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https://www.readbyqxmd.com/read/28088839/pharmacokinetic-pharmacodynamic-modeling-of-the-pde4-inhibitor-tak-648-in-type-2-diabetes-early-translational-approaches-for-human-dose-prediction
#1
N Plock, S Vollert, M Mayer, G Hanauer, G Lahu
TAK-648 is a PDE4 inhibitor with demonstrated preclinical antidiabetic properties. Our objective was to develop a translational pharmacokinetic/pharmacodynamic (PK/PD) model for human type 2 diabetes (T2D) dose prediction using HbA1c results from a db/db mouse study. Estimated parameters in combination with tPDE4i values calculated for the clinical roflumilast dose of 500 μg were used to translate preclinical effects of TAK-648 to required exposure in humans. A first-in-human study with single TAK-648 doses of 0...
January 15, 2017: Clinical and Translational Science
https://www.readbyqxmd.com/read/28088791/sinomenine-hydrochloride-inhibits-breast-cancer-metastasis-by-attenuating-inflammation-related-epithelial-mesenchymal-transition-and-cancer-stemness
#2
Xiao Li, Pingping Li, Chao Liu, Yu Ren, Xiaojiang Tang, Ke Wang, Jianjun He
Sinomenine hydrochloride (SH) has been investigated for its anti-tumor growth effect. We have previously reported that SH inhibited breast cancer cell proliferation via MAPKs signaling. However, whether SH could inhibit tumor metastasis has not been fully explored. In this study, we found that SH suppressed the metastasis potential of breast cancer cells. The wound healing and transwell assays showed that SH inhibited the migration and invasion ability of both 4T1 and MDA-MB-231 breast cancer cells. The orthotopic mouse model of 4T1 and the experimental mouse model of MDA-MB-231-luc (MDA-MB-231 cell line expressing firefly luciferase) demonstrated that SH treatment inhibited breast cancer metastasis by inhibiting epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties without obvious hepatotoxicity and renal toxicity...
January 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28088671/melatonin-attenuates-titanium-particle-induced-osteolysis-via-activation-of-wnt-%C3%AE-catenin-signaling-pathway
#3
Zichuan Ping, Xuanyang Hu, Liangliang Wang, Jiawei Shi, Yunxia Tao, Xiexing Wu, Zhenyang Hou, Xiaobin Guo, Wen Zhang, Huilin Yang, Yaozeng Xu, Zhirong Wang, Dechun Geng
: Wear debris-induced inhibition of bone regeneration and extensive bone resorption were common features in peri-prosthetic osteolysis (PPO). Here, we investigated the effect of melatonin on titanium particle-stimulated osteolysis in a murine calvariae model and mouse-mesenchymal-stem cells (mMSCs) culture system. Melatonin inhibited titanium particle-induced osteolysis and increased bone formation at osteolytic sites, confirmed by radiological and histomorphometric data. Furthermore, osteoclast numbers decreased dramatically in the low- and high-melatonin administration mice, as respectively, compared with the untreated animals...
January 11, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28088658/exposure-to-chronic-early-life-stress-lastingly-alters-the-adipose-tissue-the-leptin-system-and-changes-the-vulnerability-to-western-style-diet-later-in-life-in-mice
#4
K Y Yam, E F G Naninck, M R Abbink, S E la Fleur, L Schipper, J C van den Beukel, A Grefhorst, A Oosting, E M van der Beek, P J Lucassen, A Korosi
Early-life stress (ES) increases the vulnerability to develop psychopathologies and cognitive decline in adulthood. Interestingly, this is often comorbid with metabolic disorders, such as obesity. However, it is unclear whether ES leads to lasting metabolic changes and to what extent this is associated with the ES-induced cognitive impairments. Here, we used an established chronic ES mouse model (from postnatal day (P) 2 to P9) to investigate the short- and long-term effects of ES exposure on parameters of the adipose tissue and the leptin system (i...
December 23, 2016: Psychoneuroendocrinology
https://www.readbyqxmd.com/read/28088623/a-novel-role-of-topical-iodine-in-skin-activation-of-the-nrf2-pathway
#5
Maya Ben-Yehuda Greenwald, Marina Frušić-Zlotkin, Yoram Soroka, Shmuel Ben-Sasson, Havazelet Bianco-Peled, Ron Kohen
For a long time iodine has been used as an active dermal agent in the treatment of inflammatory, immune-mediated and infectious diseases. Moreover, topical iodine application has been reported to provide protection against sulfur-mustard-induced skin lesions, heat-induced and acid-induced skin burns in both haired guinea-pigs and mouse ear swelling models. However, the exact mechanism of action underlying these benefits of iodine has not yet been elucidated. In the current study, a novel mechanism of action by which iodine provides skin protection and relief, based on its electrophilic nature, is suggested...
