Journal of Molecular Neuroscience最新文献

Advanced glycation end products (AGEs) have attracted interest as therapeutic targets for neurodegenerative diseases. AGEs facilitate the onset and progression of various neurogenerative disorders due to their ability to promote cross-linking and aggregation of proteins. Further, the interaction between AGEs and receptor for AGEs (RAGE) activates neuroinflammatory, oxidative stress and excitotoxicity processes that contribute to neuronal cell death. Various therapeutic efforts have targeted lowering the production of AGEs, inhibiting RAGE or inhibiting some of the processes of the AGE-RAGE axis as potential treatments for these disorders. Whereas effective treatments for many neurodegenerative disorders remain elusive, such efforts offer promise to slow the progression of diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD).

In 2019, coronavirus disease 2019 (COVID-19) started a global health crisis and was associated with high rates of depression and anxiety. Both mental disorders and COVID-19 exhibit similarities in pathophysiology, characterized by immune system overactivation, involvement of the purinergic system, and oxidative stress, besides additional factors and systems likely contributing to the complexities of these conditions. The purinergic system contributes to the disease-influenced immune response, an essential strategy for controlling pathophysiological effects. In this context, the hormone melatonin emerges as a substance that can modulate the purinergic system and contribute positively to the pathophysiology of SARS-CoV-2 infection and associated mental disorders. Melatonin is a hormone that regulates the body’s circadian rhythms, plays an essential role in regulating sleep and mood, and modulates the purinergic system. Recent studies suggest melatonin’s anti-inflammatory and antioxidant properties may benefit COVID-19. This review explores melatonin’s impact on inflammatory cytokine storm in COVID-19 through purinergic system modulation.

The cardinal clinical features of complex regional pain syndrome type I (CRPS-I) are pain, edema, autonomic changes, and limitation of motoric movement, which may indicate the role of inflammation and cytokines. We report the effect of prednisolone on the clinical severity and mRNA profiling of proinflammatory (tumor necrosis factor (TNF)-α and interleukin (IL)-2) and anti-inflammatory cytokines (IL-10 and transforming growth factor (TGF)-β) in the patient with CRPS-I. Thirty-nine patients with CRPS-I of shoulder joint were enrolled. Their CRPS, Visual Analog Scale (VAS) and Daily Sleep Interference Scale (DSIS) scores were recorded. TNF-α, IL-2, IL-10, and TGF-β gene expressions at mRNA of whole blood were measured by reverse transcriptase polymerase chain reaction. Patients were randomized to prednisolone 20 mg or 40 mg using 1: 1 randomization. The primary outcome was change in VAS score, and secondary outcomes were change in CRPS and DSIS scores at 1 month. Side effects were noted. The patients had increased expressions of TNF-α (p < 0.001) and IL-2 (p < 0.001) and reduced IL-10 (p < 0.01) mRNA compared to the healthy controls. The baseline characteristics were matched between the two treatment arms. At 1 month, CRPS, VAS, and DSIS scores improved significantly compared to baseline, which paralleled with improvement in IL-10 (p < 0.032) and reduction in TNF-α (p = 0.046). The improvement in clinical and biomarkers was similar in prednisolone 20 mg and 40 mg arms. None had to be withdrawn due to severe side effects. Future study in larger cohort may validate these findings.

It is well known that the development of neurodegeneration, and especially Alzheimer’s disease (AD), is often accompanied by impaired olfaction which precedes memory loss. A neuropeptidase neprilysin (NEP)—a principal amyloid-degrading enzyme in the brain—was also shown to be involved in olfactory signalling. Previously we have demonstrated that 5xFAD mice develop olfactory deficit by the age of 6 months which correlated with reduced NEP expression in the brain areas involved in olfactory signalling. The aim of this study was to analyse the effect of administration of a histone deacetylase inhibitor, valproic acid (VA), to adult 5xFAD mice on their olfaction and memory as well as on brain morphology and NEP expression in the parietal cortex (PC) and hippocampus (Hip). The data obtained demonstrated that administration of VA to 7-month-old mice (200 mg/kg of body weight) for 28 days resulted in improvement of their memory in the Morris water maze as well as olfaction in the odor preference and food search tests. This correlated with increased expression of NEP in the PC and Hip as well as a reduced number of amyloid plaques in these brain areas. This strongly suggests that NEP can be considered an important therapeutic target not only in AD but also in olfactory loss.

