In Silico Analysis Highlights Potential Predictive Indicators Associated with Secondary Progressive Multiple Sclerosis.

Multiple sclerosis (MS) is a complex inflammatory disease affecting the central nervous system. Most commonly, it begins with recurrent symptoms followed by partial or complete recovery, known as relapsing-remitting MS (RRMS). Over time, many RRMS patients progress to secondary progressive MS (SPMS), marked by gradual symptom deterioration. The factors triggering this transition remain unknown, lacking predictive biomarkers. This study aims to identify blood biomarkers specific to SPMS. We analyzed six datasets of SPMS and RRMS patients' blood and brain tissues, and compared the differential expressed genes (DEGs) obtained to highlight DEGs reflecting alterations occurring in both brain and blood tissues and the potential biological processes involved. We observed a total of 38 DEGs up-regulated in both blood and brain tissues, and their interaction network was evaluated through network analysis. Among the aforementioned DEGs, 21 may be directly involved with SPMS transition. Further, we highlighted three biological processes, including the calcineurin-NFAT pathway, related to this transition. The investigated DEGs may serve as a promising means to monitor the transition from RRMS to SPMS, which is still elusive. Given that they can also be sourced from blood samples, this approach could offer a relatively rapid and convenient method for monitoring MS and facilitating expedited assessments.

Multiple Sclerosis: Roles of miRNA, lcnRNA, and circRNA and Their Implications in Cellular Pathways.

Multiple sclerosis (MS) is a degenerative condition characterized by axonal damage and demyelination induced by autoreactive immune cells that occur in the Central Nervous System (CNS). The interaction between epigenetic changes and genetic factors can be widely involved in the onset, development, and progression of the disease. Although numerous efforts were made to discover new therapies able to prevent and improve the course of MS, definitive curative treatments have not been found yet. However, in recent years, it has been reported that non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), acting as gene expression regulators, could be used as potential therapeutic targets or biomarkers to diagnose and fight MS. In this review, we discussed the role of miRNAs, lncRNAs, and circRNAs, as well as their expression level changes and signaling pathways that are related to preclinical and human MS studies. Hence, the investigation of ncRNAs could be important to provide additional information regarding MS pathogenesis as well as promote the discovery of new therapeutic strategies or biomarkers.

Innovative Insights into Traumatic Brain Injuries: Biomarkers and New Pharmacological Targets.

A traumatic brain injury (TBI) is a major health issue affecting many people across the world, causing significant morbidity and mortality. TBIs often have long-lasting effects, disrupting daily life and functionality. They cause two types of damage to the brain: primary and secondary. Secondary damage is particularly critical as it involves complex processes unfolding after the initial injury. These processes can lead to cell damage and death in the brain. Understanding how these processes damage the brain is crucial for finding new treatments. This review examines a wide range of literature from 2021 to 2023, focusing on biomarkers and molecular mechanisms in TBIs to pinpoint therapeutic advancements. Baseline levels of biomarkers, including neurofilament light chain (NF-L), ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1), Tau, and glial fibrillary acidic protein (GFAP) in TBI, have demonstrated prognostic value for cognitive outcomes, laying the groundwork for personalized treatment strategies. In terms of pharmacological progress, the most promising approaches currently target neuroinflammation, oxidative stress, and apoptotic mechanisms. Agents that can modulate these pathways offer the potential to reduce a TBI's impact and aid in neurological rehabilitation. Future research is poised to refine these therapeutic approaches, potentially revolutionizing TBI treatment.

Cannabinerol (CBNR) Influences Synaptic Genes Associated with Cytoskeleton and Ion Channels in NSC-34 Cell Line: A Transcriptomic Study.

Cannabinoids are receiving great attention as a novel approach in the treatment of cognitive and motor disabilities, which characterize neurological disorders. To date, over 100 phytocannabinoids have been extracted from Cannabis sativa, and some of them have shown neuroprotective properties and the capacity to influence synaptic transmission. In this study, we investigated the effects of a less-known phytocannabinoid, cannabinerol (CBNR), on neuronal physiology. Using the NSC-34 motor-neuron-like cell line and next-generation sequencing analysis, we discovered that CBNR influences synaptic genes associated with synapse organization and specialization, including genes related to the cytoskeleton and ion channels. Specifically, the calcium, sodium, and potassium channel subunits (Cacna1b, Cacna1c, Cacnb1, Grin1, Scn8a, Kcnc1, Kcnj9) were upregulated, along with genes related to NMDAR (Agap3, Syngap1) and calcium (Cabp1, Camkv) signaling. Moreover, cytoskeletal and cytoskeleton-associated genes (Actn2, Ina, Trio, Marcks, Bsn, Rtn4, Dgkz, Htt) were also regulated by CBNR. These findings highlight the important role played by CBNR in the regulation of synaptogenesis and synaptic transmission, suggesting the need for further studies to evaluate the neuroprotective role of CBNR in the treatment of synaptic dysfunctions that characterize motor disabilities in many neurological disorders.

