Canthin-6-One Accelerates Alpha-Synuclein Degradation by Enhancing UPS Activity: Drug Target Identification by CRISPR-Cas9 Whole Genome-Wide Screening Technology.

Abstract:

:Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the accumulation of protein aggregates (namely Lewy bodies) in dopaminergic neurons in the substantia nigra region of the brain. Alpha-synuclein (α-syn) is the major component of Lewy bodies in PD patients, and impairment of the ubiquitin-proteasome system has been linked to its accumulation. In this work, we developed a tetracycline-inducible expression system, with simultaneous induced expression of α-syn-EGFP and a bright red fluorescent protein marker (mCherry) to screen for potential compounds for degrading α-syn. We identified canthin-6-one as an α-syn lowering compound which promoted both wild type and mutants α-syn degradation in an ubiquitin-proteasome-system (UPS) dependent manner. By CRISPR/Cas9 genome-wide screening technology, we identified RPN2/PSMD1, the 26S proteasome non-ATPase regulatory subunit 1, as the targeting gene for pharmacological activity of canthin-6-one. Finally, we showed that canthin-6-one up-regulates PSMD1 and enhances UPS function by activating PKA.

journal_name

Front Pharmacol

authors

Yuan NN,Cai CZ,Wu MY,Zhu Q,Su H,Li M,Ren J,Tan JQ,Lu JH

doi

10.3389/fphar.2019.00016

subject

Has Abstract

pub_date

2019-01-28 00:00:00

pages

16

issn

1663-9812

journal_volume

10

pub_type

杂志文章
  • β-Sheet Breaker Peptide-HPYD for the Treatment of Alzheimer's Disease: Primary Studies on Behavioral Test and Transcriptional Profiling.

    abstract::Background: Alzheimer's disease (AD), is a progressive neurodegenerative disease that is characterized by cognitive loss. Most researchers believe that aggregation and accumulation of β-amyloid peptides (Aβ) in brain cells are the central pathological hallmark of this disease. Methods: Based on the amyloid hypothesis,...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2017.00969

    authors: Liu W,Sun F,Wan M,Jiang F,Bo X,Lin L,Tang H,Xu S

    更新日期:2018-01-08 00:00:00

  • Methylene Blue Inhibits the SARS-CoV-2 Spike-ACE2 Protein-Protein Interaction-a Mechanism that can Contribute to its Antiviral Activity Against COVID-19.

    abstract::Due to our interest in the chemical space of organic dyes to identify potential small-molecule inhibitors (SMIs) for protein-protein interactions (PPIs), we initiated a screen of such compounds to assess their inhibitory activity against the interaction between SARS-CoV-2 spike protein and its cognate receptor ACE2, w...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2020.600372

    authors: Bojadzic D,Alcazar O,Buchwald P

    更新日期:2021-01-13 00:00:00

  • Hydrogen Sulfide and Endoplasmic Reticulum Stress: A Potential Therapeutic Target for Central Nervous System Degeneration Diseases.

    abstract::There are three members of the endogenous gas transmitter family. The first two are nitric oxide and carbon monoxide, and the third newly added member is hydrogen sulfide (H2S). They all have similar functions: relaxing blood vessels, smoothing muscles, and getting involved in the regulation of neuronal excitation, le...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章,评审

    doi:10.3389/fphar.2020.00702

    authors: Zhong H,Yu H,Chen J,Sun J,Guo L,Huang P,Zhong Y

    更新日期:2020-05-14 00:00:00

  • Scutellarin Increases Cisplatin-Induced Apoptosis and Autophagy to Overcome Cisplatin Resistance in Non-small Cell Lung Cancer via ERK/p53 and c-met/AKT Signaling Pathways.

    abstract::Cisplatin, as the first-line anti-tumor agent, is widely used for treatment of a variety of malignancies including non-small cell lung cancer (NSCLC). However, the acquired resistance has been a major obstacle for the clinical application. Scutellarin is a active flavone extracted from Erigeron breviscapus Hand-Mazz t...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2018.00092

    authors: Sun CY,Zhu Y,Li XF,Wang XQ,Tang LP,Su ZQ,Li CY,Zheng GJ,Feng B

    更新日期:2018-02-13 00:00:00

  • Trends in qualifying biomarkers in drug safety. Consensus of the 2011 meeting of the spanish society of clinical pharmacology.

