Browsing by Subject "Animals"

Now showing 1 - 10 of 77
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    12-Lipoxygenase Promotes Obesity-Induced Oxidative Stress in Pancreatic Islets
    (American Society for Microbiology (ASM), 2014-10) Tersey, Sarah A.; Maier, Bernhard; Nishiki, Yurika; Maganti, Aarthi V.; Nadler, Jerry L.; Mirmira, Raghavendra G.; Department of Pediatrics, IU School of Medicine
    High-fat diets lead to obesity, inflammation, and dysglycemia. 12-Lipoxygenase (12-LO) is activated by high-fat diets and catalyzes the oxygenation of cellular arachidonic acid to form proinflammatory intermediates. We hypothesized that 12-LO in the pancreatic islet is sufficient to cause dysglycemia in the setting of high-fat feeding. To test this, we generated pancreas-specific 12-LO knockout mice and studied their metabolic and molecular adaptations to high-fat diets. Whereas knockout mice and control littermates displayed identical weight gain, body fat distribution, and macrophage infiltration into fat, knockout mice exhibited greater adaptive islet hyperplasia, improved insulin secretion, and complete protection from dysglycemia. At the molecular level, 12-LO deletion resulted in increases in islet antioxidant enzymes Sod1 and Gpx1 in response to high-fat feeding. The absence or inhibition of 12-LO led to increases in nuclear Nrf2, a transcription factor responsible for activation of genes encoding antioxidant enzymes. Our data reveal a novel pathway in which islet 12-LO suppresses antioxidant enzymes and prevents the adaptive islet responses in the setting of high-fat diets.
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    Activation of OCT4 enhances ex vivo expansion of human cord blood hematopoietic stem and progenitor cells by regulating HOXB4 expression
    (SpringerNature, 2016-01) Huang, Xinxin; Lee, Man-Ryul; Cooper, Scott; Hangoc, Giao; Hong, Ki-Sung; Chung, Hyung-Min; Broxmeyer, Hal E.; Department of Microbiology & Immunology, IU School of Medicine
    Although hematopoietic stem cells (HSC) are the best characterized and the most clinically used adult stem cells, efforts are still needed to understand how to best ex vivo expand these cells. Here we present our unexpected finding that OCT4 is involved in the enhancement of cytokine-induced expansion capabilities of human cord blood (CB) HSC. Activation of OCT4 by Oct4-activating compound 1 (OAC1) in CB CD34(+) cells enhanced ex vivo expansion of HSC, as determined by a rigorously defined set of markers for human HSC, and in vivo short-term and long-term repopulating ability in NSG mice. Limiting dilution analysis revealed that OAC1 treatment resulted in 3.5-fold increase in the number of SCID repopulating cells (SRCs) compared with that in day 0 uncultured CD34(+) cells and 6.3-fold increase compared with that in cells treated with control vehicle. Hematopoietic progenitor cells, as assessed by in vitro colony formation, were also enhanced. Furthermore, we showed that OAC1 treatment led to OCT4-mediated upregulation of HOXB4. Consistently, siRNA-mediated knockdown of HOXB4 expression suppressed effects of OAC1 on ex vivo expansion of HSC. Our study has identified the OCT4-HOXB4 axis in ex vivo expansion of human CB HSC.
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    Adaptive changes of the Insig1/SREBP1/SCD1 set point help adipose tissue to cope with increased storage demands of obesity
    (American Diabetes Association, 2013-11) Carobbio, Stefania; Hagen, Rachel M.; Lelliott, Christopher J.; Slawik, Marc; Medina-Gomez, Gema; Tan, Chong-Yew; Sicard, Audrey; Atherton, Helen J.; Barbarroja, Nuria; Bjursell, Mikael; Bohlooly-Y, Mohammad; Virtue, Sam; Tuthill, Antoinette; Lefai, Etienne; Laville, Martine; Wu, Tingting; Considine, Robert V.; Vidal, Hubert; Langin, Dominique; Oresic, Matej; Tinahones, Francisco J.; Manuel Fernandez-Real, Jose; Griffin, Julian L.; Sethi, Jaswinder K.; López, Miguel; Vidal-Puig, Antonio; Medicine, School of Medicine
    The epidemic of obesity imposes unprecedented challenges on human adipose tissue (WAT) storage capacity that may benefit from adaptive mechanisms to maintain adipocyte functionality. Here, we demonstrate that changes in the regulatory feedback set point control of Insig1/SREBP1 represent an adaptive response that preserves WAT lipid homeostasis in obese and insulin-resistant states. In our experiments, we show that Insig1 mRNA expression decreases in WAT from mice with obesity-associated insulin resistance and from morbidly obese humans and in in vitro models of adipocyte insulin resistance. Insig1 downregulation is part of an adaptive response that promotes the maintenance of SREBP1 maturation and facilitates lipogenesis and availability of appropriate levels of fatty acid unsaturation, partially compensating the antilipogenic effect associated with insulin resistance. We describe for the first time the existence of this adaptive mechanism in WAT, which involves Insig1/SREBP1 and preserves the degree of lipid unsaturation under conditions of obesity-induced insulin resistance. These adaptive mechanisms contribute to maintain lipid desaturation through preferential SCD1 regulation and facilitate fat storage in WAT, despite on-going metabolic stress.
