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Splicing inhibitor

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https://www.readbyqxmd.com/read/29788973/homoharringtonine-regulates-the-alternative-splicing-of-bcl-x-and-caspase-9-through-a-protein-phosphatase-1-dependent-mechanism
#1
Qi Sun, Shiyue Li, Junjun Li, Qiuxia Fu, Zhongyuan Wang, Bo Li, Shan-Shan Liu, Zijie Su, Jiaxing Song, Desheng Lu
BACKGROUND: Homoharringtonine (HHT) is a natural alkaloid with potent antitumor activity, but its precise mechanism of action is still poorly understood. METHODS: We examined the effect of HHT on alternative splicing of Bcl-x and Caspase 9 in various cells using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). The mechanism of HHT-affected alternative splicing in these cells was investigated by treatment with protein phosphatase inhibitors and overexpression of a protein phosphatase...
May 22, 2018: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/29787565/expression-purification-and-inhibition-profile-of-dihydrofolate-reductase-from-the-filarial-nematode-wuchereria-bancrofti
#2
Andrew M Tobias, Dea Toska, Keith Lange, Tyler Eck, Rohit Bhat, Cheryl A Janson, David P Rotella, Ueli Gubler, Nina M Goodey
Filariasis is a tropical disease caused by the parasitic nematodes Wuchereria bancrofti and Brugia malayi. Known inhibitors of dihydrofolate reductase (DHFR) have been previously shown to kill Brugia malayi nematodes and to inhibit Brugia malayi DHFR (BmDHFR) at nanomolar concentrations. These data suggest that BmDHFR is a potential target for the treatment of filariasis. Here, protocols for cloning, expression and purification of Wuchereria bancrofti DHFR (WbDHFR) were developed. The Uniprot entry J9F199-1 predicts a 172 amino acid protein for WbDHFR but alignment of this sequence to the previously described BmDHFR shows that this WbDHFR sequence lacks a crucial, conserved 13 amino acid loop...
2018: PloS One
https://www.readbyqxmd.com/read/29774201/investigation-of-experimental-factors-that-underlie-brca1-2-mrna-isoform-expression-variation-recommendations-for-utilizing-targeted-rna-sequencing-to-evaluate-potential-spliceogenic-variants
#3
Vanessa L Lattimore, John F Pearson, Margaret J Currie, Amanda B Spurdle, Bridget A Robinson, Logan C Walker
PCR-based RNA splicing assays are commonly used in diagnostic and research settings to assess the potential effects of variants of uncertain clinical significance in BRCA1 and BRCA2 . The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium completed a multicentre investigation to evaluate differences in assay design and the integrity of published data, raising a number of methodological questions associated with cell culture conditions and PCR-based protocols. We utilized targeted RNA-seq to re-assess BRCA1 and BRCA2 mRNA isoform expression patterns in lymphoblastoid cell lines (LCLs) previously used in the multicentre ENIGMA study...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29769258/anti-tumor-efficacy-of-a-novel-clk-inhibitor-via-targeting-rna-splicing-and-myc-dependent-vulnerability
#4
Kenichi Iwai, Masahiro Yaguchi, Kazuho Nishimura, Yukiko Yamamoto, Toshiya Tamura, Daisuke Nakata, Ryo Dairiki, Yoichi Kawakita, Ryo Mizojiri, Yoshiteru Ito, Moriteru Asano, Hironobu Maezaki, Yusuke Nakayama, Misato Kaishima, Kozo Hayashi, Mika Teratani, Shuichi Miyakawa, Misa Iwatani, Maki Miyamoto, Michael G Klein, Wes Lane, Gyorgy Snell, Richard Tjhen, Xingyue He, Sai Pulukuri, Toshiyuki Nomura
The modulation of pre-mRNA splicing is proposed as an attractive anti-neoplastic strategy, especially for the cancers that exhibit aberrant pre-mRNA splicing. Here, we discovered that T-025 functions as an orally available and potent inhibitor of Cdc2-like kinases (CLKs), evolutionally conserved kinases that facilitate exon recognition in the splicing machinery. Treatment with T-025 reduced CLK-dependent phosphorylation, resulting in the induction of skipped exons, cell death, and growth suppression in vitro and in vivo Further, through growth inhibitory characterization, we identified high CLK2 expression or MYC amplification as a sensitive-associated biomarker of T-025...
