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https://www.readbyqxmd.com/read/29759964/risk-of-fragility-fracture-among-patients-with-gout-and-the-effect-of-urate-lowering-therapy
#1
Alyshah Abdul Sultan, Rebecca Whittle, Sara Muller, Edward Roddy, Christian D Mallen, Milica Bucknall, Toby Helliwell, Samantha Hider, Zoe Paskins
BACKGROUND: Previous studies that quantified the risk of fracture among patients with gout and assessed the potential effect of urate-lowering therapy have provided conflicting results. Our study aims to provide better estimates of risk by minimizing the effect of selection bias and confounding on the observed association. METHODS: We used data from the Clinical Practice Research Datalink, which records primary care consultations of patients from across the United Kingdom...
May 14, 2018: CMAJ: Canadian Medical Association Journal, Journal de L'Association Medicale Canadienne
https://www.readbyqxmd.com/read/29757281/analyses-of-mitochondrial-calcium-influx-in-isolated-mitochondria-and-cultured-cells
#2
Joshua T Maxwell, Chin-Hsien Tsai, Tahmina A Mohiuddin, Jennifer Q Kwong
Ca2+ handling by mitochondria is a critical function regulating both physiological and pathophysiological processes in a broad spectrum of cells. The ability to accurately measure the influx and efflux of Ca2+ from mitochondria is important for determining the role of mitochondrial Ca2+ handling in these processes. In this report, we present two methods for the measurement of mitochondrial Ca2+ handling in both isolated mitochondria and cultured cells. We first detail a plate reader-based platform for measuring mitochondrial Ca2+ uptake using the Ca2+ sensitive dye calcium green-5N...
April 27, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29754957/pharmacological-inhibition-of-the-ubiquitin-ligase-rnf5-rescues-f508del-cftr-in-cystic-fibrosis-airway-epithelia
#3
Elvira Sondo, Federico Falchi, Emanuela Caci, Loretta Ferrera, Elisa Giacomini, Emanuela Pesce, Valeria Tomati, Sine Mandrup Bertozzi, Luca Goldoni, Andrea Armirotti, Roberto Ravazzolo, Andrea Cavalli, Nicoletta Pedemonte
In cystic fibrosis (CF), deletion of phenylalanine 508 (F508del) in the CFTR channel is associated with misfolding and premature degradation of the mutant protein. Among the known proteins associated with F508del-CFTR processing, the ubiquitin ligase RNF5/RMA1 is particularly interesting. We previously demonstrated that genetic suppression of RNF5 in vivo leads to an attenuation of intestinal pathological phenotypes in CF mice, validating the relevance of RNF5 as a drug target for CF. Here, we used a computational approach, based on ligand docking and virtual screening, to discover inh-02, a drug-like small molecule that inhibits RNF5...
April 26, 2018: Cell Chemical Biology
https://www.readbyqxmd.com/read/29748974/sensing-of-silver-nanoparticles-on-in-endothelial-cells-using-atomic-force-spectroscopy
#4
Agnieszka Kolodziejczyk, Aleksandra Jakubowska, Magdalena Kucinska, Tomasz Wasiak, Piotr Komorowski, Krzysztof Makowski, Bogdan Walkowiak
Endothelial cells, due to their location, are interesting objects for atomic force spectroscopy study. They constitute a barrier between blood and vessel tissues located deeper, and therefore they are the first line of contact with various substances present in blood, eg, drugs or nanoparticles. This work intends to verify whether the mechanical response of immortalized human umbilical vein endothelial cells (EA.hy926), when exposed to silver nanoparticles, as measured using force spectroscopy, could be effectively used as a bio-indicator of the physiological state of the cells...