    abstract::In this paper we discuss the consensus view on the use of qualifying biomarkers in drug safety, raised within the frame of the XXIV meeting of the Spanish Society of Clinical Pharmacology held in Málaga (Spain) in October, 2011. The widespread use of biomarkers as surrogate endpoints is a goal that scientists have lon...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2012.00002

    authors: Agúndez JA,Del Barrio J,Padró T,Stephens C,Farré M,Andrade RJ,Badimon L,García-Martín E,Vilahur G,Lucena MI

    更新日期:2012-01-19 00:00:00

  • A probabilistic model of human variability in physiology for future application to dose reconstruction and QIVIVE.

    abstract::The risk assessment of environmental chemicals and drugs is undergoing a paradigm shift in approach which seeks the full replacement of animal testing with high throughput, mechanistic, in vitro systems. This new approach will be reliant on the measurement in vitro, of concentration-dependent responses where prolonged...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2015.00213

    authors: McNally K,Loizou GD

    更新日期:2015-10-12 00:00:00

  • Type 2β Corticotrophin Releasing Factor Receptor Forms a Heteromeric Complex With Dopamine D1 Receptor in Living Cells.

    abstract::Corticotrophin releasing factor (CRF) and its related peptides differentially bind to CRF receptors to modulate stress-related behaviors. CRF receptors comprise two G-protein coupled receptors (GPCR), type-1 CRF receptors (CRF1), and type-2 CRF receptors (CRF2). CRF2 encompasses three spliced variants in humans, alpha...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2019.01501

    authors: Yarur HE,Andrés ME,Gysling K

    更新日期:2020-01-08 00:00:00

  • Krukovine Suppresses KRAS-Mutated Lung Cancer Cell Growth and Proliferation by Inhibiting the RAF-ERK Pathway and Inactivating AKT Pathway.

    abstract::Oncogenic activation of the KRAS gene via point mutations occurs in 20-30% of patients with non-small cell lung cancer (NSCLC). The RAS-RAF-ERK and RAS-PI3K-AKT pathways are the major hyper-activated downstream pathways in RAS mutation, which promotes the unlimited lifecycle of cancer cells and their metastasis in hum...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2018.00958

    authors: Lai H,Wang Y,Duan F,Li Y,Jiang Z,Luo L,Liu L,Leung ELH,Yao X

    更新日期:2018-08-22 00:00:00

  • Novel Anti-fibrotic Therapies.

    abstract::Fibrosis is a major player in cardiovascular disease, both as a contributor to the development of disease, as well as a post-injury response that drives progression. Despite the identification of many mechanisms responsible for cardiovascular fibrosis, to date no treatments have emerged that have effectively reduced t...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章,评审

    doi:10.3389/fphar.2017.00318

    authors: McVicker BL,Bennett RG

    更新日期:2017-05-31 00:00:00

  • Selective Serotonin Reuptake Inhibitor Pharmaco-Omics: Mechanisms and Prediction.

    abstract::Selective serotonin reuptake inhibitors (SSRIs) are a standard of care for the pharmacotherapy of patients suffering from Major Depressive Disorder (MDD). However, only one-half to two-thirds of MDD patients respond to SSRI therapy. Recently, a "multiple omics" research strategy was applied to identify genetic differe...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章,评审

    doi:10.3389/fphar.2020.614048

    authors: Nguyen TTL,Liu D,Ho MF,Athreya AP,Weinshilboum R

    更新日期:2021-01-11 00:00:00

  • Convenience versus Biological Significance: Are PMA-Differentiated THP-1 Cells a Reliable Substitute for Blood-Derived Macrophages When Studying in Vitro Polarization?

