysiological models and enhance therapeutic interventions. This review aims to summarize the cellular signaling pathways activated by various mechanical and electromagnetic stimuli with a particular focus on the mammalian nervous system. Furthermore, we briefly discuss potential cellular mechanosensors involved in these processes.

The pathogenesis of epilepsy is related to the microbiota-gut-brain axis, but the mechanism has not been clarified. The microbiota-gut-brain axis is divided into the microbiota-gut-brain axis (upward pathways) and the brain-gut-microbiota axis (downward pathways) according to the direction of conduction. Gut microorganisms are involved in pathological and physiological processes in the human body and participate in epileptogenesis through neurological, immunological, endocrine, and metabolic pathways, as well as through the gut barrier and blood brain barrier mediated upward pathways. After epilepsy, the downward pathway mediated by the HPA axis and autonomic nerves triggers "leaky brain "and "leaky gut," resulting in the formation of microbial structures and enterobacterial metabolites associated with epileptogenicity, re-initiating seizures via the upward pathway. Characteristic changes in microbial and metabolic pathways in the gut of epileptic patients provide new targets for clinical prevention and treatment of epilepsy through the upward pathway. Based on these changes, this review further redescribes the pathogenesis of epilepsy and provides a new direction for its prevention and treatment.

Introduction: Resurgent current (I_NaR ) generated by voltage-gated sodium channels (VGSCs) plays an essential role in maintaining high-frequency firing of many neurons and contributes to disease pathophysiology such as epilepsy and painful disorders. Targeting I_NaR may present a highly promising strategy in the treatment of these diseases. Navβ4 and A-type fibroblast growth factor homologous factors (FHFs) have been identified as two classes of important I_NaR mediators; however, their receptor sites in VGSCs remain unknown, which hinders the development of novel agents to effectively target I_NaR .

Methods: Navβ4 and FHF4A can mediate I_NaR generation through the amino acid segment located in their C-terminus and N-terminus, respectively. We mainly employed site-directed mutagenesis, chimera construction and whole-cell patch-clamp recording to explore the receptor sites of Navβ4 peptide and FHF4A in Nav1.7 and Nav1.8.

Results: We show that the receptor of Navβ4-peptide involves four residues, N395, N945, F1737 and Y1744, in Nav1.7 DI-S6, DII-S6, and DIV-S6. We show that A-type FHFs generating I_NaR depends on the segment located at the very beginning, not at the distal end, of the FHF4 N-terminus domain. We show that the receptor site of A-type FHFs also resides in VGSC inner pore region. We further show that an asparagine at DIIS6, N891 in Nav1.8, is a major determinant of I_NaR generated by A-type FHFs in VGSCs.

Discussion: Cryo-EM structures reveal that the side chains of the critical residues project into the VGSC channel pore. Our findings provide additional evidence that Navβ4 peptide and A-type FHFs function as open-channel pore blockers and highlight channel inner pore region as a hotspot for development of novel agents targeting I_NaR .

Background: Zoster-associated neuralgia (ZAN) is recognized as a challenging neuralgia that often leads to poor prognosis in patients receiving interventional pain management. Identifying risk factors early can enable clinicians to develop personalized treatment plans; however, research in this area is limited.

Methods: We retrospectively screened all patients with ZAN who received interventional therapy in the Pain Department of Soochow University First Affiliated Hospital from January 1, 2022 to August 31, 2023. Data on patient demographics, medical history, neutrophil-to-lymphocyte ratio (NLR), clinical scoring, and treatment methods were collected. Interventional therapy included short-term nerve electrical stimulation (st-NES), pulsed radiofrequency (PRF) and radiofrequency thermocoagulation (RF-TC). Patients were categorized into poor prognosis and control groups based on outcomes 3 months post-discharge. Multivariate logistic regression was used to identify risk factors for poor prognosis.

Results: The final analysis included 282 patients. The rate of poor prognosis was 32.6% (92/282). Multivariate logistic regression analysis revealed that age ≥ 65 years (odds ratio, 2.985; 95% confidence interval, 1.449-6.148; p = 0.003), disease duration >3 months (odds ratio, 3.135; 95% confidence interval, 1.685-5.832; p < 0.001), head and face pain (odds ratio, 3.140; 95% confidence interval, 1.557-6.330; p = 0.001), use of immunosuppressants (odds ratio, 2.737; 95% confidence interval, 1.168-6.416; p = 0.021), higher NLR (odds ratio, 1.454; 95% confidence interval, 1.233-1.715; p < 0.001), PRF (st-NES as reference) (odds ratio, 2.324; 95% confidence interval, 1.116-4.844; p = 0.024) and RF-TC (st-NES as reference) (odds ratio, 5.028; 95% confidence interval, 2.139-11.820; p < 0.001) were found to be independent risk factors for poor prognosis in patients with ZAN who underwent interventional pain management.

