Innate Immunity: A Balance between Disease and Adaption to Stress

Since first being documented in ancient times, the relation of inflammation with injury and disease has evolved in complexity and causality. Early observations supported a cause (injury) and effect (inflammation) relationship, but the number of pathologies linked to chronic inflammation suggests that inflammation itself acts as a potent promoter of injury and disease. Additionally, results from studies over the last 25 years point to chronic inflammation and innate immune signaling as a critical link between stress (exogenous and endogenous) and adaptation. This brief review looks to highlight the role of the innate immune response in disease pathology, and recent findings indicating the innate immune response to chronic stresses as an influence in driving ad-aptation

From interaction to function: Phospholipase C beta 1 protects cells from stress-induced apoptosis

The phosphoinositide-dependent signal transduction pathway has been implicated in the control of a variety of biological processes, such as the regulation of cellular metabolism and omeostasis, cell proliferation and differentiation. One of the key player in the regulation of inositol lipid signaling is phospholipase C beta 1 (PI-PLCβ1), which hydrolyses PtIns(4,5)P2, giving rise to the second messengers IP3 and DAG. The complete mapping of the PI-PLCβ1 interactome was undertaken, to understand its diverse functions within the nuclear compartment and to determine its contribution to physiological and pathological processes. Affinity purification-mass spectrometry (AP-MS) allowed for the identification of 160 proteins present in association with PI-PLCβ1 in the nucleus of erythroleukemia cells. Co-immunoprecipitation analysis of selected proteins confirmed the data obtained from mass spectrometry. Of particular interest was the identification of proteins involved in nuclear trafficking, as well as factors involved in hematological malignancies and several anti-apoptotic proteins (Piazzi et al., 2013). PI-PLCβ1 has been associated with the regulation of several cellular functions, some of which are not yet fully understood. In particular, it has been reported that PI-PLCβ1 protects murine fibroblasts from oxidative stress-induced cell death, through signaling events which remain unclear. Reactive oxygen species (ROS) have been shown to regulate major epigenetic processes causing the silencing of tumor suppressors and enhancing the proliferation of leukemic cells under oxidative stress. Investigation of the role for ROS and their signaling mediators in the pathogenesis of leukemia might, therefore, outline innovative approaches for the improvement of pharmacological therapies to treat leukemia. We demonstrate that in acute lymphoid leukemia cells (pro-B cells), treated with 250 μM of hydrogen peroxide (H2O2), PI-PLCβ1b conferred resistance to cell death, promoting cell cycle progression and cell proliferation. Interestingly, we found that, upon H2O2 exposure, the expression of PI-PLCβ1b affects the activity of several protein kinases, in particular it completely abolished the phosphorylation of Erk1/2 MAP kinases, down-regulated PTEN and up-regulated the phosphorylation of Akt; thereby sustaining cellular proliferation

PLC-beta 1 regulates the expression of miR-210 during mithramycin-mediated erythroid differentiation in K562 cells

PLC-beta 1 (PLCβ1) inhibits erythroid differentiation induced by mithramycin (MTH) by targeting miR-210 expression. MicroRNA-210 (miR-210) has been reported to be upregulated in various types of human malignancy suggesting that it has an important role in tumorigenesis. Inhibition of miR-210 affects the erythroid differentiation pathway and it occurs to a greater extent in MTH-treated cells. In this paper we have analyzed the effect of MTH on human K562 cells differentiation. Overexpression of PLCβ1 suppresses the differentiation of K562 elicited by MTH as demonstrated by the absence of γ-globin expression. Inhibition of PLCβ1 expression is capable to promote the differentiation process leading to a recovery of γ-globin gene even in the absence of MTH. Our experimental evidences suggest that PLCβ1 signalling regulates erythropoiesis through miR-210. Indeed overexpression of PLCβ1 leads to a decrease of miR-210 expression after MTH treatment. Moreover miR-210 is up-regulated through both proliferation and differentiation events when PLCβ1 expression is down-regulated. Therefore we suggest a novel role for PLCβ1 in regulating miR-210 and our data hint at the fact that, in human K562 erythroleukemia cells, the modulation of PLCβ1 expression is able to exert an impairment of normal erythropoiesis as assessed by γ-globin expression

Three-Dimensional Virtual Anatomy as a New Approach for Medical Student’s Learning

none8noMost medical and health science schools adopt innovative tools to implement the teaching of anatomy to their undergraduate students. The increase in technological resources for educational purposes allows the use of virtual systems in the field of medicine, which can be considered decisive for improving anatomical knowledge, a requisite for safe and competent medical practice. Among these virtual tools, the Anatomage Table 7.0 represents, to date, a pivotal anatomical device for student education and training medical professionals. This review focuses attention on the potential of the Anatomage Table in the anatomical learning process and clinical practice by discussing these topics based on recent publication findings and describing their trends during the COVID-19 pandemic period. The reports documented a great interest in and a positive impact of the use of this technological table by medical students for teaching gross anatomy. Anatomage allows to describe, with accuracy and at high resolution, organ structure, vascularization, and innervation, as well as enables to familiarize with radiological images of real patients by improving knowledge in the radiological and surgical fields. Furthermore, its use can be considered strategic in a pandemic period, since it ensures, through an online platform, the continuation of anatomical and surgical training on dissecting cadavers.openBartoletti-Stella, Anna; Gatta, Valentina; Mariani, Giulia Adalgisa; Gobbi, Pietro; Falconi, Mirella; Manzoli, Lucia; Faenza, Irene; Salucci, SaraBartoletti-Stella, Anna; Gatta, Valentina; Mariani, Giulia Adalgisa; Gobbi, Pietro; Falconi, Mirella; Manzoli, Lucia; Faenza, Irene; Salucci, Sar

