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.

MicroRNAs and MAPKs: Evidence of These Molecular Interactions in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder known to be the leading cause of dementia worldwide. Many microRNAs (miRNAs) were found deregulated in the brain or blood of AD patients, suggesting a possible key role in different stages of neurodegeneration. In particular, mitogen-activated protein kinases (MAPK) signaling can be impaired by miRNA dysregulation during AD. Indeed, the aberrant MAPK pathway may facilitate the development of amyloid-beta (Aß) and Tau pathology, oxidative stress, neuroinflammation, and brain cell death. The aim of this review was to describe the molecular interactions between miRNAs and MAPKs during AD pathogenesis by selecting evidence from experimental AD models. Publications ranging from 2010 to 2023 were considered, based on PubMed and Web of Science databases. According to obtained data, several miRNA deregulations may regulate MAPK signaling in different stages of AD and conversely. Moreover, overexpressing or silencing miRNAs involved in MAPK regulation was seen to improve cognitive deficits in AD animal models. In particular, miR-132 is of particular interest due to its neuroprotective functions by inhibiting Aß and Tau depositions, as well as oxidative stress, through ERK/MAPK1 signaling modulation. However, further investigations are required to confirm and implement these promising results.

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.

Nrf2 Activation: Involvement in Central Nervous System Traumatic Injuries. A Promising Therapeutic Target of Natural Compounds.

Central nervous system (CNS) trauma, such as traumatic brain injury (TBI) and spinal cord injury (SCI), represents an increasingly important health burden in view of the preventability of most injuries and the complex and expensive medical care that they necessitate. These injuries are characterized by different signs of neurodegeneration, such as oxidative stress, mitochondrial dysfunction, and neuronal apoptosis. Cumulative evidence suggests that the transcriptional factor nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial defensive role in regulating the antioxidant response. It has been demonstrated that several natural compounds are able to activate Nrf2, mediating its antioxidant response. Some of these compounds have been tested in experimental models of SCI and TBI, showing different neuroprotective properties. In this review, an overview of the preclinical studies that highlight the positive effects of natural bioactive compounds in SCI and TBI experimental models through the activation of the Nrf2 pathway has been provided. Interestingly, several natural compounds can activate Nrf2 through multiple pathways, inducing a strong antioxidant response against CNS trauma. Therefore, some of these compounds could represent promising therapeutic strategies for these pathological conditions.

Aducanumab and Its Effects on Tau Pathology: Is This the Turning Point of Amyloid Hypothesis?

Alzheimer's disease (AD) is a neurodegenerative disorder affecting millions of people around the world. The two main pathological mechanisms underlying the disease are beta-amyloid (Aß) plaques and intracellular neurofibrillary tangles (NFTs) of Tau proteins in the brain. Their reduction has been associated with slowing of cognitive decline and disease progression. Several antibodies aimed to target Aß or Tau in order to represent hope for millions of patients, but only a small number managed to be selected to participate in clinical trials. Aducanumab is a monoclonal antibody recently approved by the Food and Drug Administration (FDA), which, targeting (Aß) oligomers and fibrils, was able to reduce Aß accumulation and slow the progression of cognitive impairment. It was also claimed to have an effect on the second hallmark of AD, decreasing the level of phospho-Tau evaluated in cerebrospinal fluid (CSF) and by positron emission tomography (PET). This evidence may represent a turning point in the development of AD-efficient drugs.

Cannabinerol and NSC-34 Transcriptomic Analysis: Is the Dose Who Makes Neuronal Differentiation?

Cannabis sativa L. proved to be a source of several phytocompounds able to help patients facing different diseases. Moreover, these phytocompounds can help ameliorate general conditions and control certain unpleasant effects of diseases. Some cannabinoids, however, provided more benefits applicable to settings other than palliative care. Using the NSC-34 cell line, we evaluated the barely known phytocompound named cannabinerol (CBNR) at different doses, in order to understand its unique characteristics and the ones shared with other cannabinoids. The transcriptomic analysis suggests a possible ongoing neuronal differentiation, principally due to the activation of cannabinoid receptor 1 (CB1), to which the phosphorylation of serine-threonine protein kinase (Akt) followed, especially between 20 and 7.5 µM. The increase of Neurod1 and Map2 genes at 7.5 µM, accompanied by a decrease of Vim, as well as the increase of Syp at all the other doses, point toward the initiation of differentiation signals. Our preliminary results indicate CBNR as a promising candidate to be added to the list of cannabinoids with neuronal differentiation-enhancer properties. However, further studies are needed to confirm this initial insight.

