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Splicing inhibitor

Kun Qian, Hao Hu, Hui Xu, Y George Zheng
Protein arginine methyltransferases (PRMTs) are crucial epigenetic regulators in eukaryotic organisms that serve as histone writers for chromatin remodeling. PRMTs also methylate a variety of non-histone protein substrates to modulate their function and activity. The development of potent PRMT inhibitors has become an emerging and imperative research area in the drug discovery field to provide novel therapeutic agents for treating diseases and as tools to investigate the biological functions of PRMTs. PRMT1 is the major type I enzyme that catalyzes the formation of asymmetric dimethyl arginine, and PRMT1 plays important regulatory roles in signal transduction, transcriptional activation, RNA splicing, and DNA repair...
2018: Signal Transduction and Targeted Therapy
Vesna Grivčeva-Panovska, Mitja Košnik, Peter Korošec, Slađana Andrejević, Ljerka Karadža-Lapić, Matija Rijavec
OBJECTIVE: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare disease, characterized by swellings. We aimed to characterize on a clinical and molecular basis C1-INH-HAE patients in the Republic of Macedonia. RESULTS: All 15 patients from six unrelated families were diagnosed with C1-INH-HAE type I, with a mean age of symptom onset of 11 years and an average delay of diagnosis of 7 years. Patients reported on average 31 angioedema attacks/year, with a median clinical severity score (CSS) of 7...
March 7, 2018: Annals of Medicine
X-F Tang, X-L Zhou, Q Zhang, P Chen, C Lu, M-H Pan
Cyclin-dependent kinase inhibitors (CKIs) are negative regulators of the cell cycle. They can bind to cyclin-dependent kinase (CDK)-cyclin complexes and inhibit CDK activities. We identified a single homologous gene of the CDK interacting protein/kinase inhibitory protein (Cip/Kip) family, BmCKI, in the silkworm, Bombyx mori. The gene transcribes two splice variants: a 654-bp-long BmCKI-L (the longer splice variant) encoding a protein with 217 amino acids and a 579-bp-long BmCKI-S (the shorter splice variant) encoding a protein with 192 amino acids...
March 7, 2018: Insect Molecular Biology
Tarunkumar Hemraj Madne, Mark Edward Carl Dockrell
Alternative splicing is a fundamental phenomenon to build protein diversity in health and diseases. Extra Domain A+ Fibronectin (EDA+Fn) is an alternatively spliced form of fibronectin protein present in the extra cellular matrix (ECM) in renal fibrosis. Podocytes are spectacular cell type and play a key role in filtration and synthesise ECM proteins in renal physiology and pathology. TGFβ1 is a strong stimulator of ECM proteins in renal injury. In this study, we have investigated alternative splicing of EDA+ Fn in human podocytes in response to TGFβ1...
February 28, 2018: Cellular and Molecular Biology
Christian Niederwanger, Silvia Lechner, Lisa König, Andreas R Janecke, Claus Pototschnig, Beatrice Häussler, Sabine Scholl-Bürgi, Thomas Müller, Peter Heinz-Erian
BACKGROUND: Choanal (CA) and gastrointestinal atresias (GA) are an important feature of syndromic congenital sodium diarrhea (sCSD), a disorder recently associated with mutations in the gene for serine protease inhibitor type 2 (SPINT2). It is, however, not known whether isolated non-syndromic CA and GA themselves might result from SPINT2 mutations. METHODS: We performed a prospective cohort study to investigate 19 CA and/or GA patients without diarrhea ("non-sCSD") for potential sCSD characteristic clinical features and SPINT2 mutations...
