scholarly journals Cellular and intracellular mechanisms involved in the cognitive impairment of cannabinoids

2012 ◽  
Vol 367 (1607) ◽  
pp. 3254-3263 ◽  
Author(s):  
Emma Puighermanal ◽  
Arnau Busquets-Garcia ◽  
Rafael Maldonado ◽  
Andrés Ozaita
Keyword(s):  
Cognitive Function ◽  
Molecular Mechanisms ◽  
Cannabinoid Receptors ◽  
Critical Role ◽  
Mammalian Target Of Rapamycin ◽  
Endocannabinoid System ◽  
Protein Translation ◽  
Signalling Pathways ◽  
Cellular Processes ◽  
Extracellular Signal

Exogenous cannabinoids, such as delta9-tetrahydrocannabinol (THC), as well as the modulation of endogenous cannabinoids, affect cognitive function through the activation of cannabinoid receptors. Indeed, these compounds modulate a number of signalling pathways critically implicated in the deleterious effect of cannabinoids on learning and memory. Thus, the involvement of the mammalian target of rapamycin pathway and extracellular signal-regulated kinases, together with their consequent regulation of cellular processes such as protein translation, play a critical role in the amnesic-like effects of cannabinoids. In this study, we summarize the cellular and molecular mechanisms reported in the modulation of cognitive function by the endocannabinoid system.

scholarly journals Checking NEKs: Overcoming a Bottleneck in Human Diseases

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1778 ◽  
Author(s):  
Andressa Peres de Oliveira ◽  
Luidy Kazuo Issayama ◽  
Isadora Carolina Betim Pavan ◽  
Fernando Riback Silva ◽  
Talita Diniz Melo-Hanchuk ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Mammalian Target Of Rapamycin ◽  
Human Diseases ◽  
Therapeutic Approaches ◽  
Cellular Processes ◽  
Extracellular Signal ◽  
Damage Response ◽  
Cilia Formation ◽  
Potential Applications ◽  
Phosphoinositide 3 Kinase

In previous years, several kinases, such as phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and extracellular-signal-regulated kinase (ERK), have been linked to important human diseases, although some kinase families remain neglected in terms of research, hiding their relevance to therapeutic approaches. Here, a review regarding the NEK family is presented, shedding light on important information related to NEKs and human diseases. NEKs are a large group of homologous kinases with related functions and structures that participate in several cellular processes such as the cell cycle, cell division, cilia formation, and the DNA damage response. The review of the literature points to the pivotal participation of NEKs in important human diseases, like different types of cancer, diabetes, ciliopathies and central nervous system related and inflammatory-related diseases. The different known regulatory molecular mechanisms specific to each NEK are also presented, relating to their involvement in different diseases. In addition, important information about NEKs remains to be elucidated and is highlighted in this review, showing the need for other studies and research regarding this kinase family. Therefore, the NEK family represents an important group of kinases with potential applications in the therapy of human diseases.

Neuroimmmune interactions of cannabinoids in neurogenesis: focus on interleukin-1β (IL-1β) signalling

2013 ◽  
Vol 41 (6) ◽  
pp. 1577-1582 ◽  
Author(s):  
Daniel García-Ovejero ◽  
Ángel Arévalo-Martín ◽  
Beatriz Navarro-Galve ◽  
Emmanuel Pinteaux ◽  
Eduardo Molina-Holgado ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cannabinoid Receptors ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Endocannabinoid System ◽  
Interleukin 1Β ◽  
Signalling Pathways ◽  
Brain Repair ◽  
Adult Nscs ◽  
The Brain

