Bitter Taste Receptor Agonist Denatonium Inhibits Stemness Characteristics in Hematopoietic Stem/Progenitor Cells.

Bone marrow microenvironmental stimuli profoundly impact hematopoietic stem cell fate and biology. As G protein-coupled receptors, the bitter taste receptors (TAS2Rs) are key in transmitting extracellular stimuli into an intracellular response, within the oral cavity but also in extraoral tissues. Their expression in the bone marrow (BM)-derived cells suggests their involvement in sensing the BM microenvironmental fluctuation.

Lamin B1 as a key modulator of the developing and aging brain.

Lamin B1 is an essential protein of the nuclear lamina that plays a crucial role in nuclear function and organization. It has been demonstrated that lamin B1 is essential for organogenesis and particularly brain development. The important role of lamin B1 in physiological brain development and aging has only recently been at the epicenter of attention and is yet to be fully elucidated.

Emerging Roles of Phospholipase C Beta Isozymes as Potential Biomarkers in Cardiac Disorders.

Phospholipase C (PLC) enzymes represent crucial participants in the plasma membrane of mammalian cells, including the cardiac sarcolemmal (SL) membrane of cardiomyocytes. They are responsible for the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P) into 1,2-diacylglycerol (DAG) and inositol (1,4,5) trisphosphate (Ins(1,4,5)P), both essential lipid mediators. These second messengers regulate the intracellular calcium (Ca) concentration, which activates signal transduction cascades involved in the regulation of cardiomyocyte activity.

Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models.

Autosomal dominant leukodystrophy (ADLD) is an ultra-rare, slowly progressive, and fatal neurodegenerative disorder associated with the loss of white matter in the central nervous system (CNS). Several years after its first clinical description, ADLD was found to be caused by coding and non-coding variants in the LMNB1 gene that cause its overexpression in at least the brain of patients. LMNB1 encodes for Lamin B1, a protein of the nuclear lamina.

A miRNA screening identifies miR-192-5p as associated with response to azacitidine and lenalidomide therapy in myelodysplastic syndromes.

Background: miRNAs are small non-coding RNAs that regulate gene expression and are linked to cancer development and progression. miRNA profiles are currently studied as new prognostic factors or therapeutic perspectives. Among hematological cancers, myelodysplastic syndromes at higher risk of evolution into acute myeloid leukemia are treated with hypomethylating agents, like azacitidine, alone or in combination with other drugs, such as lenalidomide.

Roles of PI3K/AKT/mTOR Axis in Arteriovenous Fistula.

Renal failure is a worldwide disease with a continuously increasing prevalence and involving a rising need for long-term treatment, mainly by haemodialysis. Arteriovenous fistula (AVF) is the favourite type of vascular access for haemodialysis; however, the lasting success of this therapy depends on its maturation, which is directly influenced by many concomitant processes such as vein wall thickening or inflammation. Understanding the molecular mechanisms that drive AVF maturation and failure can highlight new or combinatorial drugs for more personalized therapy.

The wide and growing range of lamin B-related diseases: from laminopathies to cancer.

B-type lamins are fundamental components of the nuclear lamina, a complex structure that acts as a scaffold for organization and function of the nucleus. Lamin B1 and B2, the most represented isoforms, are encoded by LMNB1 and LMNB2 gene, respectively. All B-type lamins are synthesized as precursors and undergo sequential post-translational modifications to generate the mature protein.

Near-Peer Teaching in Human Anatomy from a Tutors' Perspective: An Eighteen-Year-Old Experience at the University of Bologna.

The University of Bologna School of Medicine in 2003 adopted a near-peer teaching (NPT) program with senior medical students teaching and assisting younger students in human anatomy laboratories. This study aimed to evaluate the effectiveness and outcomes of this program-unique on the Italian academic panorama-from the tutors' perspective. An anonymous online survey was administered to all those who acted as peer tutors in the period from 2003 to 2021; it evaluated tutors' perceptions regarding the influence of the tutoring experience on their skillset gains, academic performance, and professional career.

