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https://www.readbyqxmd.com/read/28220790/in-vivo-genome-editing-with-a-small-cas9-orthologue-derived-from-campylobacter-jejuni
#1
Eunji Kim, Taeyoung Koo, Sung Wook Park, Daesik Kim, Kyoungmi Kim, Hee-Yeon Cho, Dong Woo Song, Kyu Jun Lee, Min Hee Jung, Seokjoong Kim, Jin Hyoung Kim, Jeong Hun Kim, Jin-Soo Kim
Several CRISPR-Cas9 orthologues have been used for genome editing. Here, we present the smallest Cas9 orthologue characterized to date, derived from Campylobacter jejuni (CjCas9), for efficient genome editing in vivo. After determining protospacer-adjacent motif (PAM) sequences and optimizing single-guide RNA (sgRNA) length, we package the CjCas9 gene, its sgRNA sequence, and a marker gene in an all-in-one adeno-associated virus (AAV) vector and produce the resulting virus at a high titer. CjCas9 is highly specific, cleaving only a limited number of sites in the human or mouse genome...
February 21, 2017: Nature Communications
https://www.readbyqxmd.com/read/28181149/genome-wide-sequencing-reveals-micrornas-downregulated-in-cerebral-cavernous-malformations
#2
Souvik Kar, Kiran Kumar Bali, Arpita Baisantry, Robert Geffers, Amir Samii, Helmut Bertalanffy
Cerebral cavernous malformations (CCM) are vascular lesions associated with loss-of-function mutations in one of the three genes encoding KRIT1 (CCM1), CCM2, and PDCD10. Recent understanding of the molecular mechanisms that lead to CCM development is limited. The role of microRNAs (miRNAs) has been demonstrated in vascular pathologies resulting in loss of tight junction proteins, increased vascular permeability and endothelial cell dysfunction. Since the relevance of miRNAs in CCM pathophysiology has not been elucidated, the primary aim of the study was to identify the miRNA-mRNA expression network associated with CCM...
February 8, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28165644/hif1a-gene-polymorphisms-and-human-diseases-graphical-review-of-97-association-studies
#3
REVIEW
I Gladek, J Ferdin, S Horvat, G A Calin, T Kunej
Hypoxia-inducible factors (HIFs) belong to a family of transcription factors (TF) responsive to a low O2 availability, which is often a characteristic feature of solid tumors. The alpha subunit of the HIF heterodimer is O2 -sensitive, and once stabilized in hypoxia, it functions as a master regulator of various genes involved in hypoxia pathway. Changes in the HIF1A (hypoxia inducible factor 1, alpha subunit) nucleotide sequence or expression has been shown to be associated with development of several diseases...
February 6, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28143503/genetic-polymorphisms-in-key-hypoxia-regulated-downstream-molecules-and-phenotypic-correlation-in-prostate-cancer
#4
Avelino Fraga, Ricardo Ribeiro, André Coelho, José Ramon Vizcaíno, Helena Coutinho, José Manuel Lopes, Paulo Príncipe, Carlos Lobato, Carlos Lopes, Rui Medeiros
BACKGROUND: In this study we sought if, in their quest to handle hypoxia, prostate tumors express target hypoxia-associated molecules and their correlation with putative functional genetic polymorphisms. METHODS: Representative areas of prostate carcinoma (n = 51) and of nodular prostate hyperplasia (n = 20) were analysed for hypoxia-inducible factor 1 alpha (HIF-1α), carbonic anhydrase IX (CAIX), lysyl oxidase (LOX) and vascular endothelial growth factor (VEGFR2) immunohistochemistry expression using a tissue microarray...
