NeuroMolecular Medicine最新文献

Alzheimer's disease (AD) and atherosclerosis (AS) are two chronic diseases with seemingly distinct pathologies. However, emerging research points to a bidirectional relationship driven by common mechanisms, such as inflammation, oxidative stress, and dysregulation of Amyloid-Beta (Aβ). This review focuses on the role of Aβ as a critical molecular link between AD and AS, emphasizing its contribution to neuronal impairment and vascular damage. Specifically, peripheral Aβ produced in the pancreas and skeletal muscle tissues exacerbates AS by promoting endothelial dysfunction and insulin resistance (IR). Furthermore, AS accelerates AD progression by impairing cerebral blood flow and inducing chronic hypoxia, causing Aβ accumulation. This review critically evaluates recent findings, highlighting inconsistencies in clinical studies and suggesting future research directions. Understanding the bidirectional influence of AD and AS could pave the way for novel therapeutic approaches targeting shared molecular pathways, particularly emphasizing Aβ clearance and inflammation.

Obesity, a pandemic health problem, is now considered as a chronic inflammatory state, related to many autoimmune diseases, such as multiple sclerosis. Thus, adipokines, inflammatory mediators secreted by adipose tissue, play an important role modulating the immune response. In this context, obesity, especially during adolescent age, seems to be a key factor for the development of multiple sclerosis. Leptin, the main pro-inflammatory adipokine secreted by the adipose tissue, has been found increased in patients with multiple sclerosis and is able to regulate the immune system promoting a pro-inflammatory response. Leptin signaling in both innate and adaptative immune cells might have immunomodulatory effects in the context of multiple sclerosis. In this way, leptin has been found to produce a Th1 and Th17 response, increasing M1 macrophages and decreasing regulatory T cells and Th2 response. Moreover, circulating inflammatory adipokines, such as leptin, have been found in people with multiple sclerosis. In the present work, we are reviewing literature to update the body of knowledge regarding the role of obesity and leptin in multiple sclerosis.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common genetic form of stroke. It is caused by a cysteine-altering variant in one of the 34 epidermal growth factor-like repeat (EGFr) domains of Notch3. NOTCH3 pathogenic variants in EGFr 1-6 are associated with high disease severity, whereas those in EGFr 7-34 are associated with late stroke onset and increased survival. However, whether and how the position of the NOTCH3 variant directly affects the disease severity remains unclear. In this study, we aimed to generate human-induced pluripotent stem cells (hiPSCs) from patients with CADASIL with EGFr 1-6 and 7-34 pathogenic variants to evaluate whether the NOTCH3 position affects the cell phenotype and protein profile of the generated hiPSCs lines. Six hiPSCs lines were generated: two from patients with CADASIL with EGFr 1-6 pathogenic variants, two from patients with EGFr 7-34 variants, and two from controls. Notch3 aggregation and protein profiles were tested in the established six hiPSCs lines. Cell analysis revealed that the NOTCH3 variants did not limit the cell reprogramming efficiency. However, EGFr 1-6 variant position was associated with increased accumulation of Notch3 protein in pluripotent stem cells and proteomic changes related with cytoplasmic reorganization mechanisms. In conclusion, our analysis of hiPSCs derived from patients with CADASIL support the clinical association between the NOTCH3 variant position and severity of CADASIL.

Microglial cells occupy a crucial position as potential therapeutic targets in the context of ischemic stroke (IS). Nonetheless, the intrinsic mechanisms that govern microglial activation in the aftermath of IS remain incompletely elucidated. ADAR1 p150 plays a significant role in immune regulation and stress responses; however, the specific pathways through which it modulates microglial activation and the subsequent mechanisms that unfold following IS have yet to be clearly delineated. The distal middle cerebral artery occlusion (dMCAO) mouse model was utilized to induce IS. The evaluation of infarct volume was conducted through TTC staining, while neurological function was assessed using the modified Neurological Severity Score (mNSS). To evaluate the expression of ADAR1 and apoptosis-related proteins, immunofluorescence and Western blot techniques were employed. BV2 cells were subjected to oxygen-glucose deprivation followed by reperfusion (OGD/R). Additionally, a co-culture system of BV2 cells and neurons was established, and subsequent assessments of neuronal viability and apoptosis were performed using CCK-8 assays and LDH release assays. ADAR1 p150 expression was significantly upregulated in the brains of ischemic mice, particularly within microglial cells. The overexpression of ADAR1 p150 was found to promote microglial activation and enhance pro-inflammatory responses, whereas the knockdown of ADAR1 p150 yielded the opposite effect. Additionally, the knockdown of ADAR1 p150 in microglia resulted in a marked reduction in neuronal apoptosis within the co-culture system. Rescue experiments indicated that the knockdown of NUPR1 partially reinstated the inflammatory response previously induced by ADAR1 p150 knockdown. Notably, ADAR1 p150 knockdown also inhibited A-to-I RNA editing while simultaneously upregulating NUPR1. Furthermore, the reduction of ADAR1 expression was associated with decreased infarct volume, improved neurological outcomes, and a significant attenuation of neuroinflammation in dMCAO mice. ADAR1 p150 enhances the microglial inflammatory response and neuronal apoptosis in IS by facilitating A to I RNA editing of NUPR1.

