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https://www.readbyqxmd.com/read/28107516/liver-amp-activated-protein-kinase-is-unnecessary-for-gluconeogenesis-but-protects-energy-state-during-nutrient-deprivation
#1
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
#2
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
#3
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
#4
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
https://www.readbyqxmd.com/read/28102564/pkn2-is-essential-for-mouse-embryonic-development-and-proliferation-of-mouse-fibroblasts
#5
Sally Danno, Koji Kubouchi, Mona Mehruba, Manabu Abe, Rie Natsume, Kenji Sakimura, Satoshi Eguchi, Masahiro Oka, Masanori Hirashima, Hiroki Yasuda, Hideyuki Mukai
PKN2, a member of the protein kinase N (PKN) family, has been suggested by in vitro culture cell experiments to bind to Rho/Rac GTPases and contributes to cell-cell contact and cell migration. To unravel the in vivo physiological function of PKN2, we targeted the PKN2 gene. Constitutive disruption of the mouse PKN2 gene resulted in growth retardation and lethality before embryonic day (E) 10.5. PKN2(-/-) embryo did not undergo axial turning and showed insufficient closure of the neural tube. Mouse embryonic fibroblasts (MEFs) derived from PKN2(-/-) embryos at E9...
January 19, 2017: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/28100467/an-essential-role-of-cbl-and-cbl-b-ubiquitin-ligases-in-mammary-stem-cell-maintenance
#6
Bhopal Mohapatra, Neha Zutshi, Wei An, Benjamin Goetz, Priyanka Arya, Timothy A Bielecki, Insha Mustaq, Matthew D Storck, Jane L Meza, Vimla Band, Hamid Band
CBL and CBL-B ubiquitin ligases are negative regulators of tyrosine kinase signaling with established roles in the immune system. However, their physiological roles in epithelial tissues are unknown. Here we used the MMTV-Cre-mediated Cbl gene deletion on a Cbl-b-null background as well as a tamoxifen-inducible mammary stem cell (MaSC)-specific Cbl/Cbl-b double knockout (DKO), using Lgr5-GFP-CreERT, to demonstrate a mammary epithelial cell-autonomous requirement of CBL and CBL-B in the maintenance of MaSCs...
January 18, 2017: Development
https://www.readbyqxmd.com/read/28100033/relaxin-3-inputs-target-hippocampal-interneurons-and-deletion-of-hilar-relaxin-3-receptors-in-floxed-rxfp3-mice-impairs-spatial-memory
#7
M Haidar, G Guèvremont, C Zhang, Rad Bathgate, E Timofeeva, C M Smith, A L Gundlach
Hippocampus is innervated by γ-aminobutyric acid (GABA) 'projection' neurons of the nucleus incertus (NI), including a population expressing the neuropeptide, relaxin-3 (RLN3). In studies aimed at gaining an understanding of the role of RLN3 signaling in hippocampus via its Gi/o -protein-coupled receptor, RXFP3, we examined the distribution of RLN3-immunoreactive nerve fibres and RXFP3 mRNA-positive neurons in relation to hippocampal GABA neuron populations. RLN3-positive elements were detected in close-apposition with a substantial population of somatostatin (SST)- and GABA-immunoreactive neurons, and a smaller population of parvalbumin- and calretinin-immunoreactive neurons in different hippocampal areas, consistent with the relative distribution patterns of RXFP3 mRNA and these marker transcripts...