January 31, 2017: BMC Urology
https://www.readbyqxmd.com/read/28131740/adipose-tissue-is-influenced-by-hypoxia-of-obstructive-sleep-apnea-syndrome-independent-of-obesity
#5
C E Thorn, B Knight, E Pastel, L J McCulloch, B Patel, A C Shore, K Kos
AIMS: Obstructive sleep apnea syndrome (OSAS) is associated with increased cardiovascular risk and diabetes independent of obesity. We investigated whether adipose tissue dysfunction is exacerbated due to increased tissue hypoxia. METHODS: Adipose tissue (AT) oxygenation was measured with a Clarke-type electrode (pATO2) in 16 men with OSAS before and after 4 months of continuous positive airway pressure therapy (CPAP) and in BMI-matched controls. Oxygenation was simultaneously monitored in arterial blood by pulse oximetry (SaO2); mixed blood in AT microcirculation by reflectance spectroscopy (SATO2) along with blood flow...
January 25, 2017: Diabetes & Metabolism
https://www.readbyqxmd.com/read/28115626/prmt5-regulates-ires-dependent-translation-via-methylation-of-hnrnp-a1
#6
Guozhen Gao, Surbhi Dhar, Mark T Bedford
The type II arginine methyltransferase PRMT5 is responsible for the symmetric dimethylation of histone to generate the H3R8me2s and H4R3me2s marks, which correlate with the repression of transcription. However, the protein level of a number of genes (MEP50, CCND1, MYC, HIF1a, MTIF and CDKN1B) are reported to be downregulated by the loss of PRMT5, while their mRNA levels remain unchanged, which is counterintuitive for PRMT5's proposed role as a transcription repressor. We noticed that the majority of the genes regulated by PRMT5, at the posttranscriptional level, express mRNA containing an internal ribosome entry site (IRES)...
January 23, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28115494/hif1a-and-epas1-potentiate-hypoxia-induced-upregulation-of-inhibin-alpha-chain-expression-in-human-term-cytotrophoblasts-in-vitro
#7
C L Depoix, I de Selliers, C Hubinont, F Debieve
STUDY QUESTION: Are hypoxia-inducible factors (HIF) responsible for the potentiation of inhibin alpha subunit (INHA) gene expression in primary cultures of human term cytotrophoblasts under low-oxygen tension? SUMMARY ANSWER: Both HIF1A and endothelial PAS domain protein 1 (EPAS1) are involved in the potentiation of INHA gene upregulation in cytotrophoblasts cultured under hypoxia. WHAT IS KNOWN ALREADY: During the in vitro differentiation of cytotrophoblasts into syncytiotrophoblasts under 21% O2, INHA expression increases...
January 23, 2017: Molecular Human Reproduction
https://www.readbyqxmd.com/read/28112274/hypoxia-inducible-factors-are-dispensable-for-myeloid-cell-migration-into-the-inflamed-mouse-eye
#8
Peter J Gardner, Sidath E Liyanage, Enrico Cristante, Robert D Sampson, Andrew D Dick, Robin R Ali, James W Bainbridge
Hypoxia inducible factors (HIFs) are ubiquitously expressed transcription factors important for cell homeostasis during dynamic oxygen levels. Myeloid specific HIFs are crucial for aspects of myeloid cell function, including their ability to migrate into inflamed tissues during autoimmune disease. This contrasts with the concept that accumulation of myeloid cells at ischemic and hypoxic sites results from a lack of chemotactic responsiveness. Here we seek to address the role of HIFs in myeloid trafficking during inflammation in a mouse model of human uveitis...
January 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28104508/exposure-to-high-levels-of-fumarate-and-succinate-leads-to-apoptotic-cytotoxicity-and-altered-global-dna-methylation-profiles-in-vitro
#9
Johannes F Wentzel, Angélique Lewies, Abel J Bronkhorst, Etresia van Dyk, Lissinda H du Plessis, Piet J Pretorius
In the Krebs cycle, succinate is oxidized to fumarate by succinate dehydrogenase (SDH), followed by the conversion of fumarate to malate by fumarate hydratase (FH). In cells with defective SDH and FH, the Krebs cycle is congested, respiration impaired and fumarate and succinate accumulates. Several studies have indicated that the accumulation of these substrates are associated with cytotoxicity and oncogenesis. High levels of succinate and fumarate induce hypoxia inducible factor (HIF1A) hydroxylases, leading to the activation of oncogenic HIF pathways...
