ABSTRACT
Glioblastoma, also referred to as glioblastoma multiforme (GBM), is grade IV astrocytoma characterized by being fast-growing and the most aggressive brain tumor. In adults, it is the most prevalent type of malignant brain tumor. Despite the advancements in both diagnosis tools and therapeutic treatments, GBM is still associated with poor survival rate without any statistically significant improvement in the past three decades. Patient's genome signature is one of the key factors causing the development of this tumor, in addition to previous radiation exposure and other environmental factors. Researchers have identified genomic and subsequent molecular alterations affecting core pathways that trigger the malignant phenotype of this tumor. Targeting intrinsically altered molecules and pathways is seen as a novel avenue in GBM treatment. The present review shed light on signaling pathways and intrinsically altered molecules implicated in GBM development. It discussed the main challenges impeding successful GBM treatment, such as the blood brain barrier and tumor microenvironment (TME), the plasticity and heterogeneity of both GBM and TME and the glioblastoma stem cells. The present review also presented current advancements in GBM molecular targeted therapy in clinical trials. Profound and comprehensive understanding of molecular participants opens doors for innovative, more targeted and personalized GBM therapeutic modalities.
ABSTRACT
Status epilepticus (SE) induces a number of events leading to programmed cell death (PCD). The aim of our work is to study the time sequence of activation of different factors in experimental SE (intraperitoneal kainic acid (KA) model). We studied ceramide, a known mediator of apoptosis in multiple models, sphingomyelinases (SMases), enzymes that break down sphingomyelin and increase ceramide thus leading to apoptosis in many models, Bcl(2), Bax, and caspase-3. SE induced a sustained ceramide increase starting 2h after kainic acid injection followed by an increase in Bax protein at 6 and 12h, and the appearance of caspase-3-activated fragment (caspase-3a) immunostaining and TUNEL positivity at 12h. Status epilepticus also induced an increase in acidic and neutral sphingomyelinases that preceded (acidic sphingomyelinase) and parallelled (acidic and neutral sphingomyelinase) the increases in ceramide. These data suggest that, in this model, Bax is activated early in the process and that its increase is sustained till 12h after kainic acid injection which is the time of first appearance of caspase-3 activation and TUNEL positivity, and that SMases contribute to increases in ceramide levels during and after status epilepticus.