May 16, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29768040/myristate-induced-endoplasmic-reticulum-stress-requires-ceramide-synthases-5-6-and-generation-of-c14-ceramide-in-intestinal-epithelial-cells
#5
Songhwa Choi, Justin M Snider, Nicole Olakkengil, Johana M Lambert, Andrea K Anderson, Jessica S Ross-Evans, L Ashley Cowart, Ashley J Snider
Saturated fatty acids (SFAs) have been shown to induce endoplasmic reticulum (ER) stress and chronic inflammatory responses, as well as alter sphingolipid metabolism. Disruptions in ER stress and sphingolipid metabolism have also been implicated in intestinal inflammation. Therefore, to elucidate the roles of SFAs in ER stress and inflammation in intestinal epithelial cells, we examined myristate (C14:0) and palmitate (C16:0). Myristate, but not palmitate, induced ER stress signaling, including activation of inositol-requiring enzyme 1 (IRE1) and X-box binding protein 1 (XBP1) signaling...
May 16, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29764864/targeting-the-hsp40-hsp70-chaperone-axis-as-a-novel-strategy-to-treat-castration-resistant-prostate-cancer
#6
Michael A Moses, Yeong Sang Kim, Genesis M Rivera-Marquez, Nobu Oshima, Matthew J Watson, Kristin Beebe, Catherine Wells, Sunmin Lee, Abbey D Zuehlke, Hao Shao, William E Bingman, Vineet Kumar, Sanjay Malhotra, Nancy L Weigel, Jason E Gestwicki, Jane Trepel, Leonard M Neckers
Castration-resistant prostate cancer (CRPC) is characterized by reactivation of androgen receptor (AR) signaling in part by elevated expression of AR splice variants (ARv) including ARv7, a constitutively active, ligand binding domain (LBD)-deficient variant whose expression has been correlated with therapeutic resistance and poor prognosis. In a screen to identify small molecule dual inhibitors of both androgen-dependent and androgen-independent AR gene signatures, we identified the chalcone C86. Binding studies using purified proteins and CRPC cell lysates revealed C86 to interact with heat shock protein 40 (Hsp40)...
May 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29752433/palmitic-acid-but-not-high-glucose-induced-myocardial-apoptosis-is-alleviated-by-n%C3%A2-acetylcysteine-due-to-attenuated-mitochondrial-derived-ros-accumulation-induced-endoplasmic-reticulum-stress
#7
Yang He, Lingyun Zhou, Zhiqiang Fan, Shikun Liu, Weijin Fang
Pharmacological inhibition of reactive oxygen species (ROS) is a potential strategy to prevent diabetes-induced cardiac dysfunction. This study was designed to investigate precise effects of antioxidant N‑acetylcysteine (NAC) in alleviating diabetic cardiomyopathy (DCM). Echocardiography and histologic studies were performed 12 weeks after streptozocin injection. Protein levels involved in endoplasmic reticulum stress (ERS) and apoptosis were analyzed by western blotting in diabetic hearts or high-glucose (HG, 30 mM)- and palmitic acid (PA, 300 μM)-cultured neonatal rat cardiomyocytes (NRCMs)...
May 11, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29751762/hiv-latency-reversing-agents-act-through-tat-post-translational-modifications
#8
Georges Khoury, Talia M Mota, Shuang Li, Carolin Tumpach, Michelle Y Lee, Jonathan Jacobson, Leigh Harty, Jenny L Anderson, Sharon R Lewin, Damian F J Purcell
BACKGROUND: Different classes of latency reversing agents (LRAs) are being evaluated to measure their effects in reactivating HIV replication from latently infected cells. A limited number of studies have demonstrated additive effects of LRAs with the viral protein Tat in initiating transcription, but less is known about how LRAs interact with Tat, particularly through basic residues that may be post-translationally modified to alter the behaviour of Tat for processive transcription and co-transcriptional RNA processing...
May 11, 2018: Retrovirology
https://www.readbyqxmd.com/read/29743891/a-loss-of-function-screen-of-epigenetic-modifiers-and-splicing-factors-during-early-stage-of-cardiac-reprogramming
#9
Yang Zhou, Sahar Alimohamadi, Li Wang, Ziqing Liu, Joseph B Wall, Chaoying Yin, Jiandong Liu, Li Qian
Direct reprogramming of cardiac fibroblasts (CFs) to induced cardiomyocytes (iCMs) is a newly emerged promising approach for cardiac regeneration, disease modeling, and drug discovery. However, its potential has been drastically limited due to the low reprogramming efficiency and largely unknown underlying molecular mechanisms. We have previously screened and identified epigenetic factors related to histone modification during iCM reprogramming. Here, we used shRNAs targeting an additional battery of epigenetic factors involved in chromatin remodeling and RNA splicing factors to further identify inhibitors and facilitators of direct cardiac reprogramming...
