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https://www.readbyqxmd.com/read/29333953/the-irreversible-erbb1-2-4-inhibitor-neratinib-interacts-with-the-bcl-2-inhibitor-venetoclax-to-kill-mammary-cancer-cells
#1
Laurence Booth, Jane L Roberts, Francesca Avogadri-Connors, Richard E CutlerJr, Alshad S Lalani, Andrew Poklepovic, Paul Dent
The irreversible ERBB1/2/4 inhibitor, neratinib, down-regulates the expression of ERBB1/2/4 as well as the levels of MCL-1 and BCL-XL. Venetoclax (ABT199) is a BCL-2 inhibitor. At physiologic concentrations neratinib interacted in a synergistic fashion with venetoclax to kill HER2+ and TNBC mammary carcinoma cells. This was associated with the drug-combination: reducing the expression and phosphorylation of ERBB1/2/3; in an eIF2α-dependent fashion reducing the expression of MCL-1 and BCL-XL and increasing the expression of Beclin1 and ATG5; and increasing the activity of the ATM-AMPKα-ULK1 S317 pathway which was causal in the formation of toxic autophagosomes...
January 15, 2018: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/29327025/unraveling-the-mechanical-behaviour-of-hydrazine-borane-nh2-nh2-bh3
#2
Pascal G Yot, Vibhav Yadav, Salem Ould Amara, Jean-Paul Itiè, Umit B Demirci, Guillaume Maurin
Crystalline B-N-H compounds of low molecular weight have been intensively investigated over the past two decades owing to their promises for chemical hydrogen storage. Hydrazine borane NH2-NH2-BH3 is one of the most recent examples of this family of materials. In the present work, we explored its structural behaviour under mechanical stimulus by synchrotron high pressure X-ray diffraction. It has been evidenced that hydrazine borane shows a gradual pressure-induced decrease of its unit cell dimension and the process is reversible when the applied pressure is released...
January 12, 2018: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/29322123/dehydrogenation-of-dimethylamine-borane-mediated-by-group-1-pincer-complexes
#3
Roberto Nolla-Saltiel, Ana M Geer, William Lewis, Alexander J Blake, Deborah L Kays
Group 1 salts containing carbazolido NNN pincer ligands are precatalysts for the dehydrogenation of Me2NH·BH3. NMR monitoring and DOSY studies show a heavy dependence on the metal and solvent, allowing in some cases selective formation of dehydrogenation products consistent with hydrogen liberation.
January 11, 2018: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/29321062/notch-signaling-triggered-via-the-ligand-dll4-impedes-m2-macrophage-differentiation-and-promotes-their-apoptosis
#4
Sylvain Pagie, Nathalie Gérard, Béatrice Charreau
BACKGROUND: Notch signaling controls many cellular processes, including cell fate determination, cell differentiation, proliferation and apoptosis. In mammals, four Notch receptors (Notch 1-4) can interact with five distinct ligands [Jagged1, Jagged2, Delta-like 1 (DLL1), DLL3, and DLL4]. We previously reported that Notch activation is modulated in endothelial cells and monocytes during inflammation and showed that inflammation upregulates DLL4 on endothelial cells. DLL4 promotes differentiation of blood monocytes into proinflammatory M1 macrophages...
January 10, 2018: Cell Communication and Signaling: CCS
https://www.readbyqxmd.com/read/29319082/%C3%AF-holes-and-%C3%AF-lumps-direct-the-lewis-basic-and-acidic-interactions-of-noble-metal-nanoparticles-introducing-regium-bonds
#5
Joakim Halldin Stenlid, Adam Johannes Johansson, Tore Brinck
Using local DFT-based probes for electrostatic as well as charge transfer/polarization interactions, we are able to characterize Lewis basic and acidic sites on copper, silver and gold nanoparticles. The predictions obtained using the DFT-probes are compared to the interaction energies of the electron donating (CO, H2O, NH3 and H2S) and the electron accepting (BH3, BF3, HCl [H-down] and Na+) compounds. The probes include the local electron attachment energy [E(r)], the average local ionization energy [Ī(r)], and the electrostatic potential [V(r)] and are evaluated on isodensity surfaces located at distances corresponding to typical interaction distances...