March 2, 2018: European Journal of Medical Research
Takuji Yamauchi, Takeshi Masuda, Matthew C Canver, Michael Seiler, Yuichiro Semba, Mohammad Shboul, Mohammed Al-Raqad, Manami Maeda, Vivien A C Schoonenberg, Mitchel A Cole, Claudio Macias-Trevino, Yuichi Ishikawa, Qiuming Yao, Michitaka Nakano, Fumio Arai, Stuart H Orkin, Bruno Reversade, Silvia Buonamici, Luca Pinello, Koichi Akashi, Daniel E Bauer, Takahiro Maeda
To identify novel targets for acute myeloid leukemia (AML) therapy, we performed genome-wide CRISPR-Cas9 screening using AML cell lines, followed by a second screen in vivo. Here, we show that the mRNA decapping enzyme scavenger (DCPS) gene is essential for AML cell survival. The DCPS enzyme interacted with components of pre-mRNA metabolic pathways, including spliceosomes, as revealed by mass spectrometry. RG3039, a DCPS inhibitor originally developed to treat spinal muscular atrophy, exhibited anti-leukemic activity via inducing pre-mRNA mis-splicing...
February 8, 2018: Cancer Cell
John M Hatcher, Guowei Wu, Chuyue Zeng, Jie Zhu, Fan Meng, Sherrina Patel, Wenqiu Wang, Scott B Ficarro, Alan L Leggett, Chelsea E Powell, Jarrod A Marto, Kang Zhang, Jacky Chi Ki Ngo, Xiang-Dong Fu, Tinghu Zhang, Nathanael S Gray
The SRPK family of kinases regulates pre-mRNA splicing by phosphorylating serine/arginine (SR)-rich splicing factors, signals splicing control in response to extracellular stimuli, and contributes to tumorigenesis, suggesting that these splicing kinases are potential therapeutic targets. Here, we report the development of the first irreversible SRPK inhibitor, SRPKIN-1, which is also the first kinase inhibitor that forms a covalent bond with a tyrosine phenol group in the ATP-binding pocket. Kinome-wide profiling demonstrates its selectivity for SRPK1/2, and SRPKIN-1 attenuates SR protein phosphorylation at submicromolar concentrations...
February 14, 2018: Cell Chemical Biology
Nicola Aceto, Aditya Bardia, Ben S Wittner, Maria C Donaldson, Ryan O'Keefe, Amanda Engstrom, Francesca Bersani, Yu Zheng, Valentine Comaills, Kira Niederhoffer, Huili Zhu, Olivia MacKenzie, Toshi Shioda, Dennis Sgroi, Ravi Kapur, David T Ting, Beverly Moy, Sridhar Ramaswamy, Mehmet Toner, Daniel A Haber, Shyamala Maheswaran
Molecular drivers underlying bone metastases in human cancer are not well understood, in part due to constraints in bone tissue sampling. Here, RNA sequencing (RNA-seq) was performed of circulating tumor cells (CTCs) isolated from blood samples of women with metastatic estrogen receptor (ER)+ breast cancer, comparing cases with progression in bone versus visceral organs. Among the activated cellular pathways in CTCs from bone-predominant breast cancer is androgen receptor (AR) signaling. AR gene expression is evident, as is its constitutively active splice variant AR-v7...
February 16, 2018: Molecular Cancer Research: MCR
Xinhong Zhu, Ting Xiong, Peiyi Liu, Xiaoping Guo, Lin Xiao, Feng Zhou, Yuhan Tang, Ping Yao
The consumption of a quercetin-rich diet has been well-established as a feasible method against non-alcoholic fatty liver disease (NAFLD); however, the molecular mechanisms underlying the progression of NAFLD and its intervention by quercetin remain largely obscure. Male Sprague-Dawley rats fed high-fat diet (HFD), and HepG2 cells stimulated with free fatty acid, were treated with quercetin and various pharmacological reagents to explore the effect of signaling pathways involved in endoplasmic reticulum stress on very low-density lipoprotein (VLDL) assembly and lipophagy...
