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Drug repurposing

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https://www.readbyqxmd.com/read/28526617/cyclin-dependent-kinase-5-a-novel-avenue-for-alzheimer-s-disease
#1
REVIEW
Anisha S Bhounsule, Lokesh Kumar Bhatt, Kedar S Prabhavalkar, Manisha Oza
Alzheimer's disease (AD) is one of the most frequently encountered diseases in adults with progressive loss of memory and behavioral changes. Inspite of there being an intense research in the field of AD, only a few chemical entities exhibiting anti-AD activity make it through the clinical trials and it is thus need of an hour to develop new drugs or repurpose the existing ones for better management of Alzheimer's disease. Novel therapeutic targets can influence drug discovery in the field of AD. Cyclin Dependent Kinase 5 (Cdk5) which is a serine/threonine kinase can prove to be an upcoming beneficial target to be studied for treating AD...
May 17, 2017: Brain Research Bulletin
https://www.readbyqxmd.com/read/28525376/exploiting-ros-and-metabolic-differences-to-kill-cisplatin-resistant-lung-cancer
#2
Medhi Wangpaichitr, Chunjing Wu, Ying Ying Li, Dan J M Nguyen, Hande Kandemir, Sumedh Shah, Shumei Chen, Lynn G Feun, Jeffrey S Prince, Macus T Kuo, Niramol Savaraj
Cisplatin resistance remains a major problem in the treatment of lung cancer. We have discovered that cisplatin resistant (CR) lung cancer cells, regardless of the signaling pathway status, share the common parameter which is an increase in reactive oxygen species (ROS) and undergo metabolic reprogramming. CR cells were no longer addicted to the glycolytic pathway, but rather relied on oxidative metabolism. They took up twice as much glutamine and were highly sensitive to glutamine deprivation. Glutamine is hydrolyzed to glutamate for glutathione synthesis, an essential factor to abrogate high ROS via xCT antiporter...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28521682/repurposing-of-copper-ii-chelating-drugs-for-the-treatment-of-neurodegenerative-diseases
#3
Valeria Lanza, Danilo Milardi, Giuseppe Di Natale, Giuseppe Pappalardo
BACKGROUND: There is mounting urgency to find new drugs for the treatment of neurodegenerative disorders. A large number of reviews has exhaustively described either the molecular or clinical aspects of neurodegenerative diseases as Alzheimer's (AD) and Parkinson's (PD). Conversely, reports outlining how known drugs in use for other diseases can be also effective as therapeutic agents in neurodegenerative diseases are less reported. This review focuses on the current uses of some copper(II) interacting molecules as potential drug candidates in neurodegeneration...
May 17, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28518151/disulfiram-copper-selectively-eradicates-aml-leukemia-stem-cells-in-vitro-and-in-vivo-by-simultaneous-induction-of-ros-jnk-and-inhibition-of-nf-%C3%AE%C2%BAb-and-nrf2
#4
Bing Xu, Shiyun Wang, Rongwei Li, Kai Chen, Lingli He, Manman Deng, Vinodh Kannappan, Jie Zha, Huijuan Dong, Weiguang Wang
Acute myeloid leukemia (AML) is a heterogeneous malignancy. Despite the advances in past decades, the clinical outcomes of AML patients remain poor. Leukemia stem cells (LSCs) is the major cause of the recurrence of AML even after aggressive treatment making, promoting development of LSC-targeted agents is an urgent clinical need. Although the antitumor activity of disulfiram (DS), an approved anti-alcoholism drug, has been demonstrated in multiple types of tumors including hematological malignancies such as AML, it remains unknown whether this agent would also be able to target cancer stem cells like LSCs...
