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https://www.readbyqxmd.com/read/28806067/immunosensor-employing-stable-solid-1-amino-2-naphthyl-phosphate-and-ammonia-borane-toward-ultrasensitive-and-simple-point-of-care-testing
#1
Jeongwook Seo, Hyeri Ha, Seonhwa Park, Al-Monsur Jiaul Haque, Sinyoung Kim, Jung Min Joo, Haesik Yang
Biosensors for ultrasensitive point-of-care testing require dried reagents with long-term stability and a high signal-to-background ratio. Although ortho-substituted diaromatic dihydroxy and aminohydroxy compounds undergo fast redox reactions, they are not used as electrochemical signaling species because they are readily oxidized and polymerized by dissolved oxygen. In this report, stable, solid 1-amino-2-naphthyl phosphate (1A2N-P) and ammonia-borane (H3N-BH3) are respectively employed as a substrate for alkaline phosphatase (ALP) and a reductant for electrochemical-chemical (EC) redox cycling...
August 14, 2017: ACS Sensors
https://www.readbyqxmd.com/read/28804913/on-bh3-mimetics-and-ca-2-signaling
#2
Pawel E Ferdek, Monika A Jakubowska
Preclinical Research BH3 mimetics are anticancer agents that reproduce the spatial arrangement of the BH3 domain of Bcl-2 family proteins. Just like the BH3-only proteins, these compounds bind to the hydrophobic cleft of the pro-survival Bcl-2 members such as Bcl-2 or Bcl-xL, and disrupt their heterodimerization with pro-apoptotic Bax or Bak, sensitizing cells to chemotherapy. In recent years, it has become clear that Bcl-2 family proteins are engaged in regulation of intracellular Ca(2+) homeostasis, including Ca(2+) release from the intracellular stores as well as Ca(2+) fluxes across the plasma membrane...
August 13, 2017: Drug Development Research
https://www.readbyqxmd.com/read/28802908/apoptosis-signaling-and-bcl-2-pathways-provide-opportunities-for-novel-targeted-therapeutic-strategies-in-hematologic-malignances
#3
REVIEW
Huanling Wu, L Jeffrey Medeiros, Ken H Young
Apoptosis is an essential biological process involved in tissue homeostasis and immunity. Aberrations of the two main apoptotic pathways, extrinsic and intrinsic, have been identified in hematological malignancies; many of these aberrations are associated with pathogenesis, prognosis and resistance to standard chemotherapeutic agents. Targeting components of the apoptotic pathways, especially the chief regulatory BCL-2 family in the intrinsic pathway, has proved to be a promising therapeutic approach for patients with hematological malignances, with the expectation of enhanced efficacy and reduced adverse events...
August 8, 2017: Blood Reviews
https://www.readbyqxmd.com/read/28802066/targeting-senescent-cholangiocytes-and-activated-fibroblasts-with-bcl-xl-inhibitors-ameliorates-fibrosis-in-mdr2-mice
#4
Anja Moncsek, Mohammed S Al-Suraih, Christy E Trussoni, Steven P O'Hara, Patrick L Splinter, Camille Zuber, Eleonora Patsenker, Piero V Valli, Christian D Fingas, Achim Weber, Yi Zhu, Tamar Tchkonia, James L Kirkland, Gregory J Gores, Beat Müllhaupt, Nicholas F LaRusso, Joachim C Mertens
Cholangiocyte senescence has been linked to primary sclerosing cholangitis (PSC). Persistent secretion of growth factors by senescent cholangiocytes leads to the activation of stromal fibroblasts (ASF), which are drivers of fibrosis. The activated phenotype of ASF is characterized by an increased sensitivity to apoptotic stimuli. Here, we examined the mechanisms of apoptotic priming in ASF and explored a combined targeting strategy to deplete senescent cholangiocytes and ASF from fibrotic tissue to ameliorate liver fibrosis...
August 12, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28799432/targeted-therapies-in-acute-myeloid-leukemia-a-focus-on-flt-3-inhibitors-and-abt199
#5
Kiran Naqvi, Marina Konopleva, Farhad Ravandi
Acute myeloid leukemia (AML) remains a therapeutic challenge. Despite ongoing research, the standard therapy for AML has not changed significantly in the past four decades. With the identification of cytogenetic and molecular abnormalities, several promising therapeutic agents are currently being investigated. FLT3 mutation is a well-recognized target seen in 30% of the cytogenetically normal AML. More recently, the BCL2 family of anti-apoptotic proteins have also generated great interest as a therapeutic target...