January 18, 2017: Hippocampus
https://www.readbyqxmd.com/read/28096257/inhibition-of-gastric-inhibitory-polypeptide-receptor-signaling-in-adipose-tissue-reduces-insulin-resistance-and-hepatic-steatosis-in-high-fat-diet-fed-mice
#8
Erina Joo, Norio Harada, Shunsuke Yamane, Toru Fukushima, Daisuke Taura, Kanako Iwasaki, Akiko Sankoda, Kimitaka Shibue, Takanari Harada, Kazuyo Suzuki, Akihiro Hamasaki, Nobuya Inagaki
Gastric inhibitory polypeptide receptor (GIPR) directly induces energy accumulation in adipose tissue in vitro However, the importance of the direct effect of GIPR signaling on adipose tissue in vivo remains unclear. In the present study, we generated adipose tissue- specific GIPR-knockout (GIPR(adipo-/-)) mice and investigated the direct actions of GIP in adipose tissue. Under high fat diet (HFD)-fed conditions, GIPR(adipo-/-) mice had significantly lower body weight and lean body mass compared with those in floxed GIPR (GIPR(fl/fl)) mice, although the fat volume was not significantly different between the two groups...
January 17, 2017: Diabetes
https://www.readbyqxmd.com/read/28090570/targeted-inhibition-of-pancreatic-acinar-cell-calcineurin-is-a-novel-strategy-to-prevent-post-ercp-pancreatitis
#9
Abrahim I Orabi, Li Wen, Tanveer A Javed, Tianming Le, Ping Guo, Subramaniam Sanker, David Ricks, Kristy Boggs, John F Eisses, Carlos Castro, Xiangwei Xiao, Krishna Prasadan, Farzad Esni, George K Gittes, Sohail Z Husain
BACKGROUND AND AIMS: There is a pressing need to develop effective preventative therapies for post-ERCP pancreatitis (PEP). We demonstrated that early PEP events are induced through the calcium-activated phosphatase calcineurin and that global calcineurin deletion abolishes PEP in mice. A crucial question is whether acinar cell calcineurin controls the initiation of PEP in vivo. METHODS: We used a mouse model of PEP and examined the effects of in vivo acinar cell-specific calcineurin deletion by either generating a conditional knockout line or infusing a novel AAV-Ela-iCre into the pancreatic duct of a calcineurin floxed line...
January 2017: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28078648/generation-of-a-floxed-allele-of-the-mouse-microrna-200-clusters
#10
Hongyan Ren, Cong Tao, Kui Li, Yanzhen Bi, Xinmin Zheng
MicroRNA-8 and its target gene, u-shaped (ush), regulate body size in Drosophila. As the mouse homolog of the Drosophila miR-8, whether the miR-200 family has similar functions and how they perform their regulatory roles in body size control is unknown. In order to discover the biological function of the miR-200s in vivo, we generated mice lacking the miR-200b/200a/429 gene cluster using the Cre/loxp system. miR-200b/200a/429 null mutant mice were viable, fertile, and showed normal development.
January 11, 2017: Applied Biochemistry and Biotechnology
https://www.readbyqxmd.com/read/28062415/cardiomyocyte-specific-ablation-of-cd36-accelerates-the-progression-from-compensated-cardiac-hypertrophy-to-heart-failure
#11
Miranda M Sung, Nikole J Byrne, Ty T Kim, Jody Levasseur, Grant Masson, Jamie Boisvenue, Maria Febbraio, Jason R B Dyck
Previous studies have shown that loss of CD36 protects the heart from dysfunction induced by pressure overload in the presence of diet-induced insulin resistance and/or obesity. The beneficial effects of CD36 ablation in this context are mediated by preventing excessive cardiac fatty acid (FA) entry and reducing lipotoxic injury. However, whether or not the loss of CD36 can prevent pressure overload-induced cardiac dysfunction in the absence of chronic exposure to high circulating FAs is currently unknown. To address this, we utilized a tamoxifen inducible cardiomyocyte-specific CD36 knockout (icCD36KO) mouse and genetically deleted CD36 in adulthood...
January 6, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28039362/defining-the-temporal-course-of-murine-neurofibromatosis-1-optic-gliomagenesis-reveals-a-therapeutic-window-to-attenuate-retinal-dysfunction
#12
Joseph A Toonen, Yu Ma, David H Gutmann
BACKGROUND: Optic gliomas arising in the neurofibromatosis type 1 (NF1) cancer predisposition syndrome cause reduced visual acuity in 30%-50% of affected children. Since human specimens are rare, genetically engineered mouse (GEM) models have been successfully employed for preclinical therapeutic discovery and validation. However, the sequence of cellular and molecular events that culminate in retinal dysfunction and vision loss has not been fully defined relevant to potential neuroprotective treatment strategies...
