Notch signaling is an evolutionarily conserved pathway that regulates important biological processes, such as cell proliferation, apoptosis, migration, self-renewal, and differentiation. In mammals, Notch signaling is composed of four receptors (Notch1–4) and five ligands (Dll1-3–4, Jagged1–2) that mainly contribute to the development and maintenance of the central nervous system (CNS). Neural stem cells (NSCs) are the starting point for neurogenesis and other neurological functions, representing an essential aspect for the homeostasis of the CNS. Therefore, genetic and functional alterations to NSCs can lead to the development of brain tumors, including glioblastoma. Glioblastoma remains an incurable disease, and the reason for the failure of current therapies and tumor relapse is the presence of a small subpopulation of tumor cells known as glioma stem cells (GSCs), characterized by their stem cell-like properties and aggressive phenotype. Growing evidence reveals that Notch signaling is highly active in GSCs, where it suppresses differentiation and maintains stem-like properties, contributing to Glioblastoma tumorigenesis and conventional-treatment resistance. In this review, we try to give a comprehensive view of the contribution of Notch signaling to Glioblastoma and its possible implication as a target for new therapeutic approaches.

The role of Notch signaling in acute myeloid leukemia (AML) is still under investigation. We have previously shown that high levels of Notch receptors and ligands could interfere with drug response. In this study, the protein expression of 79 AML blast samples collected from newly diagnosed patients was examined through flow cytometry. Gamma-secretase inhibitors were used in AML mouse xenograft models to evaluate the contribution of Notch pharmacological inhibition to mouse survival. We used univariate analysis for testing the correlation and/or association between protein expression and well-known prognostics markers. All the four receptors (Notch1–4) and some ligands (Jagged2, DLL-3) were highly expressed in less mature subtypes (M0–M1). Notch3, Notch4, and Jagged2 were overexpressed in an adverse cytogenetic risk group compared to good cytogenetic risk patients. Chi-square analysis revealed a positive association between the complete remission rate after induction therapy and weak expression of Notch2 and Notch3. We also found an association between low levels of Notch4 and Jagged2 and three-year remission following allogeneic stem cell transplantation (HSCT). Accordingly, Kaplan–Meier analysis showed improved OS for patients lacking significant expression of Notch4, Jagged2, and DLL3. In vivo experiments in an AML mouse model highlighted both improved survival and a significant reduction of leukemia cell burden in the bone marrow of mice treated with the combination of Notch pan-inhibitors (GSIs) plus chemotherapy (Ara-C). Our results suggest that Notch can be useful as a prognostic marker and therapeutic target in AML.

Wnt/β-catenin signaling has been reported in Acute Myeloid leukemia, but little is known about its significance as a prognostic biomarker and drug target. In this study, we first evaluated the correlation between expression levels of Wnt molecules and clinical outcome. Then, we studied—in vitro and in vivo—the anti-leukemic value of combinatorial treatment between Wnt inhibitors and classic anti-leukemia drugs. Higher levels of β-catenin, Ser675-phospho-β-catenin and GSK-3α (total and Ser 9) were found in AML cells from intermediate or poor risk patients; nevertheless, patients presenting high activity of Wnt/β-catenin displayed shorter progression-free survival (PFS) according to univariate analysis. In vitro, many pharmacological inhibitors of Wnt signalling, i.e., LRP6 (Niclosamide), GSK-3 (LiCl, AR-A014418), and TCF/LEF (PNU-74654) but not Porcupine (IWP-2), significantly reduced proliferation and improved the drug sensitivity of AML cells cultured alone or in the presence of bone marrow stromal cells. In vivo, PNU-74654, Niclosamide and LiCl administration significantly reduced the bone marrow leukemic burden acting synergistically with Ara-C, thus improving mouse survival. Overall, our study demonstrates the antileukemic role of Wnt/β-catenin inhibition that may represent a potential new therapeutics strategy in AML.

Notch signaling is an evolutionary conserved pathway that plays a central role in development and differentiation of eukaryotic cells. It has been well documented that Notch signaling is inevitable for neuronal cell growth and homeostasis. It regulates process of differentiation from early embryonic stages to fully developed brain. To achieve this streamlined development of neuronal cells, a number of cellular processes are being orchestrated by the Notch signaling. Abrogated Notch signaling is related to several brain tumors, including glioblastomas. On the other hand, microRNAs are small molecules that play decisive role in mediating and modulating Notch signaling. This review discusses the crucial role of Notch signaling in development of nervous system and how this versatile pathway interplay with microRNAs in glioblastoma. This review sheds light on interplay between abrogated Notch signaling and miRNAs in the regulation of neuronal differentiation with special focus on miRNAs mediated regulation of tumorigenesis in glioblastoma. Furthermore, it discusses different aspects of neurogenesis modulated by the Notch signaling that could be exploited for the identification of new diagnostic tools and therapies for the treatment of glioblastoma.

The SDRG rat, characterized by a Sprague-Dawley (SD) genetic background with deletion of Rag1 and Il2rg genes, has deficiencies in B, T, and natural killer (NK) cells, making it a valuable model for preclinical applications such as tissue transplantation/humanization and assessment of advanced therapeutic products. Limited data exists on spontaneous background findings in this strain, particularly in aging animals. To address this gap, this study investigated clinical and anatomical pathology findings in 83 SDRG rats (40 males and 43 females), aged 10 to 26 weeks. Analyses included hematology, clinical chemistry, bone marrow smears, blood immunophenotyping, necropsy, and histology. Hematology revealed severely reduced lymphocyte counts, with a mild age-related increase in counts. Compared with SD rats, both sexes of SDRG rats had higher neutrophil, monocyte, and eosinophil counts; increased urea and cholesterol; lower albumin and total protein; and higher age-related glutamate dehydrogenase concentrations. Males had longer prothrombin times, while females showed sporadic age-related increases in alanine aminotransferase, aspartate aminotransferase, and triglycerides. Blood immunophenotyping confirmed the absence of circulating B and T lymphocytes and NK cells, alongside increased monocytes. Salient microscopic findings included lymphoid organ hypoplasia and inflammation in kidneys and lungs, with urinary bacterial infections, contributing to a single mortality. Age-related changes included progressive cardiomyopathy, early chronic progressive nephropathy, and early reproductive senescence in females. These findings underscore the SDRG strain’s potential as a model for preclinical evaluations of cell-based products and provide an initial reference into background features of this immunodeficient model that might help interpretations of experimental results.