January 11, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28088582/ripk1-protects-hepatocytes-from-kupffer-cells-mediated-tnf-induced-apoptosis-in-mouse-models-of-pamp-induced-hepatitis
#6
Aveline Filliol, Claire Piquet-Pellorce, Céline Raguénès-Nicol, Sarah Dion, Muhammad Farooq, Catherine Lucas-Clerc, Peter Vandenabeele, Mathieu J M Bertrand, Jacques Le Seyec, Michel Samson
BACKGROUND & AIMS: The severity of liver diseases is exacerbated by the death of hepatocytes, which can be induced by the sensing of Pathogen Associated Molecular Patterns (PAMPs) derived from the gut microbiota. The molecular mechanisms regulating these cell death pathways are poorly documented. In this study, we investigated the role of the Receptor Interacting Protein Kinase 1 (RIPK1), a protein known to regulate cell fate decisions, in the death of hepatocytes using two in vivo models of PAMP-induced hepatitis...
January 11, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28088579/the-microrna-449-family-inhibits-tgf-%C3%AE-mediated-liver-cancer-cell-migration-by-targeting-sox4
#7
Maria Sandbothe, Reena Buurman, Nicole Reich, Luisa Greiwe, Beate Vajen, Engin Gürlevik, Vera Schäffer, Marlies Eilers, Florian Kühnel, Alejandro Vaquero, Thomas Longerich, Stephanie Roessler, Peter Schirmacher, Michael P Manns, Thomas Illig, Brigitte Schlegelberger, Britta Skawran
BACKGROUND & AIMS: Modulation of microRNA expression is considered for treatment of hepatocellular carcinoma (HCC). Therefore, we characterized the epigenetically regulated microRNA-449 family (miR-449a, miR-449b, miR-449c) with regards to its functional effects and target genes in HCC. METHODS: After transfection of miR-449a, miR-449b, and/or miR-449c, tumor-relevant functional effects were analyzed using in vitro assays and a xenograft mouse model. Binding specificities, target genes, and regulated pathways of each microRNA were identified by microarray analyses...
January 11, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28088578/the-effect-of-long-term-hindlimb-unloading-on-the-expression-of-risk-neurogenes-encoding-elements-of-serotonin-dopaminergic-systems-and-apoptosis-comparison-with-the-effect-of-actual-spaceflight-on-mouse-brain
#8
E A Kulikova, V A Kulikov, N A Sinyakova, A V Kulikov, N K Popova
The study of spaceflight effects on the brain is technically complex concern; complicated by the problem of applying an adequate ground model. The most-widely used experimental model to study the effect of microgravity is the tail-suspension hindlimb unloading model; however, its compliance with the effect of actual spaceflight on the brain is still unclear. We evaluated the effect of one month hindlimb unloading on the expression of genes related to the brain neuroplasticity - brain neutotrophic factors (Gdnf, Cdnf), apoptotic factors (Bcl-xl, Bax), serotonin- and dopaminergic systems (5-HT2A, Maoa, Maob, Th, D1r, Comt), and compared the results with the data obtained on mice that spent one month in spaceflight on Russian biosatellite Bion-M1...
January 11, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28088537/mouse-models-of-frontotemporal-dementia-a-comparison-of-phenotypes-with-clinical-symptomatology
#9
REVIEW
Rebekah M Ahmed, Muireann Irish, Janet van Eersel, Arne Ittner, Yazi D Ke, Alexander Volkerling, Julia van der Hoven, Kimi Tanaka, Tim Karl, Michael Kassiou, Jillian J Kril, Olivier Piguet, Jürgen Götz, Matthew C Kiernan, Glenda M Halliday, John R Hodges, Lars M Ittner
Frontotemporal dementia (FTD) is the second most common cause of young onset dementia. It is increasingly recognized that there is a clinical continuum between FTD and amyotrophic lateral sclerosis (ALS). At a clinical, pathological and genetic level there is much heterogeneity in FTD, meaning that our understanding of this condition, pathophysiology and development of treatments has been limited. A number of mouse models focusing predominantly on recapitulating neuropathological and molecular changes of disease have been developed, with most transgenic lines expressing a single specific protein or genetic mutation...
January 11, 2017: Neuroscience and Biobehavioral Reviews
https://www.readbyqxmd.com/read/28088401/pharmacological-rescue-of-adult-hippocampal-neurogenesis-in-a-mouse-model-of-x-linked-intellectual-disability
#10
Manuela Allegra, Cristina Spalletti, Beatrice Vignoli, Stefano Azzimondi, Irene Busti, Pierre Billuart, Marco Canossa, Matteo Caleo
Oligophrenin-1 (OPHN1) is a Rho GTPase activating protein whose mutations cause X-linked intellectual disability (XLID). How loss of function of Ophn1 affects neuronal development is only partly understood. Here we have exploited adult hippocampal neurogenesis to dissect the steps of neuronal differentiation that are affected by Ophn1 deletion. We found that mice lacking Ophn1 display a reduction in the number of newborn neurons in the dentate gyrus. A significant fraction of the Ophn1-deficient newly generated neurons failed to extend an axon towards CA3, and showed an altered density of dendritic protrusions...