December 29, 2016: Neuro-oncology
https://www.readbyqxmd.com/read/28028193/smooth-muscle-endothelin-b-receptors-regulate-blood-pressure-but-not-vascular-function-or-neointimal-remodeling
#13
Eileen Miller, Alicja Czopek, Karolina M Duthie, Nicholas S Kirkby, Elisabeth E Fransen van de Putte, Sibylle Christen, Robert A Kimmitt, Rebecca Moorhouse, Raphael F P Castellan, Yuri V Kotelevtsev, Rhoda E Kuc, Anthony P Davenport, Neeraj Dhaun, David J Webb, Patrick W F Hadoke
The role of smooth muscle endothelinB (ETB) receptors in regulating vascular function, blood pressure (BP), and neointimal remodeling has not been established. Selective knockout mice were generated to address the hypothesis that loss of smooth muscle ETB receptors would reduce BP, alter vascular contractility, and inhibit neointimal remodeling. ETB receptors were selectively deleted from smooth muscle by crossing floxed ETB mice with those expressing cre-recombinase controlled by the transgelin promoter. Functional consequences of ETB deletion were assessed using myography...
February 2017: Hypertension
https://www.readbyqxmd.com/read/28028143/abca1-apoe-hdl-pathway-mediates-gw3965-induced-neurorestoration-after-stroke
#14
Xu Cui, Michael Chopp, Zhenggang Zhang, Rongwen Li, Alex Zacharek, Julie Landschoot-Ward, Poornima Venkat, Jieli Chen
BACKGROUND AND PURPOSE: ATP-binding cassette transporter A1 (ABCA1) is a major reverse cholesterol transporter and plays critical role in the formation of brain high-density lipoprotein (HDL) cholesterol. Apolipoprotein E (ApoE) is the most abundant apolipoprotein and transports cholesterol into cells in brain. ABCA1 and ApoE are upregulated by liver-X receptors. Activation of liver-X receptors has neurorestorative benefit for stroke. The current study investigates whether ABCA1/ApoE/HDL pathway mediates GW3965, a synthetic dual liver-X receptor agonist, induced neurorestoration after stroke...
December 27, 2016: Stroke; a Journal of Cerebral Circulation
https://www.readbyqxmd.com/read/28028037/muscle-interleukin-6-and-fasting-induced-pdh-regulation-in-mouse-skeletal-muscle
#15
Anders Gudiksen, Lærke Bertholdt, Mikkel Birkkjær Vingborg, Henriette Watson Hansen, Stine Ringholm Ringholm, Henriette Pilegaard
Fasting prompts a metabolic shift in substrate utilization from carbohydrate to predominant fat oxidation in skeletal muscle and pyruvate dehydrogenase (PDH) is seen as a controlling link between the competitive oxidation of carbohydrate and fat during metabolic challenges like fasting. Interleukin (IL)-6 has been proposed to be released from muscle with concomitant effects on both glucose and fat utilization. The aim was to test the hypothesis that IL-6 has a regulatory impact on fasting-induced suppression of skeletal muscle PDH...
December 27, 2016: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28024880/embryonic-ablation-of-neuronal-vgf-increases-energy-expenditure-and-reduces-body-weight
#16
Cheng Jiang, Wei-Jye Lin, Masato Sadahiro, Andrew C Shin, Christoph Buettner, Stephen R Salton
Germline ablation of VGF, a secreted neuronal, neuroendocrine, and endocrine peptide precursor, results in lean, hypermetabolic, and infertile adult mice that are resistant to diet-, lesion-, and genetically-induced obesity and diabetes (Hahm et al., 1999, 2002). To assess whether this phenotype is predominantly driven by reduced VGF expression in developing and/or adult neurons, or in peripheral endocrine and neuroendocrine tissues, we generated and analyzed conditional VGF knockout mice, obtained by mating loxP-flanked (floxed) Vgf mice with either pan-neuronal Synapsin-Cre- or forebrain alpha-CaMKII-Cre-recombinase-expressing transgenic mice...