January 10, 2018: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/29316737/the-effect-of-lipopolysaccharide-on-noxa-expression-is-mediated-through-irf-1-3-and-7
#6
Sujan Piya, Tae-Hyoung Kim
Lipopolysaccharide (LPS), a component of the cell wall of gram-negative bacteria, elicits the secretion of cytokines, such as interferons, that stimulate the host defense system. Previously, we demonstrated that interferons induce interferon regulatory factors (IRFs) 1, 3, and 7 that regulate transcription of Noxa and alter expression profiles of Bcl-2 family proteins in tumors. However, the immediate consequences of LPS stimulation on Noxa and BH3 expression in tumor cells remain uncharacterized. Here, we determined that LPS induced Noxa expression in CT26 cells...
January 11, 2018: Journal of Microbiology and Biotechnology
https://www.readbyqxmd.com/read/29312548/mimicking-the-bim-bh3-domain-overcomes-resistance-to-egfr-tyrosine-kinase-inhibitors-in-egfr-mutant-non-small-cell-lung-cancer
#7
Jinjing Xia, Hao Bai, Bo Yan, Rong Li, Minhua Shao, Liwen Xiong, Baohui Han
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are widely applied to treat EGFR-mutant non-small cell lung cancer (NSCLC). BIM is a BH3 domain-containing protein encoded by BCL2L11. Some EGFR-mutant NSCLC patients showing BIM deletion polymorphism are resistant to EGFR TKIs. We retrospectively investigated BIM deletion polymorphism in NSCLC patients, its correlation with EGFR TKI (erlotinib) resistance, and the mechanism underlying the drug resistance. Among 245 EGFR-mutant NSCLC patients examined, BIM deletion polymorphism was detected in 43 (12...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29298347/predicting-effective-pro-apoptotic-anti-leukaemic-drug-combinations-using-co-operative-dynamic-bh3-profiling
#8
Martin Grundy, Claire Seedhouse, Thomas Jones, Liban Elmi, Michael Hall, Adam Graham, Nigel Russell, Monica Pallis
The BH3-only apoptosis agonists BAD and NOXA target BCL-2 and MCL-1 respectively and co-operate to induce apoptosis. On this basis, therapeutic drugs targeting BCL-2 and MCL-1 might have enhanced activity if used in combination. We identified anti-leukaemic drugs sensitising to BCL-2 antagonism and drugs sensitising to MCL-1 antagonism using the technique of dynamic BH3 profiling, whereby cells were primed with drugs to discover whether this would elicit mitochondrial outer membrane permeabilisation in response to BCL-2-targeting BAD-BH3 peptide or MCL-1-targeting MS1-BH3 peptide...
2018: PloS One
https://www.readbyqxmd.com/read/29298131/a-systematic-review-of-p53-regulation-of-oxidative-stress-in-skeletal-muscle
#9
Kaitlyn Beyfuss, David A Hood
BACKGROUND: p53 is a tumor suppressor protein involved in regulating a wide array of signaling pathways. The role of p53 in the cell is determined by the type of imposed oxidative stress, its intensity and duration. The last decade of research has unravelled a dual nature in the function of p53 in mediating the oxidative stress burden. However, this is dependent on the specific properties of the applied stress and thus requires further analysis. METHODS: A systematic review was performed following an electronic search of Pubmed, Google Scholar, and ScienceDirect databases...
January 3, 2018: Redox Report: Communications in Free Radical Research
https://www.readbyqxmd.com/read/29296202/cell-death-and-restoration-of-trail-sensitivity-by-ciglitazone-in-resistant-cervical-cancer-cells
#10
Marie-Laure Plissonnier, Sylvie Fauconnet, Hugues Bittard, Christiane Mougin, Jean Rommelaere, Isabelle Lascombe
Known activators of the Peroxisome Proliferator-Activated Receptor γ (PPARγ), thiazolidinediones (TZD) induce apoptosis in a variety of cancer cells through dependent and/or independent mechanisms of the receptor. We tested a panel of TZD (Rosiglitazone, Pioglitazone, Ciglitazone) to shed light on their potential therapeutic effects on three cervical cancer cell lines (HeLa, Ca Ski, C-33 A). In these cells, only ciglitazone triggered apoptosis through PPARγ-independent mechanisms and in particular via both extrinsic and intrinsic pathways in Ca Ski cells containing Human PapillomaVirus (HPV) type 16...
December 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/29288466/solvent-effect-on-the-degree-of-a-synchronicity-in-polar-diels-alder-reactions-from-the-perspective-of-the-reaction-force-constant-analysis
#11
Diana Yepes, Jorge I Martínez-Araya, Pablo Jaque
In this work, we computationally evaluated the influence of six different molecular solvents, described as a polarizable continuum model at the M06-2X/6-31+G(d,p) level, on the activation barrier/reaction rate, overall energy change, TS geometry, and degree of (a)synchronicity of two concerted Diels-Alder cycloadditions of acrolein (R1) and its complex with Lewis acid acrolein···BH3 (R2) to cyclopentadiene. In gas-phase, we found that both exothermicity and activation barrier are only reduced by about 2...
