Comprehensive analysis of lncRNA-associated ceRNA network reveals novel potential prognostic regulatory axes in glioblastoma multiforme.

Deciphering the lncRNA-associated competitive endogenous RNA (ceRNA) network is essential in decoding glioblastoma multiforme (GBM) pathogenesis by regulating miRNA availability and controlling mRNA stability. This study aimed to explore novel biomarkers for GBM by constructing a lncRNA-miRNA-mRNA network. A ceRNA network in GBM was constructed using lncRNA, mRNA and miRNA expression profiles from the TCGA and GEO datasets. Seed nodes were identified by protein-protein interaction (PPI) network analysis of deregulated-mRNAs (DEmRNAs) in the ceRNA network. A lncRNA-miRNA-seed network was constructed by mapping the seed nodes into the preliminary ceRNA network. The impact of the seed nodes on the overall survival (OS) of patients was assessed by the GSCA database. Functional enrichment analysis of the deregulated-lncRNAs (DElncRNA) in the ceRNA network and genes interacting with OS-related genes in the PPI network were performed. Finally, the positive correlation between seed nodes and their associated lncRNAs and the expression level of these molecules in GBM tissue compared with normal samples was validated using the GEPIA database. Our analyzes revealed that three novel regulatory axes AL161785.1/miR-139-5p/MS4A6A, LINC02611/miR-139-5p/MS4A6A and PCED1B-AS1/miR-433-3p/MS4A6A may play essential roles in GBM pathogenesis. MS4A6A is upregulated in GBM and closely associated with shorter survival time of patients. We also identified that MS4A6A expression positively correlates with genes related to tumour-associated macrophages, which induce macrophage infiltration and immune suppression. The functional enrichment analysis demonstrated that DElncRNAs are mainly involved in neuroactive ligand-receptor interaction, calcium/MAPK signalling pathway, ribosome, GABAergic/Serotonergic/Glutamatergic synapse and immune system process. In addition, genes related to MS4A6A contribute to immune and inflammatory-related biological processes. Our findings provide novel insights to understand the ceRNA regulation in GBM and identify novel prognostic biomarkers or therapeutic targets.

Deciphering molecular bridges: Unveiling the interplay between metabolic syndrome and Alzheimer's disease through a systems biology approach and drug repurposing.

The association between Alzheimer's disease and metabolic disorders as significant risk factors is widely acknowledged. However, the intricate molecular mechanism intertwining these conditions remains elusive. To address this knowledge gap, we conducted a thorough investigation using a bioinformatics method to illuminate the molecular connections and pathways that provide novel perspectives on these disorders' pathological and clinical features. Microarray datasets (GSE5281, GSE122063) from the Gene Expression Omnibus (GEO) database facilitated the way to identify genes with differential expression in Alzheimer's disease (141 genes). Leveraging CoreMine, CTD, and Gene Card databases, we extracted genes associated with metabolic conditions, including hypertension, non-alcoholic fatty liver disease, and diabetes. Subsequent analysis uncovered overlapping genes implicated in metabolic conditions and Alzheimer's disease, revealing shared molecular links. We utilized String and HIPPIE databases to visualize these shared genes' protein-protein interactions (PPI) and constructed a PPI network using Cytoscape and MCODE plugin. SPP1, CD44, IGF1, and FLT1 were identified as crucial molecules in the main cluster of Alzheimer's disease and metabolic syndrome. Enrichment analysis by the DAVID dataset was employed and highlighted the SPP1 as a novel target, with its receptor CD44 playing a significant role in the inflammatory cascade and disruption of insulin signaling, contributing to the neurodegenerative aspects of Alzheimer's disease. ECM-receptor interactions, focal adhesion, and the PI3K/Akt pathways may all mediate these effects. Additionally, we investigated potential medications by repurposing the molecular links using the DGIdb database, revealing Tacrolimus and Calcitonin as promising candidates, particularly since they possess binding sites on the SPP1 molecule. In conclusion, our study unveils crucial molecular bridges between metabolic syndrome and AD, providing insights into their pathophysiology for therapeutic interventions.