May 10, 2018: Journal of Molecular Recognition: JMR
https://www.readbyqxmd.com/read/29743404/-epigenetic-aberrations-in-adult-t-cell-leukemia-lymphoma-and-development-of-a-novel-ezh1-2-inhibitor
#5
Makoto Yamagishi
Histone H3 lysine 27 tri-methylation (H3K27me3) -dependent transcription regulation is a fundamental process of gene control. Although EZH2 mutation is observed in certain lymphoma types, many other cancers show global H3K27me3 accumulation irrespective of mutation. However, the underlying mechanisms of gene silencing and therapeutic efficacies of epigenetic drugs remain unclear. In this study, we showed that globally-accumulated H3K27me3 is induced by both cis-bound EZH1 and EZH2 in mature lymphocyte-derived malignancies...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/29736745/activation-of-the-cannabinoid-type-2-receptor-by-a-novel-indazole-derivative-normalizes-the-survival-pattern-of-lymphoblasts-from-patients-with-late-onset-alzheimer-s-disease
#6
Patricia Del Cerro, Carolina Alquézar, Fernando Bartolomé, Pedro González-Naranjo, Concepción Pérez, Eva Carro, Juan A Páez, Nuria E Campillo, Ángeles Martín-Requero
BACKGROUND: Alzheimer's disease is a multifactorial disorder for which there is no disease-modifying treatment yet. CB2 receptors have emerged as a promising therapeutic target for Alzheimer's disease because they are expressed in neuronal and glial cells and their activation has no psychoactive effects. OBJECTIVE: The aim of this study was to investigate whether activation of the CB2 receptor would restore the aberrant enhanced proliferative activity characteristic of immortalized lymphocytes from patients with late-onset Alzheimer's disease...
May 7, 2018: CNS Drugs
https://www.readbyqxmd.com/read/29736535/a-microengineered-human-corneal-epithelium-on-a-chip-for-eye-drops-mass-transport-evaluation
#7
Devasier Bennet, Zachary Estlack, Ted Reid, Jungkyu Kim
Animals are commonly used for pharmacokinetic studies which are the most frequent events tested during ocular drug development and preclinical evaluation. Inaccuracy, cost, and ethical criticism in these tests have created a need to construct an in vitro model for studying corneal constraints. In this work, a porous membrane embedded microfluidic platform is fabricated that separates a chip into an apical and basal side. After functionalizing the membrane surface with fibronectin, the membrane's mechanical and surface properties are measured to ensure correct modeling of in vivo characteristics...
May 8, 2018: Lab on a Chip
https://www.readbyqxmd.com/read/29735480/comparative-transcriptomic-response-of-primary-and-immortalized-macrophage-to-murine-norovirus-infection
#8
Eric A Levenson, Craig Martens, Kishore Kanakabandi, Charles V Turner, Kimmo Virtaneva, Monica Paneru, Stacy Ricklefs, Stanislav V Sosnovtsev, Jordan A Johnson, Stephen F Porcella, Kim Y Green
Murine norovirus (NoV) is genetically similar to human NoV and offers both an efficient in vitro cell culture system and an animal model by which to investigate the molecular basis of replication. In this study, we present a detailed global view of host alterations to cellular pathways that occur during the progression of a NoV infection. This was accomplished for both Mus musculus BALB/c-derived RAW264.7 (RAW) cells, an immortalized cell line widely used in in vitro replication studies, and primary bone marrow-derived macrophages (BMDM), representing a permissive in vivo target cell in the host...
May 7, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29719832/microenvironment-induced-non-sporadic-expression-of-the-axl-and-ckit-receptors-are-related-to-epithelial-plasticity-and-drug-resistance
#9
Tiina A Jokela, Agnete S T Engelsen, Agata Rybicka, Fanny A Pelissier Vatter, James C Garbe, Masaru Miyano, Crina Tiron, Dan Ferariu, Lars A Akslen, Martha R Stampfer, James B Lorens, Mark A LaBarge
The existence of rare cancer cells that sporadically acquire drug-tolerance through epigenetic mechanisms is proposed as one mechanism that drives cancer therapy failure. Here we provide evidence that specific microenvironments impose non-sporadic expression of proteins related to epithelial plasticity and drug resistance. Microarrays of robotically printed combinatorial microenvironments of known composition were used to make cell-based functional associations between microenvironments, which were design-inspired by normal and tumor-burdened breast tissues, and cell phenotypes...
2018: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/29716926/studying-the-effects-of-nonindicated-medications-on-cancer-etiologic-versus-action-focused-analysis-of-epidemiologic-data
#10
John W Jackson, Xabier García-Albéniz
The study of nonindicated medications on cancer outcomes is challenged by potential time-related biases. The literature has strongly advocated for treating the exposure as time-varying and summarizing the outcomes through a dose-response model (an etiologic-focused analysis). An alternative is to refashion the data to resemble a hypothetical randomized trial of drug use (an action-focused analysis). To our knowledge, their relative treatment of time-related bias and aspects of interpretation have not been compared...
