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https://www.readbyqxmd.com/read/28213819/conditional-knockout-of-activin-like-kinase-1-alk-1-leads-to-heart-failure-without-maladaptive-remodeling
#1
Kevin J Morine, Xiaoying Qiao, Vikram Paruchuri, Mark J Aronovitz, Emily E Mackey, Lyanne Buiten, Jonathan Levine, Keshan Ughreja, Prerna Nepali, Robert M Blanton, Richard H Karas, S Paul Oh, Navin K Kapur
Activin like kinase-1 (AlK-1) mediates signaling via the transforming growth factor beta (TGFβ) family of ligands. AlK-1 activity promotes endothelial proliferation and migration. Reduced AlK-1 activity is associated with arteriovenous malformations. No studies have examined the effect of global AlK-1 deletion on indices of cardiac remodeling. We hypothesized that reduced levels of AlK-1 promote maladaptive cardiac remodeling. To test this hypothesis, we employed AlK-1 conditional knockout mice (cKO) harboring the ROSA26-CreER knock-in allele, whereby a single dose of intraperitoneal tamoxifen triggered ubiquitous Cre recombinase-mediated excision of floxed AlK-1 alleles...
February 17, 2017: Heart and Vessels
https://www.readbyqxmd.com/read/28210097/epac1-agonist-decreased-inflammatory-proteins-in-retinal-endothelial-cells-and-loss-of-epac1-increased-inflammatory-proteins-in-the-retinal-vasculature-of-mice
#2
Li Liu, Youde Jiang, Adam Chahine, Elizabeth Curtiss, Jena J Steinle
PURPOSE: Increased inflammatory mediator levels are reported in diabetic retinopathy. We previously reported that β-adrenergic receptor agonists reduced inflammatory mediators in the diabetic retina; however, these agents cannot be given systemically. Here, we investigated whether Epac1 is key to the protective effects of β-adrenergic receptor agonists. METHODS: We cultured primary human retinal endothelial cells (RECs) in normal (5 mM) or high (25 mM) glucose and treated them with an Epac1-specific agonist...
2017: Molecular Vision
https://www.readbyqxmd.com/read/28191756/aberrant-transforming-growth-factor-%C3%AE-activation-recruits-mesenchymal-stem-cells-during-prostatic-hyperplasia
#3
Long Wang, Liang Xie, Francis Tintani, Hui Xie, Changjun Li, Zhuang Cui, Mei Wan, Xiongbing Zu, Lin Qi, Xu Cao
Benign prostatic hyperplasia (BPH) is the overgrowth of prostate tissues with high prevalence in older men. BPH pathogenesis is not completely understood, but it is believed to be a result of de novo overgrowth of prostatic stroma. In this study, we show that aberrant activation of transforming growth factor-β (TGF-β) mobilizes mesenchymal/stromal stem cells (MSCs) in circulating blood, which are recruited for the prostatic stromal hyperplasia. Elevated levels of active TGF-β were observed in both a phenylephrine-induced prostatic hyperplasia mouse model and human BPH tissues...
February 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28186681/skin-derived-precursors-as-a-source-of-progenitors-for-corneal-endothelial-regeneration
#4
Emi Inagaki, Shin Hatou, Kazunari Higa, Satoru Yoshida, Shinsuke Shibata, Hideyuki Okano, Kazuo Tsubota, Shigeto Shimmura
Corneal blindness is the fourth leading cause of blindness in the world. Current treatment is allogenic corneal transplantation, which is limited by shortage of donors and immunological rejection. Skin-derived precursors (SKPs) are postnatal stem cells, which are self-renewing, multipotent precursors that can be isolated and expanded from the dermis. Facial skin may therefore be an accessible autologous source of neural crest derived cells. SKPs were isolated from facial skin of Wnt1-Cre/Floxed EGFP mouse. After inducing differentiation with medium containing retinoic acid and GSK 3-β inhibitor, SKPs formed polygonal corneal endothelial-like cells (sTECE)...
February 6, 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28182703/nephropathy-in-pparg-null-mice-highlights-ppar%C3%AE-systemic-activities-in-metabolism-and-in-the-immune-system
#5
Barbara Toffoli, Federica Gilardi, Carine Winkler, Magnus Soderberg, Laura Kowalczuk, Yvan Arsenijevic, Krister Bamberg, Olivier Bonny, Béatrice Desvergne
Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-dependent transcription factor involved in many aspects of metabolism, immune response, and development. Total-body deletion of the two Pparg alleles provoked generalized lipoatrophy along with severe type 2 diabetes. Herein, we explore the appearance and development of structural and functional alterations of the kidney, comparing Pparg null-mice to their littermate controls (carrying Pparg floxed alleles). We show that renal hypertrophy and functional alterations with increased glucosuria and albuminuria are already present in 3 weeks-old Pparg null-mice...