2018: Stem Cells International
https://www.readbyqxmd.com/read/29741506/recent-advances-in-the-cellular-and-molecular-understanding-of-myelodysplastic-syndromes-implications-for-new-therapeutic-approaches
#10
Andrew M Brunner, David P Steensma
It has been more than 10 years since any new disease-modifying therapies have received regulatory approval for indications related to myelodysplastic syndromes (MDS). Advances in our collective biological understanding of MDS in the last decade, however, have made it possible to hope that effective therapeutics can be designed to improve MDS-associated cytopenias and patients' quality of life, and perhaps even delay clonal progression and extend survival. Classes of MDS-associated mutations and disordered biological pathways targeted by developmental therapeutics include the following: aberrant messenger RNA splicing, neomorphic enzymes in the citric acid cycle with oncogenic activity, overactivated tyrosine and serine-threonine kinases, epigenetic and chromatin remodeling alterations, abnormal telomere dynamics, and failed protection of DNA integrity...
January 2018: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/29739791/%C3%AE-np63%C3%AE-src-slug-signalling-axis-promotes-epithelial-to-mesenchymal-transition-in-squamous-cancers
#11
Kirtiman Srivastava, Adam Pickard, Stephanie G Craig, Gerard P Quinn, Shauna M Lambe, Jacqueline A James, Simon McDade, Dennis McCance
PURPOSE: To investigate the regulation of epithelial-to-mesenchymal transition (EMT) in  Head and Neck Squamous Cell Carcinoma (HNSCC) and its importance in tumour invasion. EXPERIMENTAL DESIGN: We use a 3D invasive organotypic raft culture model of human foreskin keratinocytes expressing the E6/E7 genes of the Human Papilloma Virus-16, coupled with bioinformatics and immunohistochemical analysis of patient samples to investigate  the role played by EMT in invasion and identify effectors and upstream regulatory pathways...
May 8, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29729706/tgf%C3%AE-1-mediated-pi3k-akt-and-p38-map-kinase-dependent-alternative-splicing-of-fibronectin-extra-domain-a-in-human-podocyte-culture
#12
Tarunkumar Hemraj Madne, Mark Edward Carl Dockrell
Alternative splicing is an important gene regulation process to distribute proteins in health and diseases. Extra Domain A+ Fibronectin (EDA+Fn) is an alternatively spliced form of fibronectin (Fn) protein, present in the extra cellular matrix (ECM) and a recognised marker of various pathologies. TGFβ1 has been shown to induce alternative splicing of EDA+Fn in many cell types. Podocytes are spectacular cell type and play a key role in filtration and synthesise ECM proteins in renal physiology and pathology...
April 30, 2018: Cellular and Molecular Biology
https://www.readbyqxmd.com/read/29729314/the-human-mapt-locus-generates-circular-rnas
#13
Justin R Welden, Jacob van Doorn, Peter T Nelson, Stefan Stamm
The microtubule-associated protein Tau, generated by the MAPT gene is involved in dozens of neurodegenerative conditions ("tauopathies"), including Alzheimer's disease (AD) and frontotemporal lobar degeneration/frontotemporal dementia (FTLD/FTD). The pre-mRNA of MAPT is well studied and its aberrant pre-mRNA splicing is associated with frontotemporal dementia. Using a PCR screen of RNA from human brain tissues, we found that the MAPT locus generates circular RNAs through a backsplicing mechanism from exon 12 to either exon 10 or 7...
May 2, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29723265/molecular-structures-of-cdc2-like-kinases-in-complex-with-a-new-inhibitor-chemotype
#14
Anne Walter, Apirat Chaikuad, Renate Helmer, Nadège Loaëc, Lutz Preu, Ingo Ott, Stefan Knapp, Laurent Meijer, Conrad Kunick
Cdc2-like kinases (CLKs) represent a family of serine-threonine kinases involved in the regulation of splicing by phosphorylation of SR-proteins and other splicing factors. Although compounds acting against CLKs have been described, only a few show selectivity against dual-specificity tyrosine phosphorylation regulated-kinases (DYRKs). We here report a novel CLK inhibitor family based on a 6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one core scaffold. Within the series, 3-(3-chlorophenyl)-6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one (KuWal151) was identified as inhibitor of CLK1, CLK2 and CLK4 with a high selectivity margin towards DYRK kinases...
2018: PloS One
https://www.readbyqxmd.com/read/29696980/enantioselective-synthesis-of-thailanstatin-a-methyl-ester-and-evaluation-of-in-vitro-splicing-inhibition
#15
Arun K Ghosh, Anne M Veitschegger, Shenyou Nie, Nicola Relitti, Andrew J MacRae, Melissa S Jurica
Thailanstatin A has been isolated recently from the fermentation broth of B. thailandensis MSMB43. We describe here an enantioselective convergent synthesis of thailanstatin A methyl ester and evaluation of its splicing activity. Synthesis of both highly functionalized tetrahydropyran rings were carried out from commercially available tri- O-acetyl-d-glucal as the key starting material. Our convergent synthesis involved the synthesis of both tetrahydropyran fragments in a highly stereoselective manner. The fragments were then coupled using cross-metathesis as the key step...