Cannabidiol Promotes Neuronal Differentiation Using Akt and Erk Pathways Triggered by Cb1 Signaling.

Recently, the scientific community has started to focus on the neurogenic potential of cannabinoids. The phytocompound cannabidiol (CBD) shows different mechanism of signaling on cannabinoid receptor 1 (CB1), depending on its concentration. In this study, we investigated if CBD may induce in vitro neuronal differentiation after treatment at 5 µM and 10 µM. For this purpose, we decided to use the spinal cord × neuroblastoma hybrid cell line (NSC-34) because of its proliferative and undifferentiated state. The messenger RNAs (mRNAs) expression profiles were tested using high-throughput sequencing technology and Western blot assay was used to determine the number of main proteins in different pathways. Interestingly, the treatment shows different genes associated with neurodifferentiation statistically significant, such as Rbfox3, Tubb3, Pax6 and Eno2. The CB1 signaling pathway is responsible for neuronal differentiation at 10 µM, as suggested by the presence of p-ERK and p-AKT, but not at 5 µM. A new correlation between CBD, neurodifferentiation and retinoic acid receptor-related orphan receptors (RORs) has been observed.

The Moringin/α-CD Pretreatment Induces Neuroprotection in an In Vitro Model of Alzheimer's Disease: A Transcriptomic Study.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and represents the most common form of senile dementia. Autophagy and mitophagy are cellular processes that play a key role in the aggregation of ß-amyloid (Aß) and tau phosphorylation. As a consequence, impairment of these processes leads to the progression of AD. Thus, interest is growing in the search for new natural compounds, such as Moringin (MOR), with neuroprotective, anti-amyloidogenic, antioxidative, and anti-inflammatory properties that could be used for AD prevention. However, MOR appears to be poorly soluble and stable in water. To increase its solubility MOR was conjugated with α-cyclodextrin (MOR/α-CD). In this work, it was evaluated if MOR/α-CD pretreatment was able to exert neuroprotective effects in an AD in vitro model through the evaluation of the transcriptional profile by next-generation sequencing (NGS). To induce the AD model, retinoic acid-differentiated SH-SY5Y cells were exposed to Aß1-42. The MOR/α-CD pretreatment reduced the expression of the genes which encode proteins involved in senescence, autophagy, and mitophagy processes. Additionally, MOR/α-CD was able to induce neuronal remodeling modulating the axon guidance, principally downregulating the Slit/Robo signaling pathway. Noteworthy, MOR/α-CD, modulating these important pathways, may induce neuronal protection against Aß1-42 toxicity as demonstrated also by the reduction of cleaved caspase 3. These data indicated that MOR/α-CD could attenuate the progression of the disease and promote neuronal repair.

A State of the Art of Antioxidant Properties of Curcuminoids in Neurodegenerative Diseases.

Neurodegenerative diseases represent a set of pathologies characterized by an irreversible and progressive, and a loss of neuronal cells in specific areas of the brain. Oxidative phosphorylation is a source of energy production by which many cells, such as the neuronal cells, meet their energy needs. Dysregulations of oxidative phosphorylation induce oxidative stress, which plays a key role in the onset of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). To date, for most neurodegenerative diseases, there are no resolute treatments, but only interventions capable of alleviating the symptoms or slowing the course of the disease. Therefore, effective neuroprotection strategies are needed. In recent years, natural products, such as curcuminoids, have been intensively explored and studied for their therapeutic potentials in several neurodegenerative diseases. Curcuminoids are, nutraceutical compouns, that owen several therapeutic properties such as anti-oxidant, anti-inflammatory and neuroprotective effects. In this context, the aim of this review was to provide an overview of preclinical and clinical evidence aimed to illustrate the antioxidant effects of curcuminoids in neurodegenerative diseases. Promising results from preclinical studies encourage the use of curcuminoids for neurodegeneration prevention and treatment.

SARS-CoV-2 Exposed Mesenchymal Stromal Cell from Congenital Pulmonary Airway Malformations: Transcriptomic Analysis and the Expression of Immunomodulatory Genes.