Specific learning disorder (SLD) is prevalent worldwide and is a complex disorder with variable symptoms and significant differences among individuals. Epigenetic markers may alter susceptibility to neurodevelopmental disorders (NDDs). Aberrant expression of protein-coding (mRNA) genes in this pathology shows that the detection of epigenetic molecular biomarkers is of increasing importance in the diagnosis and treatment of individuals with SLD. We compared gene expression level of dyslexia susceptibility 1 candidate gene 1 (DYX1C1), dyslexia-associated protein KIAA0319 (KIAA0319), and roundabout guidance receptor 1 (ROBO1) between children with SLD and healthy children by performing quantitative polymerase chain reaction (qPCR). In addition, we evaluated these gene expressions of severe children with SLD compared to non-severe and male SLD children compared to females. The expression of the DYX1C1, KIAA0319, and ROBO1 genes was statistically significantly upregulated in children with SLD (P < 0.05*). DYX1C1 was also upregulated in severe SLD children (P = 0.03*). In addition, KIAA0319 and ROBO1 genes were differentially expressed in male SLD children compared to females (P < 0.05*). Furthermore, we found that DYX1C1 and ROBO1 genes significantly affect the likelihood of the SLD (respectively, P < 0.001** and P = 0.007*). We expect that the findings provided from this study may contribute to the determination expression level of the relevant genes in the diagnosis, prognosis, and treatment of SLD. In addition, our findings could be a guide for future epigenetics studies on the use of the DYX1C1, KIAA0319, and ROBO1 in therapeutic applications in the SLD.

Regeneration of the sciatic nerve is a sophisticated process that involves the interplay of several signaling pathways that orchestrate the cellular responses critical to regeneration. Among the key pathways are the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/AKT, cyclic adenosine monophosphate (cAMP), and Janus kinase/signal transducers and transcription activators (JAK/STAT) pathways. In particular, the cAMP pathway modulates neuronal survival and axonal regrowth. It influences various cellular behaviors and gene expression that are essential for nerve regeneration. MAPK is indispensable for Schwann cell differentiation and myelination, whereas PI3K/AKT is integral to the transcription, translation, and cell survival processes that are vital for nerve regeneration. Furthermore, GTP-binding proteins, including those of the Ras homolog gene family (Rho), regulate neural cell adhesion, migration, and survival. Notch signaling also appears to be effective in the early stages of nerve regeneration and in preventing skeletal muscle fibrosis after injury. Understanding the intricate mechanisms and interactions of these pathways is vital for the development of effective therapeutic strategies for sciatic nerve injuries. This review underscores the need for further research to fill existing knowledge gaps and improve therapeutic outcomes.

Graphical Abstract

Mitochondria play a pivotal role in cellular metabolism, energy production, and apoptotic signaling, making mitophagy, the selective degradation of damaged mitochondria, crucial for mitochondrial health. Dysregulation of mitophagy has been implicated in various neuroendocrinopathies, yet the mechanisms linking these processes remain poorly understood. This review aims to explore the intersection between mitophagy and neuroendocrinopathy, addressing the critical gaps in knowledge regarding how mitochondrial dysfunction may contribute to the pathophysiology of neuroendocrine disorders. We conducted a comprehensive literature review of studies published on mitophagy and neuroendocrinopathies, focusing on data that elucidate the pathways involved and the clinical implications of mitochondrial health in neuroendocrine contexts. Our findings indicate that altered mitophagy may lead to the accumulation of dysfunctional mitochondria, contributing to neuroendocrine dysregulation. We present evidence linking impaired mitochondrial clearance to disease models of conditions such as metabolic syndrome, depression, and stress-related disorders, highlighting the potential for therapeutic interventions targeting mitophagy. While significant advances have been made in understanding mitochondrial biology, the direct interplay between mitophagy and neuroendocrinopathies remains underexplored. This review underscores the necessity for further research to elucidate these connections, which may offer novel insights into disease mechanisms and therapeutic strategies for treating maladaptive neuroendocrine responses.

