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20S proteasome

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https://www.readbyqxmd.com/read/29674291/molecular-modeling-on-porphyrin-derivatives-as-%C3%AE-5-subunit-inhibitor-of-20s-proteasome
#1
Muhammad Arba, Andry Nur-Hidayat, Ruslin, Muhammad Yusuf, Sumarlin, Rukman Hertadi, Setyanto Tri Wahyudi, Slamet Ibrahim Surantaadmaja, Daryono H Tjahjono
The ubiquitin-proteasome system plays an important role in protein quality control. Currently, inhibition of the proteasome has been validated as a promising approach in anticancer therapy. The 20S core particle of the proteasome harbors β5 subunit which is a crucial active site in proteolysis. Targeting proteasome β5 subunit which is responsible for the chymotrypsin-like activity of small molecules has been regarded as an important way for achieving therapeutics target. In the present study, a series of porphyrin derivatives bearing either pyridine or pyrazole rings as meso-substituents were designed and evaluated as an inhibitor for the β5 subunit of the proteasome by employing molecular docking and dynamics simulations...
April 16, 2018: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/29670681/diaphragm-muscle-weakness-following-acute-sustained-hypoxic-stress-in-the-mouse-is-prevented-by-pretreatment-with-n-acetyl-cysteine
#2
Andrew J O'Leary, Sarah E Drummond, Deirdre Edge, Ken D O'Halloran
Oxygen deficit (hypoxia) is a major feature of cardiorespiratory diseases characterized by diaphragm dysfunction, yet the putative role of hypoxic stress as a driver of diaphragm dysfunction is understudied. We explored the cellular and functional consequences of sustained hypoxic stress in a mouse model. Adult male mice were exposed to 8 hours of normoxia, or hypoxia (FiO2  = 0.10) with or without antioxidant pretreatment (N-acetyl cysteine, 200 mg/kg i.p.). Ventilation and metabolism were measured. Diaphragm muscle contractile function, myofibre size and distribution, gene expression, protein signalling cascades, and oxidative stress (TBARS) were determined...
2018: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/29669860/thermal-proteome-profiling-of-breast-cancer-cells-reveals-proteasomal-activation-by-cdk4-6-inhibitor-palbociclib
#3
Teemu P Miettinen, Julien Peltier, Anetta Härtlova, Marek Gierliński, Valerie M Jansen, Matthias Trost, Mikael Björklund
Palbociclib is a CDK4/6 inhibitor approved for metastatic estrogen receptor-positive breast cancer. In addition to G1 cell cycle arrest, palbociclib treatment results in cell senescence, a phenotype that is not readily explained by CDK4/6 inhibition. In order to identify a molecular mechanism responsible for palbociclib-induced senescence, we performed thermal proteome profiling of MCF7 breast cancer cells. In addition to affecting known CDK4/6 targets, palbociclib induces a thermal stabilization of the 20S proteasome, despite not directly binding to it...
April 18, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29669333/the-role-of-proteasome-inhibitor-mg132-in-2-4-dinitrofluorobenzene-induced-atopic-dermatitis-in-nc-nga-mice
#4
Kozo Ohkusu-Tsukada, Daiki Ito, Kimimasa Takahashi
BACKGROUND: Although immunosuppressants for therapy of atopic dermatitis (AD) are still being sought, proteasome inhibitors are also potential candidates for the treatment of AD. Proteasome inhibitors exert various effects by blocking proteasomal degradation and help regulate processes such as apoptosis induction via caspase-9, cell cycle progression via cyclins, NF-κB inactivation via IκB, and downregulation of antigen cross-presentation. The cells targeted by proteasome inhibitors are therefore activated cells undergoing proliferation or differentiation, and antigen-presenting cells carrying out protein degradation...