December 29, 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/29287939/phosphoinositide-dependent-protein-kinase-1-is-a-potential-novel-therapeutic-target-in-mantle-cell-lymphoma
#12
Saori Maegawa, Yoshiaki Chinen, Yuji Shimura, Kazuna Tanba, Tomoko Takimoto, Yoshimi Mizuno, Yayoi Matsumura-Kimoto, Saeko Kuwahara-Ota, Taku Tsukamoto, Tsutomu Kobayashi, Shigeo Horiike, Masafumi Taniwaki, Junya Kuroda
Mantle cell lymphoma (MCL) is a relatively rare subtype of B-cell non-Hodgkin lymphoma (NHL) that has a poor prognosis, despite recent advances in immunochemotherapy and molecular targeted therapeutics against NHL. Therefore, development of a new therapeutic strategy for MCL is urgently needed. In this study, we first show that 3-phosphoinositide-dependent protein kinase 1 (PDPK1), an oncogenic serine-threonine protein kinase, is commonly expressed in its phosphorylated activate form in patient-derived tumor cells of various types of B-cell NHL cells, including diffuse large B cell lymphoma, follicular lymphoma and MCL...
December 26, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/29278499/bim-binding-remotely-regulates-bax-activation-insights-from-the-free-energy-landscapes
#13
Souvik Sinha, Atanu Maity, Shubhra Ghosh Dastidar
Activation of the pro-apoptotic BAX protein, a BCl-2 family member, is known to trigger the apoptosis by forming pores in the mitochondrial outer membrane (MOM). While in the cytosol, release of its transmembrane C-terminal helix (called α9 helix) from a well-characterized binding pocket (BC groove) and subsequent permeabilization of MOM is understood to be the initiating events of the activation. In concern of what initiates the BAX activation, so far one plausible suggestion has been that the transient attachment of BH3-only peptide on a distal site from BC groove triggers the activation process...
December 26, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/29276033/crystal-structures-of-anti-apoptotic-bfl-1-and-its-complex-with-a-covalent-stapled-peptide-inhibitor
#14
Edward P Harvey, Hyuk-Soo Seo, Rachel M Guerra, Gregory H Bird, Sirano Dhe-Paganon, Loren D Walensky
BCL-2 family proteins are high-priority cancer targets whose structures provide essential blueprints for drug design. Whereas numerous structures of anti-apoptotic BCL-2 protein complexes with α-helical BH3 peptides have been reported, the corresponding panel of apo structures remains incomplete. Here, we report the crystal structure of apo BFL-1 at 1.69-Å resolution, revealing similarities and key differences among unliganded anti-apoptotic proteins. Unlike all other BCL-2 proteins, apo BFL-1 contains a surface-accessible cysteine within its BH3-binding groove, allowing for selective covalent targeting by a NOXA BH3-based stapled peptide inhibitor...
December 6, 2017: Structure
https://www.readbyqxmd.com/read/29247826/cytostatic-hydroxycoumarin-ot52-induces-er-golgi-stress-and-stat3-inhibition-triggering-non-canonical-cell-death-and-synergy-with-bh3-mimetics-in-lung-cancer
#15
Jin-Young Lee, Oualid Talhi, Dongman Jang, Claudia Cerella, Anthoula Gaigneaux, Kyu-Won Kim, Jung Weon Lee, Mario Dicato, Khaldoun Bachari, Byung Woo Han, Artur M S Silva, Barbora Orlikova, Marc Diederich
Coumarins are natural compounds with antioxidant, anti-inflammatory and anti-cancer potential known to modulate inflammatory pathways. Here, non-toxic biscoumarin OT52 strongly inhibited proliferation of non-small cell lung cancer cells with KRAS mutations, inhibited stem-like characteristics by reducing aldehyde dehydrogenase expression and abrogated spheroid formation capacity. This cytostatic effect was characterized by cell cycle arrest and onset of senescence concomitant with endoplasmic reticulum and Golgi stress, leading to metabolic alterations...