April 26, 2018: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/29696609/apocynin-protects-endothelial-cells-from-endoplasmic-reticulum-stress-induced-apoptosis-via-ire1%C3%AE-engagement
#16
Jie Wu, Weijin Zhang, Xiaohui Liu, Lili Wu, Guangting He, Peixin Li, Xiaohua Guo, Zhongqing Chen, Qiaobing Huang
Endoplasmic reticulum (ER) stress-induced endothelial cell (EC) apoptosis has been implicated in a variety of human diseases. In addition to being regarded as an NADPH oxidase (NOX) inhibitor, apocynin (APO) exhibits an anti-apoptotic effect in various cells. The present study aimed to identify the protective role of apocynin in ER stress-mediated EC apoptosis and the underlying mechanisms. We found that ER stress resulted in a significant increase in c-Jun N-terminal kinase phosphorylation, and elicited caspase 3 cleavage and apoptosis...
April 25, 2018: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/29695649/stf-083010-an-inhibitor-of-xbp1-splicing-attenuates-acute-renal-failure-in-rats-by-suppressing-endoplasmic-reticulum-stress-induced-apoptosis-and-inflammation
#17
Lei Liu, Lu Xu, Shaoqing Zhang, Dong Wang, Guoxia Dong, Hanwen Chen, Xinjian Li, Chi Shu, Rong Wang
Endoplasmic reticulum (ER) stress is one of the driving forces of ischemia/reperfusion (IR)-induced acute renal failure (ARF). STF-083010, an inhibitor of the endonuclease activity of inositol-requiring enzyme-1 (IRE1), has the potential to block the initiation of a prolonged unfolded protein response (UPR) that is stimulated by ER stress and alleviates the impairments due to ER stress. In the current study, it was hypothesized that STF-083010 was capable of ameliorating ER stress-related damages in IR-induced ARF...
April 25, 2018: Experimental Animals
https://www.readbyqxmd.com/read/29693622/targeting-splicing-in-prostate-cancer
#18
REVIEW
Effrosyni Antonopoulou, Michael Ladomery
Over 95% of human genes are alternatively spliced, expressing splice isoforms that often exhibit antagonistic functions. We describe genes whose alternative splicing has been linked to prostate cancer; namely VEGFA , KLF6 , BCL2L2 , ERG , and AR . We discuss opportunities to develop novel therapies that target specific splice isoforms, or that target the machinery of splicing. Therapeutic approaches include the development of small molecule inhibitors of splice factor kinases, splice isoform specific siRNAs, and splice switching oligonucleotides...
April 25, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29684050/intronic-pah-gene-mutations-cause-a-splicing-defect-by-a-novel-mechanism-involving-u1snrnp-binding-downstream-of-the-5-splice-site
#19
Ainhoa Martínez-Pizarro, Maja Dembic, Belén Pérez, Brage S Andresen, Lourdes R Desviat
Phenylketonuria (PKU), one of the most common inherited diseases of amino acid metabolism, is caused by mutations in the phenylalanine hydroxylase (PAH) gene. Recently, PAH exon 11 was identified as a vulnerable exon due to a weak 3' splice site, with different exonic mutations affecting exon 11 splicing through disruption of exonic splicing regulatory elements. In this study, we report a novel intron 11 regulatory element, which is involved in exon 11 splicing, as revealed by the investigated pathogenic effect of variants c...
April 23, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29673712/update-on-systemic-prostate-cancer-therapies-management-of-metastatic-castration-resistant-prostate-cancer-in-the-era-of-precision-oncology
#20
REVIEW
Philipp Nuhn, Johann S De Bono, Karim Fizazi, Stephen J Freedland, Maurizio Grilli, Philip W Kantoff, Guru Sonpavde, Cora N Sternberg, Srinivasan Yegnasubramanian, Emmanuel S Antonarakis
CONTEXT: Introduction of novel agents for the management of advanced prostate cancer provides a range of treatment options with notable benefits for men with metastatic castration-resistant prostate cancer (mCRPC). At the same time, understanding of optimal patient selection, effective sequential use, and development of resistance patterns remains incomplete. OBJECTIVE: To review current systemic therapies and recent advances in drug development for mCRPC and strategies to aid in patient selection and optimal sequencing...
April 16, 2018: European Urology
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