NeuroMolecular Medicine最新文献

The characteristics of Alzheimer's disease (AD) include behavioral deficits, amyloid-β (Aβ) accumulation, and mitochondrial impairment. Activating of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway significantly increases the production of inflammatory cytokines, which can exacerbate neuroinflammation and accelerate the progression of AD. Platycodin D (PD) has been reported to exhibit anti-inflammatory and neuroprotective properties and is believed to play a role in the progression of AD. Our study aimed to investigate the protective effects of PD in AD and to determine whether these protective effects are associated with the cGAS-STING pathway. In this research, APP/PS1 transgenic mice, an animal model of AD, were administered with PD via intracerebroventricular injection. SHSY5Y cells stably transfected with APPswe gene (APPswe cells) were used as a cell model of AD and treated with PD. Our findings demonstrated that PD attenuated behavioral deficits, Aβ accumulation, mitochondrial impairment, and decreased the expression level of cGAS-STING pathway proteins (cGAS and STING) as well as inflammatory cytokines (TNF-α, IL-1β and IL-18) in AD models. However, cGAMP acts as an agonist of the cGAS-STING pathway upregulated the cGAS-STING pathway and inflammatory cytokines, exacerbated Aβ accumulation and mitochondrial impairment in APPswe cells. In conclusion, our findings suggested that PD attenuated behavioral deficits, Aβ accumulation and mitochondrial impairment in AD models by inhibiting cGAS-STING pathway.

Ischemic stroke (IS) is a complex neurological disorder caused by reduced cerebral blood flow, typically resulting in tissue damage due to hypoxia and nutrient deficiency. Hyperbaric oxygen therapy (HBOT) has shown great potential as an adjunctive treatment for IS, though its mechanisms of action are not fully understood. This study employed a middle cerebral artery occlusion (MCAO) mouse model to explore the molecular mechanisms and therapeutic effects of HBOT. Transcriptomic analysis revealed significant changes in gene expression related to ischemia, including differentially expressed genes (DEGs) involved in inflammatory responses, BBB damage, and neural repair, such as Lcn2, Bcl3, Olr1, Pdpn, Gpnmb, and Gfap. HBOT significantly reduced brain damage, modulated the expression of these key genes, and decreased m⁶A methylation levels, thereby affecting post-transcriptional modifications of RNA. These findings provide new insights into the molecular mechanisms of IS and the development of precise treatment strategies, highlighting the potential of HBOT to reduce brain damage and promote neural repair at the molecular level.

This study estimates the association between blood levels of inflammatory markers and cognitive function in adults with Alzheimer's disease or mild cognitive impairment. A systematic review and meta-analysis were conducted to synthesize data from studies examining the relationship between blood levels of inflammatory markers and cognitive function in adults with Alzheimer's disease or mild cognitive impairment. The search strategy was applied to the Medline database through MEDLINE (OVID), WEB OF SCIENCE, SCOPUS, LILACS, and the Cochrane Central Register of Controlled Trials (CENTRAL). Studies were selected based on predefined criteria. We included 84 studies in the qualitative synthesis, with 75 incorporated into the meta-analysis. In blood samples, subjects with Alzheimer's disease showed significantly higher concentrations of IL-1β (mean difference 0.46 [95% CI: 0.35, 0.58]), IL-6 (3.41 [3.05, 3.78]), MCP-1 (26.20 [14.57, 37.82]), and TNF-α (6.68 [5.97, 7.39]), along with lower concentrations of IL-8 (- 1.46 [- 1.85, - 1.08]) and IL-10 (- 3.20 [- 4.21, - 2.20]). This systematic review and meta-analysis demonstrate significant alterations in inflammatory marker concentrations in blood samples of individuals with Alzheimer's disease and mild cognitive impairment. Elevated levels of IL-1β, IL-6, MCP-1, and TNF-α, alongside reduced IL-8 and IL-10 levels, suggest a robust inflammatory response associated with Alzheimer's disease.