2017: PloS One
https://www.readbyqxmd.com/read/28180061/kinase-suppressor-of-ras-2-ksr2-expression-in-the-brain-regulates-energy-balance-and-glucose-homeostasis
#6
Lili Guo, Diane L Costanzo-Garvey, Deandra R Smith, Beth K Neilsen, Richard G MacDonald, Robert E Lewis
OBJECTIVE: Kinase Suppressor of Ras 2 (KSR2) is a molecular scaffold coordinating Raf/MEK/ERK signaling that is expressed at high levels in the brain. KSR2 disruption in humans and mice causes obesity and insulin resistance. Understanding the anatomical location and mechanism of KSR2 function should lead to a better understanding of physiological regulation over energy balance. METHODS: Mice bearing floxed alleles of KSR2 (KSR2(fl/fl)) were crossed with mice expressing the Cre recombinase expressed by the Nestin promoter (Nes-Cre) to produce Nes-CreKSR2(fl/fl) mice...
February 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28178391/amino-terminal-enhancer-of-split-gene-aes-encodes-a-tumor-and-metastasis-suppressor-of-prostate-cancer
#7
Yoshiyuki Okada, Masahiro Sonoshita, Fumihiko Kakizaki, Naoki Aoyama, Yoshiro Itatani, Masayuki Uegaki, Hiromasa Sakamoto, Takashi Kobayashi, Takahiro Inoue, Tomomi Kamba, Akira Suzuki, Osamu Ogawa, M Mark Taketo
Major cause of cancer death is its metastasis to the vital organs. Few effective therapies are available for metastatic castration-resistant prostate cancer (PCa), and progressive metastatic lesions such as lymph nodes and bones cause mortality. We recently identified AES as a metastasis suppressor for colon cancer. Here, we have studied the roles of AES in PCa progression. We analyzed the relationship between AES expression and PCa stages of progression by immunohistochemistry of human needle biopsy samples...
February 8, 2017: Cancer Science
https://www.readbyqxmd.com/read/28176880/crispr-cas9-mediated-gene-manipulation-to-create-single-amino-acid-substituted-and-floxed-mice-with-a-cloning-free-method
#8
Xiaolong Ma, Chao Chen, Jennifer Veevers, XinMin Zhou, Robert S Ross, Wei Feng, Ju Chen
Clustered regulatory interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology is a powerful tool to manipulate the genome with extraordinary simplicity and speed. To generate genetically modified animals, CRISPR/Cas9-mediated genome editing is typically accomplished by microinjection of a mixture of Cas9 DNA/mRNA and single-guide RNA (sgRNA) into zygotes. However, sgRNAs used for this approach require manipulation via molecular cloning as well as in vitro transcription. Beyond these complexities, most mutants obtained with this traditional approach are genetically mosaic, yielding several types of cells with different genetic mutations...
February 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28176446/generation-and-characterization-of-mice-for-conditional-inactivation-of-zeb1
#9
Simone Brabletz, María Lasierra Losada, Otto Schmalhofer, Julia Mitschke, Angela Krebs, Thomas Brabletz, Marc P Stemmler
The multi-zinc finger containing transcription factor ZEB1 plays crucial roles during various aspects of mammalian development and tumorigenesis. Best studied in human tumors, ZEB1 is activating the embryo-derived program of epithelial-mesenchymal transition (EMT). The aberrant activation of EMT confers an invasive metastasizing phenotype with acquisition of stem cell properties and resistance to radio- and chemotherapy. Although ZEB1 has very important functions in tumor progression, not much is known about its role in physiological contexts and during development and homeostasis...
February 8, 2017: Genesis: the Journal of Genetics and Development
https://www.readbyqxmd.com/read/28174748/requirement-of-g%C3%AE-q-g%C3%AE-11-signaling-in-the-preservation-of-mouse-intestinal-epithelial-homeostasis
#10
Noboru Watanabe, Hirosato Mashima, Kouichi Miura, Takashi Goto, Makoto Yoshida, Akiteru Goto, Hirohide Ohnishi
BACKGROUND & AIMS: Proliferation, differentiation, and morphogenesis of the intestinal epithelium are tightly regulated by a number of molecular pathways. Coordinated action of intestine is achieved by gastrointestinal hormones, most of which exert these actions through G-protein-coupled receptors. We herein investigated the role of Gαq/11-mediated signaling in intestinal homeostasis. METHODS: Intestinal tissues from control (Gnaq(flox/flox)Gna11(+/+) ), Int-Gq knock-out (KO) (VilCre(+/-)Gnaq(flox/flox)Gna11(+/+) ), G11 KO (Gnaq(flox/flox)Gna11(-/-) ), and Int-Gq/G11 double knock-out (DKO) (VilCre(+/-)Gnaq(flox/flox)Gna11(-/-) ) mice were examined by microscopy, transmission electron microscopy, and immunohistochemistry...