Conclusion: Age ≥ 65 years (odds ratio, 2.985; 95% confidence interval, 1.449-6.148; p = 0.003), disease duration >3 months (odds ratio, 3.135; 95% confidence interval, 1.685-5.832; p < 0.001), head and face pain (odds ratio, 3.140; 95% confidence interval, 1.557-6.330; p = 0.001), immunosuppressants use (odds ratio, 2.737; 95% confidence interval, 1.168-6.416; p = 0.021), higher NLR (odds ratio, 1.454; 95% confidence interval, 1.233-1.715; p < 0.001), PRF (odds ratio, 2.324; 95% confidence interval, 1.116-4.844; p = 0.024) and RF-TC (odds ratio, 5.028; 95% confidence interval, 2.139-11.820; p < 0.001) were identified as independent risk factors for poor prognosis in patients with ZAN who underwent interventional pain management.

The Transient Receptor Potential (TRP) constitutes a family of channels subdivided into seven subfamilies: Ankyrin (TRPA), Canonical (TRPC), Melastatin (TRPM), Mucolipin (TRPML), no-mechano-potential C (TRPN), Polycystic (TRPP), and Vanilloid (TRPV). Although they are structurally similar to one another, the peculiarities of each subfamily are key to the response to stimuli and the signaling pathway that each one triggers. TRPs are non-selective cation channels, most of which are permeable to Ca²⁺, which is a well-established second messenger that modulates several intracellular signaling pathways and is involved in physiological and pathological conditions in various cell types. TRPs depolarize excitable cells by increasing the influx of Ca²⁺, Na⁺, and other cations. Most TRP families are activated by temperature variations, membrane stretching, or chemical agents and, therefore, are defined as polymodal channels. All TPRs are expressed, at some level, in the central nervous system (CNS) and ocular-related structures, such as the retina and optic nerve (ON), except the TRPP in the ON. TRPC, TRPM, TRPV, and TRPML are found in the retinal pigmented cells, whereas only TRPA1 and TRPM are detected in the uvea. Accordingly, several studies have focused on the search to unravel the role of TRPs in physiological and pathological conditions related to the eyes. Thus, this review aims to shed light on endogenous and exogenous modulators, triggered cell signaling pathways, and localization and roles of each subfamily of TRP channels in physiological and pathological conditions in the retina, optic nerve, and retinal pigmented epithelium of vertebrates.

Introduction: Genetic studies have shown that variants in the microtubule-associated protein tau (MAPT) gene, which encodes tau protein, can increase the risk for Alzheimer's disease (AD). Additionally, two haplotypes of the MAPT gene (H1 and H2) are associated with various neurodegenerative disorders, including AD. This study aimed to test the association of MAPT haplotypes (H1 and H2) and MAPT haplotype-tagging polymorphisms (rs1467967, rs242557, rs3785883, rs2471738, del-In9, rs7521) with AD.

Methods: The study included 964 individuals: 113 with AD, 53 with mild cognitive impairment (MCI), 54 with other dementias, and 744 healthy controls.

Results: The results showed that individuals carrying the A allele in the MAPT rs1467967 polymorphism, the GG genotype in the MAPT rs7521 polymorphism, and the G allele in the MAPT rs242557 polymorphism had worse performance on various neuropsychological tests. Carriers of the C allele in MAPT rs2471738 polymorphism and CC homozygotes also showed worse performance on neuropsychological tests and pathological levels of several cerebrospinal fluid (CSF) biomarkers. However, T allele carriers in the MAPT rs2471738 polymorphism were more represented among patients with dementia and apolipoprotein E (APOE) ɛ4 carriers. Carriers of the H2 MAPT haplotype had worse performance on various neuropsychological tests, consistent with our previous study, which associated the H2 MAPT haplotype with pathological levels of CSF AD biomarkers. Regarding the MAPT rs3785883 polymorphism, further research is needed since both the AA and GG genotypes were associated with pathological levels of CSF and plasma AD biomarkers.

Discussion: In conclusion, further genetic studies are needed to elucidate the role of MAPT haplotypes and MAPT haplotype-tagging polymorphisms in the development of AD.

Although salt is an essential substance vital to life, excessive salt intake could cause various health issues. Therefore, new technologies and strategies should be developed to reduce salt intake without compromising taste. However, the underlying physiological mechanisms of salt taste reception is complex and not completely understood. Sodium chloride is a typical salty substance. It is widely believed that only sodium is important for the generation of salty taste. On the other hand, from a psychophysical perspective, the importance of chloride in salty taste has been indicated. Thus, understanding the mechanisms of both sodium- and chloride-tastes generation is necessary to completely comprehended the fundamentals of salt taste reception. However, the mechanism for detecting chloride taste has remained unclear for many years. Recently, we have identified transmembrane channel-like 4 (TMC4) as the first molecule that mediates the reception of chloride taste. TMC4 functions as a voltage-dependent chloride channel and plays an important role in the reception of the chloride taste by detecting chloride ions. In this mini-review, we first introduce the known reception mechanism of salty taste, and then discuss the roles of TMC4 in the salt taste reception. The finding of TMC4 may serve as a basis for developing new technologies and formulating strategies to reduce salt intake without compromising taste.