April 18, 2018: International Archives of Allergy and Immunology
https://www.readbyqxmd.com/read/29628465/-pharmacological-characteristics-and-clinical-study-results-of-the-oral-proteasome-inhibitor-ixazomib-ninlaro-%C3%A2-capsules-2-3-mg-3-mg-and-4-mg
#5
Michiko Machida, Shinichi Fukunaga, Takahito Hara
Ixazomib (Ninlaro® capsule) is an oral small molecule 20S proteasome inhibitor created by Millennium Pharmaceuticals, Inc (Takeda Oncology Company). Ubiquitin proteasome system is a major regulatory system for maintaining protein homeostasis, and an important mechanism for degrading proteins, such as those involved in proliferation regulation, cell cycle regulation and apoptosis, in cells. Ixazomib selectively and reversibly binds to the β5 subunit of the 20S proteasome, inhibits its chymotrypsin-like activity, and thereby accumulates ubiquitinated proteins...
2018: Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica
https://www.readbyqxmd.com/read/29599065/the-retinoid-x-receptor-agonist-9-cis-uab30-inhibits-cutaneous-t-cell-lymphoma-proliferation-through-the-skp2-p27kip1-axis
#6
Chu-Fang Chou, Yu-Hua Hsieh, Clinton J Grubbs, Venkatram R Atigadda, James A Mobley, Reinhard Dummer, Donald D Muccio, Isao Eto, Craig A Elmets, W Timothy Garvey, Pi-Ling Chang
BACKGROUND: Bexarotene (Targretin® ) is currently the only FDA approved retinoid X receptor (RXR) -selective agonist for the treatment of cutaneous T-cell lymphomas (CTCLs). The main side effects of bexarotene are hypothyroidism and elevation of serum triglycerides (TGs). The novel RXR ligand, 9-cis UAB30 (UAB30) does not elevate serum TGs or induce hypothyroidism in normal subjects. OBJECTIVES: To assess preclinical efficacy and mechanism of action of UAB30 in the treatment of CTCLs and compare its action with bexarotene...
March 15, 2018: Journal of Dermatological Science
https://www.readbyqxmd.com/read/29594388/the-insulin-degrading-enzyme-is-an-allosteric-modulator-of-the-20s-proteasome-and-a-potential-competitor-of-the-19s
#7
Diego Sbardella, Grazia R Tundo, Andrea Coletta, Julien Marcoux, Efthymia Ioanna Koufogeorgou, Chiara Ciaccio, Anna M Santoro, Danilo Milardi, Giuseppe Grasso, Paola Cozza, Marie-Pierre Bousquet-Dubouch, Stefano Marini, Massimo Coletta
The interaction of insulin-degrading enzyme (IDE) with the main intracellular proteasome assemblies (i.e, 30S, 26S and 20S) was analyzed by enzymatic activity, mass spectrometry and native gel electrophoresis. IDE was mainly detected in association with assemblies with at least one free 20S end and biochemical investigations suggest that IDE competes with the 19S in vitro. IDE directly binds the 20S and affects its proteolytic activities in a bimodal fashion, very similar in human and yeast 20S, inhibiting at (IDE) ≤ 30 nM and activating at (IDE) ≥ 30 nM...
March 28, 2018: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29556699/the-novel-deubiquitinase-inhibitor-b-ap15-induces-direct-and-nk-cell-mediated-antitumor-effects-in-human-mantle-cell-lymphoma
#8
Korbinian N Kropp, Stefanie Maurer, Kathrin Rothfelder, Bastian J Schmied, Kim L Clar, Moritz Schmidt, Benedikt Strunz, Hans-Georg Kopp, Alexander Steinle, Frank Grünebach, Susanne M Rittig, Helmut R Salih, Daniela Dörfel
The first therapeutic proteasome inhibitor bortezomib has clinical efficacy in mantle cell lymphoma (MCL) which resulted in its incorporation in treatment algorithms for this disease. Impairment of proteasomal function by bortezomib is mediated via inhibition of the 20S core particle. However, proteasome function can also be modified by targeting upstream components of the ubiquitin-proteasome system. Recently, b-AP15 has been identified as a small molecule achieving proteasome inhibition by targeting the deubiquitinase (DUB) activity of the 19S regulatory subunit and was found to inhibit cancer cell growth in preclinical analyses...