November 2016: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28154007/loss-of-endothelial-cxcr7-impairs-vascular-homeostasis-and-cardiac-remodeling-after-myocardial-infarction-implications-for-cardiovascular-drug-discovery
#11
Huifeng Hao, Sheng Hu, Hong Chen, Dawei Bu, Liyuan Zhu, Chuansheng Xu, Fei Chu, Xingyu Huo, Yue Tang, Xiaogang Sun, Bisen Ding, Depei Liu, Shengshou Hu, Miao Wang
BACKGROUND: -Genome-wide association studies identified the association of the CXCL12 genetic locus (which encodes the chemokine CXCL12, also known as stromal cell-derived factor 1) with coronary artery disease (CAD) and myocardial infarction (MI). Unlike CXCR4, the classical receptor for CXCL12, the function of CXCR7 (the most recently identified receptor) in vascular responses to injury and in MI remains unclear. METHODS: -Tissue expression of CXCR7 was examined in arteries from mice and humans...
February 2, 2017: Circulation
https://www.readbyqxmd.com/read/28130067/farnesoid-x-receptor-activation-promotes-hepatic-amino-acid-catabolism-and-ammonium-clearance-in-mice
#12
Vittoria Massafra, Alexandra Milona, Harmjan R Vos, Rúben J J Ramos, Johan Gerrits, Ellen C L Willemsen, José M Ramos Pittol, Noortje Ijssennagger, Martin Houweling, Hubertus C M T Prinsen, Nanda M Verhoeven-Duif, Boudewijn M Burgering, Saskia W C van Mil
BACKGROUND & AIMS: The nuclear receptor subfamily 1 group H member 4 (NR1H4 or farnesoid X receptor, FXR) regulates bile acid synthesis, transport, and catabolism. FXR also regulates post-prandial lipid and glucose metabolism. We performed quantitative proteomic analyses of liver tissues from mice to evaluate these functions and investigate whether FXR regulates amino acid metabolism. METHODS: To study the role of FXR in mouse liver, we used mice with a disruption of Nr1h4 (FXR-knockout mice) and compared them to floxed control mice...
January 24, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28120642/a-novel-mouse-model-of-conditional-irak-m-deficiency-in-myeloid-cells-application-in-lung-pseudomonas-aeruginosa-infection
#13
Di Jiang, Jennifer Matsuda, Reena Berman, Niccolette Schaefer, Connor Stevenson, James Gross, Bicheng Zhang, Amelia Sanchez, Liwu Li, Hong Wei Chu
Myeloid cells such as macrophages are critical to innate defense against infection. IL-1 receptor-associated kinase M (IRAK-M) is a negative regulator of TLR signaling during bacterial infection, but the role of myeloid cell IRAK-M in bacterial infection is unclear. Our goal was to generate a novel conditional knockout mouse model to define the role of myeloid cell IRAK-M during bacterial infection. Myeloid cell-specific IRAK-M knockout mice were generated by crossing IRAK-M floxed mice with LysM-Cre knock-in mice...
February 2017: Innate Immunity
https://www.readbyqxmd.com/read/28120397/the-linear-ubiquitin-chain-assembly-complex-acts-as-a-liver-tumor-suppressor-and-inhibits-hepatocyte-apoptosis-and-hepatitis
#14
Yutaka Shimizu, Nieves Peltzer, Alexandra Sevko, Elodie Lafont, Aida Sarr, Helena Draberova, Henning Walczak
: Linear ubiquitination is a key post-translational modification that regulates immune signaling and cell death pathways, notably TNFR1 signaling. The only known enzyme complex capable of forming linear ubiquitin chains under native conditions to date is the linear ubiquitin chain assembly complex (LUBAC), of which the catalytic core component is HOIP. To understand the underlying mechanisms of maintenance of liver homeostasis and the role of linear ubiquitination specifically in liver parenchymal cells, we investigated the physiological role of HOIP in the liver parenchyma...