The Annexin A (ANXA) family plays a critical role in cancer, with particular emphasis on their prognostic significance in pan-cancer analyses and gliomas. By integrating multi-omics data from The Cancer Genome Atlas (TCGA) and single-cell sequencing analysis, we conducted a comprehensive evaluation of ANXA2 and ANXA4 to investigate their expression patterns and functional impacts across various cancers, with a focus on glioblastoma (GBM). Our analysis encompassed several key components, including literature review, identification of differentially expressed genes (DEGs) in cancer, survival analysis, co-expression studies, competing endogenous RNA networks, cellular functional analysis, tumor microenvironment response to chemotherapy, and tumor stemness. Special attention was given to glioblastoma and low-grade glioma. Notably, our findings highlighted discrepancies among the analytical tools used, underscoring the necessity of employing multiple methods for accurate identification of DEGs. Additionally, we determined that ANXA2 and ANXA4 are predominantly expressed by M2 macrophages in GBM, based on our characterization of human glioma macrophages. These results suggest a strong correlation between ANXA2 and ANXA4 expression levels and the presence of macrophages and CD4 + resting memory T cells in gliomas, offering valuable insights into the complex interplay between the ANXA family and cancer progression.

This in vivo study explored the impact of TUBB6 inhibition in intracerebral hemorrhage (ICH), focusing on its effects on hematoma volume, microtubule stability, inflammation, neuronal preservation, and sensorimotor recovery. Sprague-Dawley rats was used to induce ICH by collagenase injection into the right striatum, followed by administration of TUBB6 antisense oligonucleotide (ASO) or Control ASO directly into the hematoma site 3 h post-ICH. Outcomes measured included hematoma volume, microtubule stability (acetylated α-tubulin), levels of inflammatory cytokines, mitogen-activated protein kinase (MAPK) pathway activity, neuronal degeneration (Fluoro-Jade C staining), and cell integrity (Cresyl Violet staining). Functional recovery was assessed using neurological severity scores (mNSS), corner turn, forelimb-placing, and rotarod tests, with body weight tracked for up to 28 days. TUBB6 expression increased with the severity of hemorrhage in the ICH models. TUBB6 ASO significantly reduced hematoma volume at 24- and 72-h post-ICH, restored acetylated α-tubulin levels, suppressed MAPK signaling pathway, and decreased pro-inflammatory markers with increased IL-10. TUBB6 ASO also reduced neuronal degeneration and improved cell viability. In terms of functional outcomes, the TUBB6 ASO + ICH group exhibited reduced mNSS scores, improved body weight maintenance, and better performance on corner turn, forelimb-placing and rotarod tests compared to the Control ASO + ICH group. TUBB6 ASO treatment demonstrated therapeutic potential in a rat model of ICH by reducing hematoma volume, stabilizing microtubules, modulating the MAPK signaling pathway, and mitigating inflammation. It also preserved neuronal integrity and enhanced sensorimotor recovery, suggesting its effectiveness as a therapeutic approach to improve ICH outcomes.

Multiple sclerosis constitutes a chronic, inflammatory, and demyelinating disorder affecting the central nervous system, with an estimated global prevalence of 2.5 million individuals. Emerging research underscores the significant influence of the gut microbiota on the immune system, suggesting a potential role in the initiation and progression of inflammatory diseases. This study investigated the potential therapeutic effects of Lactobacillus and Bifidobacterium species isolated from traditional dairy products on cuprizone-induced demyelination in a rat model. 48 adults male Wistar rats were randomly assigned to six groups. Demyelination was induced by daily oral administration of 0.6% (w/w) cuprizone mixed with food for 30 days. Subsequently, treated groups received oral administration of mixed of Lactiplantibacillus plantarum, Lactobacillus acidophilus, and Lactobacillus reuteri: and mixed of Bifidobacterium bifidum and Bifidobacterium animalis. A control group received no bacteria intervention. Behavioral deficits were assessed using grip-traction, beam-walking, and grid-walking tests. Oxidative stress biomarkers were quantified using colorimetric assays. The extent of demyelination was evaluated by hematoxylin and eosin staining of the corpus callosum. Serum levels of vitamin D₃ and B₁₂ were measured by ELISA. The results demonstrated that lactic acid bacteria supplementation significantly improved behavioral deficits and reduced demyelination in the corpus callosum. Furthermore, these bacteria administration was associated with reduced oxidative stress and increased serum levels of vitamin D₃ and B₁₂. These findings suggest that Lactobacillus and Bifidobacterium species may offer a supplementary therapeutic strategy for demyelinating disorders such as multiple sclerosis, potentially by mitigating oxidative stress, promoting remyelination, and enhancing vitamin D₃ and B₁₂ levels.