February 10, 2018: Food and Chemical Toxicology
Judit M Pérez Ortiz, Harry T Orr
Spinocerebellar ataxia type 1 (SCA1) is an adult-onset, inherited disease that leads to degeneration of Purkinje cells of the cerebellum and culminates in death 10-30 years after disease onset. SCA1 is caused by a CAG repeat mutation in the ATXN1 gene, encoding the ATXN1 protein with an abnormally expanded polyglutamine tract. As neurodegeneration progresses, other brain regions become involved and contribute to cognitive deficits as well as problems with speech, swallowing, and control of breathing. The fundamental basis of pathology is an aberration in the normal function of Purkinje cells affecting regulation of gene transcription and RNA splicing...
2018: Advances in Experimental Medicine and Biology
Thomas Wilhelm, Fabian Bick, Kerstin Peters, Vrinda Mohta, Boaz Tirosh, John B Patterson, Behzad Kharabi-Masouleh, Michael Huber
The intensity and duration of endoplasmic reticulum (ER) stress converts the unfolded protein response (UPR) from an adaptive into a terminal response. The first regulates homeostasis, the latter triggers apoptosis. Cells that rapidly proliferate and possess developed secretory capabilities, such as leukemia cells, depend on an efficiently operating UPR to maintain proteostasis. Activation of terminal UPR by either blockade of adaptive UPR or exaggeration of ER stress has been explored as a novel approach in cancer therapy...
January 9, 2018: Oncotarget
Minchul Seo, S K M Azizul Islam, Seong-Su Moon
Hypothalamus is the regulatory center of both appetite and energy balance, and endoplasmic reticulum (ER) stress in the hypothalamus is involved in the pathogenesis of obesity. Recently, inhibition of 11 β hydroxysteroid dehydrogenase type1 (11β-HSD1) was reported to have an anti-obesity effect by reducing fat mass. However, link between the role of 11β-HSD1 in hypothalamus and obesity has yet to be elucidated. In this study, embryonal primary hypothalamic neurons and high fat diet (HFD) fed mice were used to investigate the anorexigenic effects of 11β-HSD1 inhibitors in in vitro and in vivo...
February 8, 2018: Journal of Neuroendocrinology
Jean-François Groulx, Salah Boudjadi, Jean-François Beaulieu
The α6 integrin subunit (ITGA6) pre-mRNA undergoes alternative splicing to form two splicing variants, named ITGA6A and ITGA6B. In primary human colorectal cancer cells, the levels of both ITGA6 and β4 integrin subunit (ITGB4) subunits of the α6β4 integrin are increased. We previously found that the upregulation of ITGA6 is a direct consequence of the increase of the pro-proliferative ITGA6A variant. However, the mechanisms that control ITGA6 expression and splicing into the ITGA6A variant over ITGA6B in colorectal cancer cells remain poorly understood...
February 3, 2018: Cancers
S Spena, I Garagiola, A Cannavò, M Mortarino, P M Mannucci, F R Rosendaal, F Peyvandi
BACKGROUND: The type of F8 mutation is the main predictor of inhibitor development in patients with severe hemophilia A. Mutations expected to allow a residual synthesis of FVIII are likely to play a protective role towards alloantibody development by inducing immune tolerance. According to the expected full or partial impairment of FVIII synthesis, F8 variants are commonly classified as null and non-null. OBJECTIVES: To explore the mutation type-inhibitor risk association in a cohort of 231 patients with severe hemophilia A enrolled in the SIPPET (Survey of Inhibitors in Plasma-Product Exposed Toddlers) randomized trial...
February 5, 2018: Journal of Thrombosis and Haemostasis: JTH
Jibin John, Aditya Sharma, Prachi Kukshal, Triptish Bhatia, Vishwajit L Nimgaonkar, Smita N Deshpande, B K Thelma
Candidate gene and genome-wide association study based common risk variant identification is being complemented by whole exome sequencing (WES)/whole genome sequencing based rare variant discovery in elucidation of genetic landscape of schizophrenia (SZ), a common neuropsychiatric disorder. WES findings of de novo mutations in case-parent trios have further implied genetic etiology, but do not explain the high genetic risk in general populations. Conversely, WES in multiplex families may be an insightful strategy for the identification of highly penetrant rare variants in SZ and possibly enhance our understanding of disease biology...