January 24, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28116732/generation-of-a-mouse-model-with-smooth-muscle-cell-specific-loss-of-the-expression-of-ppar%C3%AE
#15
Yohann Rautureau, Pierre Paradis, Ernesto L Schiffrin
An inducible tissue-specific knockout (KO) technique has been used to study the role of genes in the adult heart. This KO technique circumvents the developmental effect that could otherwise be observed in a tissue-specific KO. The peroxisome proliferator-activated receptor (PPAR) γ is a transcription factor that when activated has been shown to improve vascular remodeling and endothelial function in hypertensive rodents. Here we describe an inducible tissue specific KO protocol used to study the role of PPARγ in smooth muscle cells (SMC) in angiotensin (Ang) II-induced hypertension in adult mice...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28114578/compound-49b-regulates-zo-1-and-occludin-levels-in-human-retinal-endothelial-cells-and-in-mouse-retinal-vasculature
#16
Youde Jiang, Li Liu, Jena J Steinle
Purpose: To investigate whether Epac1 is key to Compound 49b's regulation of zonula occluden 1 (ZO-1) and occludin levels in human retinal endothelial cells (REC) and in an Epac1 vascular-specific conditional knockout mouse retina. Methods: Primary REC were grown in normal (5 mM) or high glucose (25 mM). Some cells were treated with a novel β-adrenergic receptor agonist, Compound 49b. Additional dishes were treated with Epac1 siRNA or Compound 49b + Epac1 siRNA...
January 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28107516/liver-amp-activated-protein-kinase-is-unnecessary-for-gluconeogenesis-but-protects-energy-state-during-nutrient-deprivation
#17
Clinton M Hasenour, D Emerson Ridley, Freyja D James, Curtis C Hughey, E Patrick Donahue, Benoit Viollet, Marc Foretz, Jamey D Young, David H Wasserman
AMPK is an energy sensor that protects cellular energy state by attenuating anabolic and promoting catabolic processes. AMPK signaling is purported to regulate hepatic gluconeogenesis and substrate oxidation; coordination of these processes is vital during nutrient deprivation or pathogenic during overnutrition. Here we directly test hepatic AMPK function in regulating metabolic fluxes that converge to produce glucose and energy in vivo. Flux analysis was applied in mice with a liver-specific deletion of AMPK (L-KO) or floxed control littermates to assess rates of hepatic glucose producing and citric acid cycle (CAC) fluxes...
2017: PloS One
https://www.readbyqxmd.com/read/28107458/neuropilin-1-involvement-in-choroidal-and-retinal-neovascularisation
#18
Patricia Fernández-Robredo, Senthil Selvam, Michael B Powner, Dawn A Sim, Marcus Fruttiger
PURPOSE: Inhibiting VEGF is the gold standard treatment for neovascular age-related macular degeneration (AMD). It is also effective in preventing retinal oedema and neovascularisation (NV) in diabetic retinopathy (DR) and retinal vein occlusions (RVO). Neuropilin 1 (Nrp1) is a co-receptor for VEGF and many other growth factors, and therefore a possible alternative drug target in intra ocular neovascular disease. Here we assessed choroidal and retinal NV in an inducible, endothelial specific knock out model for Nrp1...
2017: PloS One
https://www.readbyqxmd.com/read/28107345/syk-regulates-neutrophilic-airway-hyper-responsiveness-in-a-chronic-mouse-model-of-allergic-airways-inflammation
#19
Sepehr Salehi, Xiaomin Wang, Stephen Juvet, Jeremy A Scott, Chung-Wai Chow
BACKGROUND: Asthma is a chronic inflammatory disease characterized by airways hyper-responsiveness (AHR), reversible airway obstruction, and airway inflammation and remodeling. We previously showed that Syk modulates methacholine-induced airways contractility in naïve mice and in mice with allergic airways inflammation. We hypothesize that Syk plays a role in the pathogenesis of AHR; this was evaluated in a chronic 8-week mouse model of house dust mite (HDM)-induced allergic airways inflammation...
2017: PloS One
https://www.readbyqxmd.com/read/28104789/a-novel-humanized-mouse-model-of-huntington-disease-for-preclinical-development-of-therapeutics-targeting-mutant-huntingtin-alleles
#20
Amber L Southwell, Niels H Skotte, Erika B Villanueva, Michael E Østergaard, Xiaofeng Gu, Holly B Kordasiewicz, Chris Kay, Daphne Cheung, Yuanyun Xie, Sabine Waltl, Louisa Dal Cengio, Hailey Findlay-Black, Crystal N Doty, Eugenia Petoukhov, Diepiriye Iworima, Ramy Slama, Jolene Ooi, Mahmoud A Pouladi, William X Yang, Eric E Swayze, Punit P Seth, Michael R Hayden
Huntington disease (HD) is a neurodegenerative disease caused by a mutation in the huntingtin (HTT) gene. HTT is a large protein, interacts with many partners and is involved in many cellular pathways, which are perturbed in HD. Therapies targeting HTT directly are likely to provide the most global benefit. Thus there is a need for preclinical models of HD recapitulating human HTT genetics. We previously generated a humanized mouse model of HD, Hu97/18, by intercrossing BACHD and YAC18 mice with knockout of the endogenous mouse HD homolog (Hdh)...
January 18, 2017: Human Molecular Genetics
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