Synaptotagmins (Syts) are a family of crucial Ca²⁺ sensors for cellular secretions, while half of the Syt isoforms are evolutionarily non-Ca²⁺-affinitive, which are less studied but associated with several neuro-system diseases. Some Syt isoforms exhibited importance in specific cancer types, but a comprehensive study of all Syts in pan-cancer is lacking. Here, using informatics tools and proteome/transcriptome databases, the expression, phosphorylation, CpG methylation profiles, and the correlation with genome heterogeneity, tumor stemness, and immune infiltration of all human Syts are analyzed in human pan-cancer, resulting in significant associations of each Syt in various types of cancer, including pathological stage and prognosis. Most Syts exhibit noteworthy expression level changes in GBM/LGG and PCPG, and Syt11 has a strong association with immune infiltration. The Ca²⁺-affinitive and non-Ca²⁺-affinitive Syt groups show opposite changes in both expression and methylation levels in an overview scale suggesting different mechanisms of them in cancers. Detection of similar expression genes suggests that Ca²⁺-affinitive Syts may participate in the RNA-splicing process, while non-Ca²⁺-affinitive Syts are involved in NF-κB signaling and immune regulation. This study uncovers the clinical potential of each Syt isoform and discusses clues to their roles, such as Ca²⁺ sensitivity and immune regulation, in tumor progression. The overall data are informative for future refining and mining.

Neurodegenerative diseases consist of a group of progressive disorders characterized by the gradual decline in the structure or function of neurons, which ultimately results in neuronal death. The occurrence and societal effects of these disorders have been consistently rising, presenting considerable public health challenges globally. Multiple interconnected pathways, including oxidative stress, neuroinflammation, nitrosative stress, and apoptosis, drive their progression. NOX-induced ROS disrupts neuronal function, impairs mitochondrial activity, and triggers lipid peroxidation, contributing to neuronal death. Activation of the TLR-4/MAPK/NF-κB pathway triggers neuroinflammation and NLRP3 inflammasome activation. This inflammasome-driven inflammation accelerates neuronal injury and death. Moreover, reduced estrogen receptor expression weakens neuronal defenses, impairing synaptic function, thereby worsening neurodegeneration. Neurodegenerative diseases continue to be without a cure, as existing treatments focus on alleviating symptoms and modifying the disease. Due to their intricate and multifactorial pathophysiology, there is a pressing need for agents capable of targeting multiple pathological mechanisms to effectively combat these disorders. Various phytomolecules have shown promise in tackling different neurodegenerative diseases by modulating key molecular targets. Equol (4',7-isoflavandiol) is a metabolite of daidzein, a soy isoflavone present in soybeans and various other plant sources. Equol has shown significant promise in combating neurodegeneration by modulating mediators involved in oxidative stress, neuroinflammation, nitrosative stress, and apoptosis. Key signaling molecules influenced by equol include TLR-4, MAPKs, NLRP3 inflammasome, ROS, and inflammatory mediators, among others. Considering equol's ability to modulate these signaling mediators, this review explores the mechanistic pathways through which equol confers neuroprotection.

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a neurodegenerative disorder marked by the progressive degeneration of motor neurons in the brain and spinal cord. Despite decades of research, ALS remains incurable, diagnostically elusive, and is accompanied by rapid clinical decline, morbidity, and mortality. Its pathophysiology involves a complex interplay of genetic mutations (SOD1, C9/f72), environmental triggers, oxidative stress, neuroinflammation, and the accumulation of misfolded proteins, such as TDP-43 and SOD1. These factors disrupt cellular homeostasis aggravates excitotoxicity and neuronal death. Existing treatments, such as riluzole (a glutamate release modulator) and edaravone (a free radical scavenger), offer limited benefits, modestly prolonging survival or slowing functional decline without halting progression. Investigational approaches include antisense oligonucleotides targeting mutant SOD1 or C9orf72 genes, stem cell-based motor neuron replacement, and biomarker discovery to enable earlier diagnosis and progression monitoring. ALS patients frequently exhibit gastrointestinal (GI) symptoms, including dysphagia, sialorrhea, constipation, delayed gastric emptying, and pancreatic/parotid deficiencies. These observations underscore a close association between GI dysfunction and ALS pathogenesis. Also, recent studies implicate the gut-brain-microbiota axis in disease evolution, with microbial metabolites influencing neuroimmune interactions, synaptic plasticity, myelination, and skeletal muscle function. These studies indicate that dysbiosis-an imbalance in gut microbiota-may have a crucial role in ALS progression by impairing intestinal barrier integrity, promoting endotoxemia, and driving systemic inflammation. Conversely, ALS progression itself worsens dysbiosis, creating a vicious cycle of neuroinflammation and neurodegeneration. Preclinical and clinical evidence suggests that interventions targeting gut microbiota-such as prebiotics, probiotics, antibiotics, or phage therapy-could alleviate symptoms and slow disease progression and specific probiotic strains have also shown promise in reducing oxidative stress and inflammation in animal models. These findings highlight the urgent need to elucidate the functional role of gut microbiota in ALS to unlock novel diagnostic and therapeutic avenues. This review synthesizes current knowledge on the pathophysiology of ALS, with a focus on the emerging role of the gut-brain-microbiota axis. It highlights how dysbiosis influences diverse disease markers and neurodegenerative mechanisms, offering insights into potential therapeutic strategies and identifying key research gaps and future directions.