August 11, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28796811/biphasic-ros-production-p53-and-bik-dictate-the-mode-of-cell-death-in-response-to-dna-damage-in-colon-cancer-cells
#6
Ozgur Kutuk, Nurgul Aytan, Bahriye Karakas, Asli Giray Kurt, Ufuk Acikbas, Sehime Gulsun Temel, Huveyda Basaga
Necrosis, apoptosis and autophagic cell death are the main cell death pathways in multicellular organisms, all with distinct and overlapping cellular and biochemical features. DNA damage may trigger different types of cell death in cancer cells but the molecular events governing the mode of cell death remain elusive. Here we showed that increased BH3-only protein BIK levels promoted cisplatin- and UV-induced mitochondrial apoptosis and biphasic ROS production in HCT-116 wild-type cells. Nonetheless, early single peak of ROS formation along with lysosomal membrane permeabilization and cathepsin activation regulated cisplatin- and UV-induced necrosis in p53-null HCT-116 cells...
2017: PloS One
https://www.readbyqxmd.com/read/28793767/ginsenoside-20-s-rh2-induces-apoptosis-and-differentiation-of-acute-myeloid-leukemia-cells-role-of-orphan-nuclear-receptor-nur77
#7
Chengqiang Wang, Hui He, Guojun Dou, Juan Li, Xiaomei Zhang, Mingdong Jiang, Pan Li, Xiaobo Huang, Hongxi Chen, Li Li, da-Jian Yang, Hongyi Qi
Ginsenoside 20(S)-Rh2 has been shown to induce apoptosis and differentiation of acute myeloid leukemia (AML) cells. However, the underlying molecular mechanisms are not fully understood. In our study, 20(S)-Rh2 induced the expression of orphan nuclear receptor Nur77 and death receptor proteins Fas, FasL, DR5 and TRAIL, as well as the cleavage of caspase 8 and caspase 3 in HL-60 cells. Importantly, shNur77 attenuated 20(S)-Rh2-induced apoptosis and Fas and DR5 expression. Meanwhile, 20(S)-Rh2 promoted Nur77 translocation from nucleus to mitochondria and enhanced the interaction between Nur77 and Bcl-2, resulting in the exposure of BH3 domain of Bcl-2 and activation of Bax...
August 9, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/28778072/bid-deficient-fish-delay-grass-carp-reovirus-gcrv-replication-and-attenuate-gcrv-triggered-apoptosis
#8
Libo He, Hao Wang, Lifei Luo, Yongming Li, Rong Huang, Lanjie Liao, Zuoyan Zhu, Yaping Wang
Bid, BH3-interacting domain death agonist, is a pro-apoptotic BH3-only member of Bcl-2 family, playing an important role in apoptosis. In the study, Bid genes from grass carp (Ctenopharyngodon idellus) and rare minnow (Gobiocypris rarus), named CiBid and GrBid, were cloned and analyzed. Bid was constitutively expressed in all examined tissues of grass carp, but the expression level varied in different tissues. Following grass carp reovirus (GCRV) stimulation in vivo, Bid and apoptosis related genes Caspase-9 and Caspase-3 was up-regulated significantly at the late stage of infection...
July 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28777375/inhibition-of-bcl-xl-prevents-pro-death-actions-of-%C3%AE-n-bcl-xl-at-the-mitochondrial-inner-membrane-during-glutamate-excitotoxicity
#9
Han-A Park, Pawel Licznerski, Nelli Mnatsakanyan, Yulong Niu, Silvio Sacchetti, Jing Wu, Brian M Polster, Kambiz N Alavian, Elizabeth A Jonas
ABT-737 is a pharmacological inhibitor of the anti-apoptotic activity of B-cell lymphoma-extra large (Bcl-xL) protein; it promotes apoptosis of cancer cells by occupying the BH3-binding pocket. We have shown previously that ABT-737 lowers cell metabolic efficiency by inhibiting ATP synthase activity. However, we also found that ABT-737 protects rodent brain from ischemic injury in vivo by inhibiting formation of the pro-apoptotic, cleaved form of Bcl-xL, ΔN-Bcl-xL. We now report that a high concentration of ABT-737 (1 μM), or a more selective Bcl-xL inhibitor WEHI-539 (5 μM) enhances glutamate-induced neurotoxicity while a low concentration of ABT-737 (10 nM) or WEHI-539 (10 nM) is neuroprotective...