    abstract::Human peripheral-blood monocytes are used as an established in vitro system for generating macrophages. For several reasons, monocytic cell lines such as THP-1 have been considered as a possible alternative. In view of their distinct developmental origins and phenotypic attributes, we set out to assess the extent to w...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2018.00071

    authors: Tedesco S,De Majo F,Kim J,Trenti A,Trevisi L,Fadini GP,Bolego C,Zandstra PW,Cignarella A,Vitiello L

    更新日期:2018-02-22 00:00:00

  • A Novel Network Pharmacology Strategy to Decode Mechanism of Lang Chuang Wan in Treating Systemic Lupus Erythematosus.

    abstract::Complex disease is a cascade process which is associated with functional abnormalities in multiple proteins and protein-protein interaction (PPI) networks. One drug one target has not been able to perfectly intervene complex diseases. Increasing evidences show that Chinese herb formula usually treats complex diseases ...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2020.512877

    authors: Gao Y,Wang KX,Wang P,Li X,Chen JJ,Zhou BY,Tian JS,Guan DG,Qin XM,Lu AP

    更新日期:2020-10-02 00:00:00

  • Immune Checkpoint Inhibitor-Associated Cardiotoxicity: Current Understanding on Its Mechanism, Diagnosis and Management.

    abstract::Immune checkpoint inhibitors (ICIs) that target cytotoxic T lymphocyte antigen 4, programmed cell death-1, and PD-ligand 1 have revolutionized cancer treatment, achieving unprecedented efficacy in multiple malignancies. ICIs are increasingly being used in early cancer settings and in combination with various other typ...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章,评审

    doi:10.3389/fphar.2019.01350

    authors: Zhou YW,Zhu YJ,Wang MN,Xie Y,Chen CY,Zhang T,Xia F,Ding ZY,Liu JY

    更新日期:2019-11-29 00:00:00

  • Impact of Biologic Treatment of Crohn's Disease on the Rate of Surgeries and Other Healthcare Resources: An Analysis of a Nationwide Database From Poland.

    abstract::Background: There is conflicting evidence on the impact of biologic treatment on the rate of complications and surgeries in Crohn's disease (CD). We aimed to assess real-world consequences of biologic treatment of CD. Methods: All adult patients with CD treated with infliximab and adalimumab in the years 2012-2014 wer...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2018.00621

    authors: Holko P,Kawalec P,Pilc A

    更新日期:2018-06-11 00:00:00

  • A Significant Association Between Rhein and Diabetic Nephropathy in Animals: A Systematic Review and Meta-Analysis.

    abstract::Background: Rhein is considered to have beneficial influence on diabetic nephropathy. Animal experiments suggested that the mechanisms of rhein against diabetic nephropathy may involve many processes, but the credibility of the evidence is unclear. Therefore, we conducted systematic review and meta-analysis of pre-cli...

    journal_title:Frontiers in pharmacology

    pub_type:

    doi:10.3389/fphar.2019.01473

    authors: Hu HC,Zheng LT,Yin HY,Tao Y,Luo XQ,Wei KS,Yin LP

    更新日期:2019-12-13 00:00:00

  • Ontological and Non-Ontological Resources for Associating Medical Dictionary for Regulatory Activities Terms to SNOMED Clinical Terms With Semantic Properties.

    abstract::Background: Formal definitions allow selecting terms (e.g., identifying all terms related to "Infectious disease" using the query "has causative agent organism") and terminological reasoning (e.g., "hepatitis B" is a "hepatitis" and is an "infectious disease"). However, the standard international terminology Medical D...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2019.00975

    authors: Bousquet C,Souvignet J,Sadou É,Jaulent MC,Declerck G

    更新日期:2019-09-10 00:00:00

  • The Protective Effect of Luteolin in Glucocorticoid-Induced Osteonecrosis of the Femoral Head.

    abstract::Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is a frequently occurring type of nontraumatic osteonecrosis. A failure of the timely treatment can eventually result in the collapse of the subchondral bone structure. Luteolin (Lut), a compound extracted from Rhizoma Drynariae, is reported to possess ...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2020.01195

    authors: Yan Z,Zhan J,Qi W,Lin J,Huang Y,Xue X,Pan X

    更新日期:2020-08-12 00:00:00

  • In Vivo Cannabidiol Treatment Improves Endothelium-Dependent Vasorelaxation in Mesenteric Arteries of Zucker Diabetic Fatty Rats.