The inflammatory response plays a central role in the complications of congenital pulmonary airway malformations (CPAM) and severe coronavirus disease 2019 (COVID-19). The aim of this study was to evaluate the transcriptional changes induced by SARS-CoV-2 exposure in pediatric MSCs derived from pediatric lung (MSCs-lung) and CPAM tissues (MSCs-CPAM) in order to elucidate potential pathways involved in SARS-CoV-2 infection in a condition of exacerbated inflammatory response. MSCs-lung and MSCs-CPAM do not express angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TRMPSS2). SARS-CoV-2 appears to be unable to replicate in MSCs-CPAM and MSCs-lung. MSCs-lung and MSCs-CPAM maintained the expression of stemness markers MSCs-lung show an inflammatory response (IL6, IL1B, CXCL8, and CXCL10), and the activation of Notch3 non-canonical pathway; this route appears silent in MSCs-CPAM, and cytokine genes expression is reduced. Decreased value of p21 in MSCs-lung suggested no cell cycle block, and cells did not undergo apoptosis. MSCs-lung appears to increase genes associated with immunomodulatory function but could contribute to inflammation, while MSCs-CPAM keeps stable or reduce the immunomodulatory receptors expression, but they also reduce their cytokines expression. These data indicated that, independently from their perilesional or cystic origin, the MSCs populations already present in a patient affected with CPAM are not permissive for SARS-CoV-2 entry, and they will not spread the disease in case of infection. Moreover, these MSCs will not undergo apoptosis when they come in contact with SARS-CoV-2; on the contrary, they maintain their staminality profile.

MiRNA: Involvement of the MAPK Pathway in Ischemic Stroke. A Promising Therapeutic Target.

Ischemic stroke (IS) is a cerebrovascular disease with a high rate of disability and mortality. It is classified as the second leading cause of death that arises from the sudden occlusion of small vessels in the brain with consequent lack of oxygen and nutrients in the brain tissue. Following an acute ischemic event, the cascade of events promotes the activation of multiple signaling pathways responsible for irreversible neuronal damage. The mitogen-activated protein kinase (MAPK) signaling pathway transmits signals from the cell membrane to the nucleus in response to different stimuli, regulating proliferation, differentiation, inflammation, and apoptosis. Several lines of evidence showed that MAPK is an important regulator of ischemic and hemorrhagic cerebral vascular disease; indeed, it can impair blood-brain barrier (BBB) integrity and exacerbate neuroinflammation through the release of pro-inflammatory mediators implementing neurovascular damage after ischemic stroke. This review aims to illustrate the miRNAs involved in the regulation of MAPK in IS, in order to highlight possible targets for potential neuroprotective treatments. We also discuss some miRNAs (miR), including miR-145, miR-137, miR-493, and miR-126, that are important as they modulate processes such as apoptosis, neuroinflammation, neurogenesis, and angiogenesis through the regulation of the MAPK pathway in cerebral IS. To date, limited drug therapies are available for the treatment of IS; therefore, it is necessary to implement preclinical and clinical studies aimed at discovering novel therapeutic approaches to minimize post-stroke neurological damage.

Temporomandibular Disorders Slow Down the Regeneration Process of Masticatory Muscles: Transcriptomic Analysis.

Background and Objectives: Musculoskeletal injuries represent a pathological condition due to limited joint motility and morphological and functional alterations of the muscles. Temporomandibular disorders (TMDs) are pathological conditions due to alterations in the musculoskeletal system. TMDs mainly cause temporomandibular joint and masticatory muscle dysfunctions following trauma, along with various pathologies and inflammatory processes. TMD affects approximately 15% of the population and causes malocclusion problems and common symptoms such as myofascial pain and migraine. The aim of this work was to provide a transcriptomic profile of masticatory muscles obtained from TMD migraine patients compared to control. Materials and Methods: We used Next Generation Sequencing (NGS) technology to evaluate transcriptomes in masseter and temporalis muscle samples. Results: The transcriptomic analysis showed a prevalent downregulation of the genes involved in the myogenesis process. Conclusions: In conclusion, our findings suggest that the muscle regeneration process in TMD migraine patients may be slowed, therefore therapeutic interventions are needed to restore temporomandibular joint function and promote healing processes.

Toxic impacts induced by Sodium lauryl sulfate in Mytilus galloprovincialis.