Neuroimmune networks and the brain endocannabinoid system contribute to the maintenance of neurogenesis. Activation of cannabinoid receptors suppresses chronic inflammatory responses through the attenuation of pro-inflammatory mediators. Moreover, the endocannabinoid system directs cell fate specification of NSCs (neural stem cells) in the CNS (central nervous sytem). The aim of our work is to understand better the relationship between the endocannabinoid and the IL-1β (interleukin-1β) associated signalling pathways and NSC biology, in order to develop therapeutical strategies on CNS diseases that may facilitate brain repair. NSCs express functional CB1 and CB2 cannabinoid receptors, DAGLα (diacylglycerol lipase α) and the NSC markers SOX-2 and nestin. We have investigated the role of CB1 and CB2 cannabinoid receptors in the control of NSC proliferation and in the release of immunomodulators [IL-1β and IL-1Ra (IL-1 receptor antagonist)] that control NSC fate decisions. Pharmacological blockade of CB1 and/or CB2 cannabinoid receptors abolish or decrease NSC proliferation, indicating a critical role for both CB1 and CB2 receptors in the proliferation of NSC via IL-1 signalling pathways. Thus the endocannabinoid system, which has neuroprotective and immunomodulatory actions mediated by IL-1 signalling cascades in the brain, could assist the process of proliferation and differentiation of embryonic or adult NSCs, and this may be of therapeutic interest in the emerging field of brain repair.

scholarly journals c-Jun, Foxo3a, and c-Myc Transcription Factors are Key Regulators of ATP-Mediated Angiogenic Responses in Pulmonary Artery Vasa Vasorum Endothelial Cells †

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 416
Author(s):  
Derek Strassheim ◽  
Vijaya Karoor ◽  
Hala Nijmeh ◽  
Philip Weston ◽  
Martin Lapel ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcription Factors ◽  
Pulmonary Artery ◽  
Molecular Mechanisms ◽  
Cell Cycle Control ◽  
Critical Role ◽  
Mammalian Target Of Rapamycin ◽  
Vasa Vasorum ◽  
Angiogenic Factor ◽  
Angiogenic Genes

Angiogenic vasa vasorum (VV) expansion plays an essential role in the pathogenesis of hypoxia-induced pulmonary hypertension (PH), a cardiovascular disease. We previously showed that extracellular ATP released under hypoxic conditions is an autocrine/paracrine, the angiogenic factor for pulmonary artery (PA) VV endothelial cells (VVECs), acting via P2Y purinergic receptors (P2YR) and the Phosphoinositide 3-kinase (PI3K)-Akt-Mammalian Target of Rapamycin (mTOR) signaling. To further elucidate the molecular mechanisms of ATP-mediated VV angiogenesis, we determined the profile of ATP-inducible transcription factors (TFs) in VVECs using a TranSignal protein/DNA array. C-Jun, c-Myc, and Foxo3 were found to be upregulated in most VVEC populations and formed nodes connecting several signaling networks. siRNA-mediated knockdown (KD) of these TFs revealed their critical role in ATP-induced VVEC angiogenic responses and the regulation of downstream targets involved in tissue remodeling, cell cycle control, expression of endothelial markers, cell adhesion, and junction proteins. Our results showed that c-Jun was required for the expression of ATP-stimulated angiogenic genes, c-Myc was repressive to anti-angiogenic genes, and Foxo3a predominantly controlled the expression of anti-apoptotic and junctional proteins. The findings from our study suggest that pharmacological targeting of the components of P2YR-PI3K-Akt-mTOR axis and specific TFs reduced ATP-mediated VVEC angiogenic response and may have a potential translational significance in attenuating pathological vascular remodeling.

scholarly journals Extracellular signal-regulated kinases associate with and phosphorylate DHPS to promote cell proliferation

Oncogenesis ◽  
2020 ◽  
Vol 9 (9) ◽  
Author(s):  
Chao Wang ◽  
Zhen Chen ◽  
Litong Nie ◽  
Mengfan Tang ◽  
Xu Feng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Lung Adenocarcinoma ◽  
Poor Prognosis ◽  
Protein Translation ◽  
Deoxyhypusine Synthase ◽  
Promote Cell Proliferation ◽  
Cellular Processes ◽  
Extracellular Signal ◽  
Direct Binding ◽  
Kinase Substrates