Pain and depression frequently are comorbid and have common mechanisms such as monoamine depletion, inflammation, and oxidative stress. Hence, this study aimed to investigate the effects of bioactive coumarin on reserpine induced pain-depression dyad in mice. Mechanical allodynia, depressive-like behavior, and cognitive deficits were induced by reserpine (0.5 mg/kg, subcutaneously, once daily on days 1-3) in male BALB/c mice. Scopoletin (50 mg/kg, p.o.) or gabapentin (10 mg/kg, p.o.) was given twice daily (at 9:00 am and 5:00 pm) for 5 days. For days 1-3, the initial daily dose of scopoletin or gabapentin was given 30 min before reserpine injection, with the second dose at the evening. Control animals, which received vehicle, were given 0.1% CMC. Behavioural tests (Electronic von Frey (eVF) test, Pressure Application Measurement (PAM) test) (Forced Swim Test (FST) and Morris Water Maze (MWM) test) were performed on day 4 and 6, and tissue collection was conducted on day 6 for biochemical analyses (cytokines (TNF-α and IL-1β), neurotransmitters (Serotonin, Norepinephrine, and Glutamate), MAO-A activity, GSH, TBARS). Paw withdrawal thresholds (eVF day 4: F(3,20) = 28.75, p < 0.001; PAM: F(3,20) = 35.17, p < 0.001) were markedly diminished and immobility time in FST (F(3,20) = 29.11, p < 0.001) was notably prolonged by reserpine. Moreover, it impaired the spatial memory (MWM: F(3,20) = 30.56, p < 0.001), and increased the serum TNF-α and IL-1β (F(3,20) = 24.32 and 18.50, respectively; p < 0.01), the brain MAO-A activity (F(3,20) = 16.83, p < 0.01), glutamate and TBARS (F(3,20) = 25.11, p < 0.001; F(3,20) = 19.76, p < 0.01), and decreased the brain serotonin, norepinephrine and GSH (p < 0.01-0.001). Supplementation with scopoletin markedly retarded deficits in behavior (eVF and PAL, p < 0.001; FST, p < 0.001; MWM, p < 0.001) and biochemistry (reduction of UG [TNF-α, IL-1β], MAO-A activity and glutamate level along with restoration of monoamine and antioxidant status, p < 0.05-0.001). Scopoletin is a promising candidate drug for comorbid pain and depression due to its significant counteracting effects on reserpine-induced behavioral and biochemical alterations.