January 16, 2017: Biochimie
https://www.readbyqxmd.com/read/28092369/context-dependent-role-for-chromatin-remodeling-component-pbrm1-baf180-in-clear-cell-renal-cell-carcinoma
#10
A Murakami, L Wang, S Kalhorn, P Schraml, W K Rathmell, A C Tan, R Nemenoff, K Stenmark, B-H Jiang, M E Reyland, L Heasley, C-J Hu
A subset of clear cell renal cell carcinoma (ccRCC) tumors exhibit a HIF1A gene mutation, yielding two ccRCC tumor types, H1H2 type expressing both HIF1α and HIF2α, and H2 type expressing HIF2α, but not functional HIF1α protein. However, it is unclear how the H1H2 type ccRCC tumors escape HIF1's tumor-suppressive activity. The polybromo-1 (PBRM1) gene coding for the BAF180 protein, a component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, is inactivated in 40% ccRCCs, the function and mechanism of BAF180 mutation is unknown...
January 16, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28088462/activation-of-the-hypoxia-inducible-factor-1-alpha-subunit-pathway-in-steatotic-liver-contributes-to-formation-of-cholesterol-gallstones
#11
Yoichiro Asai, Tetsuya Yamada, Sohei Tsukita, Kei Takahashi, Masamitsu Maekawa, Midori Honma, Masanori Ikeda, Keigo Murakami, Yuichiro Munakata, Yuta Shirai, Shinjiro Kodama, Takashi Sugisawa, Yumiko Chiba, Yasuteru Kondo, Keizo Kaneko, Kenji Uno, Shojiro Sawada, Junta Imai, Yasuhiro Nakamura, Hiroaki Yamaguchi, Kozo Tanaka, Hironobu Sasano, Nariyasu Mano, Yoshiyuki Ueno, Tooru Shimosegawa, Hideki Katagiri
BACKGROUND AND AIMS: Hypoxia inducible factor 1 alpha subunit (HIF1A) is a transcription factor that controls the cellular response to hypoxia and is activated in hepatocytes of patients with non-alcoholic fatty liver disease (NAFLD). NAFLD increases risk for cholesterol gallstone disease by unclear mechanisms. We studied the relationship between HIF1A and gallstone formation associated with liver steatosis. METHODS: We performed studies with mice with inducible disruption of Hif1a in hepatocytes, via a Cre adenoviral vector (iH-HIFKO mice), and mice without disruption of Hif1a (control mice)...
January 11, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28077088/integrated-rna-seq-and-dnase-seq-analyses-identify-phenotype-specific-bmp4-signaling-in-breast-cancer
#12
M Ampuja, T Rantapero, A Rodriguez-Martinez, M Palmroth, E L Alarmo, M Nykter, A Kallioniemi
BACKGROUND: Bone morphogenetic protein 4 (BMP4) plays an important role in cancer pathogenesis. In breast cancer, it reduces proliferation and increases migration in a cell line-dependent manner. To characterize the transcriptional mediators of these phenotypes, we performed RNA-seq and DNase-seq analyses after BMP4 treatment in MDA-MB-231 and T-47D breast cancer cells that respond to BMP4 with enhanced migration and decreased cell growth, respectively. RESULTS: The RNA-seq data revealed gene expression changes that were consistent with the in vitro phenotypes of the cell lines, particularly in MDA-MB-231, where migration-related processes were enriched...
