The combined strategy of mesenchymal stem cells and tissue-engineered scaffolds for spinal cord injury regeneration.

Spinal cord injury (SCI) is a traumatic lesion that can result in the loss of motor or sensory neurons. Stem cell (SC)-based therapies have been demonstrated to promote neuronal regeneration following SCI, by releasing a range of trophic factors that support endogenous repair or by differentiating into neurons, or glial cells in order to replace the damaged cells. However, numerous limitations remain for therapies based on SC transplantion alone, including a low rate of survival/engraftment. Nevertheless, scaffolds are 3-dimentional substrates that have revealed to support cell survival, proliferation and differentiation in vivo, by mimicking a more favorable endogenous microenvironment. A multidisciplinary approach, which combines engineered scaffolds with SCs has been proposed as a promising strategy for encouraging spinal cord regeneration. The present review has focused on the regenerative potential of mesenchymal SCs isolated from different sources and combined with various scaffold types, in preclinical and clinical SCI studies.

Endogenous glucocorticoids: role in the etiopathogenesis of Alzheimer's disease.

Endogenous glucocorticoids (eGCs) are steroid hormones with a wide spectrum of physiological effects. However, enhanced basal eGCs levels have been observed in patients affected by Alzheimer's disease (AD) and they have been correlated with dysregulation of the hypothalamic-pituitary-adrenocortical axis, hippocampal degeneration and reduced cognitive/memory performance. Therefore, it has been proposed that elevated concentration of eGCs might have a role in AD pathogenesis. AD is the most common form of dementia, characterized by the pathological accumulation of two proteins: the Amyloid Beta (Aß) and the microtubule-associated protein tau in the neurons of the hippocampus and prefrontal cortex. In particular, the hippocampus, the cerebral area involved in learning and memory, is the brain region more vulnerable to chronic eGCs exposure. Although clinical studies have failed to establish a direct causative link between eGCs e and AD pathogenesis, evidences from pre-clinical studies have shown that increased eGCs levels accelerate the formation of Aß in AD animal models by promoting the amyloidogenic pathway, and in parallel by reducing Aß clearance, through transcriptional mechanisms involving the Glucocorticoid receptors. Instead, the effects of stress on tau phosphorylation seem to be mainly mediated bv the corticotropin-releasing factor receptor (CRFR1) and independent from stress-induced eGCs elevation.

Cannabidiol Modulates the Expression of Alzheimer's Disease-Related Genes in Mesenchymal Stem Cells.

Mesenchymal stem cells (MSCs) have emerged as a promising tool for the treatment of several neurodegenerative disorders, including Alzheimer's disease (AD). The main neuropathological hallmarks of AD are senile plaques, composed of amyloid beta (Aß), and neurofibrillary tangles, formed by hyperphosphorylated tau. However, current therapies for AD have shown limited efficacy. In this study, we evaluated whether pre-treatment with cannabidiol (CBD), at 5 µM concentration, modulated the transcriptional profile of MSCs derived from gingiva (GMSCs) in order to improve their therapeutic potential, by performing a transcriptomic analysis by the next-generation sequencing (NGS) platform. By comparing the expression profiles between GMSCs treated with CBD (CBD-GMSCs) and control GMSCs (CTR-GMSCs), we found that CBD led to the downregulation of genes linked to AD, including genes coding for the kinases responsible of tau phosphorylation and for the secretases involved in Aß generation. In parallel, immunocytochemistry analysis has shown that CBD inhibited the expression of GSK3ß, a central player in AD pathogenesis, by promoting PI3K/Akt signalling. In order to understand through which receptor CBD exerted these effects, we have performed pre-treatments with receptor antagonists for the cannabinoid receptors (SR141716A and AM630) or for the vanilloid receptor 1 (TRPVI). Here, we have proved that TRPV1 was able to mediate the modulatory effect of CBD on the PI3K/Akt/GSK3ß axis. In conclusion, we have found that pre-treatment with CBD prevented the expression of proteins potentially involved in tau phosphorylation and Aß production in GMSCs. Therefore, we suggested that GMSCs preconditioned with CBD possess a molecular profile that might be more beneficial for the treatment of AD.

Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells.

Human Gingival Mesenchymal Stem Cells (hGMSCs) are multipotential cells that can expand and differentiate in culture under specific and standardized conditions. In the present study, we have investigated whether in vitro pre-treatment of hGMSCs with Cannabidiol (CBD) can influence their expression profile, improving the therapeutic potential of this cell culture. Following CBD treatment (5 µM) for 24 h, gene expression analysis through Next Generation Sequencing (NGS) has revealed several genes differentially expressed between CBD-treated hGMSCs (CBD-hGMSCs) and control cells (CTR-hGMSCs) that were linked to inflammation and apoptosis. In particular, we have demonstrated that CBD treatment in hGMSCs prevented the activation of the NALP3-inflammasome pathway by suppressing the levels of NALP3, CASP1, and IL18, and in parallel, inhibited apoptosis, as demonstrated by the suppression of Bax. CBD treatment was also able to modulate the expression of the well-known mesenchymal stem cell markers (CD13, CD29, CD73, CD44, CD90, and CD166), and other surface antigens. Specifically, CBD led to the downregulation of genes codifying for antigens involved in the activation of the immune system (CD109, CD151, CD40, CD46, CD59, CD68, CD81, CD82, CD99), while it led to the upregulation of those implicated in the inhibition of the immune responses (CD47, CD55, CD276). In conclusion, the present study will provide a new simple and reproducible method for preconditioning hGMSCs with CBD, before transplantation, as an interesting strategy for improving the hGMSCs molecular phenotype, reducing the risk of immune or inflammatory reactions in the host, and in parallel, for increasing their survival and thus, their long-term therapeutic efficacy.