Pharmaceuticals and personal care products (PPCPs) are continuously dispersed into the environment, as a result of human and veterinary use, reaching aquatic coastal systems and inhabiting organisms. However, information regarding to toxic effects of these compounds towards marine invertebrates is still scarce, especially in what regards to metabolic capacity and oxidative status alterations induced in bivalves after chronic exposure. In the present study, the toxic impacts of Sodium lauryl sulfate (SLS), an anionic surfactant widely used as an emulsifying cleaning agent in household and cosmetics, were evaluated in the mussel Mytilus galloprovincialis, after exposure for 28 days to different concentrations (0.0; 0.5; 1.0; 2.0 and 4.0 mg/L). For this, effects on mussels respitation rate, metabolic capacity and oxidative status were evaluated. The obtained results indicate a significant decrease on mussel's respiration rate after exposure to different SLS concentrations, an alteration that was accompanied by a decrease of bioconcentration factor along the increasing exposure gradient, especially at the highest exposure concentration. Nonetheless, the amount of SLS accumulated in organisms originated alterations in mussel's metabolic performance, with higher metabolic capacity up to 2.0 mg/L followed by a decrease at the highest tested concentration (4.0 mg/L). Mussels exposed to SLS revealed limited antioxidant defense mecanhisms but cellular damage was only observed at the highest exposure concentration (4.0 mg/L). In fact, up to 2.0 mg/L of SLS limited toxic impacts were observed, namely in terms of oxidative stress and redox balance. However, since mussel's respiration rate was greatly affected by the presence of SLS, the present study may highlight the potential threat of SLS towards marine bivalves, limiting their filtration capacity and, thus, affecting their global physiological development (including growth and reproduction) and ultimely their biochemical performance (afecting their defense capacity towards stressful conditons).

Caffeine: An Overview of Its Beneficial Effects in Experimental Models and Clinical Trials of Parkinson's Disease.

Parkinson's Disease (PD) is a neurological disease characterized by the progressive degeneration of the nigrostriatal dopaminergic pathway with consequent loss of neurons in the substantia nigra pars compacta and dopamine depletion. The cytoplasmic inclusions of α-synuclein (α-Syn), known as Lewy bodies, are the cytologic hallmark of PD. The presence of α-Syn aggregates causes mitochondrial degeneration, responsible for the increase in oxidative stress and consequent neurodegeneration. PD is a progressive disease that shows a complicated pathogenesis. The current therapies are used to alleviate the symptoms of the disease without changing its clinical course. Recently, phytocompounds with neuroprotective effects and antioxidant properties such as caffeine have aroused the interest of researchers. The purpose of this review is to summarize the preclinical studies present in the literature and clinical trials recorded in ClinicalTrial.gov, aimed at illustrating the effects of caffeine used as a nutraceutical compound combined with the current PD therapies. Therefore, the preventive effects of caffeine in the neurodegeneration of dopaminergic neurons encourage the use of this alkaloid as a supplement to reduce the progress of the PD.

Stem Cells Therapy for Spinal Cord Injury: An Overview of Clinical Trials.

Spinal cord injury (SCI) is a traumatic lesion that causes disability with temporary or permanent sensory and/or motor deficits. The pharmacological approach still in use for the treatment of SCI involves the employment of corticosteroid drugs. However, SCI remains a very complex disorder that needs future studies to find effective pharmacological treatments. SCI actives a strong inflammatory response that induces a loss of neurons followed by a cascade of events that lead to further spinal cord damage. Many experimental studies demonstrate the therapeutic effect of stem cells in SCI due to their capacity to differentiate into neuronal cells and by releasing neurotrophic factors. Therefore, they appear to be a valid strategy to use in the field of regenerative medicine. The purpose of this paper is to provide an overview of clinical trials, recorded in clinical trial.gov during 2005-2019, aimed to evaluate the use of stem cell-based therapy in SCI. The results available thus far show the safety and efficacy of stem cell therapy in patients with SCI. However, future trials are needed to investigate the safety and efficacy of stem cell transplantation.

Molecular Targets of Cannabidiol in Experimental Models of Neurological Disease.

Cannabidiol (CBD) is a non-psychoactive phytocannabinoid known for its beneficial effects including antioxidant and anti-inflammatory properties. Moreover, CBD is a compound with antidepressant, anxiolytic, anticonvulsant and antipsychotic effects. Thanks to all these properties, the interest of the scientific community for it has grown. Indeed, CBD is a great candidate for the management of neurological diseases. The purpose of our review is to summarize the in vitro and in vivo studies published in the last 15 years that describe the biochemical and molecular mechanisms underlying the effects of CBD and its therapeutic application in neurological diseases. CBD exerts its neuroprotective effects through three G protein coupled-receptors (adenosine receptor subtype 2A, serotonin receptor subtype 1A and G protein-coupled receptor 55), one ligand-gated ion channel (transient receptor potential vanilloid channel-1) and one nuclear factor (peroxisome proliferator-activated receptor γ). Moreover, the therapeutical properties of CBD are also due to GABAergic modulation. In conclusion, CBD, through multi-target mechanisms, represents a valid therapeutic tool for the management of epilepsy, Alzheimer's disease, multiple sclerosis and Parkinson's disease.