    abstract::Background and purpose: We have shown that in vitro treatment with cannabidiol (CBD, 2 h) enhances endothelial function in arteries from Zucker diabetic fatty (ZDF) rats, partly due to a cyclooxygenase (COX)-mediated mechanism. The aim of the present study was to determine whether treatment with CBD in vivo would also...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2017.00248

    authors: Wheal AJ,Jadoon K,Randall MD,O'Sullivan SE

    更新日期:2017-05-18 00:00:00

  • Recent Progress in CFTR Interactome Mapping and Its Importance for Cystic Fibrosis.

    abstract::Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a chloride channel found in secretory epithelia with a plethora of known interacting proteins. Mutations in the CFTR gene cause cystic fibrosis (CF), a disease that leads to progressive respiratory illness and other complications of phenotypic variance resu...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章,评审

    doi:10.3389/fphar.2017.00997

    authors: Lim SH,Legere EA,Snider J,Stagljar I

    更新日期:2018-01-17 00:00:00

  • The Impacts of Herbal Medicines and Natural Products on Regulating the Hepatic Lipid Metabolism.

    abstract::The dysregulation of hepatic lipid metabolism is one of the hallmarks in many liver diseases including alcoholic liver diseases (ALD) and non-alcoholic fatty liver diseases (NAFLD). Hepatic inflammation, lipoperoxidative stress as well as the imbalance between lipid availability and lipid disposal, are direct causes o...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章,评审

    doi:10.3389/fphar.2020.00351

    authors: Li S,Xu Y,Guo W,Chen F,Zhang C,Tan HY,Wang N,Feng Y

    更新日期:2020-03-24 00:00:00

  • Prognostic and Predictive Factors in Patients with Advanced Penile Cancer Receiving Salvage (2nd or Later Line) Systemic Treatment: A Retrospective, Multi-Center Study.

    abstract::Introduction and objectives: Metastatic penile squamous cell carcinoma (PSCC) is associated with dismal outcomes with median overall survival (OS) of 6-12 months in the first-line and <6 months in the salvage setting. Given the rarity of this disease, randomized trials are difficult. Prognostic risk models may assist ...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2016.00487

    authors: Buonerba C,Di Lorenzo G,Pond G,Cartenì G,Scagliarini S,Rozzi A,Quevedo FJ,Dorff T,Nappi L,Lanzetta G,Pagliaro L,Eigl BJ,Naik G,Ferro M,Galdiero M,De Placido S,Sonpavde G

    更新日期:2016-12-20 00:00:00

  • Duloxetine, a Balanced Serotonin-Norepinephrine Reuptake Inhibitor, Improves Painful Chemotherapy-Induced Peripheral Neuropathy by Inhibiting Activation of p38 MAPK and NF-κB.

    abstract::Chemotherapy-induced peripheral neuropathy (CIPN) is a severe, toxic side effect that frequently occurs in anticancer treatment and may result in discontinuation of treatment as well as a serious reduction in life quality. The CIPN incidence rate is as high as 85-90%. Unfortunately, there is currently no standard evid...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2019.00365

    authors: Meng J,Zhang Q,Yang C,Xiao L,Xue Z,Zhu J

    更新日期:2019-04-09 00:00:00

  • The Ultrasmall Biocompatible CuS@BSA Nanoparticle and Its Photothermal Effects.

    abstract::Nanomaterials with localized surface plasmon resonance (LSPR) have exquisite optical properties, which allow a wide range of applications. Non-stoichiometric copper sulfides with active LSPR have drawn great attention, because its LSPR peak falls in the NIR region that is suitable for deep bioimaging and photothermal ...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2019.00141

    authors: Wan X,Liu M,Ma M,Chen D,Wu N,Li L,Li Z,Lin G,Wang X,Xu G

    更新日期:2019-02-26 00:00:00

  • Src Tyrosine Kinase Inhibitors: New Perspectives on Their Immune, Antiviral, and Senotherapeutic Potential.

