NeuroMolecular Medicine最新文献

The review aims to focus on the role of miRNA in gene regulation, related to differentiation and apoptosis of neurons, focusing on the array of miRNAs involved in the processes. miRNAs are a known class of small regulatory RNAs, which in association with RNA processing bodies, play major roles in different cellular events, such as neurogenesis and neuronal differentiation. miRNAs function in controlling neuronal events by targeting different important molecules of cellular signalling. The post-translational modification of Ago2 is crucial in modulating the neurons' miRNA-mediated regulation. Thus, understanding the crosstalk between cellular signalling and miRNA activity affecting neuronal events is very important to decipher novel targets and related signalling pathways, involved in neuronal survival and neurodegeneration.

Ischemic stroke (IS) is a disease with high mortality and disability rates worldwide and is a serious threat to patient health. Owing to the narrow therapeutic window, effective treatments during the recovery period are limited. However, in recent years, mesenchymal stem cells (MSCs) have attracted attention and have shown therapeutic potential in IS treatment because of their abilities to home and secrete multiple bioactive substances and potential for differentiation and substitution. The therapeutic mechanisms of MSCs in IS include the regulatory effects of MSCs on microglia, the dual role of MSCs in astrocytes, how MSCs connect innate and adaptive immunity, the secretion of cytokines by MSCs to counteract apoptosis and MSC apoptosis, the promotion of angiogenesis by MSCs to favor the restoration of the blood‒brain barrier (BBB), and the potential function of local neural replacement by MSCs. However, the low graft survival rate, insufficient homing, poor targeting, and inability to achieve directional differentiation of MSCs limit their wide application. As an approach to compensate for the shortcomings of MSCs, scientists have used nanomaterials to assist MSCs in homing, survival and proliferation. In addition, the unique material of nanomaterials adds tracking, imaging and real-time monitoring to stroke treatment. The identification of effective treatments for stroke is urgently needed; thus, an understanding of how MSCs treat stroke and further improvements in the use of nanomaterials are necessary.

Schizophrenia is a chronic illness that imposes a significant burden on patients, their families, and the health care system. While it has a substantial genetic component, its heterogeneous nature-both genetic and clinical-limits the ability to identify causal genes and mechanisms. In this study, we analyzed the blood transcriptomes of 398 samples (212 patients with schizophrenia and 186 controls) obtained from five public datasets. We demonstrated this heterogeneity by clustering patients with schizophrenia into two molecular subtypes using an unsupervised machine-learning algorithm. We found that the genes most influential in clustering were enriched in pathways related to the ribosome and ubiquitin-proteasomes system, which are known to be associated with schizophrenia. Based on the expression levels of these genes, we developed a logistic regression model capable of predicting schizophrenia samples in unrelated datasets with a positive predictive value of 64% (p value = 0.039). In the future, integrating blood transcriptomics with clinical characteristics may enable the definition of distinct molecular subtypes, leading to a better understanding of schizophrenia pathophysiology and aiding in the development of personalized drugs and treatment options.

Cerebral ischemic stroke ranks among the leading causes of death and disability worldwide. A significant challenge, beyond the lack of effective therapies, is the frequent oversight of sex as a vital factor in stroke research. This study focuses on elucidating the sex-specific epigenetic mechanisms that contribute to neural damage and recovery in cerebral ischemia. In our previously reported study, we demonstrated that following ischemia-induced cerebral artery occlusion (ICAO), female striatal tissue exhibited an early reinstatement of H3K9me2 marks on the promoters of inflammatory genes compared to male striatal tissue. This restoration led to a reduction in the expression of inflammatory cytokines, ultimately contributing to accelerated recovery in females. Building upon these findings, the current study aimed to investigate the unidentified molecular pathways responsible for the accelerated recovery observed in females. To explore this, we performed illumina-RNA sequencing on striatal tissues 24-h post-ICAO. Interestingly, our analysis revealed differential regulation of H3K27me2 marks on the promoters of various neurogenic genes at an early stage, which facilitated early neurogenesis in the female striatum. This investigation identifies an epigenetic modulator, kdm6b/jmjd3, targeting H3K27, and delineates its sex-specific role in neural stem cell proliferation. The findings contribute to a comprehensive model linking gender-specific epigenetic regulation, neurogenesis, and post-ICAO recovery. In conclusion, the identified epigenetic modulators and their roles in neurogenesis offer potential targets for refined therapeutic interventions, emphasizing the importance of personalized and sex-specific considerations in stroke studies.