Network Analysis Performed on Transcriptomes of Parkinson's Disease Patients Reveals Dysfunction in Protein Translation.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra region of the brain. The hallmark pathological feature of PD is the accumulation of misfolded proteins, leading to the formation of intracellular aggregates known as Lewy bodies. Recent data evidenced how disruptions in protein synthesis, folding, and degradation are events commonly observed in PD and may provide information on the molecular background behind its etiopathogenesis. In the present study, we used a publicly available transcriptomic microarray dataset of peripheral blood of PD patients and healthy controls (GSE6613) to investigate the potential dysregulation of elements involved in proteostasis-related processes at the transcriptomic level. Our bioinformatics analysis revealed 375 differentially expressed genes (DEGs), of which 281 were down-regulated and 94 were up-regulated. Network analysis performed on the observed DEGs highlighted a cluster of 36 elements mainly involved in the protein synthesis processes. Different enriched ontologies were related to translation initiation and regulation, ribosome structure, and ribosome components nuclear export. Overall, this data consistently points to a generalized impairment of the translational machinery and proteostasis. Dysregulation of these mechanics has been associated with PD pathogenesis. Understanding the precise regulation of such processes may shed light on the molecular mechanisms of PD and provide potential data for early diagnosis.

LncRNAs and CircRNAs as Strategies against Pathological Conditions Caused by a Hypoxic/Anoxic State.

Brain damage can be induced by oxygen deprivation. It is known that hypoxic or anoxic conditions can lead to changes in the expression levels of non-coding RNAs (ncRNAs), which, in turn, can be related to Central Nervous System (CNS) injuries. Therefore, it could be useful to investigate the involvement of non-coding RNAs (ncRNAs), as well as the underlying mechanisms which are able to modulate them in brain damage induced by hypoxic or anoxic conditions. In this review, we focused on recent research that associates these conditions with long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). The results of this review demonstrate that the expression of both lncRNAs and circRNAs can be influenced by oxygen deprivation conditions and so they can contribute to inducing damage or providing neuroprotection by affecting specific molecular pathways. Furthermore, several experimental studies have shown that ncRNA activity can be regulated by compounds, thus also modifying their transcriptomic profile and their effects on CNS damages induced by hypoxic/anoxic events.

Modulating Stress Proteins in Response to Therapeutic Interventions for Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative illness characterized by the degeneration of dopaminergic neurons in the substantia nigra, resulting in motor symptoms and without debilitating motors. A hallmark of this condition is the accumulation of misfolded proteins, a phenomenon that drives disease progression. In this regard, heat shock proteins (HSPs) play a central role in the cellular response to stress, shielding cells from damage induced by protein aggregates and oxidative stress. As a result, researchers have become increasingly interested in modulating these proteins through pharmacological and non-pharmacological therapeutic interventions. This review aims to provide an overview of the preclinical experiments performed over the last decade in this research field. Specifically, it focuses on preclinical studies that center on the modulation of stress proteins for the treatment potential of PD. The findings display promise in targeting HSPs to ameliorate PD outcomes. Despite the complexity of HSPs and their co-chaperones, proteins such as HSP70, HSP27, HSP90, and glucose-regulated protein-78 (GRP78) may be efficacious in slowing or preventing disease progression. Nevertheless, clinical validation is essential to confirm the safety and effectiveness of these preclinical approaches.

In Silico Analysis Reveals the Modulation of Ion Transmembrane Transporters in the Cerebellum of Alzheimer's Disease Patients.

