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Sanjay Kumar Dey, Pankaj Prabhakar, Manisha Saini, Toyanji Joseph, B K Thelma, Subir K Maulik, Suman Kundu
OBJECTIVE: To identify novel inhibitors of dopamine beta hydroxylase (DBH) and evaluate their antihypertensive properties in L-NAME induced hypertensive rat model. DESIGN AND METHOD: An experimentally validated computational model for hDBH, built in our lab, was used for structure-based, rational drug-design. The three-dimensional model was used for virtual-screening against small molecule databases from NCI, USA and elsewhere. Identified top hits were then tested in vitro against DBH with known inhibitors nepicastat and disulfiram as controls...
September 2016: Journal of Hypertension
Noriaki Nagai
 The ophthalmic application of drugs is the primary route of administration for the therapy of glaucoma; however, in traditional formulations, only small amounts of the administered drug penetrate the cornea to reach the desired intraocular tissue due to corneal barriers. Recently, nanoparticulate drug delivery is expected as a technology to overcome the difficulties in delivering drugs across biological barriers (improvement of bioavailability). In this study, we attempted to establish a new method for preparing solid drug nanoparticles by using a bead mill and various additives, and succeeded in preparing a high quality dispersion containing drug nanoparticles...
2016: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
Patricia Erebi Tawari, Zhipeng Wang, Mohammad Najlah, Chi Wai Tsang, Vinodh Kannappan, Peng Liu, Christopher McConville, Bin He, Angel L Armesilla, Weiguang Wang
The anticancer activity of disulfiram (DS) is copper(ii) (Cu)-dependent. This study investigated the anticancer mechanisms of DS/Cu using in vitro cytotoxicity and metabolic kinetic analysis. Our study indicates that DS/Cu targets cancer cells by the combination of two types of actions: (1) instant killing executed by DS/Cu reaction generated reactive oxygen species; (2) delayed cytotoxicity introduced by the end product, DDC-Cu. Nanoencapsulation of DS might shed light on repositioning of DS into cancer treatment...
November 19, 2015: Toxicology Research
Sarah D Ahadome, David J Abraham, Suryanarayana Rayapureddi, Valerie P Saw, Daniel R Saban, Virginia L Calder, Jill T Norman, Markella Ponticos, Julie T Daniels, John K Dart
Mucous membrane pemphigoid (MMP) is a systemic mucosal scarring disease, commonly causing blindness, for which there is no antifibrotic therapy. Aldehyde dehydrogenase family 1 (ALDH1) is upregulated in both ocular MMP (OMMP) conjunctiva and cultured fibroblasts. Application of the ALDH metabolite, retinoic acid (RA), to normal human conjunctival fibroblasts in vitro induced a diseased phenotype. Conversely, application of ALDH inhibitors, including disulfiram, to OMMP fibroblasts in vitro restored their functionality to that of normal controls...
August 4, 2016: JCI Insight
Ashish R Kadia, Gaurang B Shah
No abstract text is available yet for this article.
July 2016: Journal of Pharmacology & Pharmacotherapeutics
Lauren D Van Wassenhove, Daria Mochly-Rosen, Kenneth I Weinberg
Maintenance of the hematopoietic stem cell (HSC) compartment depends on the ability to metabolize exogenously and endogenously generated toxins, and to repair cellular damage caused by such toxins. Reactive aldehydes have been demonstrated to cause specific genotoxic injury, namely DNA interstrand cross-links. Aldehyde dehydrogenase 2 (ALDH2) is a member of a 19 isoenzyme ALDH family with different substrate specificities, subcellular localization, and patterns of expression. ALDH2 is localized in mitochondria and is essential for the metabolism of acetaldehyde, thereby placing it directly downstream of ethanol metabolism...
September 2016: Molecular Genetics and Metabolism
Sanjay Kumar Dey, Pankaj Prabhakar, Manisha Saini, Toyanji Joseph, B K Thelma, Subir K Maulik, Suman Kundu
OBJECTIVE: To identify novel inhibitors of dopamine beta hydroxylase (DBH) and evaluate their antihypertensive properties in L-NAME induced hypertensive rat model. DESIGN AND METHOD: An experimentally validated computational model for hDBH, built in our lab, was used for structure-based, rational drug-design. The three-dimensional model was used for virtual-screening against small molecule databases from NCI, USA and elsewhere. Identified top hits were then tested in vitro against DBH with known inhibitors nepicastat and disulfiram as controls...
September 2016: Journal of Hypertension
Laura K Stone, Michael Baym, Tami D Lieberman, Remy Chait, Jon Clardy, Roy Kishony
We developed a competition-based screening strategy to identify compounds that invert the selective advantage of antibiotic resistance. Using our assay, we screened over 19,000 compounds for the ability to select against the TetA tetracycline-resistance efflux pump in Escherichia coli and identified two hits, β-thujaplicin and disulfiram. Treating a tetracycline-resistant population with β-thujaplicin selects for loss of the resistance gene, enabling an effective second-phase treatment with doxycycline.
