scholarly journals Inhibiting microcephaly genes as alternative to microtubule targeting agents to treat brain tumors

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Giorgia Iegiani ◽  
Ferdinando Di Cunto ◽  
Gianmarco Pallavicini
Keyword(s):  
Brain Tumors ◽  
Radial Glia ◽  
Patient Survival ◽  
Current Knowledge ◽  
Cell Types ◽  
Proliferating Cells ◽  
Microtubule Stability ◽  
Microtubule Targeting Agents ◽  
Cancerous Cells ◽  
Cerebellar Granules

AbstractMedulloblastoma (MB) and gliomas are the most frequent high-grade brain tumors (HGBT) in children and adulthood, respectively. The general treatment for these tumors consists in surgery, followed by radiotherapy and chemotherapy. Despite the improvement in patient survival, these therapies are only partially effective, and many patients still die. In the last decades, microtubules have emerged as interesting molecular targets for HGBT, as various microtubule targeting agents (MTAs) have been developed and tested pre-clinically and clinically with encouraging results. Nevertheless, these treatments produce relevant side effects since they target microtubules in normal as well as in cancerous cells. A possible strategy to overcome this toxicity could be to target proteins that control microtubule dynamics but are required by HGBT cells much more than in normal cell types. The genes mutated in primary hereditary microcephaly (MCPH) are ubiquitously expressed in proliferating cells, but under normal conditions are selectively required during brain development, in neural progenitors. There is evidence that MB and glioma cells share molecular profiles with progenitors of cerebellar granules and of cortical radial glia cells, in which MCPH gene functions are fundamental. Moreover, several studies indicate that MCPH genes are required for HGBT expansion. Among the 25 known MCPH genes, we focus this review on KNL1, ASPM, CENPE, CITK and KIF14, which have been found to control microtubule stability during cell division. We summarize the current knowledge about the molecular basis of their interaction with microtubules. Moreover, we will discuss data that suggest these genes are promising candidates as HGBT-specific targets.

scholarly journals Assessment of PARP-1 Distribution in Tissues of Cynomolgus Monkeys

2020 ◽  
Vol 68 (6) ◽  
pp. 413-435 ◽  
Author(s):  
Maria Tedim Ferreira ◽  
Louise Berger ◽  
Michèle Rouleau ◽  
Guy G. Poirier
Keyword(s):  
Current Knowledge ◽  
Cancer Therapeutics ◽  
Cell Types ◽  
Tissue Expression ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Cellular Distribution ◽  
Proliferating Cells ◽  
Cynomolgus Monkeys ◽  
Parp 1

The poly(ADP-ribose) polymerase 1 (PARP-1) enzyme has received much attention in the last decade due to its promising role in cancer therapeutics. Despite the expanding use of PARP inhibitors in cancer therapy, little is known about PARP-1 tissue distribution. Our study provides a detailed survey of PARP-1 tissue and cellular distribution using well-preserved cynomolgus monkey organs and a well-characterized, highly specific monoclonal PARP-1 antibody. Overall, PARP-1 was detected in most organs, but its distribution was restricted to specific cells within each tissue, suggesting that PARP-1 expression is tightly regulated. The strongest expression was in the pituitary, the ovary, the male adrenal gland, and the thymus. One of the key findings of this study was the stronger expression of PARP-1 in proliferating cells rather than mature cells. This observation not only provides clues to the importance of PARP-1 in processes such as DNA replication and transcription in these cell types, but it also provides the basis for further investigation into the effects of its inhibition in the context of malignancy. Overall, this study greatly expands the current knowledge of PARP-1 tissue expression, enabling the identification of tissues where PARP inhibition may be most efficacious.

scholarly journals The Role of Aryl Hydrocarbon Receptor (AhR) in Brain Tumors

2020 ◽  
Vol 21 (8) ◽  
pp. 2863 ◽  
Author(s):  
Maria L. Perepechaeva ◽  
Alevtina Y. Grishanova
Keyword(s):  
Brain Tumors ◽  
Aryl Hydrocarbon Receptor ◽  
Therapeutic Target ◽  
Current Knowledge ◽  
Cell Types ◽  
Pathological Process ◽  
Aryl Hydrocarbon ◽  
Oncogenic Protein ◽  
Different Cell Types