Abstract The ERK1/2 pathway is one of the most commonly dysregulated pathways in human cancers and controls many vital cellular processes. Although many ERK1/2 kinase substrates have been identified, the diversity of ERK1/2 mediated processes suggests the existence of additional targets. Here, we identified Deoxyhypusine synthase (DHPS), an essential hypusination enzyme regulating protein translation, as a major and direct-binding protein of ERK1/2. Further experiments showed that ERK1/2 phosphorylate DHPS at Ser-233 site. The Ser-233 phosphorylation of DHPS by ERK1/2 is important for its function in cell proliferation. Moreover, we found that higher DHPS expression correlated with poor prognosis in lung adenocarcinoma and increased resistance to inhibitors of the ERK1/2 pathway. In summary, our results suggest that ERK1/2-mediated DHPS phosphorylation is an important mechanism that underlies protein translation and that DHPS expression is a potent biomarker of response to therapies targeting ERK1/2-pathway.

scholarly journals THC Exposure is Reflected in the Microstructure of the Cerebral Cortex and Amygdala of Young Adults

2020 ◽  
Vol 30 (9) ◽  
pp. 4949-4963 ◽  
Author(s):  
Ryan P Cabeen ◽  
John M Allman ◽  
Arthur W Toga
Keyword(s):  
Young Adults ◽  
Cerebral Cortex ◽  
Molecular Mechanisms ◽  
Cannabinoid Receptor ◽  
Memory Performance ◽  
Critical Role ◽  
Endocannabinoid System ◽  
Imaging Data ◽  
Brain Areas ◽  
Human Connectome Project

Abstract The endocannabinoid system serves a critical role in homeostatic regulation through its influence on processes underlying appetite, pain, reward, and stress, and cannabis has long been used for the related modulatory effects it provides through tetrahydrocannabinol (THC). We investigated how THC exposure relates to tissue microstructure of the cerebral cortex and subcortical nuclei using computational modeling of diffusion magnetic resonance imaging data in a large cohort of young adults from the Human Connectome Project. We report strong associations between biospecimen-defined THC exposure and microstructure parameters in discrete gray matter brain areas, including frontoinsular cortex, ventromedial prefrontal cortex, and the lateral amygdala subfields, with independent effects in behavioral measures of memory performance, negative intrusive thinking, and paternal substance abuse. These results shed new light on the relationship between THC exposure and microstructure variation in brain areas related to salience processing, emotion regulation, and decision making. The absence of effects in some other cannabinoid-receptor-rich brain areas prompts the consideration of cellular and molecular mechanisms that we discuss. Further studies are needed to characterize the nature of these effects across the lifespan and to investigate the mechanistic neurobiological factors connecting THC exposure and microstructural parameters.

The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic Target

2018 ◽  
Vol 108 (2) ◽  
pp. 121-131 ◽  
Author(s):  
Karen Flores ◽  
Suresh Singh Yadav ◽  
Arieh A. Katz ◽  
Rony Seger
Keyword(s):  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Processes ◽  
Development Of Resistance ◽  
Mapk Cascades ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Importin Α ◽  
Cancer And Inflammation

The mitogen-activated protein kinase (MAPK) cascades are central signaling pathways that play a central role in the regulation of most stimulated cellular processes including proliferation, differentiation, stress response and apoptosis. Currently 4 such cascades are known, each termed by its downstream MAPK components: the extracellular signal-regulated kinase 1/2 (ERK1/2), cJun-N-terminal kinase (JNK), p38 and ERK5. One of the hallmarks of these cascades is the stimulated nuclear translocation of their MAPK components using distinct mechanisms. ERK1/2 are shuttled into the nucleus by importin7, JNK and p38 by a dimer of importin3 with either importin9 or importin7, and ERK5 by importin-α/β. Dysregulation of these cascades often results in diseases, including cancer and inflammation, as well as developmental and neurological disorders. Much effort has been invested over the years in developing inhibitors to the MAPK cascades to combat these diseases. Although some inhibitors are already in clinical use or clinical trials, their effects are hampered by development of resistance or adverse side-effects. Recently, our group developed 2 myristoylated peptides: EPE peptide, which inhibits the interaction of ERK1/2 with importin7, and PERY peptide, which prevents JNK/p38 interaction with either importin7 or importin9. These peptides block the nuclear translocation of their corresponding kinases, resulting in prevention of several cancers, while the PERY peptide also inhibits inflammation-induced diseases. These peptides provide a proof of concept for the use of the nuclear translocation of MAPKs as therapeutic targets for cancer and/or inflammation.

