Epilepsy represents one of the most common neurological disorders characterized by abnormal electrical activity in the central nervous system (CNS). Recurrent seizures are the cardinal clinical ...manifestation. Although it has been reported that the underlying pathological processes include inflammation, changes in synaptic strength, apoptosis, and ion channels dysfunction, currently the pathogenesis of epilepsy is not yet completely understood. Long non-coding RNAs (lncRNAs), a class of long transcripts without protein-coding capacity, have emerged as regulatory molecules that are involved in a wide variety of biological processes. A growing number of studies reported that lncRNAs participate in the regulation of pathological processes of epilepsy and they are dysregulated during epileptogenesis. Moreover, an aberrant expression of lncRNAs linked to epilepsy has been observed both in patients and in animal models. In this review, we summarize latest advances concerning the mechanisms of action and the involvement of the most dysregulated lncRNAs in epilepsy. However, the functional roles of lncRNAs in the disease pathogenesis are still to be explored and we are only at the beginning. Additional studies are needed for the complete understanding of the underlying mechanisms and they would result in the use of lncRNAs as diagnostic biomarkers and novel therapeutic targets.
Glioblastoma multiforme (GBM) is a grade IV astrocytoma and the most common form of malignant brain tumor in adults. GBM remains one of the most fatal and least successfully treated solid tumors: ...current therapies provide a median survival of 12-15 months after diagnosis, due to the high recurrence rate. Glioma Stem Cells (GSCs) are believed to be the real driving force of tumor initiation, progression and relapse. Therefore, better therapeutic strategies GSCs-targeted are needed. Resveratrol is a polyphenolic phytoalexin found in fruits and vegetables displaying pleiotropic health benefits. Many studies have highlighted its chemo-preventive and chemotherapeutic activities in a wide range of solid tumors. In this work, we analyzed the effects of Resveratrol exposure on cell viability, proliferation and motility in seven GSC lines isolated from GBM patients. For the first time in our knowledge, we investigated Resveratrol impact on Wnt signaling pathway in GSCs, evaluating the expression of seven Wnt signaling pathway-related genes and the protein levels of c-Myc and β-catenin. Finally, we analyzed Twist1 and Snail1 protein levels, two pivotal activators of epithelial-mesenchymal transition (EMT) program. Results showed that although response to Resveratrol exposure was highly heterogeneous among GSC lines, generally it was able to inhibit cell proliferation, increase cell mortality, and strongly decrease cell motility, modulating the Wnt signaling pathway and the EMT activators. Treatment with Resveratrol may represent a new interesting therapeutic approach, in order to affect GSCs proliferation and motility, even if further investigations are needed to deeply understand the GSCs heterogeneous response.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Different functional states determine glioblastoma (GBM) heterogeneity. Brain cancer cells coexist with the glial cells in a functional syncytium based on a continuous metabolic rewiring. However, ...standard glioma therapies do not account for the effects of the glial cells within the tumor microenvironment. This may be a possible reason for the lack of improvements in patients with high-grade gliomas therapies. Cell metabolism and bioenergetic fitness depend on the availability of nutrients and interactions in the microenvironment. It is strictly related to the cell location in the tumor mass, proximity to blood vessels, biochemical gradients, and tumor evolution, underlying the influence of the context and the timeline in anti-tumor therapeutic approaches. Besides the cancer metabolic strategies, here we review the modifications found in the GBM-associated glia, focusing on morphological, molecular, and metabolic features. We propose to analyze the GBM metabolic rewiring processes from a systems biology perspective. We aim at defining the crosstalk between GBM and the glial cells as modules. The complex networking may be expressed by metabolic modules corresponding to the GBM growth and spreading phases. Variation in the oxidative phosphorylation (OXPHOS) rate and regulation appears to be the most important part of the metabolic and functional heterogeneity, correlating with glycolysis and response to hypoxia. Integrated metabolic modules along with molecular and morphological features could allow the identification of key factors for controlling the GBM-stroma metabolism in multi-targeted, time-dependent therapies.
