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With the rapid progression of global population aging, the incidence of cognitive dysfunction-related disorders is steadily increasing. In recent years, growing attention has been directed toward the interaction between the gut microbiota and the central nervous system (CNS). The gut-brain axis (GBA), as a bidirectional communication pathway, plays an increasingly recognized role in regulating cognitive functions. Ganoderma lucidum polysaccharides (GLP), a traditional medicinal and edible substance, can regulate gut microbiota homeostasis and short-chain fatty acid (SCFAs) levels through the GBA. GLP reduces the Firmicutes/Bacteroidetes ratio, significantly increases the abundance of Lactobacillus, and further suppresses oxidative stress and inflammatory responses by controlling microglial overactivation and neuroinflammation, thereby enhancing the expression of synapse-associated proteins and brain-derived neurotrophic factor (BDNF). Consequently, GLP shows potential for improving cognitive dysfunction. This review systematically summarizes the bioactivities of GLP, explores the neurodegenerative mechanisms of aging, and proposes the possibility that GLP mitigates aging-induced inflammation and improves cognitive function via modulation of the gut microbiota. Show less

The central nervous system (CNS) is a common site of metastatic spread for both non-small cell and small cell lung cancer, yet the therapeutic strategies to prevent and decrease lung cancer brain metastases remain limited. Tyrosine kinase inhibitors have shown promising results in increasing the overall response in brain metastases, owing to their brain penetrance and increased effectiveness; however, their use is limited to the small group of tumors carrying specific oncogenic drivers. Among these, inhibitors with activity against neurotrophic tyrosine receptor kinases (NTRKs) are showing promising effects in reducing CNS metastases in cancers driven by gene rearrangements of these drugs' targets. However, wild-type NTRKs are susceptible to activation by their canonical ligands, which are expressed throughout the brain metastatic niche and can, in a paracrine manner, activate NTRK function in cancer cells. Here we show that NTRKs are expressed in primary tumors, brain metastases, and lung cancer cells with various driver mutations expressing wild-type NTRK2 (WT-TrkB). We demonstrate that WT-TrkB activates downstream signaling and proliferation in response to exogenous BDNF and conditioned media from reactive astrocytes known to secrete BDNF in the brain niche. Importantly, the FDA-approved NTRK inhibitor entrectinib blocked BDNF and astrocyte-induced survival pathways in multiple lung cancer cell lines, decreased their proliferation These studies demonstrate that NTRK wild-type receptors are important drivers of brain metastatic colonization and progression in different subtypes of lung cancer, independent of their driver alterations. Thus, they provide rationale to expand the use of FDA-approved NTRK inhibitors with brain penetrance for the prevention of CNS metastases. Show less

Spinal cord injury (SCI) represents significant central nervous system trauma and has consistently been a focal point of research in the domain of neural regeneration and repair. Currently, there is no effective treatment available. Various modalities of magnetic stimulation have emerged for recovery from spinal cord injuries; however, the underlying mechanisms remain unclear, significantly hindering the application of magnetic stimulation technologies in treating such injuries. This study aims to elucidate these relevant mechanisms by establishing a simulated closed-loop magnetic stimulation system. In this study, we established a right hemisection model at T8 in mice and administered continuous simulated closed-loop magnetic stimulation targeting the left motor cortex and right L5 nerve root over six weeks. We subsequently utilized a spinal cord dorsal hemisection model to examine regeneration of the corticospinal tract (CST). Motor-evoked potential assessments and calcium imaging techniques were employed to explore neural circuit repair. Additionally, we integrated transcriptomics, proteomics, and metabolomics approaches to investigate related mechanisms. The findings indicate that simulated closed-loop magnetic stimulation effectively restores motor function in the hind limbs, promotes the regeneration of corticospinal tracts in mice with spinal cord injuries, and facilitates the reconstruction of sensorimotor circuits and functions within the spinal cord. Simulated closed-loop magnetic stimulation significantly enhances axonal regeneration of the CST following SCI. This effect may be mediated through the activation of the AMPK-CREB-BDNF signaling pathway, which promotes neurotrophic factor secretion and subsequently induces nerve axon regeneration. This study suggests that simulated closed-loop magnetic stimulation represents a promising therapeutic approach for the treatment for impaired gait following SCI. Show less

Microglia are the brain's resident immune cells that respond to injury and disease by transitioning between homeostatic and reactive states. These cell state transitions determine whether microglia promote or resolve inflammation in the central nervous system (CNS). In this study, we explored the role of Ca Show less