Recent evidence highlights microparticles (MPs) as crucial players in intercellular communication among immune cells, yet their role in inflammation-induced chronic pain remains unexplored. In this study, we investigated the involvement of MPs in the progression of inflammation and associated pain using mouse models of chronic neuroinflammation induced by repeated intraperitoneal injections of lipopolysaccharide (LPS; 1 mg/kg for four consecutive days) in C57BL/6 mice. Chronic pain was analyzed at baseline (day 0) and on day 21 post-LPS injection using von Frey and the hot metal plate tests. We found a significant increase in the levels of proinflammatory mediators and activation of the TLR4-NFκB signaling pathways following LPS administration.  Additionally, transcriptional upregulation of chronic pain-associated TRP channels and glutamate receptors, including TRPA1, TRPM2, and mGluR2 in the cortex and hippocampus as well as mGluR5 in the cortex, was noted on day 21 post-LPS injection. Moreover, upregulation of TRPM2, mGluR2, and mGluR5 was found in the spinal cord, along with increased TRPA1 protein expression in the brain cortex. Plasma-derived MPs were isolated, revealing a significant increase in concentration 21 days after LPS injection, accompanied by TNF-α DNA encapsulation and increased TNF-α mRNA expression within MPs. Furthermore, MPs concentration positively correlated with the expression of TRPA1, TRPM2, mGluR2, and mGluR5. These findings suggest that MPs contribute to inflammation-induced chronic pain, highlighting their potential as therapeutic targets.

Intermittent fasting has been shown to alleviate stress, anxiety, and depressive symptoms. Although noradrenaline, also known as norepinephrine (NE), is implicated in stress regulation, the dynamics of NE release and the associated neural pathways during stress coping behaviors in fasting mice remain poorly understood. In this study, we employed the forced swimming test (FST) to evaluate the effects of intermittent fasting on stress coping behavior in mice. Our results demonstrate that mice subjected to long-term intermittent fasting exhibited significantly more active coping behaviors in the FST compared to control mice. In contrast, acute fasting did not produce similar effects. Using the fluorescent GRAB-NE sensor to measure NE release with sub-second temporal resolution during the FST, we found that intermittent fasting modulates the locus coeruleus-medial prefrontal cortex (LC-mPFC) pathway, which underlies these behavioral adaptations. Moreover, chemogenetic activation of LC-mPFC projections strongly promoted active coping in the FST. These findings suggest that enhanced LC-mPFC activity mediates the increased active coping behavior observed in fasting mice. This study provides new insights into the neural mechanisms through which intermittent fasting may ameliorate depressive-like behaviors, offering potential therapeutic targets for stress-related disorders.

Astrocytes are the most abundant cells in the brain and show neuroprotective function in CNS and reactive astrocytes are characteristic in neurodegenerative diseases. The JAK2-STAT3 pathway plays a crucial role in the process of astrocyte activation. However, as a hallmark of Parkinson's disease, the change in α-syn under the influence of STAT3 inhibitor and the underlying cellular mechanisms remain elusive. Here, we show that PFF can induce an increase in α-syn in SVG p12 cells, which is further enhanced after the inhibition of STAT3. The underlying mechanisms involve the downregulation of autophagy levels and a concurrent decrease in lysosomal function after inhibition of STAT3. Additionally, we observed inhibition of STAT3 resulted in reduced exosome secretion in SVG p12 cells. This is attributed to alterations in SNARE, leading to impaired fusion between MVBs and the cell membrane, subsequently causing the accumulation of intracellular MVBs. Taken together, our data demonstrates that inhibition of STAT3 decreases both the autophagy and lysosome function, which may increase MVBs production. However, we found a potentially decreased exosome production that may be implicated with SNARE complex and need further exploration.