Role of PLCγ1 in the modulation of cell migration and cell invasion in glioblastoma.

Phosphoinositide-specific phospholipases C (PLCs) are a class of enzymes involved in several cell activities, such as cell cycle regulation, proliferation, differentiation and cytoskeletal dynamics. Among these enzymes, PLCγ1 is one of the most expressed PLCs in the brain, contributing to a complex network in the developing nervous system. Several studies have shown that PLCγ1 signaling imbalance is linked to several brain disorders, including glioblastoma, the most aggressive brain tumor in adults.

Lamin B1 Accumulation's Effects on Autosomal Dominant Leukodystrophy (ADLD): Induction of Reactivity in the Astrocytes.

Autosomal dominant leukodystrophy (ADLD) is an extremely rare and fatal neurodegenerative disease due to the overexpression of the nuclear lamina component Lamin B1. Many aspects of the pathology still remain unrevealed. This work highlights the effect of Lamin B1 accumulation on different cellular functions in an ADLD astrocytic in vitro model.

"Modulating Phosphoinositide Profiles as a Roadmap for Treatment in Acute Myeloid Leukemia".

Polyphosphoinositides (PPIns) and their modulating enzymes are involved in regulating many important cellular functions including proliferation, differentiation or gene expression, and their deregulation is involved in human diseases such as metabolic syndromes, neurodegenerative disorders and cancer, including Acute Myeloid Leukemia (AML). Given that PPIns regulating enzymes are highly druggable targets, several studies have recently highlighted the potential of targeting them in AML. For instance many inhibitors targeting the PI3K pathway are in various stages of clinical development and more recently other novel enzymes such as PIP4K2A have been implicated as AML targets.

Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and β-Thalassemia.

Erythropoiesis regulation is essential in normal physiology and pathology, particularly in myelodysplastic syndromes (MDS) and β-thalassemia. Several signaling transduction processes, including those regulated by inositides, are implicated in erythropoiesis, and the latest MDS or β-thalassemia preclinical and clinical studies are now based on their regulation. Among others, the main pathways involved are those regulated by transforming growth factor (TGF)-β, which negatively regulates erythrocyte differentiation and maturation, and erythropoietin (EPO), which acts on the early-stage erythropoiesis.

The whole body donation program at the university of Bologna: A report based on the experience of one of the oldest university in Western world.

Human body dissection is fundamental in medical education, as it allows future physicians to learn about the body's morphology in three dimensions, to recognize anatomical variations and to develop and increase the essential qualities of respect, compassion and empathy for patients. It is equally important in clinical training as it allows surgeons to improve their manual dexterity and practical skills and to test innovative surgical techniques and devices. In Italy prior to 2020, body acquisition and use for study and research purposes were regulated by a generic set of old directives and national decrees which dealt only marginally with these issues.

Location-dependent role of phospholipase C signaling in the brain: Physiology and pathology.

Phosphoinositide-specific phospholipases C (PI-PLCs) are a class of enzymes involved in the phosphatidylinositol metabolism, which is implicated in the activation of several signaling pathways and which controls several cellular processes. The scientific community has long accepted the existence of a nuclear phosphoinositide (PI) metabolism, independent from the cytoplasmic one, critical in nuclear function control. Indeed, nuclear PIs are involved in many activities, such as cell cycle regulation, cell proliferation, cell differentiation, membrane transport, gene expression and cytoskeletal dynamics.

Phospholipase C beta1 (PI-PLCbeta1)/Cyclin D3/protein kinase C (PKC) alpha signaling modulation during iron-induced oxidative stress in myelodysplastic syndromes (MDS).

MDS are characterized by anemia and transfusion requirements. Transfused patients frequently show iron overload that negatively affects hematopoiesis. Iron chelation therapy can be effective in these MDS cases, but the molecular consequences of this treatment need to be further investigated.

Subcellular Localization Relevance and Cancer-Associated Mechanisms of Diacylglycerol Kinases.