scholarly journals Corilagin in Cancer: A Critical Evaluation of Anticancer Activities and Molecular Mechanisms

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3399 ◽  
Author(s):  
Ashutosh Gupta ◽  
Amit Kumar Singh ◽  
Ramesh Kumar ◽  
Risha Ganguly ◽  
Harvesh Kumar Rana ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Mammalian Target Of Rapamycin ◽  
Critical Evaluation ◽  
Cancer Cell Line ◽  
Anticancer Activities ◽  
Altered Expression ◽  
Anticancer Efficacy ◽  
Extracellular Signal ◽  
M Phase ◽  
Induced Apoptosis

Corilagin (β-1-O-galloyl-3,6-(R)-hexahydroxydiphenoyl-d-glucose), an ellagitannin, is one of the major bioactive compounds present in various plants. Ellagitannins belong to the hydrolyzable tannins, a group of polyphenols. Corilagin shows broad-spectrum biological, and therapeutic activities, such as antioxidant, anti-inflammatory, hepatoprotective, and antitumor actions. Natural compounds possessing antitumor activities have attracted significant attention for treatment of cancer. Corilagin has shown inhibitory activity against the growth of numerous cancer cells by prompting cell cycle arrest at the G2/M phase and augmented apoptosis. Corilagin-induced apoptosis and autophagic cell death depends on production of intracellular reactive oxygen species in breast cancer cell line. It blocks the activation of both the canonical Smad and non-canonical extracellular-signal-regulated kinase/Akt (protein kinase B) pathways. The potential apoptotic action of corilagin is mediated by altered expression of procaspase-3, procaspase-8, procaspase-9, poly (ADP ribose) polymerase, and Bcl-2 Bax. In nude mice, corilagin suppressed cholangiocarcinoma growth and downregulated the expression of Notch1 and mammalian target of rapamycin. The aim of this review is to summarize the anticancer efficacy of corilagin with an emphasis on the molecular mechanisms involving various signaling pathways in tumor cells.

Critical Role for Histone Deacetylase 6 (HDAC6) in the Regulation of IL-6, and the JAK/STA3 Signaling Cascade in Macrophages

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1039-1039
Author(s):  
Maritza Lienlaf ◽  
Patricio Perez-Villarroel ◽  
Fengdong Cheng ◽  
Hongwei Wang ◽  
Danay Marante ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Cell Cycle Control ◽  
Critical Role ◽  
Histone Deacetylase 6 ◽  
Stat3 Pathway ◽  
Cellular Processes ◽  
Stat3 Signaling Pathway ◽  
Antigen Presenting