January 11, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28074863/herb-pair-danggui-honghua-mechanisms-underlying-blood-stasis-syndrome-by-system-pharmacology-approach
#13
Shi-Jun Yue, Lan-Ting Xin, Ya-Chu Fan, Shu-Jiao Li, Yu-Ping Tang, Jin-Ao Duan, Hua-Shi Guan, Chang-Yun Wang
Herb pair Danggui-Honghua has been frequently used for treatment of blood stasis syndrome (BSS) in China, one of the most common clinical pathological syndromes in traditional Chinese medicine (TCM). However, its therapeutic mechanism has not been clearly elucidated. In the present study, a feasible system pharmacology model based on chemical, pharmacokinetic and pharmacological data was developed via network construction approach to clarify the mechanisms of this herb pair. Thirty-one active ingredients of Danggui-Honghua possessing favorable pharmacokinetic profiles and biological activities were selected, interacting with 42 BSS-related targets to provide potential synergistic therapeutic actions...
January 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28055967/cycling-hypoxia-affects-cell-invasion-and-proliferation-through-direct-regulation-of-claudin1-claudin7-expression-and-indirect-regulation-of-p18-through-claudin7
#14
Hong Liu, Feifei Jiang, Xinshan Jia, Jing Lan, Hao Guo, Erran Li, Aihui Yan, Yan Wang
Claudins (CLDNs), the major integral membrane proteins at tight junction, play critical roles in apical cell-to-cell adhesion, maintenance of epithelial polarity, and formation of impermeable barriers between epithelial cells.We investigated in this study the expression of CLDNs- Claudin1 (CLDN1) and Claudin7 (CLDN7), and their relation to tumor progression in nasopharyngeal cancer (NPC). CLDN7, rather than CLDN1, showed higher expression in both undifferentiated tumor tissue and the poorly differentiated CNE2 cells, compared with differentiated tissue and the highly differentiated CNE1 cells...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28038356/mrna-overexpression-of-the-hypoxia-inducible-factor-1-alpha-subunit-gene-hif1a-an-independent-predictor-of-poor-overall-survival-in-chronic-lymphocytic-leukemia
#15
Christos K Kontos, Sotirios G Papageorgiou, Marios A Diamantopoulos, Andreas Scorilas, Efthimia Bazani, Diamantina Vasilatou, Konstantinos Gkontopoulos, Eirini Glezou, Georgia Stavroulaki, George Dimitriadis, Vasiliki Pappa
The hypoxia inducible factor 1 (HIF1) is a heterodimeric transcription factor that ultimately regulates cellular responses to changes in oxygen tension. In this study, we examined the potential diagnostic and prognostic potential of the mRNA expression of HIF1 regulatory α-subunit (HIF1A) in chronic lymphocytic leukemia (CLL). For this purpose, total RNA was isolated from peripheral blood mononuclear cells collected from 88 CLL patients and 33 non-leukemic blood donors, and poly(A)-RNA was reversely transcribed...
November 29, 2016: Leukemia Research
https://www.readbyqxmd.com/read/28036268/role-of-vhl-hif1a-and-sdh-on-the-expression-of-mir-210-implications-for-tumoral-pseudo-hypoxic-fate
#16
Anna Merlo, Cristóbal Bernardo-Castiñeira, Inés Sáenz-de-Santa-María, Ana S Pitiot, Milagros Balbín, Aurora Astudillo, Nuria Valdés, Bartolomé Scola, Raquel Del Toro, Simón Méndez-Ferrer, José I Piruat, Carlos Suarez, María-Dolores Chiara
The hypoxia-inducible factor 1α (HIF-1α) and its microRNA target, miR-210, are candidate tumor-drivers of metabolic reprogramming in cancer. Neuroendocrine neoplasms such as paragangliomas (PGLs) are particularly appealing for understanding the cancer metabolic adjustments because of their associations with deregulations of metabolic enzymes, such as succinate dehydrogenase (SDH), and the von Hippel Lindau (VHL) gene involved in HIF-1α stabilization. However, the role of miR-210 in the pathogenesis of SDH-related tumors remains an unmet challenge...