November 2016: Nature Chemical Biology
Emily L Ricq, Jacob M Hooker, Stephen J Haggarty
Lysine demethylation of proteins such as histones is catalyzed by several classes of enzymes, including the FAD-dependent amine oxidases KDM1A/B. The KDM1 family is homologous to the mitochondrial monoamine oxidases MAO-A/B and produces hydrogen peroxide in the nucleus as a byproduct of demethylation. Here, we show KDM1A is highly thiol-reactive in vitro and in cellular models. Enzyme activity is potently and reversibly inhibited by the drug disulfiram and by hydrogen peroxide. Hydrogen peroxide produced by KDM1A catalysis reduces thiol labeling and inactivates demethylase activity over time...
September 15, 2016: Journal of Biological Chemistry
Alex H S Harris, Thomas Bowe, Hildi Hagedorn, Andrea Nevedal, Andrea K Finlay, Risha Gidwani, Craig Rosen, Chad Kay, Melissa Christopher
BACKGROUND: Active consideration of effective medications to treat alcohol use disorder (AUD) is a consensus standard of care, yet knowledge and use of these medications are very low across diverse settings. This study evaluated the overall effectiveness a multifaceted academic detailing program to address this persistent quality problem in the US Veterans Health Administration (VHA), as well as the context and process factors that explained variation in effectiveness across sites. METHODS: An interrupted time series design, analyzed with mixed-effects segmented logistic regression, was used to evaluate changes in level and rate of change in the monthly percent of patients with a clinically documented AUD who received naltrexone, acamprosate, disulfiram, or topiramate...
2016: Addiction Science & Clinical Practice
Mildred V Duprey-Díaz, Jonathan M Blagburn, Rosa E Blanco
After lesions to the mammalian optic nerve, the great majority of retinal ganglion cells (RGCs) die before their axons have even had a chance to regenerate. Frog RGCs, on the other hand, suffer only an approximately 50% cell loss, and we have previously investigated the mechanisms by which the application of growth factors can increase their survival rate. Retinoic acid (RA) is a vitamin A-derived lipophilic molecule that plays major roles during development of the nervous system. The RA signaling pathway is also present in parts of the adult nervous system, and components of it are upregulated after injury in peripheral nerves but not in the CNS...
2016: PloS One
Kaku Goto, Naoya Kato, Raymond T Chung
We recently described that the anti-apoptotic AMPK-related kinase, SNARK, promotes transforming growth factor (TGF)-β signaling in hepatocellular carcinoma (HCC) cells, as a potentially new therapeutic target. Here we explored FDA-approved drugs inhibiting the enzymatic activity of SNARK, using an in vitro luminescence kinase assay system. Interestingly, the long-used anti-alcoholism drug disulfiram (DSF), also known as Antabuse, emerged as the top hit. Enzymatic kinetics analyses revealed that DSF inhibited SNARK kinase activity in a noncompetitive manner to ATP or phosphosubstrates...
September 2, 2016: Oncotarget
Margaret Lois Thomas, Roberto de Antueno, Krysta Mila Coyle, Mohammad Sultan, Brianne Marie Cruickshank, Michael Anthony Giacomantonio, Carman Anthony Giacomantonio, Roy Duncan, Paola Marcato
Breast cancer stem cells (CSCs) can be identified by increased Aldefluor fluorescence caused by increased expression of aldehyde dehydrogenase 1A3 (ALDH1A3), as well as ALDH1A1 and ALDH2. In addition to being a CSC marker, ALDH1A3 regulates gene expression via retinoic acid (RA) signaling and plays a key role in the progression and chemotherapy resistance of cancer. Therefore, ALDH1A3 represents a druggable anti-cancer target of interest. Since to date, there are no characterized ALDH1A3 isoform inhibitors, drugs that were previously described as inhibiting the activity of other ALDH isoforms were tested for anti-ALDH1A3 activity...
November 2016: Molecular Oncology
Ming Zhao, Dingya Sun, Yangtai Guan, Zhihong Wang, Daoqian Sang, Mingdong Liu, Yingyan Pu, Xue Fang, Dan Wang, Aijun Huang, Xiaoying Bi, Li Cao, Cheng He
UNLABELLED: T-helper 17 (Th17) cells play an important role in the pathogenesis of multiple sclerosis (MS), an autoimmune demyelinating disease that affects the CNS. In the present study, MicroRNA sequencing (miRNA-seq) was performed in mouse Th0 and Th17 cells to determine the critical miRNAs that are related to Th17 differentiation. We found that miR-30a was significantly downregulated during mouse Th17 differentiation. In addition, the level of miR-30a in CD4(+) T cells from peripheral blood of MS patients and experimental autoimmune encephalomyelitis (EAE) animal models was also decreased and inversely correlated with the expression of interleukin 17a, the canonical cytokine of Th17 cells...