    abstract::Deregulated activity of the Src tyrosine kinases leads to malignant transformation. Since the FDA approval of the tyrosine kinase inhibitor, imatinib, in 2001 for the treatment of chronic myeloid leukemia (CML), the number of these inhibitors together with Src tyrosine kinase inhibitors (STKIs) has increased notably d...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章,评审

    doi:10.3389/fphar.2019.01011

    authors: Rivera-Torres J,San José E

    更新日期:2019-09-18 00:00:00

  • From understanding cellular function to novel drug discovery: the role of planar patch-clamp array chip technology.

    abstract::All excitable cell functions rely upon ion channels that are embedded in their plasma membrane. Perturbations of ion channel structure or function result in pathologies ranging from cardiac dysfunction to neurodegenerative disorders. Consequently, to understand the functions of excitable cells and to remedy their path...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2011.00051

    authors: Py C,Martina M,Diaz-Quijada GA,Luk CC,Martinez D,Denhoff MW,Charrier A,Comas T,Monette R,Krantis A,Syed NI,Mealing GA

    更新日期:2011-10-03 00:00:00

  • Anti-gout Potential of Malaysian Medicinal Plants.

    abstract::Gout is a type of arthritis that causes painful inflammation in one or more joints. In gout, elevation of uric acid in the blood triggers the formation of crystals, causing joint pain. Malaysia is a mega-biodiversity country that is rich in medicinal plants species. Therefore, its flora might offer promising therapies...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章,评审

    doi:10.3389/fphar.2018.00261

    authors: Abu Bakar FI,Abu Bakar MF,Rahmat A,Abdullah N,Sabran SF,Endrini S

    更新日期:2018-03-23 00:00:00

  • Effect of Cognitive Style on Learning and Retrieval of Navigational Environments.

    abstract::Field independence (FI) has been found to correlate with a wide range of cognitive processes requiring cognitive restructuring. Cognitive restructuring, that is going beyond the information given by the setting, is pivotal in creating stable mental representations of the environment, the so-called "cognitive maps," an...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2017.00496

    authors: Boccia M,Vecchione F,Piccardi L,Guariglia C

    更新日期:2017-07-25 00:00:00

  • PRMT5 Prevents Cardiomyocyte Hypertrophy via Symmetric Dimethylating HoxA9 and Repressing HoxA9 Expression.

    abstract::The present study reveals a link between protein arginine methyltransferase 5 (PRMT5) and Homebox A9 (HoxA9) in the regulation of cardiomyocyte hypertrophy. In cardiomyocyte hypertrophy induced by β-adrenergic receptor agonist isoprenaline (ISO), PRMT5 expression was decreased while HoxA9 was upregulated. Silencing of...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2020.600627

    authors: Cai S,Liu R,Wang P,Li J,Xie T,Wang M,Cao Y,Li Z,Liu P

    更新日期:2020-12-10 00:00:00

  • Mifepristone for Treatment of Metabolic Syndrome: Beyond Cushing's Syndrome.

    abstract::A growing body of research indicates that cortisol, the glucocorticoid product of the activation of the hypothalamic-pituitary-adrenal axis, plays a role in the pathophysiology of metabolic syndrome. In this regard, chronic exposure to cortisol is associated with risk factors related to metabolic syndrome like weight ...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2020.00429

    authors: Díaz-Castro F,Monsalves-Álvarez M,Rojo LE,Del Campo A,Troncoso R

    更新日期:2020-04-24 00:00:00

  • Long-Distance Phasing of a Tentative "Enhancer" Single-Nucleotide Polymorphism With CYP2D6 Star Allele Definitions.

    abstract:Background:The CYP2D6 gene locus has been extensively studied over decades, yet a portion of variability in CYP2D6 activity cannot be explained by known sequence variations within the gene, copy number variation, or structural rearrangements. It was proposed that rs5758550, located 116 kb downstream of the CYP2D6 gene ...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2020.00486

    authors: Boone EC,Wang WY,Gaedigk R,Cherner M,Bérard A,Leeder JS,Miller NA,Gaedigk A

    更新日期:2020-05-08 00:00:00