Primary brain tumors, both malignant and benign, are diagnosed in adults at an incidence rate of approximately 23 people per 100 thousand. The role of AhR in carcinogenesis has been a subject of debate, given that this protein may act as either an oncogenic protein or a tumor suppressor in different cell types and contexts. Lately, there is growing evidence that aryl hydrocarbon receptor (AhR) plays an important part in the development of brain tumors. The role of AhR in brain tumors is complicated, depending on the type of tumor, on ligands that activate AhR, and other features of the pathological process. In this review, we summarize current knowledge about AhR in relation to brain tumors and provide an overview of AhR’s potential as a therapeutic target.

scholarly journals Irx3 and Irx5 - Novel Regulatory Factors of Postnatal Hypothalamic Neurogenesis

2021 ◽  
Vol 15 ◽  
Author(s):  
Zhengchao Dou ◽  
Joe Eun Son ◽  
Chi-chung Hui
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Energy Homeostasis ◽  
Adult Mouse ◽  
Radial Glia ◽  
Current Knowledge ◽  
Cell Types ◽  
Neuronal Populations ◽  
Neuronal Progenitors ◽  
Physiological Processes

The hypothalamus is a brain region that exhibits highly conserved anatomy across vertebrate species and functions as a central regulatory hub for many physiological processes such as energy homeostasis and circadian rhythm. Neurons in the arcuate nucleus of the hypothalamus are largely responsible for sensing of peripheral signals such as leptin and insulin, and are critical for the regulation of food intake and energy expenditure. While these neurons are mainly born during embryogenesis, accumulating evidence have demonstrated that neurogenesis also occurs in postnatal-adult mouse hypothalamus, particularly in the first two postnatal weeks. This second wave of active neurogenesis contributes to the remodeling of hypothalamic neuronal populations and regulation of energy homeostasis including hypothalamic leptin sensing. Radial glia cell types, such as tanycytes, are known to act as neuronal progenitors in the postnatal mouse hypothalamus. Our recent study unveiled a previously unreported radial glia-like neural stem cell (RGL-NSC) population that actively contributes to neurogenesis in the postnatal mouse hypothalamus. We also identified Irx3 and Irx5, which encode Iroquois homeodomain-containing transcription factors, as genetic determinants regulating the neurogenic property of these RGL-NSCs. These findings are significant as IRX3 and IRX5 have been implicated in FTO-associated obesity in humans, illustrating the importance of postnatal hypothalamic neurogenesis in energy homeostasis and obesity. In this review, we summarize current knowledge regarding postnatal-adult hypothalamic neurogenesis and highlight recent findings on the radial glia-like cells that contribute to the remodeling of postnatal mouse hypothalamus. We will discuss characteristics of the RGL-NSCs and potential actions of Irx3 and Irx5 in the regulation of neural stem cells in the postnatal-adult mouse brain. Understanding the behavior and regulation of neural stem cells in the postnatal-adult hypothalamus will provide novel mechanistic insights in the control of hypothalamic remodeling and energy homeostasis.

scholarly journals Hypoxia, Acidification and Inflammation: Partners in Crime in Parkinson’s Disease Pathogenesis?

Immuno ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 78-90
Author(s):  
Johannes Burtscher ◽  
Grégoire P. Millet
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Current Knowledge ◽  
Cell Types ◽  
Brain Cell ◽  
Special Focus ◽  
Molecular Alterations ◽  
Research Fields

Like in other neurodegenerative diseases, protein aggregation, mitochondrial dysfunction, oxidative stress and neuroinflammation are hallmarks of Parkinson’s disease (PD). Differentiating characteristics of PD include the central role of α-synuclein in the aggregation pathology, a distinct vulnerability of the striato-nigral system with the related motor symptoms, as well as specific mitochondrial deficits. Which molecular alterations cause neurodegeneration and drive PD pathogenesis is poorly understood. Here, we summarize evidence of the involvement of three interdependent factors in PD and suggest that their interplay is likely a trigger and/or aggravator of PD-related neurodegeneration: hypoxia, acidification and inflammation. We aim to integrate the existing knowledge on the well-established role of inflammation and immunity, the emerging interest in the contribution of hypoxic insults and the rather neglected effects of brain acidification in PD pathogenesis. Their tight association as an important aspect of the disease merits detailed investigation. Consequences of related injuries are discussed in the context of aging and the interaction of different brain cell types, in particular with regard to potential consequences on the vulnerability of dopaminergic neurons in the substantia nigra. A special focus is put on the identification of current knowledge gaps and we emphasize the importance of related insights from other research fields, such as cancer research and immunometabolism, for neurodegeneration research. The highlighted interplay of hypoxia, acidification and inflammation is likely also of relevance for other neurodegenerative diseases, despite disease-specific biochemical and metabolic alterations.