March 19, 2018: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29553711/development-and-application-of-a-sensitive-peptide-reporter-to-discover-20s-proteasome-stimulators
#9
Rachel Coleman, Darci J Trader
To attenuate an over-abundance of cellular protein, it has been hypothesized that the 20S core particle (20S CP) of the proteasome can be chemically stimulated to degrade proteins into non-toxic peptides more quickly. Screening for small molecule 20S CP stimulators is typically performed with a reporter peptide composed of four amino acids and a coumarin group that is released upon proteasome-mediated hydrolysis to generate a fluorescent signal. Screening with this small reporter can lead to false negatives because the reporter peptide is rapidly turned-over without stimulation...
March 19, 2018: ACS Combinatorial Science
https://www.readbyqxmd.com/read/29552615/sex-specific-adaptive-homeostasis-in-d-melanogaster-depends-on-increased-proteolysis-by-the-20s-proteasome-data-in-brief
#10
Laura C D Pomatto, Sarah Wong, John Tower, Kelvin J A Davies
Adaptive homeostasis enables rapid cellular signaling, leading to transcriptional and translational modifications (Davies, 2016) [1]. The Proteasome is one of the main cellular proteolytic enzymes that plays an essential role in the rapid clearance of oxidatively damaged cellular proteins, and is highly responsive to oxidative stress. Upon exposure to even very low, signaling levels of oxidants, the predominant form of the Proteasome becomes the ATP-independent 20S proteasome that enables rapid clearance of damaged proteins...
April 2018: Data in Brief
https://www.readbyqxmd.com/read/29549180/wild-type-and-cancer-related-p53-proteins-are-preferentially-degraded-by-mdm2-as-dimers-rather-than-tetramers
#11
Chen Katz, Ana Maria Low-Calle, Joshua Choe, Oleg Laptenko, David Tong, Jazmine-Saskya N Joseph-Chowdhury, Francesca Garofalo, Yan Zhu, Assaf Friedler, Carol Prives
The p53 tumor suppressor protein is the most well studied as a regulator of transcription in the nucleus, where it exists primarily as a tetramer. However, there are other oligomeric states of p53 that are relevant to its regulation and activities. In unstressed cells, p53 is normally held in check by MDM2 that targets p53 for transcriptional repression, proteasomal degradation, and cytoplasmic localization. Here we discovered a hydrophobic region within the MDM2 N-terminal domain that binds exclusively to the dimeric form of the p53 C-terminal domain in vitro...
March 16, 2018: Genes & Development
https://www.readbyqxmd.com/read/29545515/a-common-mechanism-of-proteasome-impairment-by-neurodegenerative-disease-associated-oligomers
#12
Tiffany A Thibaudeau, Raymond T Anderson, David M Smith
Protein accumulation and aggregation with a concomitant loss of proteostasis often contribute to neurodegenerative diseases, and the ubiquitin-proteasome system plays a major role in protein degradation and proteostasis. Here, we show that three different proteins from Alzheimer's, Parkinson's, and Huntington's disease that misfold and oligomerize into a shared three-dimensional structure potently impair the proteasome. This study indicates that the shared conformation allows these oligomers to bind and inhibit the proteasome with low nanomolar affinity, impairing ubiquitin-dependent and ubiquitin-independent proteasome function in brain lysates...