Alzheimer's disease (AD) is the most common neurodegenerative disorder. AD hallmarks are extracellular amyloid ß (Aß) plaques and intracellular neurofibrillary tangles in the brain. It is interesting to notice that Aß plaques appear in the cerebellum only in late stages of the disease, and then it was hypothesized that it can be resistant to specific neurodegenerative mechanisms. However, the role of cerebellum in AD pathogenesis is not clear yet. In this study, we performed an in silico analysis to evaluate the transcriptional profile of cerebellum in AD patients and non-AD subjects in order to deepen the knowledge on its role in AD. The analysis evidenced that only the molecular function (MF) "active ion transmembrane transporter activity" was overrepresented. Regarding the 21 differentially expressed genes included in this MF, some of them may be involved in the ion dyshomeostasis reported in AD, while others assumed, in the cerebellum, an opposite regulation compared to those reported in other brain regions in AD patients. They might be associated to a protective phenotype, that may explain the initial resistance of cerebellum to neurodegeneration in AD. Of note, this MF was not overrepresented in prefrontal cortex and visual cortex indicating that it is a peculiarity of the cerebellum.

Transcriptomic Profiling after In Vitro Δ8-THC Exposure Shows Cytoskeletal Remodeling in Trauma-Injured NSC-34 Cell Line.

Neuronal cell death is a physiological process that, when uncontrollable, leads to neurodegenerative disorders like spinal cord injury (SCI). SCI represents one of the major causes of trauma and disabilities worldwide for which no effective pharmacological intervention exists. Herein, we observed the beneficial effects of Δ8-Tetrahydrocannabinol (Δ8-THC) during neuronal cell death recovery. We cultured NSC-34 motoneuron cell line performing three different experiments. A traumatic scratch injury was caused in two experiments. One of the scratched was pretreated with Δ8-THC to observe the role of the cannabinoid following the trauma. An experimental control group was neither scratched nor pretreated. All the experiments underwent RNA-seq analysis. The effects of traumatic injury were observed in scratch against control comparison. Comparison of scratch models with or without pretreatment highlighted how Δ8-THC counteracts the traumatic event. Our results shown that Δ8-THC triggers the cytoskeletal remodeling probably due to the activation of the Janus Kinase Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway and the signaling cascade operated by the Mitogen-Activated Protein (MAP) Kinase signaling pathway. In light of this evidence, Δ8-THC could be a valid pharmacological approach in the treatment of abnormal neuronal cell death occurring in motoneuron cells.

Transcriptome Highlights Cannabinol Modulation of Mitophagy in a Parkinson's Disease In Vitro Model.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein aggregates, known as Lewy bodies. It is known that mitochondria dysfunctions, including impaired localization, transport and mitophagy, represent features of PD. Cannabinoids are arising as new therapeutic strategies against neurodegenerative diseases. In this study, we aimed to evaluate the potential protective effects of cannabinol (CBN) pre-treatment in an in vitro PD model, namely retinoic acid-differentiated SH-SY5Y neuroblastoma cells treated with 1-methyl-4-phenylpyridinium (MPP+). With this aim, we performed a transcriptomic analysis through next-generation sequencing. We found that CBN counteracted the loss of cell viability caused by MPP+ treatment. Then, we focused on biological processes relative to mitochondria functions and found that CBN pre-treatment was able to attenuate the MPP+-induced changes in the expression of genes involved in mitochondria transport, localization and protein targeting. Notably, MPP+ treatment increased the expression of the genes involved in PINK1/Parkin mitophagy, while CBN pre-treatment reduced their expression. The results suggested that CBN can exert a protection against MPP+ induced mitochondria impairment.

An In Silico Analysis Reveals Sustained Upregulation of Neuroprotective Genes in the Post-Stroke Human Brain.

Ischemic stroke is a cerebrovascular disease caused by an interruption of blood flow to the brain, thus determining a lack of oxygen and nutrient supply. The ischemic event leads to the activation of several molecular signaling pathways involved in inflammation and the production of reactive oxygen species, causing irreversible neuronal damage. Several studies have focused on the acute phase of ischemic stroke. It is not clear if this traumatic event can influence some of the molecular processes in the affected area even years after the clinical event. In our study, we performed an in silico analysis using freely available raw data with the purpose of evaluating the transcriptomic state of post-mortem brain tissue. The samples were taken from non-fatal ischemic stroke patients, meaning that they suffered an ischemic stroke and lived for a period of about 2 years after the event. These samples were compared with healthy controls. The aim was to evaluate possible recovery processes useful to mitigating neuronal damage and the detrimental consequences of stroke. Our results highlighted differentially expressed genes codifying for proteins along with long non-coding genes with anti-inflammatory and anti-oxidant functions. This suggests that even after an amount of time from the ischemic insult, different neuroprotective mechanisms are activated to ameliorate brain conditions and repair post-stroke neuronal injury.