scholarly journals Glucocorticoid Receptor β (GRβ): Beyond Its Dominant-Negative Function

2021 ◽  
Vol 22 (7) ◽  
pp. 3649
Author(s):  
Patricia Ramos-Ramírez ◽  
Omar Tliba
Keyword(s):  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Cell Communication ◽  
Cell Types ◽  
The Body ◽  
Dominant Negative ◽  
Negative Effects ◽  
Independent Manner ◽  
Distinct Cell ◽  
Induced Apoptosis

Glucocorticoids (GCs) act via the GC receptor (GR), a receptor ubiquitously expressed in the body where it drives a broad spectrum of responses within distinct cell types and tissues, which vary in strength and specificity. The variability of GR-mediated cell responses is further extended by the existence of GR isoforms, such as GRα and GRβ, generated through alternative splicing mechanisms. While GRα is the classic receptor responsible for GC actions, GRβ has been implicated in the impairment of GRα-mediated activities. Interestingly, in contrast to the popular belief that GRβ actions are restricted to its dominant-negative effects on GRα-mediated responses, GRβ has been shown to have intrinsic activities and “directly” regulates a plethora of genes related to inflammatory process, cell communication, migration, and malignancy, each in a GRα-independent manner. Furthermore, GRβ has been associated with increased cell migration, growth, and reduced sensitivity to GC-induced apoptosis. We will summarize the current knowledge of GRβ-mediated responses, with a focus on the GRα-independent/intrinsic effects of GRβ and the associated non-canonical signaling pathways. Where appropriate, potential links to airway inflammatory diseases will be highlighted.

scholarly journals Single-cell atlas of early human brain development highlights heterogeneity of human neuroepithelial cells and early radial glia

2021 ◽  
Author(s):  
Ugomma C. Eze ◽  
Aparna Bhaduri ◽  
Maximilian Haeussler ◽  
Tomasz J. Nowakowski ◽  
Arnold R. Kriegstein
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
Single Cell ◽  
Radial Glia ◽  
Cortical Development ◽  
Cell Types ◽  
Human Cortex ◽  
Early Stages ◽  
Human Brain Development ◽  
Neuroepithelial Cells

AbstractThe human cortex comprises diverse cell types that emerge from an initially uniform neuroepithelium that gives rise to radial glia, the neural stem cells of the cortex. To characterize the earliest stages of human brain development, we performed single-cell RNA-sequencing across regions of the developing human brain, including the telencephalon, diencephalon, midbrain, hindbrain and cerebellum. We identify nine progenitor populations physically proximal to the telencephalon, suggesting more heterogeneity than previously described, including a highly prevalent mesenchymal-like population that disappears once neurogenesis begins. Comparison of human and mouse progenitor populations at corresponding stages identifies two progenitor clusters that are enriched in the early stages of human cortical development. We also find that organoid systems display low fidelity to neuroepithelial and early radial glia cell types, but improve as neurogenesis progresses. Overall, we provide a comprehensive molecular and spatial atlas of early stages of human brain and cortical development.

scholarly journals Rho GTPases as Key Molecular Players within Intestinal Mucosa and GI Diseases

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 66
Author(s):  
Rashmita Pradhan ◽  
Phuong A. Ngo ◽  
Luz d. C. Martínez-Sánchez ◽  
Markus F. Neurath ◽  
Rocío López-Posadas
Keyword(s):  
Intestinal Mucosa ◽  
Rho Gtpases ◽  
Current Knowledge ◽  
Cell Types ◽  
Effector Proteins ◽  
Special Focus ◽  
Specific Cell ◽  
Rho Proteins

Rho proteins operate as key regulators of the cytoskeleton, cell morphology and trafficking. Acting as molecular switches, the function of Rho GTPases is determined by guanosine triphosphate (GTP)/guanosine diphosphate (GDP) exchange and their lipidation via prenylation, allowing their binding to cellular membranes and the interaction with downstream effector proteins in close proximity to the membrane. A plethora of in vitro studies demonstrate the indispensable function of Rho proteins for cytoskeleton dynamics within different cell types. However, only in the last decades we have got access to genetically modified mouse models to decipher the intricate regulation between members of the Rho family within specific cell types in the complex in vivo situation. Translationally, alterations of the expression and/or function of Rho GTPases have been associated with several pathological conditions, such as inflammation and cancer. In the context of the GI tract, the continuous crosstalk between the host and the intestinal microbiota requires a tight regulation of the complex interaction between cellular components within the intestinal tissue. Recent studies demonstrate that Rho GTPases play important roles for the maintenance of tissue homeostasis in the gut. We will summarize the current knowledge on Rho protein function within individual cell types in the intestinal mucosa in vivo, with special focus on intestinal epithelial cells and T cells.