May 18, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28512247/targetable-t-type-calcium-channels-drive-glioblastoma
#5
Ying Zhang, Nichola Cruickshanks, Fang Yuan, Baomin Wang, Mary Pahuski, Julia Wulfkuhle, Isela Gallagher, Alexander F Koeppel, Sarah Hatef, Christopher Papanicolas, Jeongwu Lee, Eli E Bar, David Schiff, Stephen Turner, Emanuel F Petricoin, Lloyd S Gray, Roger Abounader
Glioblastoma stem-like cells (GSC) promote tumor initiation, progression and therapeutic resistance. Here we show how GSC can be targeted by the FDA approved drug mibefradil which inhibits the T-type calcium channel Cav3.2. This calcium channel was highly expressed in human GBM specimens and enriched in GSC. Analyses of the TCGA and REMBRANDT databases confirmed upregulation of Cav3.2 in a subset of tumors and showed that overexpression associated with worse prognosis. Mibefradil treatment or RNAi-mediated attenuation of Cav3...
May 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28512024/repurposing-of-proton-pump-inhibitors-as-first-identified-small-molecule-inhibitors-of-endo-%C3%AE-n-acetylglucosaminidase-engase-for-the-treatment-of-ngly1-deficiency-a-rare-genetic-disease
#6
Yiling Bi, Matthew Might, Hariprasad Vankayalapati, Balagurunathan Kuberan
N-Glycanase deficiency, or NGLY1 deficiency, is an extremely rare human genetic disease. N-Glycanase, encoded by the gene NGLY1, is an important enzyme involved in protein deglycosylation of misfolded proteins. Deglycosylation of misfolded proteins precedes the endoplasmic reticulum (ER)-associated degradation (ERAD) process. NGLY1 patients produce little or no N-glycanase (Ngly1), and the symptoms include global developmental delay, frequent seizures, complex hyperkinetic movement disorder, difficulty in swallowing/aspiration, liver dysfunction, and a lack of tears...
May 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28504720/a-clinical-drug-library-screen-identifies-clobetasol-propionate-as-an-nrf2-inhibitor-with-potential-therapeutic-efficacy-in-keap1-mutant-lung-cancer
#7
E-J Choi, B-J Jung, S-H Lee, H-S Yoo, E-A Shin, H-J Ko, S Chang, S-Y Kim, S-M Jeon
The Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor E2-related factor 2 (NRF2)pathway has a central role in cellular antioxidant defense. NRF2 activation due to KEAP1 or NRF2 mutations occurs frequently in many cancers, suggesting that NRF2 inhibition could be a promising therapeutic strategy. However, no potent NRF2 inhibitors are clinically available to date. To develop potent NRF2 inhibitors for therapeutic purpose, we screened ~4000 clinical compounds and determined clobetasol propionate (CP) as the most potent NRF2 inhibitor...
May 15, 2017: Oncogene
https://www.readbyqxmd.com/read/28503778/a-topical-zinc-ionophore-blocks-tumorigenic-progression-in-uv-exposed-skh-1-high-risk-mouse-skin
#8
Rebecca Justiniano, Jessica Perer, Anh Hua, Mohammad Fazel, Andrea Krajisnik, Christopher M Cabello, Georg T Wondrak
Nonmelanoma skin cancer (NMSC) is the most common malignancy in the United States representing a considerable public health burden. Pharmacological suppression of skin photo-carcinogenesis has shown promise in preclinical and clinical studies, but more efficacious photochemopreventive agents are needed. Here, we tested feasibility of harnessing pharmacological disruption of intracellular zinc-homeostasis for photochemoprevention in vitro and in vivo. Employing the zinc-ionophore and FDA-approved microbicidal agent zinc pyrithione (ZnPT), used worldwide in over-the-counter (OTC) topical consumer products, we first demonstrated feasibility of achieving ZnPT-based intracellular Zn(2+) -overload in cultured malignant keratinocytes (HaCaT-ras II-4; SCC-25) employing membrane-permeable fluorescent probes...