MicroRNA-140-5p inhibitor attenuates memory impairment induced by amyloid-ß oligomer in vivo possibly through Pin1 regulation.

AIMS: The peptidyl-prolyl cis/trans isomerase, Pin1, has a protective role in age-related neurodegeneration by targeting different phosphorylation sites of tau and the key proteins required to produce Amyloid-ß, which are the well-known molecular signatures of Alzheimer's disease (AD) neuropathology. The direct interaction of miR-140-5p with Pin1 mRNA and its inhibitory role in protein translation has been identified. The main purpose of this study was to investigate the role of miRNA-140-5p inhibition in promoting Pin1 expression and the therapeutic potential of the AntimiR-140-5p in the Aß oligomer (AßO)-induced AD rat model. METHODS: Spatial learning and memory were assessed in the Morris water maze. RT-PCR, western blot, and histological assays were performed on hippocampal samples at various time points after treatments. miRNA-140-5p inhibition enhanced Pin1 and ADAM10 mRNA expressions but has little effect on Pin1 protein level. RESULTS: The miRNA-140-5p inhibitor markedly ameliorated spatial learning and memory deficits induced by AßO, and concomitantly suppressed the mRNA expression of inflammatory mediators TNFα and IL-1ß, and phosphorylation of tau at three key sites (thr231, ser396, and ser404) as well as increased phosphorylated Ser473-Akt. CONCLUSION: According to our results, Antimir-140-mediated improvement of AßO-induced neuronal injury and memory impairment in rats may provide an appropriate rationale for evaluating miR-140-5p inhibitors as a promising agent for the treatment of AD.

MicroRNA modulation is a potential molecular mechanism for neuroprotective effects of intranasal insulin administration in amyloid ßeta oligomer induced Alzheimer's like rat model.

Substantial evidence indicates that imbalance in the expression of miR-132-3p, miR-181b-5p, miR-125b-5p, miR-26a-5p, miR-124-3p, miR-146a-5p, miR-29a-3p, and miR-30a-5p in the AD brain are associated with amyloid-beta (Aß) aggregation, tau pathology, neuroinflammation, and synaptic dysfunction, the major pathological hallmarks of Alzheimer's disease)AD(. Several studies have reported that intranasal insulin administration ameliorates memory in AD patients and animal models. However, the underlying molecular mechanisms are not yet completely elucidated. Therefore, the aim of this study was to determine whether insulin is involved in regulating the expression of AD-related microRNAs. Pursuing this objective, we first investigated the therapeutic effect of intranasal insulin on Aß oligomer (AßO)-induced memory impairment in male rats using the Morris water maze task. Then, molecular and histological changes in response to AßO and/or insulin time course were assessed in the extracted hippocampi on days 1, 14, and 21 of the study using congo red staining, western blot and quantitative real-time PCR analyses. We observed memory impairment, Aß aggregation, tau hyper-phosphorylation, neuroinflammation, insulin signaling dys-regulation, and down-regulation of miR-26a, miR-124, miR-29a, miR-181b, miR-125b, miR-132, and miR-146a in the hippocampus of AßO-exposed rats 21 days after AßO injection. Intranasal insulin treatment ameliorated memory impairment and concomitantly increased miR-132, miR-181b, and miR-125b expression, attenuated tau phosphorylation levels, Aß aggregation, and neuroinflammation, and regulated the insulin signaling as well. In conclusion, our study suggest that the neuroprotective effects of insulin on memory observed in AD-like rats could be partially due to the restoration of miR-132, miR-181b, and miR-125b expression in the brain.

Does Alzheimer's disease stem in the gastrointestinal system?