Neurodegenerative disease characterized by the progressive damage of the nervous system, and neuropathies caused by the neuronal injury are both led to substantial impairments in neural function and quality of life among geriatric populations. Recovery from nerve damage and neurodegenerative diseases present a significant challenge, as the central nervous system (CNS) has limited capacity for self-repair. Investigating mechanism of neurodegeneration and regeneration is essential for advancing our understanding and development of effective therapies for nerve damage and degenerative conditions, which can significantly enhance patient outcomes. Collapsin response mediator protein 2 (CRMP2) was first identified as a key mediator of axonal growth and guidance is essential for neurogenesis and neuroregeneration. Phosphorylation as a primary modification approach of CRMP2 facilitates its involvement in numerous physiological processes, including axonal guidance, neuroplasticity, and cytoskeleton dynamics. Prior research on CRMP2 phosphorylation has elucidated its involvement in the mechanisms of neurodegenerative diseases and nerve damage. Pharmacological and genetic interventions that alter CRMP2 phosphorylation have shown the potential to influence neurodegenerative diseases and promote nerve regeneration. Even with decades of research delving into the intricacies of CRMP2 phosphorylation, there remains a scarcity of comprehensive literature reviews addressing this topic. This absence of synthesis and integration of findings hampers the field's progress by preventing a holistic understanding of CRMP2's implications in neurobiology, thereby impeding potential advancements in clinical treatments and interventions. This review intends to compile investigations focused on the role of CRMP2 phosphorylation in both neurodegenerative disease models and injury models to summarizing impacts and offer novel insight for clinical therapies.

This study aimed to investigate the role of ubiquitin-specific peptidase 15 (USP15) in ischemic cognitive dysfunction using a mouse model and a cerebral ischemia (CI) cell model, its impact on ferroptosis and the underlying mechanisms. Oxygen-glucose deprivation/reoxygenation (OGD/ R)-induced HT-22 cells were used to establish the CI cell model, and mice induced with CI were used as the animal model for ischemic cognitive dysfunction. Cell damage was evaluated using Cell Counting Kit-8 (CCK-8), flow cytometry (FCM), immunoblotting, and immunofluorescence assays. Cognitive dysfunction in the CI mice was assessed through water maze experiments. Ferroptosis was examined with an iron detection kit and immunoblotting, oxidative stress was evaluated using 2',7'-dichlorofluorescin diacetate (DCF) and enzyme-linked immunosorbent assay (ELISA), and mechanistic experiments were performed via immunoblotting. USP15 knockdown alleviated OGD/ R-induced damage in HT-22 cells. In vivo, USP15 depletion mitigated brain injury in middle cerebral artery occlusion (MCAO) mice and improved learning and memory function. The absence of USP15 reduced oxidative stress in MCAO mice and attenuated ferroptosis by activating nuclear factor erythroid 2-related factor 2 (Nrf2). Mechanistic investigations confirmed that USP15 depletion ameliorated cognitive impairment and ferroptosis through the activation of the Nrf2/ GPX4 axis. USP15 is associated with ferroptosis and cognitive dysfunction in mice and could serve as a potential therapeutic target in CI.

Clinical distinction between dementia with Lewy bodies (DLB) and late-onset Alzheimer's disease (AD) is difficult, while several features might affect the analyses of biomarkers. This study aimed to verify associations of anthropometric and demographic features with cerebrospinal fluid biomarkers, their ratios, and restructured traditional regression formulas in patients with DLB and AD, as well as in cognitively healthy controls. Consecutive outpatients with DLB were paired with outpatients with AD according to sex, dementia stage, and cognitive status, and with controls according to sex and age to investigate associations of sex, age, dementia duration, total sleep time, body mass index, alcohol use, smoking, sanitation, and APOE-ε4 alleles on the measurement of cerebrospinal fluid α-synuclein, biomarker ratios, and restructured traditional regression formulas involving amyloid-β (Aβ₄₂,Aβ₄₀,Aβ₃₈), tau, and phospho-tau Thr₁₈₁. Overall, 81 participants were included with DLB (n = 27;11 APOE-ε4 +) or AD (n = 27;12 APOE-ε4 +), and controls (n = 27;4 APOE-ε4 +); two thirds were women. Cerebrospinal fluid evidence of amyloidosis and tauopathy was more prevalent among women with AD, while Aβ₄₂/Aβ₃₈ could also discriminate men with DLB from men with AD. Restructured traditional regression formulas had higher diagnostic accuracy for women with AD. Aging, higher body mass index, and APOE-ε4 alleles were associated with amyloidosis in DLB, while only in AD were higher body mass index associated with lower tau pathology load, and more alcohol use associated with higher phospho-tau Thr₁₈₁/Aβ₄₂. These findings confirm the effects of anthropometric and demographic features on cerebrospinal fluid biomarkers, and also differences in aberrant amyloidosis and tauopathy between DLB and AD.