December 13, 2017: Cancer Letters
https://www.readbyqxmd.com/read/29244050/cd52-inhibits-toll-like-receptor-activation-of-nf-%C3%AE%C2%BAb-and-triggers-apoptosis-to-suppress-inflammation
#16
Maryam Rashidi, Esther Bandala-Sanchez, Kate E Lawlor, Yuxia Zhang, Alana M Neale, Swarna L Vijayaraj, Robert O'Donoghue, John M Wentworth, Timothy E Adams, James E Vince, Leonard C Harrison
Soluble CD52 is a small glycoprotein that suppresses T-cell activation, but its effect on innate immune cell function is unknown. Here we demonstrate that soluble CD52 inhibits Toll-like receptor and tumor necrosis factor receptor signaling to limit activation of NF-κB and thereby suppress the production of inflammatory cytokines by macrophages, monocytes and dendritic cells. At higher concentrations, soluble CD52 depletes the short-lived pro-survival protein MCL-1, contributing to activation of the BH3-only proteins BAX and BAK to cause intrinsic apoptotic cell death...
December 15, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29241222/flavopiridol-enhances-abt-199-sensitivity-in-unfavourable-risk-multiple-myeloma-cells-in-vitro-and-in-vivo
#17
Liang Zhou, Yu Zhang, Deepak Sampath, Joel Leverson, Yun Dai, Maciej Kmieciak, Matthew Nguyen, Robert Z Orlowski, Steven Grant
BACKGROUND: The BCL-2-specific BH3-mimetic ABT-199 (venetoclax) has been reported to be principally active against favourable-risk multiple myeloma (MM) cells, prompting efforts to extend its activity to include more resistant, higher-risk MM subsets. METHODS: Effects of the CDK9 inhibitor flavopiridol (FP; alvocidib) on responses to ABT-199 were examined in MM cells. Cell death and protein expression were evaluated by western blot and immunofluorescence. Xenograft models were used to study combination effects in vivo...
December 14, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29239604/nitrosoreductase-like-nanocatalyst-for-ultrasensitive-and-stable-biosensing
#18
Ponnusamy Nandhakumar, Byeongyoon Kim, Nam-Sihk Lee, Young Ho Yoon, Kwangyeol Lee, Haesik Yang
Enzyme-like nanocatalytic reactions developed for high signal amplification in biosensors are of limited use because of their low reaction rates and/or unwanted side reactions in aqueous electrolyte solutions containing dissolved O2. Herein, we report a nitrosoreductase-like catalytic reaction, employing 4-nitroso-1-naphthol, Pd nanoparticles, and H3N-BH3, which affords a high reaction rate and minimal side reactions, enabling its use in ultrasensitive electrochemical biosensors. 4-Nitroso-1-naphthol was chosen after five hydroxy-nitro(so)arene compounds were compared in terms of high signal and low background levels...
December 14, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/29237758/targeted-apoptosis-of-myofibroblasts-with-the-bh3-mimetic-abt-263-reverses-established-fibrosis
#19
David Lagares, Alba Santos, Paula E Grasberger, Fei Liu, Clemens K Probst, Rod A Rahimi, Norihiko Sakai, Tobias Kuehl, Jeremy Ryan, Patrick Bhola, Joan Montero, Mohit Kapoor, Murray Baron, Xaralabos Varelas, Daniel J Tschumperlin, Anthony Letai, Andrew M Tager
Persistent myofibroblast activation distinguishes pathological fibrosis from physiological wound healing, suggesting that therapies selectively inducing myofibroblast apoptosis could prevent progression and potentially reverse established fibrosis in diseases such as scleroderma, a heterogeneous autoimmune disease characterized by multiorgan fibrosis. We demonstrate that fibroblast-to-myofibroblast differentiation driven by matrix stiffness increases the mitochondrial priming (proximity to the apoptotic threshold) of these activated cells...
December 13, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29233828/e2f1-interacts-with-bcl-xl-and-regulates-its-subcellular-localization-dynamics-to-trigger-cell-death
#20
Céline Vuillier, Steven Lohard, Aurélie Fétiveau, Jennifer Allègre, Cémile Kayaci, Louise E King, Frédérique Braun, Sophie Barillé-Nion, Fabien Gautier, Laurence Dubrez, Andrew P Gilmore, Philippe P Juin, Laurent Maillet
E2F1 is the main pro-apoptotic effector of the pRB-regulated tumor suppressor pathway by promoting the transcription of various pro-apoptotic proteins. We report here that E2F1 partly localizes to mitochondria, where it favors mitochondrial outer membrane permeabilization. E2F1 interacts with BCL-xL independently from its BH3 binding interface and induces a stabilization of BCL-xL at mitochondrial membranes. This prevents efficient control of BCL-xL over its binding partners, in particular over BAK resulting in the induction of cell death...
December 12, 2017: EMBO Reports
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