December 20, 2016: Neuropeptides
https://www.readbyqxmd.com/read/28005395/conditional-ablation-of-progesterone-receptor-membrane-component-2-causes-female-premature-reproductive-senescence
#17
N C Clark, C A Pru, S P Yee, J P Lydon, J J Peluso, J K Pru
The non-classical progesterone receptors, progesterone receptor membrane component (PGRMC) 1 and PGRMC2 have been implicated in regulating cell survival of endometrial and ovarian cells in vitro and are abundantly expressed in these cell types. The objective of this study was to determine if Pgrmc1 and Pgrmc2 are essential for normal female reproduction. To accomplish this objective, Pgrmc1 and/or Pgrmc2 floxed mice (Pgrmc2(fl/fl) and Pgrmc1/2(fl/fl)) were crossed with Pgr-cre mice which resulted in the conditional ablation of Pgrmc1 and/or Pgrmc2 from female reproductive tissues (i...
December 22, 2016: Endocrinology
https://www.readbyqxmd.com/read/28003731/a-regulatory-sequence-from-the-retinoid-x-receptor-%C3%AE-gene-directs-expression-to-horizontal-cells-and-photoreceptors-in-the-embryonic-chicken-retina
#18
Maria K E Blixt, Finn Hallböök
PURPOSE: Combining techniques of episomal vector gene-specific Cre expression and genomic integration using the piggyBac transposon system enables studies of gene expression-specific cell lineage tracing in the chicken retina. In this work, we aimed to target the retinal horizontal cell progenitors. METHODS: A 208 bp gene regulatory sequence from the chicken retinoid X receptor γgene (RXRγ208) was used to drive Cre expression. RXRγ is expressed in progenitors and photoreceptors during development...
2016: Molecular Vision
https://www.readbyqxmd.com/read/28000152/inactivation-of-bone-morphogenetic-protein-1-bmp1-and-tolloid-like-1-tll1-in-cells-expressing-type-i-collagen-leads-to-dental-and-periodontal-defects-in-mice
#19
Hua Zhang, Priyam Jani, Tian Liang, Yongbo Lu, Chunlin Qin
Bone morphogenetic protein 1 (BMP1) and tolloid-like 1 (TLL1) belong to the BMP1/tolloid-like proteinase family, which cleaves secretory proteins. The constitutive deletion of the Bmp1 or Tll1 genes causes perinatal or embryonic lethality in mice. In this study, we first studied the β-galactosidase activity in mice in which an IRES-lacZ-Neo cassette was inserted in the intron of either the Bmp1 or the Tll1 gene; the β-galactosidase activities were used to reflect the expression of endogenous Bmp1 and Tll1, respectively...
December 20, 2016: Journal of Molecular Histology
https://www.readbyqxmd.com/read/27998825/hematopoietic-arginase-1-deficiency-results-in-decreased-leukocytosis-and-increased-foam-cell-formation-but-does-not-affect-atherosclerosis
#20
Baoyan Ren, Erik Van Kampen, Theo J C Van Berkel, Sheena M Cruickshank, Miranda Van Eck
BACKGROUND AND AIMS: Arginase1 (Arg1), an M2 macrophage marker, plays a critical role in a number of immunological functions in macrophages, which are the main cell type facilitating atherosclerotic lesion development. Arg1 uses the substrate l-arginine to create l-ornithine, a precursor molecule required for collagen formation and vascular smooth muscle cell differentiation. By reducing l-arginine availability, Arg1 limits the production of nitric oxide (NO), a pro-atherogenic factor in macrophages...
November 16, 2016: Atherosclerosis
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