Abstract Abstract 1039 Background Histone Deacetylases (HDACs) have divergent effects over the production of anti- and pro-inflammatory cytokines in Antigen Presenting Cells (APCs). We have previously shown that modulation of specific HDACs can alter the immunogenicity of APCs, either to an activating or tolerogenic phenotype. We recently identified HDAC6 to positively regulate IL-10 production. However, the participation of this HDAC in other immune related cellular processes remains unknown. In this work we are presenting evidence of the important role of HDAC6 in the regulation of IL-6 via activation of the JAK/STAT3 pathway. Methods Stable knockdown clones of HDAC6 (KDHDAC6) and Non-target (NT) cells were generated in RAW264.7 murine macrophages using lentiviral shRNA for HDAC6 or non-target (NT) respectively. Two KDHADC6 and two NT clones were treated with LPS or untreated and then analyzed by microarray using the Affymetrix GeneChip Mouse 430 2.0. Significantly down- or up-regulated genes were analyzed by their ontology distribution and selected genes were validated by quantitative real-time RT-PCR, ELISA, or immunoblots. Additionally, changes in the expression of these selected genes were tested in cells treated with selective HDAC6 inhibitors. Results 1542 genes were down-regulated and 775 up-regulated in KDHDAC6 cells. Their ontology distribution revealed significant changes in immune-related (632) and apoptosis/cell cycle control (47) genes. Importantly, IL-6 was one of the most highly down-regulated genes in KDHDAC6 cells. Therefore, we next analyzed the relevance of these findings by studying the tolerogenic JAK/STAT3 signaling pathway which is known to be activated by IL-6 and critical in the final outcome of APCs in response to stimuli. We observed a complete abrogation in the phosphorylation of JAK2 and STAT3 proteins in KDHDAC6 cells in response to LPS, which was reverted when these cells were treated with exogenous IL-6. Conclusions These results demonstrate the requirement of HDAC6 in the production of IL-6 in response to LPS, and therefore positions this deacetylase as an important regulator of the JAK/STAT3 pathway. These findings provide insight into the molecular mechanisms controlling the immunogenicity of APCs, supporting the use of HDAC6 inhibitors to enhance immune activation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Phosphorylation of Eukaryotic Translation Initiation Factor 2α Coordinates rRNA Transcription and Translation Inhibition during Endoplasmic Reticulum Stress

2009 ◽  
Vol 29 (15) ◽  
pp. 4295-4307 ◽  
Author(s):  
Jenny B. DuRose ◽  
Donalyn Scheuner ◽  
Randal J. Kaufman ◽  
Lawrence I. Rothblum ◽  
Maho Niwa
Keyword(s):  
Endoplasmic Reticulum ◽  
Ribosome Biogenesis ◽  
Critical Role ◽  
Mammalian Target Of Rapamycin ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Rrna Synthesis ◽  
Cell Physiology ◽  
Rrna Transcription

ABSTRACT The endoplasmic reticulum (ER) is the major cellular compartment where folding and maturation of secretory and membrane proteins take place. When protein folding needs exceed the capacity of the ER, the unfolded protein response (UPR) pathway modulates gene expression and downregulates protein translation to restore homeostasis. Here, we report that the UPR downregulates the synthesis of rRNA by inactivation of the RNA polymerase I basal transcription factor RRN3/TIF-IA. Inhibition of rRNA synthesis does not appear to involve the well-characterized mTOR (mammalian target of rapamycin) pathway; instead, PERK-dependent phosphorylation of eIF2α plays a critical role in the inactivation of RRN3/TIF-IA. Downregulation of rRNA transcription occurs simultaneously or slightly prior to eIF2α phosphorylation-induced translation repression. Since rRNA is the most abundant RNA species, constituting ∼90% of total cellular RNA, its downregulation exerts a significant impact on cell physiology. Our study demonstrates the first link between regulation of translation and rRNA synthesis with phosphorylation of eIF2α, suggesting that this pathway may be broadly utilized by stresses that activate eIF2α kinases in order to coordinately regulate translation and ribosome biogenesis during cellular stress.

Ca2+-Operated Transcriptional Networks: Molecular Mechanisms and In Vivo Models

2008 ◽  
Vol 88 (2) ◽  
pp. 421-449 ◽  
Author(s):  
Britt Mellström ◽  
Magali Savignac ◽  
Rosa Gomez-Villafuertes ◽  
Jose R. Naranjo
Keyword(s):  
Molecular Mechanisms ◽  
Critical Role ◽  
Transcriptional Networks ◽  
Calcium Signal ◽  
In Vivo Models ◽  
Cellular Processes ◽  
Calcium Sensors ◽  
Genes Encoding ◽  
Living Organisms

Calcium is the most universal signal used by living organisms to convey information to many different cellular processes. In this review we present well-known and recently identified proteins that sense and decode the calcium signal and are key elements in the nucleus to regulate the activity of various transcriptional networks. When possible, the review also presents in vivo models in which the genes encoding these calcium sensors-transducers have been modified, to emphasize the critical role of these Ca2+-operated mechanisms in many physiological functions.

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