scholarly journals Role of PFKFB3 and PFKFB4 in Cancer: Genetic Basis, Impact on Disease Development/Progression, and Potential as Therapeutic Targets

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 909
Author(s):  
Krzysztof Kotowski ◽  
Jakub Rosik ◽  
Filip Machaj ◽  
Stanisław Supplitt ◽  
Daniel Wiczew ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Treatment Options ◽  
Protein Structures ◽  
New Drugs ◽  
Proliferating Cells ◽  
Cancer Tissues ◽  
The Impact ◽  
Rate Limiting ◽  
Synthesis And Degradation

Glycolysis is a crucial metabolic process in rapidly proliferating cells such as cancer cells. Phosphofructokinase-1 (PFK-1) is a key rate-limiting enzyme of glycolysis. Its efficiency is allosterically regulated by numerous substances occurring in the cytoplasm. However, the most potent regulator of PFK-1 is fructose-2,6-bisphosphate (F-2,6-BP), the level of which is strongly associated with 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase activity (PFK-2/FBPase-2, PFKFB). PFK-2/FBPase-2 is a bifunctional enzyme responsible for F-2,6-BP synthesis and degradation. Four isozymes of PFKFB (PFKFB1, PFKFB2, PFKFB3, and PFKFB4) have been identified. Alterations in the levels of all PFK-2/FBPase-2 isozymes have been reported in different diseases. However, most recent studies have focused on an increased expression of PFKFB3 and PFKFB4 in cancer tissues and their role in carcinogenesis. In this review, we summarize our current knowledge on all PFKFB genes and protein structures, and emphasize important differences between the isoenzymes, which likely affect their kinase/phosphatase activities. The main focus is on the latest reports in this field of cancer research, and in particular the impact of PFKFB3 and PFKFB4 on tumor progression, metastasis, angiogenesis, and autophagy. We also present the most recent achievements in the development of new drugs targeting these isozymes. Finally, we discuss potential combination therapies using PFKFB3 inhibitors, which may represent important future cancer treatment options.

Epigenetics in Clinical Management of Children and Adolescents with Brain Tumors

2017 ◽  
Vol 18 (1) ◽  
pp. 57-64 ◽  
Author(s):  
Andres Morales La Madrid ◽  
Mark W. Kieran
Keyword(s):  
Nervous System ◽  
Brain Tumors ◽  
Children And Adolescents ◽  
Tumor Biology ◽  
Tumor Development ◽  
Integrated Approach ◽  
Cell Types ◽  
Pediatric Brain Tumors ◽  
Tumor Formation ◽  
Molecular Profile

Central nervous system (CNS) tumors represent the second most prevalent group of cancers in children and adolescents, yet account for the majority of childhood cancer-related deaths and considerable morbidity among survivors, due to high-intensity non-selective standard therapies delivered to immature nervous system structures undergoing development. These tumors arise at different ages –not infrequently very early in life-, in different locations and cellular contexts, have varied cell types of origin, and have heterogeneous responses to the “classic” current therapeutic approaches. Demographic, radiologic and morphological characterization have several limitations, putting into the “classic boxes” heterogeneous tumors that are diverse in their genetic and epigenetic background and that will likely behave biologically different. Given that, epigenetic disruption (i.e. DNA methylation, histone modification and chromatin remodeling) is a common feature identified more and more frequently in pediatric cancer, it is logical to speculate that interrogating epigenetic marks may help to further define the molecular profile, and therefore tumor biology, evolution and treatment of these tumors. An integrated approach that incorporates traditional features complemented with genetic and epigenenetic specific markers offers tremendous promise to “risk-group” stratification and better prognostication. Also, it will help unveil the key driver pathways for tumor formation and for the discovery of targeted therapy for neoplasms that appear in the developing brain, facilitating early identification of therapy responders and track accurately disease progression. In this paper, we reviewed the most representative pediatric brain tumors where epigenetic alterations have been identified as initiating or driving events in tumor development, maintenance or progression.

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