January 29, 2018: Schizophrenia Bulletin
Xiaoying Liu, Grace L Guo, Bo Kong, David B Hilburn, Susan C Hubchak, Seong Park, Brian LeCuyer, Antony Hsieh, Li Wang, Deyu Fang, Richard M Green
Bile acids are endogenous ligands of the nuclear receptor farnesoid X receptor (FXR), and pharmacologic FXR modulators are under development for the treatment of several liver disorders. The inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1) pathway of the unfolded protein response (UPR) is a protective cellular signaling pathway activated in response to endoplasmic reticulum stress. We investigated the role of FXR signaling in the activation of the hepatic XBP1 pathway. Mice were treated with deoxycholic acid (DCA), cholestyramine, GW4064 or underwent bile duct ligation (BDL) and the hepatic UPR activation was measured...
January 29, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Nerea Irigoyen, Adam M Dinan, Ian Brierley, Andrew E Firth
BACKGROUND: The retrovirus murine leukemia virus (MuLV) has an 8.3 kb RNA genome with a simple 5'-gag-pol-env-3' architecture. Translation of the pol gene is dependent upon readthrough of the gag UAG stop codon; whereas the env gene is translated from spliced mRNA transcripts. Here, we report the first high resolution analysis of retrovirus gene expression through tandem ribosome profiling (RiboSeq) and RNA sequencing (RNASeq) of MuLV-infected cells. RESULTS: Ribosome profiling of MuLV-infected cells was performed, using the translational inhibitors harringtonine and cycloheximide to distinguish initiating and elongating ribosomes, respectively...
January 22, 2018: Retrovirology
Bomi Kim, Jayoung Kim, Yeong Seok Kim
Cyclooxygenase-2 (COX-2) is an enzyme induced by various proinflammatory and mitogenic stimuli. Celecoxib is a selective inhibitor of COX-2 that have been shown to affect cell growth and apoptosis. Lung cancer cells expressing COX-2 is able to be a target of celecoxib, this study focuses on investigating that celecoxib induces apoptosis via endoplasmic reticulum (ER) stress on lung cancer cells. We investigated whether celecoxib induced apoptosis on non-small cell lung cancer cell line, A549 and H460. The 50 µM of celecoxib increased apoptotic cells and 100 µM of celecoxib significantly induced apoptosis...
December 2017: Anatomy & Cell Biology
Raymond W Wong, Clifford A Lingwood, Mario A Ostrowski, Tyler Cabral, Alan Cochrane
The capacity of HIV-1 to develop resistance to current drugs calls for innovative strategies to control this infection. We aimed at developing novel inhibitors of HIV-1 replication by targeting viral RNA processing-a stage dependent on conserved host processes. We previously reported that digoxin is a potent inhibitor of this stage. Herein, we identify 12 other cardiac glycoside/aglycones or cardiotonic steroids (CSs) that impede HIV growth in HIV-infected T cells from clinical patients at IC50s (1.1-1.3 nM) that are 2-26 times below concentrations used in patients with heart conditions...
January 16, 2018: Scientific Reports
Ryosuke Kida, Taiki Noguchi, Masaru Murakami, Osamu Hashimoto, Teruo Kawada, Tohru Matsui, Masayuki Funaba
We previously showed that brown (pre)adipocytes express Trpv1, a capsaicin receptor, and that capsaicin stimulates differentiation of brown preadipocytes in the late stages of brown adipogenesis. The present study revealed that treatment with 100 μM capsaicin stimulates brown adipogenesis by inducing endoplasmic reticulum (ER) stress. Treatment with capsaicin (100 μM) during brown adipogenesis enhanced lipid accumulation and the expression of Ucp1, a gene selectively expressed in brown adipocytes. Capsaicin treatment also caused an increase in the cytosolic calcium concentration even when extracellular calcium was removed...
January 16, 2018: Scientific Reports
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