Traumatic Brain Injury and Stem Cells: An Overview of Clinical Trials, the Current Treatments and Future Therapeutic Approaches.

Traumatic brain injury represents physical damage to the brain tissue that induces transitory or permanent neurological disabilities. The traumatic injury activates an important inflammatory response, followed by a cascade of events that lead to neuronal loss and further brain damage. Maintaining proper ventilation, a normal level of oxygenation, and adequate blood pressure are the main therapeutic strategies performed after injury. Surgery is often necessary for patients with more serious injuries. However, to date, there are no therapies that completely resolve the brain damage suffered following the trauma. Stem cells, due to their capacity to differentiate into neuronal cells and through releasing neurotrophic factors, seem to be a valid strategy to use in the treatment of traumatic brain injury. The purpose of this review is to provide an overview of clinical trials, aimed to evaluate the use of stem cell-based therapy in traumatic brain injury. These studies aim to assess the safety and efficacy of stem cells in this disease. The results available so far are few; therefore, future studies need in order to evaluate the safety and efficacy of stem cell transplantation in traumatic brain injury.

Role of miRNAs in Alzheimer's Disease and Possible Fields of Application.

miRNAs (or microRNAs) are a class of single-stranded RNA molecules, responsible for post-transcriptional gene silencing through binding to the coding region as well as 3' and 5' untranslated region of target genes. About 70% of experimentally detectable miRNAs are expressed in the brain and some studies suggest that miRNAs are intimately involved in synaptic function and in specific signals during memory formation. More and more evidence demonstrates the possible involvement of miRNAs in Alzheimer's disease (AD). AD is the most common form of senile dementia, a disease that affects memory and cognitive functions. It is a neurodegenerative disorder characterized by loss of synapses, extracellular amyloid plaques composed of the amyloid-ß peptide (Aß), and intracellular aggregates of hyperphosphorylated TAU protein. This review aims to provide an overview of the in vivo studies of the last 5 years in the literature describing the role of the different miRNAs involved in AD. miRNAs hold huge potential as diagnostic and prognostic biomarkers and, at the same time, their modulation could be a potential therapeutic strategy against AD.

Transcriptomic Analysis of Stem Cells Treated with Moringin or Cannabidiol: Analogies and Differences in Inflammation Pathways.

Inflammation is a common feature of many neurodegenerative diseases. The treatment of stem cells as a therapeutic approach to repair damage in the central nervous system represents a valid alternative. In this study, using Next-Generation Sequencing (NGS) technology, we analyzed the transcriptomic profile of human Gingival Mesenchymal Stem Cells (hGMSCs) treated with Moringin [4-(α-l-ramanosyloxy)-benzyl isothiocyanate] (hGMSCs-MOR) or with Cannabidiol (hGMSCs-CBD) at dose of 0.5 or 5 µM, respectively. Moreover, we compared their transcriptomic profiles in order to evaluate analogies and differences in pro- and anti-inflammatory pathways. The hGMSCs-MOR selectively downregulate TNF-α signaling from the beginning, reducing the expression of TNF-α receptor while hGMSCs-CBD limit its activity after the process started. The treatment with CBD downregulates the pro-inflammatory pathway mediated by the IL-1 family, including its receptor while MOR is less efficient. Furthermore, both the treatments are efficient in the IL-6 signaling. In particular, CBD reduces the effect of the pro-inflammatory JAK/STAT pathway while MOR enhances the pro-survival PI3K/AKT/mTOR. In addition, both hGMSCs-MOR and hGMSCs-CBD improve the anti-inflammatory activity enhancing the TGF-ß pathway.

Use of Cannabidiol in the Treatment of Epilepsy: Efficacy and Security in Clinical Trials.

Cannabidiol (CBD) is one of the cannabinoids with non-psychotropic action, extracted from Cannabis sativa. CBD is a terpenophenol and it has received a great scientific interest thanks to its medical applications. This compound showed efficacy as anti-seizure, antipsychotic, neuroprotective, antidepressant and anxiolytic. The neuroprotective activity appears linked to its excellent anti-inflammatory and antioxidant properties. The purpose of this paper is to evaluate the use of CBD, in addition to common anti-epileptic drugs, in the severe treatment-resistant epilepsy through an overview of recent literature and clinical trials aimed to study the effects of the CBD treatment in different forms of epilepsy. The results of scientific studies obtained so far the use of CBD in clinical applications could represent hope for patients who are resistant to all conventional anti-epileptic drugs.