Autism spectrum disorder (ASD) represents a group of neurodevelopmental diseases characterized by persistent deficits in social communication, interaction, and repetitive patterns of behaviors, ...interests, and activities. The etiopathogenesis is multifactorial with complex interactions between genetic and environmental factors. The clinical heterogeneity and complex etiology of this pediatric disorder have limited the development of pharmacological therapies. The major limit to ASD research remains a lack of relevant human disease models which can faithfully recapitulate key features of the human pathology and represent its genetic heterogeneity. Recent advances in induced pluripotent stem cells (iPSCs), reprogrammed from somatic cells of patients into all types of patient-specific neural cells, have provided a promising cellular tool for disease modeling and development of novel drug treatments. The iPSCs technology allowed not only a better investigation of the disease etiopathogenesis but also opened up the potential for personalized therapies and offered new opportunities for drug discovery, pharmacological screening, and toxicity assessment. Moreover, iPSCs can be differentiated and organized into three-dimensional (3D) organoids, providing a model which mimics the complexity of the brain's architecture and more accurately recapitulates tissue- and organ-level disease pathophysiology. The aims of this review were to describe the current state of the art of the use of human patient-derived iPSCs and brain organoids in modeling ASD and developing novel therapeutic strategies and to discuss the opportunities and major challenges in this rapidly moving field.
Alzheimer’s disease (AD) is the most common neurodegenerative disease among the elderly, affecting millions of people worldwide and clinically characterized by a progressive and irreversible ...cognitive decline. The rapid increase in the incidence of AD highlights the need for an easy, efficient and accurate diagnosis of the disease in its initial stages in order to halt or delay the progression. The currently used diagnostic methods rely on measures of amyloid-β (Aβ), phosphorylated (p-tau) and total tau (t-tau) protein levels in the cerebrospinal fluid (CSF) aided by advanced neuroimaging techniques like positron emission tomography (PET) and magnetic resonance imaging (MRI). However, the invasiveness of these procedures and the high cost restrict their utilization. Hence, biomarkers from biological fluids obtained using non-invasive methods and novel neuroimaging approaches provide an attractive alternative for the early diagnosis of AD. Such biomarkers may also be helpful for better understanding of the molecular mechanisms underlying the disease, allowing differential diagnosis or at least prolonging the pre-symptomatic stage in patients suffering from AD. Herein, we discuss the advantages and limits of the conventional biomarkers as well as recent promising candidates from alternative body fluids and new imaging techniques.
BTK, the new kid on the (oncology) block? Grassilli, Emanuela; Cerrito, Maria Grazia; Lavitrano, Marialuisa
Frontiers in oncology,
08/2022, Letnik:
12
Journal Article
Recenzirano
Odprti dostop
In the last decade data piled up indicating that BTK – for twenty years considered as a “private matter” of bone marrow-derived cells – it is expressed and plays important and different roles also ...outside of the hematopoietic compartment and, most notably, in tumor cells. Initial evidence that BTK plays a critical role in B cell-derived malignancies prompted the chase for specific inhibitors, the forefather of which entered the clinic in a record time and paved the way for an ever increasing number of new molecules to be trialed. The growing interests in BTK also led to the discovery that, in solid tumors, two novel isoforms are mainly expressed and actionable liabilities for target therapy. Remarkably, the different isoforms appear to be involved in different signaling pathways which will have to be attentively specified in order to define the area of therapeutic intervention. In this perspective we briefly summarize the progress made in the last decade in studying BTK and its isoforms in cancer cells and define the open questions to be addressed in order to get the most benefits from its targeting for therapeutic purposes.