How Inflammation Pathways Contribute to Cell Death in Neuro-Muscular Disorders

Neuro-muscular disorders include a variety of diseases induced by genetic mutations resulting in muscle weakness and waste, swallowing and breathing difficulties. However, muscle alterations and nerve depletions involve specific molecular and cellular mechanisms which lead to the loss of motor-nerve or skeletal-muscle function, often due to an excessive cell death. Morphological and molecular studies demonstrated that a high number of these disorders seem characterized by an upregulated apoptosis which significantly contributes to the pathology. Cell death involvement is the consequence of some cellular processes that occur during diseases, including mitochondrial dysfunction, protein aggregation, free radical generation, excitotoxicity and inflammation. The latter represents an important mediator of disease progression, which, in the central nervous system, is known as neuroinflammation, characterized by reactive microglia and astroglia, as well the infiltration of peripheral monocytes and lymphocytes. Some of the mechanisms underlying inflammation have been linked to reactive oxygen species accumulation, which trigger mitochondrial genomic and respiratory chain instability, autophagy impairment and finally neuron or muscle cell death. This review discusses the main inflammatory pathways contributing to cell death in neuro-muscular disorders by highlighting the main mechanisms, the knowledge of which appears essential in developing therapeutic strategies to prevent the consequent neuron loss and muscle wasting

IPMK and β-catenin take part in PLC-β1-dependent signaling pathway during myogenic differentiation

Phospholipase C (PLC)-β1 catalytic activity plays an essential role in the initiation of myogenic differentiation but the effectors involved in its signaling pathway are not well defined[1,2]. Here, we show that the overexpression of the Inositol Polyphosphate Multikinase (IPMK) promotes myogenic differentiation, and that IPMK targets the same cyclin D3 promoter region activated by PLC-β1. Moreover, cyclin D3 promoter activation relies upon c-jun binding to the promoter, both in response to PLC-β1 and to IPMK overexpression. Furthermore, both IPMK and PLC-β1 overexpression determines an increase in β-catenin translocation and accumulation to the nuclei of differentiating myoblasts resulting in higher MyoD activation. Therefore, our data show that PLC-β1, IPMK and β-catenin are mediators of the same signaling pathway that regulates cyclin D3 and myosin heavy chain (MYH) induction during myogenic differentiation

BMP-2 induced expression of PLC beta1 that is a positive regulator of osteoblast differentiation

C2C12 is an immortalized mouse myoblast cell line. The cells readily proliferate in high-serum conditions, and differentiate and fuse in low-serum conditions. While this cell line is a very useful tool to study aspects of myogenesis, metabolism and muscle biology, however, treatment of C2C12 cells with bone morphogenic protein (BMPs) induces cells to differentiate into osteoblasts. Osteoblast differentiation is controlled by diversified signaling proteins and transcription factors, essentially BMP-2, Osterix (Osx/Sp7) and Runx2, finally associating with the expression of late osteoblast marker genes, like ALPL and Bglap. These peculiarities make C2C12 progenitor cells a skillful prototype to investigate the molecular mechanism that control cell destiny specification and terminal differentiation. In the current investigation, we took improvement of the differentiation peculiarities of the mouse C2C12 cell line to analyze whether changes in PLCbeta1 expression and its nuclear localization might regulate or affect their terminal osteogenic differentiation. We demonstrated that overexpression of PLCβ1 enhances the osteogenic differentiation of C2C12 elicited by BMP-2 as demonstrated by the presence of osteoblast marker genes expression. In the present study we also showed that miR-214 suppressed osteogenic differentiation through the regulation of nuclear PLCβ1 by targeting Osterix

K562 cell proliferation is modulated by PLCβ1 through a PKCα-mediated pathway

Phospholipase C β1 (PLCβ1) is known to play an important role in cell proliferation. Previous studies reported aninvolvement of PLCβ1 in G0-G1/S transition and G2/M progression in Friend murine erythroleukemia cells (FELC). However,little has been found about its role in human models. Here, we used K562 cell line as human homologous of FELC inorder to investigate the possible key regulatory role of PLCβ1 during cell proliferation of this humancell line. Our studies on the effects of the overexpression of both these isoforms showed a specific and positive connection between cyclinD3 and PLCβ1 in K562 cells, which led to a prolonged S phase of the cell cycle and a delay in cell proliferation. In order to shed light on this mechanism, we decided to study the possible involvement of protein kinases C (PKC), known to be direct targets of PLC signaling and important regulators of cell proliferation. Our data showed a peculiar decrease of PKCα levels in cells overexpressing PLCβ1. Moreover, when we silenced PKCα, by RNAi technique, in order to mimic the effects of PLCβ1, we caused the same upregulation of cyclin D3 levels and the same decrease of cell proliferation found in PLCβ1-overexpressing cells. The key features emerging from our studies in K562 cells is that PLCβ1 targets cyclin D3, likely through a PKCα-mediated-pathway, and that, as a downstream effect of its activity, K562 cells undergo an accumulation in the S phase of the cell cycle