March 15, 2018: Nature Communications
https://www.readbyqxmd.com/read/29534191/immunoproteasome-in-the-plasma-of-paediatric-patients-with-moderate-and-major-burns-and-its-correlation-with-proteasome-and-uchl1-measured-by-spr-imaging-biosensors
#13
Ewa Matuszczak, Artur Weremijewicz, Marta Komarowska, Anna Sankiewicz, Diana Markowska, Wojciech Debek, Ewa Gorodkiewicz, Robert Milewski, Adam Hermanowicz
THE AIM: to determinate the immunoproteasome concentration in blood plasma of paediatric patients with moderate and major burns, and its correlation with circulating proteasome and UCHL1 with SPRI biosensor. MATERIAL AND METHODS: The study population comprised 30 patients with moderate (n=21), and severe burns (n=9), aged 9 months to 14 years. The control group represented 18 healthy, age matched patients, admitted for herniotomy. Exclusion criteria were: admission to the hospital later than 6 hours after burn, cardiovascular or immunological diseases, and severe preexisting infections...
March 9, 2018: Journal of Burn Care & Research: Official Publication of the American Burn Association
https://www.readbyqxmd.com/read/29515784/potent-anti-tumor-activity-of-a-syringolin-analog-in-multiple-myeloma-a-dual-inhibitor-of-proteasome-activity-targeting-%C3%AE-2-and-%C3%AE-5-subunits
#14
Takashi Yoshida, Masaki Ri, Takashi Kanamori, Sho Aoki, Reham Ashour, Shiori Kinoshita, Tomoko Narita, Haruhito Totani, Ayako Masaki, Asahi Ito, Shigeru Kusumoto, Takashi Ishida, Hirokazu Komatsu, Shun Kitahata, Takuya Chiba, Satoshi Ichikawa, Shinsuke Iida
Proteasome inhibitors (PI), mainly targeting the β5 subunit of the 20S proteasome, are widely used in the treatment of multiple myeloma (MM). However, PI resistance remains an unresolved problem in the therapy of relapsed and refractory MM. To develop a new PI that targets other proteasome subunits, we examined the anti-MM activity of a novel syringolin analog, syringolog-1, which inhibits the activity of both the β5 and β2 subunits. Syringolog-1 exhibited marked cytotoxicity against various MM cell lines and anti-tumor activity towards bortezomib (Btz)-resistant MM cells through the dual inhibition of chymotrypsin-like (β5 subunit) and trypsin-like (β2 subunit) activities...
February 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29504425/proteasome-20s-in-multiple-myeloma-comparison-of-concentration-and-chymotrypsin-like-activity-in-plasma-and-serum
#15
Wioletta Romaniuk, Joanna Kalita, Halina Ostrowska, Janusz Kloczko
The ubiquitin-proteasome system is relevant in the pathobiology of many haematological malignancies, including multiple myeloma. The assessment of proteasome concentration and chymotrypsin-like (ChT-L) activity might constitute a new approach to diagnosis, prognosis and monitoring of anticancer treatment of patients with haematological malignancies and other diseases. The aim of our study was to determine which material, plasma or serum, is better for measuring chymotrypsin-like (ChT-L) activity and proteasome concentration...
March 5, 2018: Scandinavian Journal of Clinical and Laboratory Investigation
https://www.readbyqxmd.com/read/29499565/early-cysteine-dependent-inactivation-of-26s-proteasomes-does-not-involve-particle-disassembly
#16
Martín Hugo, Ioanna Korovila, Markus Köhler, Carlos García-García, J Daniel Cabrera-García, Anabel Marina, Antonio Martínez-Ruiz, Tilman Grune
Under oxidative stress 26S proteasomes suffer reversible disassembly into its 20S and 19S subunits, a process mediated by HSP70. This inhibits the degradation of polyubiquitinated proteins by the 26S proteasome and allows the degradation of oxidized proteins by a free 20S proteasome. Low fluxes of antimycin A-stimulated ROS production caused dimerization of mitochondrial peroxiredoxin 3 and cytosolic peroxiredoxin 2, but not peroxiredoxin overoxidation and overall oxidation of cellular protein thiols. This moderate redox imbalance was sufficient to inhibit the ATP stimulation of 26S proteasome activity...
