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      Deletion of Cryab increases the vulnerability of mice to the addiction-like effects of the cannabinoid JWH-018 via upregulation of striatal NF-κB expression

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          Abstract

          Synthetic cannabinoids have exhibited unpredictable abuse liabilities, especially self-administration (SA) responses in normal rodent models, despite seemingly inducing addiction-like effects in humans. Thus, an efficient pre-clinical model must be developed to determine cannabinoid abuse potential in animals and describe the mechanism that may mediate cannabinoid sensitivity. The Cryab knockout (KO) mice were recently discovered to be potentially sensitive to the addictive effects of psychoactive drugs. Herein, we examined the responses of Cryab KO mice to JWH-018 using SA, conditioned place preference, and electroencephalography. Additionally, the effects of repeated JWH-018 exposure on endocannabinoid- and dopamine-related genes in various addiction-associated brain regions were examined, along with protein expressions involving neuroinflammation and synaptic plasticity. Cryab KO mice exhibited greater cannabinoid-induced SA responses and place preference, along with divergent gamma wave alterations, compared to wild-type (WT) mice, implying their higher sensitivity to cannabinoids. Endocannabinoid- or dopamine-related mRNA expressions and accumbal dopamine concentrations after repeated JWH-018 exposure were not significantly different between the WT and Cryab KO mice. Further analyses revealed that repeated JWH-018 administration led to possibly greater neuroinflammation in Cryab KO mice, which may arise from upregulated NF-κB, accompanied by higher expressions of synaptic plasticity markers, which might have contributed to the development of cannabinoid addiction-related behavior in Cryab KO mice. These findings signify that increased neuroinflammation via NF-κB may mediate the enhanced addiction-like responses of Cryab KO mice to cannabinoids. Altogether, Cryab KO mice may be a potential model for cannabinoid abuse susceptibility.

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          NF-κB signaling in inflammation

          The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory responses. NF-κB induces the expression of various pro-inflammatory genes, including those encoding cytokines and chemokines, and also participates in inflammasome regulation. In addition, NF-κB plays a critical role in regulating the survival, activation and differentiation of innate immune cells and inflammatory T cells. Consequently, deregulated NF-κB activation contributes to the pathogenic processes of various inflammatory diseases. In this review, we will discuss the activation and function of NF-κB in association with inflammatory diseases and highlight the development of therapeutic strategies based on NF-κB inhibition.
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            Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases.

            Glycogen synthase kinase-3 (GSK3) may be the busiest kinase in most cells, with over 100 known substrates to deal with. How does GSK3 maintain control to selectively phosphorylate each substrate, and why was it evolutionarily favorable for GSK3 to assume such a large responsibility? GSK3 must be particularly adaptable for incorporating new substrates into its repertoire, and we discuss the distinct properties of GSK3 that may contribute to its capacity to fulfill its roles in multiple signaling pathways. The mechanisms regulating GSK3 (predominantly post-translational modifications, substrate priming, cellular trafficking, protein complexes) have been reviewed previously, so here we focus on newly identified complexities in these mechanisms, how each of these regulatory mechanism contributes to the ability of GSK3 to select which substrates to phosphorylate, and how these mechanisms may have contributed to its adaptability as new substrates evolved. The current understanding of the mechanisms regulating GSK3 is reviewed, as are emerging topics in the actions of GSK3, particularly its interactions with receptors and receptor-coupled signal transduction events, and differential actions and regulation of the two GSK3 isoforms, GSK3α and GSK3β. Another remarkable characteristic of GSK3 is its involvement in many prevalent disorders, including psychiatric and neurological diseases, inflammatory diseases, cancer, and others. We address the feasibility of targeting GSK3 therapeutically, and provide an update of its involvement in the etiology and treatment of several disorders.
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              Twenty-five years of quantitative PCR for gene expression analysis.

              Following its invention 25 years ago, PCR has been adapted for numerous molecular biology applications. Gene expression analysis by reverse-transcription quantitative PCR (RT-qPCR) has been a key enabling technology of the post-genome era. Since the founding of BioTechniques, this journal has been a resource for the improvements in qPCR technology, experimental design, and data analysis. qPCR and, more specifically, real-time qPCR has become a routine and robust approach for measuring the expression of genes of interest, validating microarray experiments, and monitoring biomarkers. The use of real-time qPCR has nearly supplanted other approaches (e.g., Northern blotting, RNase protection assays). This review examines the current state of qPCR for gene expression analysis now that the method has reached a mature stage of development and implementation. Specifically, the different fluorescent reporter technologies of real-time qPCR are discussed as well as the selection of endogenous controls. The conceptual framework for data analysis methods is also presented to demystify these analysis techniques. The future of qPCR remains bright as the technology becomes more rapid, cost-effective, easier to use, and capable of higher throughput.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                16 March 2023
                2023
                : 14
                : 1135929
                Affiliations
                [1] 1 Department of Pharmacy , Uimyung Research Institute for Neuroscience , Sahmyook University , Seoul, Republic of Korea
                [2] 2 Department of Chemistry and Life Science , Sahmyook University , Seoul, Republic of Korea
                [3] 3 Department of Ergonomics , Leibniz Research Centre for Working Environment and Human Factors—IfADo , Dortmund, Germany
                [4] 4 College of Pharmacy and Medical Research Center , Chungbuk National University , Cheongju, Chungcheongbuk-do, Republic of Korea
                [5] 5 Medicinal Chemistry Laboratory , Department of Fundamental Pharmaceutical Sciences , College of Pharmacy , Kyung Hee University , Seoul, Republic of Korea
                [6] 6 College of Veterinary Medicine , Gyeongsang National University , Jinju, Gyeongsangnam–do, Republic of Korea
                [7] 7 Institute for New Drug Development , School of Pharmacy , Jeonbuk National University , Jeonju, Jeollabuk-do, Republic of Korea
                Author notes

                Edited by: Francisco Navarrete Rueda, Miguel Hernández University of Elche, Spain

                Reviewed by: Elena Martín-García, Pompeu Fabra University, Spain

                Hyung Nam, Louisiana State University Health Shreveport, United States

                *Correspondence: Jae Hoon Cheong, cheongjh@ 123456jbnu.ac.kr ; Hee Jin Kim, hjkim@ 123456syu.ac.kr

                This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology

                Article
                1135929
                10.3389/fphar.2023.1135929
                10060981
                8b3240a8-c62b-444f-953a-1c6219357d38
                Copyright © 2023 Sayson, Ortiz, Lee, Kim, Custodio, Yun, Lee, Lee, Cha, Cheong and Kim.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 02 January 2023
                : 07 March 2023
                Funding
                Funded by: Ministry of Food and Drug Safety , doi 10.13039/501100003569;
                Award ID: 19182MFDS410 22214MFDS252
                Funded by: National Research Foundation of Korea , doi 10.13039/501100003725;
                Award ID: 2020R1F1A1075633
                This work was supported by the Ministry of Food and Drug Safety (19182MFDS410 and 22214MFDS252) and the National Research Foundation of Korea (2020R1F1A1075633).
                Categories
                Pharmacology
                Original Research

                Pharmacology & Pharmaceutical medicine
                cannabinoid,cryab,jwh-018,neuroinflammation,nf-κb,synaptic plasticity,addiction susceptibility,drug abuse

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