Gliomas are the most common primary malignant tumors of the central nervous system. Mounting evidence highlights the crucial role of YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) in glioma treatment response. This study aimed to investigate the association between single-nucleotide polymorphisms (SNPs) of YTHDF1 and cognitive dysfunction (CD) following radiotherapy for glioma. A total of 323 glioma patients were enrolled pre-radiotherapy and followed up for 3 months post-radiotherapy. They were categorized into glioma patients with CD (group, YTHDF1 mRNA expression was significantly higher in the CD group than in the non-CD group. Among the four analyzed SNPs, only rs6090311 exhibited significant differences in both genotype and allele frequencies between the two groups, while rs6011668, rs68041888 and rs6122103 showed no significant variations. After controlling for potential confounders, including WHO grade, tumor volume, BDNF levels, and radiotherapy dose, carriers of the G allele (A/G + G/G genotypes) at rs6090311 demonstrated a significantly lower risk of developing post-radiotherapy CD (OR = 0.319, 95% CI: 0.111-0.916). YTHDF1 overexpression is associated with post-radiotherapy CD in glioma patients, and the rs6090311 G allele may act as a protective genetic marker for this complication. Show less

The role of central histamine in diabetes induced behavioral despair is still an enigma. Therefore, the current research explored the plausible impact of the central histaminergic activity on the expression of diabetes-induced behavioral despair in mice using the tail suspension test (TST) and surose preference test (SPT) along with changes in the levels of BDNF and phosphorylated CREB (pCREB) in the whole brain, hippocampus, PFC, and amygdala. Post-streptozotocin (STZ) (200 mg/kg, i.p.) injection, on the 4 Show less

The activation of glial cells in the central nervous system plays an important role in the neural signaling of chronic pain and pruritus. However, their involvement in the neural signaling of chronic pain and pruritus in ACD remains to be investigated. To determine the effect of spinal glial cell activation in the coexistence of chronic pain and pruritus in the ACD model, we observed spinal glial cell activation in a mouse model of ACD induced by SADBE. Square acid dibutyl ester (SADBE) was employed to establish ACD model mice and monitor the activation of spinal cord glial cells. Additionally, the Gene Expression Omnibus (GEO) database was utilized to analyze potential mechanisms. In the ACD model, the behaviors of licking and biting within 35 days after modeling were significantly increased. The expression levels of Iba-1, BDNF, LCN2, GRPR, and GFAP differed significantly from those of the control group. In addition, through GEO data analyses, a strong correlation has been found between pain and IFN-γ. Similarly, in vitro experiments revealed that IFN-γ increased the expression of Iba-1, CD16, and BDNF in BV2 cells and the release of LCN2 in primary astrocytes, thus activating spinal cord glial cells. IFN-γ also induced the phosphorylation of JAK1/STAT1 and the expression of IFNGR1 in BV2 cells and primary astrocytes. Collectively, the above findings suggest that the coexistence of chronic pain and pruritus in the ACD model is associated with the activation of spinal microglia and astrocytes. The underlying mechanism involves the binding of IFN-γ to its receptor IFNGR1, which is accompanied by the upregulation of JAK1/STAT1 signaling pathway phosphorylation. Show less

Traumatic injuries to the central nervous system (CNS), including traumatic brain injury (TBI) and spinal cord injury (TSCI), are among the leading causes of disability and mortality worldwide. The valuable effect of extracellular vesicles (EVs) from mesenchymal stem cells (MSCs-EVs) in the treatment of traumatic injuries has been documented. EVs, including exosomes, are heterogeneous cell-derived particles, contributing to cell communication through exchanging biomolecules between cells. MSCs-EVs can regulate physiological processes, including synaptic plasticity, neuronal firing, development and repair of myelin sheath, neuroprotection, advancement of neuroinflammation, and extent and elimination of protein aggregates. However, natural MSCs-EVs have some limitations. Recent advancements have shown that MSCs-EVs can be engineered for effective and targeted therapy in traumatic injuries. Most experiments have focused on miRNA-engineered MSCs-EVs to boost their therapeutic effects. In TBI models, MSCs-EVs have been modified to deliver miR-124, miR-17-92, miR-124-3p, or BDNF, whereas in TSCI models, EVs have been engineered with miR-216a-5p, miR-146a-5p, miR-133b, miR-146, miR-138-5p, miR-29b, miR-181c, lncGm37494, siRNAs, or Shh. Results from in vitro and animal studies show the substantial potential of engineered MSCs-EVs for protection, neuroregeneration, and functional recovery. But challenges remain in translating these outcomes into clinical trials, including standardization, safety, and delivery efficacy. In this review, we summarize recent knowledge on MSCs-EVs, focusing on their mechanisms of action in CNS traumatic injuries, and discuss the latest developments, inherent advantages, and potential hurdles in evolving these groundbreaking therapeutic approaches. Show less