August 31, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Petros N Karamanakos, Periklis Pappas, Vasiliki Boumba, Theodoros Vougiouklakis, Marios Marselos
BACKGROUND/AIMS: Isoniazid (ISO) has been reported to inhibit the hepatic aldehyde dehydrogenase (ALDH) and to cause a disulfiram (DIS)-like reaction, albeit there are no reports demonstrating increased blood acetaldehyde levels after co-administration of ISO with alcohol. The aim of our study was to clarify whether the alcohol intolerance produced by ISO is indeed due to a typical DIS-like reaction. METHODS: DIS and ISO were administered to Wistar rats and the hepatic ethanol (ETH) metabolizing enzyme activities along with the levels of brain monoamines were determined...
August 27, 2016: Pharmacology
Cody J Peer, Jonathan D Strope, Shaunna Beedie, Ariel M Ley, Alesia Holly, Karim Calis, Ronald Farkas, Jagan Parepally, Angela Men, Emmanuel O Fadiran, Pamela Scott, Marjorie Jenkins, William H Theodore, Tristan M Sissung
OBJECTIVES: The recommended zolpidem starting dose was lowered in females (5 mg vs. 10 mg) since side effects were more frequent and severe than those of males; the mechanism underlying sex differences in pharmacokinetics (PK) is unknown. We hypothesized that such differences were caused by known sex-related variability in alcohol dehydrogenase (ADH) expression. METHODS: Male, female, and castrated male rats were administered 2.6 mg/kg zolpidem, ± disulfiram (ADH/ALDH pathway inhibitor) to compare PK changes induced by sex and gonadal hormones...
2016: Frontiers in Pharmacology
Kiran K Kumar, Swapna Bondade, Fiaz Ahmed Sattar, Niharika Singh
Disulfiram is a widely used drug in the management of alcohol dependence syndrome as an aversive agent. Although a drug of high efficacy, it has a large number of side effects. Disulfiram-induced catatonia is a known rare side effect of the drug and herein we report a case of what appeared to be the sequential development of malignant catatonia and neuroleptic malignant syndrome in a patient with a diagnosis of alcohol dependence syndrome and co-morbid paranoid schizophrenia following disulfiram overdose. Clinicians need to be vigilant on the emergence of such rare side effects...
July 2016: Indian Journal of Psychological Medicine
Xinwei Liu, Lihui Wang, Wei Cui, Xiangzhong Yuan, Lulu Lin, Qi Cao, Nannan Wang, Yi Li, Wei Guo, Xun Zhang, Chunfu Wu, Jingyu Yang
The existence of cancer stem cells (CSCs) in non-small cell lung cancer (NSCLC) has profound implications for cancer therapy. In this study, a disulfiram/copper (DSF/Cu) complex was evaluated in vitro and in vivo for its efficacy to inhibit CSCs, which drive recurrence of NSCLC. First, we investigated whether DSF/Cu could inhibit ALDH-positive NSCLC stem cells in vitro and tumors derived from sorted ALDH-positive CSCs in vivo. DSF/Cu (0.5/1 μmol/l) significantly inhibited the expression of stem cell transcription factors (Sox2, Oct-4 and Nanog) and reduced the capacities of NSCLC stem cells for self-renewal, proliferation and invasion in vitro...
August 16, 2016: Oncotarget
Felipe Gil, Arthur Guerra de Andrade, João Maurício Castaldelli-Maia
The consumption of alcohol, tobacco, and other drugs has become a concern in high-performance athletes. Professional athletes are more exposed to drugs than the general population. Although some drugs are unquestionably detrimental to performance, several studies have nevertheless shown evidence of increased consumption of these substances within this sub-population. This review aimed to elucidate alcohol, tobacco, cocaine, cannabis, and opioid use among high-performance athletes, discussing the prevalence of substance use, its impacts, and alternatives to treatment in this special population...
August 18, 2016: International Review of Psychiatry
Zhipeng Wang, Jiao Tan, Christopher McConville, Vinodh Kannappan, Patricia Erebi Tawari, James Brown, Jin Ding, Angel L Armesilla, Juan M Irache, Qi-Bing Mei, Yuhuan Tan, Ying Liu, Wenguo Jiang, Xiuwu Bian, Weiguang Wang
Disulfiram (DS), an anti-alcoholism drug, shows very strong cytotoxicity in many cancer types. However its clinical application in cancer treatment is limited by the very short half-life in the bloodstream. In this study, we developed a poly lactic-co-glycolic acid (PLGA)-encapsulated DS protecting DS from the degradation in the bloodstream. The newly developed DS-PLGA was characterized. The DS-PLGA has very satisfactory encapsulation efficiency, drug-loading content and controlled release rate in vitro. PLGA encapsulation extended the half-life of DS from shorter than 2minutes to 7hours in serum...
August 10, 2016: Nanomedicine: Nanotechnology, Biology, and Medicine
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