January 11, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28088388/activation-of-gr-but-not-pxr-by-dexamethasone-attenuated-acetaminophen-hepatotoxicities-via-fgf21-induction
#11
Saurabh G Vispute, Pengli Bu, Yuan Le, Xingguo Cheng
Glucocorticoid receptor (GR) signaling is indispensable for cell growth and development, and plays important roles in drug metabolism. Fibroblast growth factor (Fgf) 21, an important regulator of glucose, lipid, and energy metabolism, plays a cytoprotective role by attenuating toxicities induced by chemicals such as dioxins, acetaminophen (APAP), and alcohols. The present study investigates the impact of dexamethasone (DEX)-activated GR on Fgf21 expression and how it affects the progression of APAP-induced hepatotoxicity...
January 11, 2017: Toxicology
https://www.readbyqxmd.com/read/28088288/a-novel-mouse-model-of-staphylococcus-aureus-vascular-graft-infection-noninvasive-imaging-of-biofilm-development-in%C3%A2-vivo
#12
Hélène Van de Vyver, Philipp R Bovenkamp, Verena Hoerr, Katrin Schwegmann, Lorena Tuchscherr, Silke Niemann, Laura Kursawe, Christina Grosse, Annette Moter, Uwe Hansen, Ute Neugebauer, Michael T Kuhlmann, Georg Peters, Sven Hermann, Bettina Löffler
Staphylococcus aureus causes very serious infections of vascular grafts. Knowledge of the molecular mechanisms of this disease is largely lacking because of the absence of representable models. Therefore, the aim of this study was to set up a mouse model of vascular graft infections that closely mimics the human situation. A catheter was inserted into the right carotid artery of mice, which acted as a vascular graft. Mice were infected i.v. using 8 different S. aureus strains, and development of the infection was followed up...
January 4, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28088038/evidence-of-functional-duplicity-of-nestin-expression-in-the-adult-mouse-midbrain
#13
Parisa Farzanehfar, Shi Sheng Lu, Anupa Dey, Dharshani Musiienko, Hamzah Baagil, Malcolm K Horne, Tim D Aumann
Whether or not neurogenesis occurs in the adult substantia nigra pars compacta (SNc) is an important question relevant for developing better treatments for the motor symptoms of Parkinson's disease (PD). Although controversial, it is generally believed that dividing cells here remain undifferentiated or differentiate into glia, not neurons. However, there is a suggestion that Nestin-expressing neural precursor cells (NPCs) in the adult SNc have a propensity to differentiate into neurons, which we sought to confirm in the present study...
January 5, 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28087740/bone-microenvironment-changes-in-latexin-expression-promote-chemoresistance
#14
Mi Zhang, Mary Osisami, Jinlu Dai, Jill M Keller, June Escara-Wilke, Atsushi Mizokami, Evan T Keller
: Although docetaxel (DOX) is the standard of care for advanced prostate cancer (PCa), most patients develop resistance to DOX. Therefore, elucidating the mechanism that underlies resistance to DOX is critical to enhance therapeutic intervention. Mining cDNA microarray from the PC-3 PCa cell line and its DOX-resistant derivative (PC3-TxR) revealed decreased latexin (LXN) expression in the resistant cells. LXN expression was inversely correlated with taxane resistance in a panel of PCa cell lines...
January 13, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28087733/metformin-restores-the-mitochondrial-network-and-reverses-mitochondrial-dysfunction-in-down-syndrome-cells
#15
Antonella Izzo, Maria Nitti, Nunzia Mollo, Simona Paladino, Claudio Procaccini, Deriggio Faicchia, Gaetano Calì, Rita Genesio, Ferdinando Bonfiglio, Rita Cicatiello, Elena Polishchuk, Roman Polishchuk, Paolo Pinton, Giuseppe Matarese, Anna Conti, Lucio Nitsch
Alterations in mitochondrial activity and morphology have been demonstrated in human cells and tissues from individuals with Down syndrome (DS), as well as in DS mouse models. An impaired activity of the transcriptional coactivator PGC-1α/PPARGC1Adue to the overexpression of chromosome 21 genes, such as NRIP1/RIP140, has emerged as an underlying cause of mitochondrial dysfunction in DS. We tested the hypothesis that the activation of the PGC-1α pathway might indeed reverse this mitochondrial dysfunction.