Traumatic brain injury (TBI) is caused by an external mechanical force to the head, resulting in abnormal brain functioning and clinical manifestations. Antisecretory factor (AF16) is a potential therapeutic agent for TBI treatment due to its ability to inhibit fluid secretion and decrease inflammation, intracranial pressure, and interstitial fluid build-up, key hallmarks presented in TBI. Here, we investigated the effect of AF16 in an in vitro model of neuronal injury, as well as its impact on key components of the autophagy pathway and mitochondrial dynamics. N2A^wt cells were treated with AF16, injured using a scratch assay, and analysed using confocal microscopy, correlative light and electron microscopy (CLEM), flow cytometry, and western blotting. Our results reveal that AF16 enhances autophagy activity, regulates mitochondrial dynamics, and provides protection as early as 6 h post-injury. Fluorescently labelled AF16 was observed to localise to lysosomes and the autophagy compartment, suggesting a role for autophagy and mitochondrial quality control in conferring AF16-associated neuronal protection. This study concludes that AF16 has potential as a therapeutic agent for TBI treatment through is regulation of autophagy and mitochondrial dynamics.

Physical activity has been demonstrated to improve cognitive function, thereby preventing/slowing neurodegenerative diseases (NDs). Biological responses to physical activity and vulnerabilities to NDs are emerging to be gender-related. Herein, known ND-associated markers (β-amyloid, tau, α-synuclein), main sex steroid hormones, antioxidant responses, and key gene transcription modulators were evaluated in the blood of physically active and sedentary women and men. In our hands, females presented higher basal erythrocytes β-amyloid and α-synuclein amounts than males. Regular physical activity was able to significantly reduce the erythrocyte content of β-amyloid in females and the tau levels in males, suggesting that these differences may be mediated by organizational actions of sex steroid hormones during development. Furthermore, despite a comparable plasma antioxidant capability (AOC) between males and females, in the latter group, physical activity significantly enhances AOC versus peroxynitrite radicals only. Finally, regular physical activity modulated the levels of transcription factor Nrf2 in erythrocytes, as well as the plasma concentration of the microRNA miR-195 and miR-153, suggesting the promotion of antioxidant/autophagic processes associated with ND-related proteins. Overall, these results could shed light on how cerebral adaptations to physical activity differ between males and females, especially with regard to blood accumulation of ND proteins and mechanisms of antioxidant responses to regular exercise.

With the persistent challenge that epilepsy presents to therapeutic avenues, the study seeks to decipher the effects of the ketogenic diet (KD) on gut microbiota and subsequent epileptic outcomes. Mouse fecal samples from distinct KD and control diet (CD) cohorts underwent 16S rRNA sequencing. Differential genes of epileptic mice under these diets were sourced from the GEO database. The study melded in vivo and in vitro techniques to explore the nuanced interactions between KD, gut microbiota, and hippocampal TRHR dynamics. The KD regimen was found to result in a notable reduction in gut microbiota diversity when compared to the CD groups. Distinctive microbial strains, which are hypothesised to interact with epilepsy through G protein-coupled receptors, were spotlighted. In vivo, explorations affirmed that gut microbiota as central to KD’s anti-epileptic efficacy. Of 211 distinguished genes, the neuroactive ligand-receptor interaction pathway was underscored, particularly emphasizing TRHR and TRH. Clinical observations revealed a surge in hippocampal TRHR and TRH expressions influenced by KD, mirroring shifts in neuronal discharges. The KD, leveraging gut microbiota alterations, amplifies hippocampal TRHR expression. This finding provides a novel intervention strategy to reduce seizures.