May 2018: Cancer Epidemiology, Biomarkers & Prevention
https://www.readbyqxmd.com/read/29715466/feraheme%C3%A2-suppresses-immune-function-of-human-t-lymphocytes-through-mitochondrial-damage-and-mitoros-production
#11
Ankit Shah, Cassandra I Mankus, Alison M Vermilya, Ferri Soheilian, Jeffrey D Clogston, Marina A Dobrovolskaia
Despite attractive properties for both therapeutic and diagnostic applications, the clinical use of iron oxide nanoparticles (IONPs) is limited to iron replacement in severely anemic patient populations. While several studies have reported about the immunotoxicity of IONPs, the mechanisms of this toxicity are mostly unknown. We conducted a mechanistic investigation using an injectable form of IONP, Feraheme®. In the cultures of primary human T cells, Feraheme induced miotochondrial oxidative stress and resulted in changes in mitochondrial dynamics, architecture, and membrane potential...
April 28, 2018: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29706467/hpv-molecular-pathways-and-targets
#12
REVIEW
Shilpi Gupta, Prabhat Kumar, Bhudev C Das
Infection of high-risk human papillomaviruses (HPVs) is a prerequisite for the development of cervical carcinoma. HPV infections are also implicated in the development of other types of carcinomas. Chronic or persistent infection of HPV is essential but HPV alone is inadequate, additional endogenous or exogenous cues are needed along with HPV to induce cervical carcinogenesis. The strategies that high-risk HPVs have developed in differentiating epithelial cells to reach a DNA-synthesis competent state leading to tumorigenic transformation are basically due to overexpression of the E6 and E7 oncoproteins and the activation of diverse cellular regulatory or signaling pathways that are targeted by them...
April 5, 2018: Current Problems in Cancer
https://www.readbyqxmd.com/read/29701781/mutant-app-and-amyloid-beta-induced-defective-autophagy-mitophagy-mitochondrial-structural-and-functional-changes-and-synaptic-damage-in-hippocampal-neurons-from-alzheimer-s-disease
#13
P Hemachandra Reddy, XiangLin Yin, Maria Manczak, Subodh Kumar, Pradeepkiran Jangampalli Adi, Murali Vijayan, Arubala P Reddy
The purpose of our study was to determine the toxic effects of hippocampal mutant APP and amyloid beta (Aβ) in human mutant APP (mAPP) cDNA transfected with primary mouse hippocampal neurons (HT22). Hippocampal tissues are the best source of studying learning and memory functions in patients with Alzheimer's disease (AD) and healthy controls. However, investigating immortalized hippocampal neurons that express AD proteins provide an excellent opportunity for drug testing. Using quantitative RT-PCR, immunoblotting & immunofluorescence, and transmission electron microscopy, we assessed mRNA and protein levels of synaptic, autophagy, mitophagy, mitochondrial dynamics, biogenesis, dendritic protein MAP2, and assessed mitochondrial number and length in mAPP-HT22 cells that express Swedish/Indiana mutations...
April 25, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29700854/development-of-3d-imaging-technique-of-reconstructed-human-epidermis-with-immortalized-human-epidermal-cell-line
#14
Yu Inoue, Seiji Hasegawa, Katsuma Miyachi, Takaaki Yamada, Satoru Nakata, Sari Ipponjima, Terumasa Hibi, Tomomi Nemoto, Masahiko Tanaka, Ryo Suzuki, Naohide Hirashima
The epidermis, the outermost layer of the skin, retains moisture and functions as a physical barrier against the external environment. Epidermal cells are continuously replaced by turnover, and thus to understand in detail the dynamic cellular events in the epidermis, techniques to observe live tissues in 3D are required. Here, we established a live 3D imaging technique for epidermis models. We first obtained immortalized human epidermal cell lines which have a normal differentiation capacity and fluorescence-labeled cytoplasm or nuclei...
April 26, 2018: Experimental Dermatology
https://www.readbyqxmd.com/read/29683403/paracellular-tightness-and-the-functional-expression-of-efflux-transporters-p-gp-and-bcrp-in-bend3-cells
#15
Shu Yang, Hong Jin, Zhigang Zhao
Objective The blood-brain barrier (BBB), regulating brain homeostasis and limiting the entry of most drugs, is characterized by intercellular tight junctions and the presence of transporters. In this study, the paracellular tightness and functional expression of efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) were evaluated in mouse brain immortalized cell line bEnd3 to prove it as a useful BBB-mimicking system for biological and pharmacological research. Methods The presence of P-gp, BCRP and tight junction proteins occludin, claudin-5 and ZO-1 were validated by RT-PCR and Western blot...