The current coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2, is affecting every aspect of global society, including public ...healthcare systems, medical care access, and the economy. Although the respiratory tract is primarily affected by SARS-CoV-2, emerging evidence suggests that the virus may also reach the central nervous system (CNS), leading to several neurological issues. In particular, people with a diagnosis of Alzheimer's disease (AD) are a vulnerable group at high risk of contracting COVID-19, and develop more severe forms and worse outcomes, including death. Therefore, understanding shared links between COVID-19 and AD could aid the development of therapeutic strategies against both. Herein, we reviewed common risk factors and potential pathogenetic mechanisms that might contribute to the acceleration of neurodegenerative processes in AD patients infected by SARS-CoV-2.
Radiomics is a promising tool that may increase the value of imaging in differential diagnosis (DDx) of glioma. However, implementation in clinical practice is still distant and concerns have been ...raised regarding the methodological quality of radiomic studies. Therefore, we aimed to systematically review the current status of radiomic studies concerning glioma DDx, also using the radiomics quality score (RQS) to assess the quality of the methodology used in each study. A systematic literature search was performed to identify original articles focused on the use of radiomics for glioma DDx from 2015. Methodological quality was assessed using the RQS tool. Spearman's correlation (ρ) analysis was performed to explore whether RQS was correlated with journal metrics and the characteristics of the studies. Finally, 42 articles were selected for the systematic qualitative analysis. Selected articles were grouped and summarized in terms of those on DDx between glioma and primary central nervous system lymphoma, those aiming at differentiating glioma from brain metastases, and those based on DDx of glioma and other brain diseases. Median RQS was 8.71 out 36, with a mean RQS of all studies of 24.21%. Our study revealed that, despite promising and encouraging results, current studies on radiomics for glioma DDx still lack the quality required to allow its introduction into clinical practice. This work could provide new insights and help to reach a consensus on the use of the radiomic approach for glioma DDx.
The lack of effective screening and successful treatment contributes to high ovarian cancer mortality, making it the second most common cause of gynecologic cancer death. Development of ...chemoresistance in up to 75% of patients is the cause of a poor treatment response and reduced survival. Therefore, identifying potential and effective biomarkers for its diagnosis and prognosis is a strong critical need. Copy number alterations are frequent in cancer, and relevant for molecular tumor stratification and patients' prognoses. In this study, array-CGH analysis was performed in three cell lines and derived cancer stem cells (CSCs) to identify genes potentially predictive for ovarian cancer patients' prognoses. Bioinformatic analyses of genes involved in copy number gains revealed that AhRR and PPP1R3C expression negatively correlated with ovarian cancer patients' overall and progression-free survival. These results, together with a significant association between AhRR and PPP1R3C expression and ovarian cancer stemness markers, suggested their potential role in CSCs. Furthermore, AhRR and PPP1R3C's increased expression was maintained in some CSC subpopulations, reinforcing their potential role in ovarian cancer. In conclusion, we reported for the first time, to the best of our knowledge, a prognostic role of AhRR and PPP1R3C expression in serous ovarian cancer.
Activation of glial cells (reactive gliosis) and the purinergic pathway, together with metalloproteinase (MMP)-induced remodeling of the neural extracellular matrix (nECM), drive maladaptive changes ...in the spinal cord following peripheral nerve injury (PNI). We evaluated the effects on spinal maladaptive plasticity through administration of oxidized ATP (oxATP), an antagonist of P2X receptors (P2XR), and/or GM6001, an inhibitor of MMPs, in rats following spared nerve injury (SNI) of the sciatic nerve. With morpho-molecular techniques, we demonstrated a reduction in spinal reactive gliosis and changes in the neuro-glial-nECM crosstalk via expression remodeling of P2XR, nerve growth factor (NGF) receptors (TrkA and p75), and histone deacetylase 2 (HDAC2) after treatments with oxATP/GM6001. Altogether, our data suggest that MMPs and purinergic inhibition have a modulatory impact on key proteins in the neuro-glial-nECM network, acting at different levels from intracellular signaling to epigenetic modifications.
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