January 13, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28087694/iso-%C3%AE-acids-bitter-components-of-beer-prevent-inflammation-and-cognitive-decline-induced-in-a-mouse-model-of-alzheimer-s-disease
#16
Yasuhisa Ano, Atsushi Dhata, Yoshimasa Taniguchi, Ayaka Hoshi, Kazuyuki Uchida, Akihiko Takashima, Hiroyuki Nakayama
Alongside the rapid growth in aging populations worldwide, prevention and therapy for age-related memory decline and dementia are in great demand to maintain a long healthy life. Here we found that iso-α-acids, hop-derived bitter compounds in beer, enhance microglial phagocytosis and suppress inflammation via activation of the peroxisome proliferator-activated receptor (PPAR-γ). In normal mice, oral administration of iso-α-acids led to a significant increase both in CD11b and CD206 double-positive anti-inflammatory type microglia (P<0...
January 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28087667/prmt5-selective-inhibitors-suppress-inflammatory-t-cell-responses-and-experimental-autoimmune-encephalomyelitis
#17
Lindsay M Webb, Stephanie A Amici, Kyle A Jablonski, Himanshu Savardekar, Amanda R Panfil, Linsen Li, Wei Zhou, Kevin Peine, Vrajesh Karkhanis, Eric M Bachelder, Kristy M Ainslie, Patrick L Green, Chenglong Li, Robert A Baiocchi, Mireia Guerau-de-Arellano
In the autoimmune disease multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), expansion of pathogenic, myelin-specific Th1 cell populations drives active disease; selectively targeting this process may be the basis for a new therapeutic approach. Previous studies have hinted at a role for protein arginine methylation in immune responses, including T cell-mediated autoimmunity and EAE. However, a conclusive role for the protein arginine methyltransferase (PRMT) enzymes that catalyze these reactions has been lacking...
January 13, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28087628/id4-levels-dictate-the-stem-cell-state-in-mouse-spermatogonia
#18
Aileen R Helsel, Qi-En Yang, Melissa J Oatley, Tessa Lord, Fred Sablitzky, Jon M Oatley
Spermatogenesis is a classic model of cycling cell lineages that depend on a balance between stem cell self-renewal for continuity and formation of progenitors as the initial step in production of differentiated cells. However, the mechanisms guiding the continuum of spermatogonial stem cell (SSC) to progenitor spermatogonial transition and precise identifiers of subtypes in the process are undefined. Here we used an Id4-eGfp reporter mouse to discover that EGFP intensity is predictive of the subsets with the ID4-EGFP(Bright) population being mostly, if not purely, SSCs while the ID4-EGFP(Dim) population is in transition to the progenitor state...
January 13, 2017: Development
https://www.readbyqxmd.com/read/28087597/membrane-depolarizing-channel-blockers-induce-selective-glioma-cell-death-by-impairing-nutrient-transport-and-unfolded-protein-amino-acid-responses
#19
Mia Niklasson, Gianluca Maddalo, Zuzana Sramkova, Ercan Mutlu, Shimei Wee, Petra Sekyrova, Linnéa Schmidt, Nicolas Fritz, Ivar Dehnisch, Gregorios Kyriatzis, Michaela Krafcikova, Brittany B Carson, Jennifer Feenstra, Voichita D Marinescu, Anna Segerman, Martin Haraldsson, Anna-Lena Gustavsson, Lars Gj Hammarström, Annika Jenmalm-Jensen, Lene Uhrbom, A F Maarten Altelaar, Sten Linnarsson, Per Uhlén, Lukas Trantirek, C Theresa Vincent, Sven Nelander, Per Øyvind Enger, Michael Andäng
Glioma-initiating cells (GIC) are considered the underlying cause of recurrences of aggressive glioblastomas, replenishing the tumor population and undermining the efficacy of conventional chemotherapy. Here we report the discovery that inhibiting T-type voltage-gated Ca2+ and KCa channels can effectively induce selective cell death of GIC and increase host survival in an orthotopic mouse model of human glioma. At present, the precise cellular pathways affected by the drugs affecting these channels are unknown...
January 13, 2017: Cancer Research
https://www.readbyqxmd.com/read/28087528/engineering-mycobacteria-for-the-production-of-self-assembling-biopolyesters-displaying-mycobacterial-antigens-for-use-as-tuberculosis-vaccine
#20
Jason W Lee, Natalie A Parlane, Bernd H A Rehm, Bryce M Buddle, Axel Heiser
: Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis or Mycobacterium bovis and still remains one of the world's biggest global health burdens. Recently, engineered polyhydroxyalkanoate (PHA) biobeads produced in both E. coli and Lactococcus lactis displaying mycobacterial antigens were found to induce significant cell mediated immune responses in mice. We observed that such PHA beads contained host cell proteins as impurities which we hypothesized to have the potential to induce immunity...
January 13, 2017: Applied and Environmental Microbiology
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