August 4, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28771225/the-ovarian-reserve-is-depleted-during-puberty-in-a-hormonally-driven-process-dependent-on-the-pro-apoptotic-protein-bmf
#10
Seng H Liew, Quynh-Nhu Nguyen, Andreas Strasser, Jock K Findlay, Karla J Hutt
In females, germ cells are maintained in ovarian structures called primordial follicles. The number of primordial follicles in the ovarian reserve is a critical determinant of the length of the fertile lifespan. Despite this significance, knowledge of the precise physiological mechanisms that regulate primordial follicle number is lacking. In this study we show that a wave of primordial follicle depletion occurs during the transition to adulthood in mice. We demonstrate that this sudden and dramatic loss of primordial follicles is hormonally triggered and identify the pro-apoptotic BH3-only protein, BCL-2 modifying factor (BMF), as essential for this process, implicating the intrinsic apoptotic pathway as a key mechanism...
August 3, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28768804/synergistic-action-of-the-mcl-1-inhibitor-s63845-with-current-therapies-in-preclinical-models-of-triple-negative-and-her2-amplified-breast-cancer
#11
Delphine Merino, James R Whittle, François Vaillant, Antonin Serrano, Jia-Nan Gong, Goknur Giner, Ana Leticia Maragno, Maïa Chanrion, Emilie Schneider, Bhupinder Pal, Xiang Li, Grant Dewson, Julius Gräsel, Kevin Liu, Najoua Lalaoui, David Segal, Marco J Herold, David C S Huang, Gordon K Smyth, Olivier Geneste, Guillaume Lessene, Jane E Visvader, Geoffrey J Lindeman
The development of BH3 mimetics, which antagonize prosurvival proteins of the BCL-2 family, represents a potential breakthrough in cancer therapy. Targeting the prosurvival member MCL-1 has been an area of intense interest because it is frequently deregulated in cancer. In breast cancer, MCL-1 is often amplified, and high expression predicts poor patient outcome. We tested the MCL-1 inhibitor S63845 in breast cancer cell lines and patient-derived xenografts with high expression of MCL-1. S63845 displayed synergistic activity with docetaxel in triple-negative breast cancer and with trastuzumab or lapatinib in HER2-amplified breast cancer...
August 2, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28767402/mimicking-the-bim-bh3-domain-overcomes-resistance-to-egfr-tyrosine-kinase-inhibitors-in-egfr-mutant-non-small-cell-lung-cancer
#12
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...
July 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28758658/exploring-the-chemistry-of-backbone-amino-chloro-phosphanyl-substituted-imidazole-2-thiones
#13
Abhishek Koner, Spencer C Serin, Gregor Schnakenburg, Brian O Patrick, Derek P Gates, Rainer Streubel
Backbone (R'2N)2P-substituted imidazole-2-thiones 2a-c [(R'2N)2P-IMS(R,R); IMS(R,R) = 1,3-dialkylimidazole-2-thione-4-yl, a: R = (i)Pr, R' = Et; b: R = Mes, R' = Et, c: R = Me, R' = (i)Pr] were treated with PCl3 to synthesize R'2N(Cl)P-substituted imidazole-2-thiones 3a-c [R'2N(Cl)P-IMS(R,R)]. The P-chloro compounds 3a,b were used to explore the chemistry further, i.e. nucleophilic substitution at phosphorus using Ph2CHLi or fluorenyl lithium afforded compounds 4a-c [R'2N(R'')P-IMS(R,R); a: R = (i)Pr, R' = Et, R'' = PH2CH; b: R = Mes, R' = Et, R'' = Flu c: R = (i)Pr, R' = Et, R'' = Flu]...
July 31, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/28741496/targeting-bcl-2-like-proteins-to-kill-cancer-cells
#14
REVIEW
Suzanne Cory, Andrew W Roberts, Peter M Colman, Jerry M Adams
Mutations that impair apoptosis contribute to cancer development and reduce the effectiveness of conventional anti-cancer therapies. These insights and understanding of how the B cell lymphoma (BCL)-2 protein family governs apoptosis have galvanized the search for a new class of cancer drugs that target its pro-survival members by mimicking their natural antagonists, the BCL-2 homology (BH)3-only proteins. Successful initial clinical trials of the BH3 mimetic venetoclax/ABT-199, specific for BCL-2, have led to its recent licensing for refractory chronic lymphocytic leukemia and to multiple ongoing trials for other malignancies...
August 2016: Trends in Cancer
https://www.readbyqxmd.com/read/28741484/suzanne-cory-life-and-death-switches-the-rise-of-bh3-mimetics
#15
(no author information available yet)
No abstract text is available yet for this article.