April 23, 2018: Neurological Research
https://www.readbyqxmd.com/read/29679596/observational-studies-of-inhaled-corticosteroid-effectiveness-in-copd-lessons-learned
#16
Samy Suissa, Pierre Ernst
BACKGROUND: Randomized controlled trials at times investigate findings suggested by observational studies. For example, the TORCH trial, which did not show a mortality reduction with inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD), was motivated by some observational studies that suggested considerable reductions in mortality with these drugs. Reasons for these discrepancies are unclear. METHODS: We searched the literature to identify all observational studies, including cohort and case-control studies, investigating the effectiveness of ICS on major outcomes in COPD patients, including death and hospitalization for COPD...
April 18, 2018: Chest
https://www.readbyqxmd.com/read/29671783/telomerase-inhibition-by-a-new-synthetic-derivative-of-the-aporphine-alkaloid-boldine
#17
Sakineh Kazemi Noureini, Mitra Kheirabadi, Fatima Masoumi, Farve Khosrogerdi, Younes Zarei, Cristian Suárez-Rozas, Julio Salas-Norambuena, Bruce Kennedy Cassels
Telomerase, the enzyme responsible for cell immortality, is an important target in anti-cancer drug discovery. Boldine, an abundant aporphine alkaloid of Peumus boldus , is known to inhibit telomerase at non-toxic concentrations. Cytotoxicity of N -benzylsecoboldine hydrochloride (BSB), a synthetic derivative of boldine, was determined using the MTT method in MCF7 and MDA-MB231 cells. Aliquots of cell lysates were incubated with various concentrations of BSB in qTRAP (quantitative telomere repeat amplification protocol)-ligand experiments before substrate elongation by telomerase or amplification by hot-start Taq polymerase...
April 19, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29670864/mechanism-of-apoptosis-induction-by-mycoplasmal-nuclease-mga_0676-in-chicken-embryo-fibroblasts
#18
Peng Li, Jian Xu, Hong-Mei Rao, Xia Li, Yun-Ke Zhang, Fei Jiang, Wen-Xue Wu
MGA_0676 has been characterized as a Mycoplasma gallisepticum nuclease that can induce apoptosis of chicken cells. However, the mechanism by which MGA_0676 induces apoptosis has remained unclear. In this study, we evaluated MGA_0676-induced apoptosis and internalization in immortalized chicken embryo fibroblasts (DF-1) and cancer cell lines. The internalization of MGA_0676 was proven through caveolin-mediated endocytosis by blocking the endocytosis with specific inhibitors or with siRNA. We identified the Thif domain of NEDD8-activating enzyme E1 regulatory subunit (NAE) in DF-1 as the target region interacting with the SNC domain of MGA_0676...
2018: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/29668859/kribb53-binds-to-oct4-and-enhances-its-degradation-through-the-proteasome-causing-apoptotic-cell-death-of-oct4-positive-testicular-germ-cell-tumors
#19
Jiyae Jung, Youngmi Kim, Jinhoi Song, Yae Jin Yoon, Da-Eun Kim, Joo Ae Kim, Yena Jin, Yu-Jin Lee, Seokho Kim, Byoung-Mog Kwon, Dong Cho Han
We hypothesized that Octamer-binding transcription factor 4 (OCT4) inhibition would have therapeutic benefits in Testicular germ cell tumors (TGCT). To identify inhibitors of OCT4, a chemical library was screened using a luciferase reporter system under the control of an OCT4 response element. A compound named KRIBB53 was identified based on its blocking of OCT4-dependent luciferase activation. When NCCIT cells were exposed to KRIBB53, the expression levels of OCT4 target genes, such as NANOG and USP44, were inhibited with an IC50 of 13 and 15 μM, respectively...
April 13, 2018: Carcinogenesis
https://www.readbyqxmd.com/read/29656349/the-designer-drug-3-fluoromethcathinone-induces-oxidative-stress-and-activates-autophagy-in-ht22-neuronal-cells
#20
Kamila Siedlecka-Kroplewska, Agata Wrońska, Grzegorz Stasiłojć, Zbigniew Kmieć
Synthetic cathinones are psychoactive substances, derivatives of a natural psychostimulant cathinone. Although many synthetic cathinones have lost their legal status in many countries, their abuse still continues worldwide. Recently, they have been reported to exert neurotoxic effects in vitro and in vivo. The molecular mechanisms of their action have not been fully elucidated. Recently, they have been linked to the induction of oxidative stress, autophagy, and apoptosis. The aim of this study was to investigate whether 3-fluoromethcathinone (3-FMC), a synthetic cathinone, is able to induce oxidative stress, autophagy, and apoptosis in HT22 immortalized mouse hippocampal cells...
April 14, 2018: Neurotoxicity Research
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