Is the Wnt/ß-catenin pathway involved in the anti-inflammatory activity of glucocorticoids in spinal cord injury?

The Wnt canonical or the Wnt/ß-catenin pathway has been implicated in the regulation of several physiopathological pathways such as inflammation. Glucocorticoids (GCs) are administered widely to treat inflammation in several diseases, including spinal cord injury (SCI). The aim of this study was to evaluate whether the Wnt canonical pathway is involved in experimental SCI and whether it is implicated in the anti-inflammatory activity of two different GCs: the methylprednisolone sodium succinate (MPSS), considered the standard treatment for acute SCI, and mometasone furoate (MF), mainly administered for the treatment of airway and skin diseases. Experimental SCI was induced in mice by surgical spinal cord compression at the T6-T7 level. Then, mice were treated with MPSS (6 mg/kg) or MF (0.1 mg/kg) for 7 days until they were killed. Both GCs were found to modulate the Wnt canonical pathway, but in particular, the MF treatment was shown to restore completely the downregulated pathway in SCI. The MF treatment also significantly increased peroxisome proliferator-activated receptor-γ, a Wnt target gene with anti-inflammatory properties, compared with MPSS, and it also inhibited the levels of the proinflammatory cytokines interleukin 1ß and tumor necrosis factor-α. Here, we suggest that MF has more efficacy than MPSS in inhibiting inflammation in an SCI experimental model and we propose the ß-catenin/peroxisome proliferator-activated receptor-γ axis as the mechanism by which MF exerts these beneficial effects.

The role of the Wnt canonical signaling in neurodegenerative diseases.

The Wnt/ß-catenin or Wnt canonical pathway controls multiple biological processes throughout development and adult life. Growing evidences have suggested that deregulation of the Wnt canonical pathway could be involved in the pathogenesis of neurodegenerative diseases. The Wnt canonical signaling is a pathway tightly regulated, which activation results in the inhibition of the Glycogen Synthase Kinase 3ß (GSK-3ß) function and in increased ß-catenin activity, that migrates into the nucleus, activating the transcription of the Wnt target genes. Conversely, when the Wnt canonical pathway is turned off, increased levels of GSK-3ß promote ß-catenin degradation. Hence, GSK-3ß could be considered as a key regulator of the Wnt canonical pathway. Of note, GSK-3ß has also been involved in the modulation of inflammation and apoptosis, determining the delicate balance between immune tolerance/inflammation and neuronal survival/neurodegeneration. In this review, we have summarized the current acknowledgements about the role of the Wnt canonical pathway in the pathogenesis of some neurodegenerative diseases including Alzheimer's disease, cerebral ischemia, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis, with particular regard to the main in vitro and in vivo studies in this field, by reviewing 85 research articles about.

Natural Phytochemicals in the Treatment and Prevention of Dementia: An Overview.

The word dementia describes a class of heterogeneous diseases which etiopathogenetic mechanisms are not well understood. There are different types of dementia, among which, Alzheimer's disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) are the more common. Currently approved pharmacological treatments for most forms of dementia seem to act only on symptoms without having profound disease-modifying effects. Thus, alternative strategies capable of preventing the progressive loss of specific neuronal populations are urgently required. In particular, the attention of researchers has been focused on phytochemical compounds that have shown antioxidative, anti-amyloidogenic, anti-inflammatory and anti-apoptotic properties and that could represent important resources in the discovery of drug candidates against dementia. In this review, we summarize the neuroprotective effects of the main phytochemicals belonging to the polyphenol, isothiocyanate, alkaloid and cannabinoid families in the prevention and treatment of the most common kinds of dementia. We believe that natural phytochemicals may represent a promising sources of alternative medicine, at least in association with therapies approved to date for dementia.

MICAL2 is a novel human cancer gene controlling mesenchymal to epithelial transition involved in cancer growth and invasion.

The MICAL (Molecules Interacting with CasL) proteins catalyze actin oxidation-reduction reactions destabilizing F-actin in cytoskeletal dynamics. Here we show for the first time that MICAL2 mRNA is significantly over-expressed in aggressive, poorly differentiated/undifferentiated, primary human epithelial cancers (gastric and renal). Immunohistochemistry showed MICAL2-positive cells on the cancer invasive front and in metastasizing cancer cells inside emboli, but not at sites of metastasis, suggesting MICAL2 expression was 'on' in a subpopulation of primary cancer cells seemingly detaching from the tissue of origin, enter emboli and travel to distant sites, and was turned 'off' upon homing at metastatic sites. In vitro, MICAL2 knock-down resulted in mesenchymal to epithelial transition, reduction of viability, and loss of motility and invasion properties of human cancer cells. Moreover, expression of MICAL2 cDNA in MICAL2-depleted cells induced epithelial to mesenchymal transition. Altogether our data indicate that MICAL2 over-expression is associated with cancer progression and metastatic disease. MICAL2 might be an important regulator of epithelial to mesenchymal transition and therefore a promising target for anti-metastatic therapy.