October 2016: Trends in Cancer
https://www.readbyqxmd.com/read/28737741/rapidly-inducible-cas9-and-dsb-ddpcr-to-probe-editing-kinetics
#16
John C Rose, Jason J Stephany, William J Valente, Bridget M Trevillian, Ha V Dang, Jason H Bielas, Dustin J Maly, Douglas M Fowler
We developed a chemically inducible Cas9 (ciCas9) and a droplet digital PCR assay for double-strand breaks (DSB-ddPCR) to investigate the kinetics of Cas9-mediated generation and repair of DSBs in cells. ciCas9 is a rapidly activated, single-component Cas9 variant engineered by replacing the protein's REC2 domain with the BCL-xL protein and fusing an interacting BH3 peptide to the C terminus. ciCas9 can be tunably activated by a compound that disrupts the BCL-xL-BH3 interaction within minutes. DSB-ddPCR demonstrates time-resolved, highly quantitative, and targeted measurement of DSBs...
July 24, 2017: Nature Methods
https://www.readbyqxmd.com/read/28724540/targeting-bcl-2-in-b-cell-lymphomas
#17
Matthew S Davids
The B-cell leukemia/lymphoma-2 (BCL-2) family of proteins governs the intrinsic pathway of mitochondrial apoptosis. Dysregulation of BCL-2 has long been known to be a crucial part of the pathophysiology of B-cell lymphomas, yet several early attempts to target this pathway therapeutically were unsuccessful due to toxicity, lack of efficacy, or both. Recently, a highly potent and selective oral BCL-2 antagonist, venetoclax, was approved in chronic lymphocytic leukemia (CLL), where it has proven to be highly active, even in patients with high risk del(17p) disease...
July 19, 2017: Blood
https://www.readbyqxmd.com/read/28724188/bisindole-oxadiazole-hybrids-t3p-%C3%A2-mediated-synthesis-and-appraisal-of-their-apoptotic-antimetastatic-and-computational-bcl-2-binding-potential
#18
Pooja R Kamath, Manu M Joseph, Abdul Ajees Abdul Salam, Sreelekha T Therakathinal, Dhanya Sunil, Subhankar Biswas, Karkala Sreedhara Ranganath Pai
In the pursuit of novel anticancer leads, new bisindole-oxadiazoles were synthesized using propyl phosphonic anhydride as a mild and efficient reagent. The molecule, 3-[5-(1H-indol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-1H-indole (3a) exhibited selective cytotoxicity to MCF-7 cells with a cell cycle arrest in the G1 phase. The mechanism of cytotoxicity of 3a involved caspase-2-dependent apoptotic pathway with characteristic apoptotic morphological alterations as observed in acridine orange/ethidium bromide and Hoechst staining...
July 19, 2017: Journal of Biochemical and Molecular Toxicology
https://www.readbyqxmd.com/read/28720543/bik-is-involved-in-braf-mek-inhibitor-induced-apoptosis-in-melanoma-cell-lines
#19
Andreas Borst, Sebastian Haferkamp, Johannes Grimm, Manuel Rösch, Guannan Zhu, Sen Guo, Chunying Li, Tianwen Gao, Svenja Meierjohann, David Schrama, Roland Houben
In patients with BRAF-mutated melanoma specific inhibitors of BRAF(V600E) and MEK1/2 frequently induce initial tumor reduction, frequently followed by relapse. As demonstrated previously, BRAF(V600E)-inhibition induces apoptosis only in a fraction of treated cells, while the remaining arrest and survive providing a source or a niche for relapse. To identify factors contributing to the differential initial response towards BRAF/MEK inhibition, we established M14 melanoma cell line-derived single cell clones responding to treatment with BRAF inhibitor vemurafenib and MEK inhibitor trametinib predominantly with either cell cycle arrest (CCA-cells) or apoptosis (A-cells)...
July 15, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28714472/targeting-the-differential-addiction-to-anti-apoptotic-bcl-2-family-for-cancer-therapy
#20
Akane Inoue-Yamauchi, Paul S Jeng, Kwanghee Kim, Hui-Chen Chen, Song Han, Yogesh Tengarai Ganesan, Kota Ishizawa, Sylvia Jebiwott, Yiyu Dong, Maria C Pietanza, Matthew D Hellmann, Mark G Kris, James J Hsieh, Emily H Cheng
BCL-2 family proteins are central regulators of mitochondrial apoptosis and validated anti-cancer targets. Using small cell lung cancer (SCLC) as a model, we demonstrated the presence of differential addiction of cancer cells to anti-apoptotic BCL-2, BCL-XL or MCL-1, which correlated with the respective protein expression ratio. ABT-263 (navitoclax), a BCL-2/BCL-XL inhibitor, prevented BCL-XL from sequestering activator BH3-only molecules (BH3s) and BAX but not BAK. Consequently, ABT-263 failed to kill BCL-XL-addicted cells with low activator BH3s and BCL-XL overabundance conferred resistance to ABT-263...
July 17, 2017: Nature Communications
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