January 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28031235/htp-nutraceutical-screening-for-histone-deacetylase-inhibitors-and-effects-of-hdacis-on-tumor-suppressing-mirnas-by-trichostatin-a-and-grapeseed-vitis-vinifera-in-hela-cells
#17
Elizabeth A Mazzio, Karam F A Soliman
BACKGROUND/AIM: Aggressive tumor malignancies are a consequence of delayed diagnosis, epigenetic/phenotype changes and chemo-radiation resistance. Histone deacetylases (HDACs) are a major epigenetic regulator of transcriptional repression, which are highly overexpressed in advanced malignancy. While original chemotherapy drugs were modeled after phytochemicals elucidated by botanical screenings, HDAC inhibitors (HDACi) such as apicidin, trichostatin A (TSA) and butyrate were discovered as products of fungus and microbes, in particular, gut microbiota...
2, 2017: Cancer Genomics & Proteomics
https://www.readbyqxmd.com/read/28030564/poorly-differentiated-medullary-phenotype-predicts-poor-survival-in-early-lymph-node-negative-gastro-esophageal-adenocarcinomas
#18
Christoph Treese, Pedro Sanchez, Patricia Grabowski, Erika Berg, Hendrik Bläker, Martin Kruschewski, Oliver Haase, Michael Hummel, Severin Daum
BACKGROUND: 5-year survival rate in patients with early adenocarcinoma of the gastro-esophageal junction or stomach (AGE/S) in Caucasian patients is reported to be 60-80%. We aimed to identify prognostic markers for patients with UICC-I without lymph-node involvement (N0). METHODS: Clinical data and tissue specimen from patients with AGE/S stage UICC-I-N0, treated by surgery only, were collected retrospectively. Tumor size, lymphatic vessel or vein invasion, grading, classification systems (WHO, Lauren, Ming), expression of BAX, BCL-2, CDX2, Cyclin E, E-cadherin, Ki-67, TP53, TP21, SHH, Survivin, HIF1A, TROP2 and mismatch repair deficiency were analyzed using tissue microarrays and correlated with overall and tumor related survival...
2016: PloS One
https://www.readbyqxmd.com/read/28030556/hepatocyte-hypoxia-inducible-factor-1-mediates-the-development-of-liver-fibrosis-in-a-mouse-model-of-nonalcoholic-fatty-liver-disease
#19
Omar A Mesarwi, Mi-Kyung Shin, Shannon Bevans-Fonti, Christina Schlesinger, Janet Shaw, Vsevolod Y Polotsky
BACKGROUND: Obstructive sleep apnea (OSA) is associated with the progression of non-alcoholic fatty liver disease (NAFLD) to steatohepatitis and fibrosis. This progression correlates with the severity of OSA-associated hypoxia. In mice with diet induced obesity, hepatic steatosis leads to liver tissue hypoxia, which worsens with exposure to intermittent hypoxia. Emerging data has implicated hepatocyte cell signaling as an important factor in hepatic fibrogenesis. We hypothesized that hepatocyte specific knockout of the oxygen sensing α subunit of hypoxia inducible factor-1 (HIF-1), a master regulator of the global response to hypoxia, may be protective against the development of liver fibrosis...
2016: PloS One
https://www.readbyqxmd.com/read/27994516/genes-involved-in-angiogenesis-and-mtor-pathways-are-frequently-mutated-in-asian-patients-with-pancreatic-neuroendocrine-tumors
#20
Wen-Chi Chou, Po-Han Lin, Yi-Chen Yeh, Yi-Ming Shyr, Wen-Liang Fang, Shin-E Wang, Chun-Yu Liu, Peter Mu-Hsin Chang, Ming-Han Chen, Yi-Ping Hung, Chung-Pin Li, Yee Chao, Ming-Huang Chen
Introduction: To address the issue of limited data on and inconsistent findings for genetic alterations in pancreatic neuroendocrine tumors (pNETs), we analyzed sequences of known pNET-associated genes for their impact on clinical outcomes in a Taiwanese cohort. Methods: Tissue samples from 40 patients with sporadic pNETs were sequenced using a customized sequencing panel that analyzed 43 genes with either an established or potential association with pNETs. Genetic mutations and clinical outcomes were analyzed for potential associations...
2016: International Journal of Biological Sciences
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