The muscle-brain axis integrates peripheral metabolic activity with central nervous system function. Among the endocrine signaling molecules regulating such crosstalk, the peptide hormone irisin released during muscle contraction seems to play relevant roles. Irisin is generated by the proteolytic cleavage of the fibronectin type III domain-containing protein 5 and has emerged as a key regulator of neurotrophic and metabolic adaptation. Although initially described as a myokine, irisin is also expressed in adipose and neural tissues, acting through autocrine, paracrine, and endocrine mechanisms. Irisin binds to the αV/β5 integrin receptor complex and activates a network of signaling pathways which promote mitochondrial biogenesis, autophagy, oxidative stress resistance, and modulation of inflammatory responses. Within the central nervous system, irisin induces brain-derived neurotrophic factor expression and contributes to synaptic plasticity, neurogenesis, and cognitive preservation. Experimental models show that irisin reduces amyloid burden, limits α-synuclein pathology, suppresses neuroinflammation, and stabilizes blood-brain barrier integrity, supporting a disease-modifying role in neurodegenerative conditions. In skeletal muscle, irisin stimulates myogenesis, enhances anabolic signaling, and improves metabolic efficiency, suggesting broader relevance for sarcopenia and age-related metabolic decline. Herein, we discuss irisin as a promising biomarker and a candidate therapeutic target for disorders characterized by concurrent muscle deterioration and cognitive impairment. Show less

People with HIV (PWH) have a higher risk of central nervous system (CNS) diseases and a timely differential diagnosis may be essential for patient management. Cerebrospinal fluid (CSF) biomarkers have proven effective in diagnosing neuronal and astrocyte involvement in neurological disorders, but the invasiveness of this method makes it difficult to obtain results; thus, easy-to-obtain matrices (e.g., plasma) have to be analysed. Consequently, the aim of this study was to quantify biomarkers in both serum and CSF with different kits, correlating levels obtained in the two matrices and understanding their impact on blood brain barrier (BBB) permeability. CSF and serum from PWH were analysed through Single Molecule Array (Simoa SR-X, Quanterix). We measured markers of neuronal damage (NfL, tau, ptau), β-amyloid peptides (Aβ Show less

Astroglia, often called as astrocytes, play a crucial role in protecting neurons and preserved the neurophysiological functions. Astrocytes' dysfunction contributes to numerous neurological disorders. Astrocytes are involved in the regulation of oxidative stress and inflammatory process within Central nervous system. Developments in specific transcriptomic and genomics have initiated the discovery of new mechanisms governing astrocyte during oxidative and inflammatory process. Despite the advancements in existing diagnostic and therapeutic methods like targeted ultrasound and NPs mediated administration, these methods still pose risks and have drawbacks. Aptamers, artificial single stranded oligonucleotides have the ability to specific target cells and exhibit strong binding affinity and enhance the administration of therapeutic agents. Research over the last few years has demonstrated that the ability to target specific molecules/intermediates such as reactive oxygen species, interleukins, tumor necrotic factor, vascular endothelial growth factor, brain-derived neurotrophic factor and penetrate the blood brain barrier makes aptamers ideal candidates for addressing the oxidative and inflammatory intermediaries within astrocytes. Present review explores the emerging applications of aptamers in cytoprotection specially focus on their potential to combat oxidative stress and inflammation in astrocytes. We also discuss the capability of aptamers as cell specific molecular probes for advancing tailored diagnostic and therapeutic interventions. Present article also addresses future directions and significant issues. Show less

The gut-brain axis represents a highly integrated communication network, connecting the gastrointestinal tract and the central nervous system via neural, immune, endocrine, and metabolic pathways. Steroid hormones, such as estrogens, androgens, and glucocorticoids, play a pivotal role in modulating these interactions across the lifespan. These hormones influence the composition of microbiota, intestinal permeability, and neuroimmune responses, thereby shaping brain function and behavior. Emerging evidence suggests a correlation between disruptions in the gut-brain axis and the onset and progression of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and multiple sclerosis. The diseases exhibit distinct sex-specific patterns in terms of prevalence, symptomatology, and progression. These patterns are often the consequence of differences in steroid hormone levels, receptor distribution, and immune responses. Despite these differences, the role of sex as a biological variable remains underrepresented in experimental and clinical research. This review synthesizes current evidence on how steroid hormones modulate gut-brain axis interactions and how these mechanisms contribute to neurodegeneration in a sex-specific manner. We highlight recent findings on hormonal regulation of the gut microbiome and its impact on neuroinflammation and neuronal vulnerability. This overview focuses not only on Parkinson's disease, in which genetic variations in the gene for brain-derived neurotrophic factor have been observed among others as triggers for dopaminergic neurodegeneration. In addition, Alzheimer's disease and multiple sclerosis are also considered, in which the prevalence of intestinal dysbiosis and impaired intestinal barrier function have been identified as significant influencing factors. This review provides a comprehensive framework for understanding the gender-specific neurobiology of gut-brain axis by integrating perspectives from the fields of endocrinology, neuroimmunology, and microbiome research. It is argued that a targeted investigation of the interactions between hormones and gut-brain axis is essential for the development of sex-specific therapeutic strategies for neurodegenerative diseases. Show less