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    Age-Related Pathology Associated with H1N1 A/California/07/2009 Influenza Virus Infection
    (Elsevier, 2019-12) Bissel, Stephanie J.; Carter, Chalise E.; Wang, Guoji; Johnson, Scott K.; Lashua, Lauren P.; Kelvin, Alyson A.; Wiley, Clayton A.; Ghedin, Elodie; Ross, Ted M.; Medical and Molecular Genetics, School of Medicine
    Influenza virus infection causes a spectrum of diseases, ranging from mild upper respiratory tract infection to severe lower respiratory tract infection, that can lead to diffuse alveolar damage, interstitial and airspace inflammation, or acute respiratory failure. Mechanisms instructing disease severity are not completely understood, but host, viral, and bacterial factors influence disease outcome. With age being one host factor associated with a higher risk of severe influenza, we investigated regional pulmonary distribution and severity of pneumonia after 2009 H1N1 influenza virus infection in newly weaned, adult, and aged ferrets to better understand age-dependent susceptibility and pathology. Aged ferrets exhibited greater weight loss and higher rates of mortality than adult ferrets, whereas most newly weaned ferrets did not lose weight but had a lack of weight gain. Newly weaned ferrets exhibited minimal pneumonia, whereas adult and aged ferrets had a spectrum of pneumonia severity. Influenza virus-induced pneumonia peaked earliest in adult ferrets, whereas aged ferrets had delayed presentation. Bronchial severity differed among groups, but bronchial pathology was comparable among all cohorts. Alveolar infection was strikingly different among groups. Newly weaned ferrets had little alveolar cell infection. Adult and aged ferrets had alveolar infection, but aged ferrets were unable to clear infection. These different age-related pneumonia and infection patterns suggest therapeutic strategies to treat influenza should be tailored contingent on age.
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    Alternatives to Animal Use in Research, Testing, and Education
    (U.S. Government Printing Office, 1986-02) Office of Technology Assessment, U.S. Congress
    In this assessment, OTA analyzes the scientific, regulatory, economic, legal, and ethical considerations involved in alternative technologies in biomedical and behavioral research, toxicity testing, and education. Included is a detailed examination of Federal, State, and institutional regulation of animal use, and a review of recent developments in 10 other countries. The report was requested by Sen. Orrin Hatch, Chairman of the Senate Committee on Labor and Human Resources.
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    Amyloid-β precursor protein synthesis inhibitors for Alzheimer's disease treatment
    (Wiley, 2014-10) Greig, Nigel H.; Sambamurti, Kumar; Lahiri, Debomoy K.; Becker, Robert E.; Department of Psychiatry, IU School of Medicine
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    Animal Use: A Conscientious Objection
    (Atlanta Clincal & Translational Science Institute, 2009) Banga, John
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    ATF4 and HIF-1α in bone: an intriguing relationship
    (Wiley, 2013-09) Schipani, Ernestina; Mangiavini, Laura; Merceron, Christophe; Department of Medicine, IU School of Medicine
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    Bleeding the laboratory mouse: Not all methods are equal
    (Elsevier, 2016-02) Hoggatt, Jonathan; Hoggatt, Amber F.; Tate, Tiffany A.; Fortman, Jeffrey; Pelus, Louis M.; Microbiology and Immunology, School of Medicine
    The laboratory mouse is the model most frequently used in hematologic studies and assessment of blood parameters across a broad range of disciplines. Often, analysis of blood occurs in a nonterminal manner. However, the small body size of the mouse limits collection based on volume, frequency, and accessible sites. Commonly used sites in the mouse include the retro-orbital sinus, facial vein, tail vein, saphenous vein, and heart. The method of blood acquisition varies considerably across laboratories and is often not reported in detail. In this study, we report significant alterations in blood parameters, particularly of total white blood cells, specific populations of dendritic cells and myeloid-derived suppressor cells, and hematopoietic progenitor cells, as a result of site and manner of sampling. Intriguingly, warming of mice prior to tail bleeding was found to significantly alter blood values. Our findings suggest that the same method should be used across an entire study, that mice should be warmed prior to tail bleeds to make levels uniform, and that accurate description of bleeding methods in publications should be provided to allow for interpretation of comparative reports and inter- and intralaboratory experimental variability.
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    Cancer-associated osteoclast differentiation takes a good look in the miR(NA)ror
    (Elsevier, 2013-10-14) Waning, David L.; Mohammad, Khalid S.; Guise, Theresa A.; Department of Medicine, School of Medicine
    Tumor-bone cell interactions are critical for the development of metastasis-related osteolytic bone destruction. In this issue of Cancer Cell, Ell and colleagues show how a discrete miRNA network regulates osteoclastogenesis during breast cancer bone metastasis. A signature of upregulated miRNAs may have diagnostic and therapeutic implications for bone metastases.