February 22, 2018: Redox Biology
https://www.readbyqxmd.com/read/29491008/circulating-exosomes-with-distinct-properties-during-chronic-lung-allograft-rejection
#17
Muthukumar Gunasekaran, Monal Sharma, Ramsey Hachem, Ross Bremner, Michael A Smith, Thalachallour Mohanakumar
Circulating exosomes containing donor HLA and lung-associated self-antigens (SAg) are thought to play an important role in allograft rejection after human lung transplantation. We characterized exosomes isolated from serum of 10 lung transplant recipients (LTxR) diagnosed with bronchiolitis obliterans syndrome (BOS) and compared them with exosomes isolated from serum of 10 stable LTxR. Lung-associated SAg (K-α-1-tubulin [Kα1T] and collagen V [Col-V]), MHC class II molecules, costimulatory molecules CD40, CD80, and CD86, and transcription factors class II MHC trans -activator, NF-κB, hypoxia-inducible factor 1-α, IL-1R-associated kinase 1, MyD88, and 20S proteasome were detected in exosomes from BOS, but not stable LTxR...
February 28, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29457374/proteasomal-function-is-impaired-in-human-osteoarthritic-chondrocytes-and-this-can-contribute-to-decreased-sox9-and-aggrecan
#18
Ramon L Serrano, Liang-Yu Chen, Martin K Lotz, Ru Liu-Bryan, Robert Terkeltaub
OBJECTIVE: Osteoarthritis (OA) chondrocytes have impaired autophagy, one arm of the proteostasis network that coordinates proteome and organelle quality control and degradation. Deficient proteostasis impacts differentiation and viability, and inflammatory processes in aging and disease. Studying OA chondrocytes, we assessed ubiquitin proteasome system proteasomal function. METHODS: We evaluated human knee cartilages by immunohistochemistry, and assessed proteasomal function, levels of proteasomal core subunits and chaperones, and autophagy in cultured chondrocytes...
February 18, 2018: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/29450867/20s-proteasome-in-the-blood-plasma-of-boys-with-cryptorchidism
#19
D Toliczenko-Bernatowicz, E Matuszczak, M Tylicka, A Sankiewicz, M Komarowska, E Gorodkiewicz, W Debek, A Hermanowicz
PURPOSE: To evaluate the concentration of 20S proteasome in the blood plasma of boys with cryptorchidism. METHODS: Patients-50 boys aged 1-4 years (median = 2.4 years) with unilateral cryptorchidism. The control group-50 healthy, age-matched boys (aged 1-4 years, median = 2.1 years), admitted for planned herniotomy. In our study, we used a novel technique Surface PLASMON RESONANCE Imaging. RESULTS: The median concentration of 20S proteasome in the blood plasma of boys with cryptorchidism was 2...
February 15, 2018: Journal of Endocrinological Investigation
https://www.readbyqxmd.com/read/29435775/quercetin-prevents-in-vivo-and-in-vitro-myocardial-hypertrophy-through-the-proteasome-gsk-3-pathway
#20
Kuixiang Chen, Mubarak Rekep, Wei Wei, Qian Wu, Qin Xue, Sujuan Li, Jiahui Tian, Quan Yi, Genshui Zhang, Guiping Zhang, Qing Xiao, Jiandong Luo, Yinghua Liu
PURPOSE: Quercetin, a flavonoid, has been reported to ameliorate cardiovascular diseases, such as cardiac hypertrophy. However, the mechanism is not completely understood. In this study, a mechanism related to proteasome-glycogen synthesis kinase 3 (GSK-3) was elucidated in rats and primary neonatal cardiomyocytes. METHODS: Rats were subjected to sham or constriction of abdominal aorta surgery groups and treated with or without quercetin for 8 weeks. Angiotensin II (Ang II)-induced primary cardiomyocytes were cultured with quercetin treatment or not for 48 h...
February 12, 2018: Cardiovascular Drugs and Therapy
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