May 15, 2017: Photochemistry and Photobiology
https://www.readbyqxmd.com/read/28503657/an-amylin-analog-used-as-a-challenge-test-for-alzheimer-s-disease
#9
Haihao Zhu, Robert A Stern, Qiushan Tao, Alexandra Bourlas, Maritza D Essis, Meenakshi Chivukula, James Rosenzweig, Devin Steenkamp, Weiming Xia, Gustavo A Mercier, Yorghos Tripodis, Martin Farlow, Neil Kowall, Wei Qiao Qiu
INTRODUCTION: Preclinical studies demonstrate the potential of amylin in the diagnosis of Alzheimer's disease (AD). We aimed to lay the foundation for repurposing the amylin analog and a diabetes drug, pramlintide, for AD in humans. METHODS: We administered a single subcutaneous injection of 60 μg of pramlintide to nondiabetic subjects under fasting conditions. RESULTS: None of the participants developed hypoglycemia after the injection of pramlintide...
January 2017: Alzheimer's & Dementia: Translational Research & Clinical Interventions
https://www.readbyqxmd.com/read/28499100/probing-for-neuroadaptations-to-unpredictable-stressors-in-addiction-translational-methods-and-emerging-evidence
#10
Jesse T Kaye, Daniel E Bradford, Katherine P Magruder, John J Curtin
Stressors clearly contribute to addiction etiology and relapse in humans, but our understanding of specific mechanisms remains limited. Rodent models of addiction offer the power, flexibility, and precision necessary to delineate the causal role and specific mechanisms through which stressors influence alcohol and other drug use. This review describes a program of research using startle potentiation to unpredictable stressors that is well positioned to translate between animal models and clinical research with humans on stress neuroadaptations in addiction...
May 2017: Journal of Studies on Alcohol and Drugs
https://www.readbyqxmd.com/read/28495415/rhinovirus-from-bench-to-bedside
#11
REVIEW
Kelvin K W To, Cyril C Y Yip, Kwok-Yung Yuen
Rhinovirus has been neglected in the past because it was generally perceived as a respiratory virus only capable of causing mild common cold. Contemporary epidemiological studies using molecular assays have shown that rhinovirus is frequently detected in adult and pediatric patients with upper or lower respiratory tract infections. Severe pulmonary and extrapulmonary complications are increasingly recognized. Contrary to popular belief, some rhinoviruses can actually replicate well at 37 °C and infect the lower airway in humans...
May 8, 2017: Journal of the Formosan Medical Association, Taiwan Yi Zhi
https://www.readbyqxmd.com/read/28488581/repurposing-albendazole-new-potential-as-a-chemotherapeutic-agent-with-preferential-activity-against-hpv-negative-head-and-neck-squamous-cell-cancer
#12
Farhad Ghasemi, Morgan Black, Frederick Vizeacoumar, Nicole Pinto, Kara M Ruicci, Carson Cao Son Huu Le, Matthew R Lowerison, Hon Sing Leong, John Yoo, Kevin Fung, Danielle MacNeil, David A Palma, Eric Winquist, Joe S Mymryk, Paul C Boutros, Alessandro Datti, John W Barrett, Anthony C Nichols
Albendazole is an anti-helminthic drug that has been shown to exhibit anti-cancer properties, however its activity in head and neck squamous cell cancer (HNSCC) was unknown. Using a series of in vitro assays, we assessed the ability of albendazole to inhibit proliferation in 20 HNSCC cell lines across a range of albendazole doses (1 nM-10 μM). Cell lines that responded to treatment were further examined for cell death, inhibition of migration and cell cycle arrest. Thirteen of fourteen human papillomavirus-negative HNSCC cell lines responded to albendazole, with an average IC50 of 152 nM...