Over the last decades, our knowledge of the key pathogenic mechanisms of Alzheimer's disease (AD) has dramatically improved. Regarding the limitation of current therapeutic strategies for the treatment of multifactorial diseases, such as AD, to be translated into the clinic, there is a growing trend in research to identify risk factors associated with the onset and progression of AD. Here, we review the current literature with a focus on the relationship between gastrointestinal (GI)/liver diseases during the lifespan and the incidence of AD, and discuss the possible mechanisms underlying the link between the diseases. We also aim to review studies evaluating the possible link between the chronic use of the most common GI medications and the future risk of AD development.

The role of microRNA-34 family in Alzheimer's disease: A potential molecular link between neurodegeneration and metabolic disorders.

Growing evidence indicates that overexpression of the microRNA-34 (miR-34) family in the brain may play a crucial role in Alzheimer's disease (AD) pathogenesis by targeting and downregulating genes associated with neuronal survival, synapse formation and plasticity, Aß clearance, mitochondrial function, antioxidant defense system, and energy metabolism. Additionally, elevated levels of the miR-34 family in the liver and pancreas promote the development of metabolic syndromes (MetS), such as diabetes and obesity. Importantly, MetS represent a well-documented risk factor for sporadic AD. This review focuses on the recent findings regarding the role of the miR-34 family in the pathogenesis of AD and MetS, and proposes miR-34 as a potential molecular link between both disorders. A comprehensive understanding of the functional roles of miR-34 family in the molecular and cellular pathogenesis of AD brains may lead to the discovery of a breakthrough treatment strategy for this disease.

Brain microRNAs dysregulation: Implication for missplicing and abnormal post-translational modifications of tau protein in Alzheimer's disease and related tauopathies.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate post-transcriptional gene expression by targeting specific mRNAs for degradation or translation repression. Changes in miRNAs expression profiles have been reported in several neurodegenerative disorders such as Alzheimer's disease (AD) and related tauopathies, which are characterized by tau aggregation and neurofibrillary tangle formation (NFTs) in the brain. There is a fundamental challenge in determining how dysregulation of miRNAs can promote a pathological condition. Therefore, identifying the target genes of dysregulated miRNAs, signaling pathways and biological processes, as well as pathogenic factors which trigger miRNA dysregulation may be helpful for subsequent therapeutic development. This article reviews studies focused on the presently known roles of miRNAs in the regulation of alternative splicing and post-translational modifications of tau, events associated with the development of AD and related tauopathies. We hope this review will help readers understand the pathogenesis and the most recent therapeutic approaches to treat tauopathies.

Melatonin ameliorates oxidative damage induced by maternal lead exposure in rat pups.

During the particular period of cerebellum development, exposure to lead (Pb) decreases cerebellum growth and can result in selective loss of neurons. The detection and prevention of Pb toxicity is a major international public health priorities. This research study was conducted to evaluate the effects of melatonin, an effective antioxidant and free radical scavenger, on Pb induced neurotoxicity and oxidative stress in the cerebellum. Pb exposure was initiated on gestation day 5 with the addition of daily doses of 0.2% lead acetate to distilled drinking water and continues until weaning. Melatonin (10mg/kg) was given once daily at the same time. 21 days after birth, several antioxidant enzyme activities including superoxide dismutase (SOD) and glutathione peroxidase (GPx) were assayed. Thiobarbituric acid reactive substance (TBARS) levels were measured as a marker of lipid peroxidation. Rotarod and locomotor activity tests were performed on postnatal days (PDs) 31-33 and a histological study was performed after completion of behavioral measurements on PD 33. The results of the present work demonstrated that Pb could induce lipid peroxidation, increase TBARS levels and decrease GPx and SOD activities in the rat cerebellum. We also observed that Pb impaired performance on the rotarod and locomotor activities of rats. However, treatment with melatonin significantly attenuated the motoric impairment and lipid peroxidation process and restored the levels of antioxidants. Histological analysis indicated that Pb could decrease Purkinje cell count and melatonin prevented this toxic effect. These results suggest that treatment with melatonin can improve motor deficits and oxidative stress by protecting the cerebellum against Pb toxicity.