An increasing number of reports suggests a significant involvement of the phosphoinositide (PI) cycle in cancer development and progression. Diacylglycerol kinases (DGKs) are very active in the PI cycle. They are a family of ten members that convert diacylglycerol (DAG) into phosphatidic acid (PA), two-second messengers with versatile cellular functions.

Exploring the controversial role of PI3K signalling in CD4 regulatory T (T-Reg) cells.

The immune system is a complex network that acts to protect vertebrates from foreign microorganisms and carries out immunosurveillance to combat cancer. In order to avoid hyper-activation of the immune system leading to collateral damage tissues and organs and to prevent self-attack, the network has the intrinsic control mechanisms that negatively regulate immune responses. Central to this negative regulation are regulatory T (T-Reg) cells, which through cytokine secretion and cell interaction limit uncontrolled clonal expansion and functions of activated immune cells.

Phosphoinositide-Dependent Signaling in Cancer: A Focus on Phospholipase C Isozymes.

Phosphoinositides (PI) form just a minor portion of the total phospholipid content in cells but are significantly involved in cancer development and progression. In several cancer types, phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P] and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P] play significant roles in regulating survival, proliferation, invasion, and growth of cancer cells. Phosphoinositide-specific phospholipase C (PLC) catalyze the generation of the essential second messengers diacylglycerol (DAG) and inositol 1,4,5 trisphosphate (InsP) by hydrolyzing PtdIns(4,5)P.

Nuclear Inositides and Inositide-Dependent Signaling Pathways in Myelodysplastic Syndromes.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by peripheral blood cytopenia and abnormal myeloproliferation, as well as a variable risk of evolution into acute myeloid leukemia (AML). The nucleus is a highly organized organelle with several distinct domains where nuclear inositides localize to mediate essential cellular events. Nuclear inositides play a critical role in the modulation of erythropoiesis or myelopoiesis.

Glycogen Synthase Kinase-3 and phospholipase C-beta signalling: Roles and possible interactions in myelodysplastic syndromes and acute myeloid leukemia.

GSK-3 and PLCbeta enzymes are responsible for the regulation of several signalling pathways related to many cellular functions. In hematopoietic cells, GSK-3 deficiency is correlated with an MDS-like phenotype and with leukemogenesis, showing a prognostic potential in AML cells. GSK-3 interacts with Wnt or MAPK signalling, but it is also linked to PI3K/Akt/mTOR pathways to regulate cell proliferation and apoptosis of hematopoietic stem cell progenitors.

Inositide-Dependent Nuclear Signalling in Health and Disease.

Nuclear inositides have a specific subcellular distribution that is linked to specific functions; thus their regulation is fundamental both in health and disease. Emerging evidence shows that alterations in multiple inositide signalling pathways are involved in pathophysiology, not only in cancer but also in other diseases. Here, we give an overview of the main features of inositides in the cell, and we discuss their potential as new molecular therapeutic targets.

Recent advances in MDS mutation landscape: Splicing and signalling.

Recurrent cytogenetic aberrations, genetic mutations and variable gene expression have been consistently recognized in solid cancers and in leukaemia, including in Myelodysplastic Syndromes (MDS). Besides conventional cytogenetics, the growing accessibility of new techniques has led to a deeper analysis of the molecular significance of genetic variations. Indeed, gene mutations affecting splicing genes, as well as genes implicated in essential signalling pathways, play a pivotal role in MDS physiology and pathophysiology, representing potential new molecular targets for innovative therapeutic strategies.

Response of high-risk MDS to azacitidine and lenalidomide is impacted by baseline and acquired mutations in a cluster of three inositide-specific genes.

Specific myeloid-related and inositide-specific gene mutations can be linked to myelodysplastic syndromes (MDS) pathogenesis and therapy. Here, 44 higher-risk MDS patients were treated with azacitidine and lenalidomide and mutations analyses were performed at baseline and during the therapy. Results were then correlated to clinical outcome, overall survival (OS), leukemia-free-survival (LFS) and response to therapy.