Although researchers began to unravel the potential significance of Runt-related transcription factor 2 (RUNX2) in some of neurological diseases, the role of RUNX2 in ischemic stroke remained unclear. Blood samples and clinical information were collected from stroke patients and control subjects. Besides, middle cerebral artery occlusion (MCAO) mice model and astrocytes oxygen-glucose deprivation/reperfusion (OGD/R) were established to simulate the pathological process of stroke in vivo and in vitro. Loss-of-function assay was used to assess the effect of RUNX2 on astrocytes function. HE staining and Nissl staining were used to examine the histopathological changes of brain tissues in mice. TTC staining was used to measure the cerebral infarct volume in mice. Morri's water maze test, the corner turn test, and the balance beam test were performed to evaluate neurobehavioral performances of mice. The results showed that the expression and serum content of RUNX2 were upregulated in stroke patients and mice. Knocking-down RUNX2 inhibited OGD/R-induced increases of proliferation and migration, while reversed the decrease of apoptosis in astrocytes. Moreover, RUNX2 knockdown also suppressed the inflammatory response in OGD/R-treated astrocytes and promoted the conversion of the reactive astrocyte phenotype from A1 to A2. The serum mRNA expression and level of RUNX2 were both notably increased in patients with cerebral edema. RUNX2 knockdown weakened cerebral edema and swelling of astrocytes. The results of HE staining and Nissl staining suggested that RUNX2 knockdown notably improved neuronal damage in the brain tissues of MCAO mice and also improved the injured performance of MCAO stroke mice in the behavioral test. In conclusion, RUNX2 expression was upregulated during the pathological progression of ischemic stroke. Furthermore, the knockdown of RUNX2 alleviated OGD/R-induced astrocytes activation and swelling, while inhibiting the polarization and inflammatory response in astrocytes. More importantly, RUNX2 interference also improved neuronal damage, cerebral edema, and neurobehavioral performances of MCAO mice.

Spinal Cord Injury (SCI) is a severe disorder of the central nervous system, typically caused by trauma or disease, which significantly impacts the quality of life of affected individuals. Secondary inflammation following spinal cord injury is a critical factor influencing prognosis, making the exploration of the inflammatory microenvironment crucial for the treatment of SCI. Xanthoxylin, a small organic molecule extracted from plants, has demonstrated notable anti-inflammatory effects. To investigate the role of Xanthoxylin in spinal cord injury, we initially employed Hoechst staining and flow cytometry, revealing that Xanthoxylin reduces neuronal apoptosis. Subsequently, through Western blot, immunofluorescence, and qPCR, we discovered that Xanthoxylin promotes the polarization of microglia from the M1 inflammatory phenotype to the M2 anti-inflammatory phenotype. Furthermore, transcriptome sequencing identified differential expression in the NF-κB pathway, which was corroborated by Western blot analysis. Finally, animal experiments were conducted to further validate the therapeutic effects of Xanthoxylin on spinal cord injury in mice. These results suggest that Xanthoxylin has a significant therapeutic effect on SCI in mice. Overall, our study is the first to demonstrate the therapeutic effect of Xanthoxylin on SCI and provides a scientific exploration of its underlying mechanisms, offering new directions for pharmacological treatment of spinal cord injury.

Rett syndrome (RTT), a severe neurodevelopmental disorder primarily affecting girls, is commonly caused by MECP2 loss-of-function mutations. Key symptoms include motor impairments, typical hand stereotypies and intellectual disability. Moreover, although not thoroughly studied, anxiety, heightened stress sensitivity, and aberrant pain perception are also an important component of the RTT phenotype. Emerging evidence suggests that early-life stress (ELS) worsens Mecp2-related phenotypic alterations in mice. Microglia, the resident immune cells within the central nervous system, play a critical role in RTT pathophysiology, yet the combined impact of ELS and Mecp2 deficiency on microglia has not been studied. Previously, we observed reduced activation of the periaqueductal grey (PAG, a cerebral structure involved in pain modulation, autonomic control, and defensive behaviours) in Mecp2-heterozygous (Mecp2-het) mice after thermal stimulation. Here, we investigated the impact of ELS on microglia morphology in the PAG under Mecp2 deficiency. To this end, we analysed microglia in the PAG of presymptomatic Mecp2-het mice previously subjected to maternal separation (MS) as a model of ELS, alongside corresponding control animals. Brain sections were immunolabelled for IBA1, a pan-microglial marker. Microglial cells within the PAG were evaluated for expression levels, morphological characteristics, and fractal properties. While global PAG analyses showed minimal differences, subdivision-specific analyses revealed significant microglial alterations. These findings suggest that ELS exacerbates Mecp2-related neurodevelopmental deficits, impairing microglia in a region-specific manner. Our data points to a microglial failure to morphologically adapt, rather than overt structural loss, in the PAG that may underlie some of the neurological dysfunctions observed in RTT.