Transcription of > 50% of the mammalian coding genes follows circadian rhythm in an organ-specific manner. Recent findings highlighted the influence of time of the day in the progression of various neurological diseases and therapies. In the present study, we evaluated the effect of time of occurrence of traumatic brain injury (TBI) on behavioral and neuropathological outcomes in mice of both sexes. Following a controlled cortical impact injury induced between Zeitgeber time (ZT)1-4 or ZT13-16, behavioral deficits and brain damage were evaluated. There were no significant differences in post-TBI motor function between groups ZT1-4 and ZT13-16 in either male or female mice compared with the sex-matched naïve control. TBI-induced anxiety-like behavior was significantly higher in the female ZT13-16 cohort compared to the naïve cohort; but, no difference was observed between injured groups in both sexes. Similarly, spatial learning and memory were not significantly different between the ZT1-4 and ZT13-16 groups in both sexes. Post-TBI cortical lesion volume was also not significantly different between ZT1-4 and ZT-13-16 groups in both sexes. The present study observed no significant effects of occurrence time on TBI-induced brain damage or behavioral deficits in male and female mice.

The integrity of the myelin sheath of the spinal cord (SC) is essential for motor coordination. Seipin is an endoplasmic reticulum transmembrane protein highly expressed in adipose tissue and motor neurons in the SC. It was reported Seipin deficiency induced lipid dysregulation and neurobehavioral deficits, but the underlying mechanism, especially in SC, remains to be elucidated. In present study, we found that Seipin and myelin basic protein (MBP) increased synchronously in SC of developmental stage of mice. Demyelination impaired motor coordination as well as MBP and Seipin expression, which were alleviated by remyelination. Moreover, Seipin deficiency impaired motor coordination of mice, accompanied by hypomyelination in spinal cord. Mechanistically, we further demonstrated that myelin content as labeled by Fluormyelin, myelin basic protein (MBP) was down-regulated by Seipin deficiency. Seipin deficiency led to reduction of myelin-forming oligodendrocytes (OLs) density in spinal cord. Notably, administration of rosiglitazone (RG), a classic PPARγ activator, successfully restored the phenotypes manifested by Seipin deficiency including reduced OLs density, hypomyelination, as well as motor dyscoordination. In summary, present study revealed that Seipin deficiency disrupted motor coordination by compromising myelination in SC, and RG treatment could rescue the phenotypes. This study throws light on the mechanism underlying Seipin deficiency associated disorders and paves ways for developing therapeutics toward those diseases.

Hypoxia is a significant stressor, and stabilized hypoxia-inducible factor-1α (HIF-1α) regulates the expression of numerous genes, leading to various biochemical, molecular, physiological and genomic changes. The body's oxygen-sensing system activates gene expression to protect brain tissues from hypoxia. Gamma-aminobutyric acid, an inhibitory neurotransmitter, regulates brain excitability during hypoxia through the activation of HIF-1 α. Herbal medicines have been widely used for managing various toxicological effects and disorders including hypoxia; however, the data on safety, efficacy and the molecular mechanisms that increase vulnerability or lethality against hypoxia are still lacking and urgently need to be investigated. The Current study aims to investigate how Bacopa monnieri extract (BME), specially CDRI-08 affects the hippocampus of mice subjected to conditions that simulate hypoxia. The pre and co-treatment of mice involved administrating BME (200 mg/kg BW) for 14 days, followed by exposure to CoCl₂ (40 mg/kg BW). BME decreased the levels of reactive oxygen species (ROS) and lipid peroxidation, while it increased the Gamma-aminobutyric acid receptor subunit-ɑ1 (GABAAR-ɑ1) level as well as the activity of antioxidant enzymes superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx). Furthermore BME reduced the levels of HIF-1α and its downstream targets glucose transporter-1 (GLUT-1) and erythropoietin (EPO) in the DG, CA1, and CA3 regions of hippocampus. Additionally, results obtained from the open field, elevated zero maze and plus maze tests indicate that BME restores anxiety caused by hypoxia. Together, these findings suggested that BME mitigates the harmful effects of oxidative stress and altered hypoxia related signaling in hippocampus; and may provide a basis for its therapeutic use in the recovery from hypoxia-led anxiety.