April 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28484954/repurposing-pentoxifylline-for-the-treatment-of-fibrosis-an-overview
#13
REVIEW
Wei Xiong Wen, Siang Yin Lee, Rafaella Siang, Rhun Yian Koh
Fibrosis is a potentially debilitating disease with high morbidity rates. It is estimated that half of all deaths that occur in the USA are attributed to fibrotic disorders. Fibrotic disorders are characterized primarily by disruption in the extracellular matrix deposition and breakdown equilibrium, leading to the accumulation of excessive amounts of extracellular matrix. Given the potentially high prevalence of fibrosis and the paucity of agents currently available for the treatment of this disease, there is an urgent need for the identification of drugs that can be utilized to treat the disease...
May 8, 2017: Advances in Therapy
https://www.readbyqxmd.com/read/28483805/treating-the-dysfunctional-placenta
#14
Colin Peter Sibley
Placental dysfunction underlies major obstetric diseases such as pre-eclampsia and fetal growth restriction (FGR). Whilst there has been a little progress in prophylaxis there are still no treatments for placental dysfunction in normal obstetric practice. However, a combination of increasingly well described in vitro systems for studying the human placenta, together with the availability of more appropriate animal models of pre-eclampsia and FGR, has facilitated a recent surge in work aimed at repurposing drugs and therapies, developed for other conditions, as treatments for placental dysfunction...
May 8, 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/28480903/metabolic-reprogramming-in-clear-cell-renal-cell-carcinoma
#15
REVIEW
Hiromi I Wettersten, Omran Abu Aboud, Primo N Lara, Robert H Weiss
Research in many cancers has uncovered changes in metabolic pathways that control tumour energetics and biosynthesis, so-called metabolic reprogramming. Studies in clear cell renal cell carcinoma (ccRCC) have been particularly revealing, leading to the concept that ccRCC is a metabolic disease. ccRCC is generally accompanied by reprogramming of glucose and fatty acid metabolism and of the tricarboxylic acid cycle. Metabolism of tryptophan, arginine and glutamine is also reprogrammed in many ccRCCs, and these changes provide opportunities for new therapeutic strategies, biomarkers and imaging modalities...
May 8, 2017: Nature Reviews. Nephrology
https://www.readbyqxmd.com/read/28480282/pediatric-drug-nitazoxanide-a-potential-choice-for-control-of-zika
#16
Rui-Yuan Cao, Yong-Fen Xu, Tian-Hong Zhang, Jing-Jing Yang, Ye Yuan, Pei Hao, Yi Shi, Jin Zhong, Wu Zhong
Zika virus (ZIKV) infection can be the cause of congenital malformations, including microcephaly in infants and can cause other disorders such as Guillain-Barré syndrome, meningoencephalitis, and myelitis, which can also occur in some infected adults. However, at this time, there is no drug approved to treat ZIKV infection. Drug repurposing is the promptest way to obtain an effective drug during a global public health emergency such as the spread of Zika virus. In this study, we report a US Food and Drug Admistration-approved drug that is safe for pediatric use...
2017: Open Forum Infectious Diseases
https://www.readbyqxmd.com/read/28479190/biosynthesis-of-plant-derived-ginsenoside-rh2-in-yeast-via-repurposing-a-key-promiscuous-microbial-enzyme
#17
Yu Zhuang, Guangyu Yang, Xiaohui Chen, Qian Liu, Xueli Zhang, Zixin Deng, Yan Feng
Ginsenoside Rh2 is a potential anticancer drug isolated from medicinal plant ginseng. Fermentative production of ginsenoside Rh2 in yeast has recently been investigated as an alternative strategy compared to extraction from plants. However, the titer was quite low due to low catalytic capability of the key ginseng glycosyltransferase in microorganisms. Herein, we have demonstrated high-level production of ginsenoside Rh2 in Saccharomyces cerevisiae via repurposing an inherently promiscuous glycosyltransferase, UGT51...
May 4, 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28474684/neurodegenerative-disease-halting-neurodegeneration-are-repurposed-drugs-the-answer
#18
Heather Wood
No abstract text is available yet for this article.
May 5, 2017: Nature Reviews. Neurology
https://www.readbyqxmd.com/read/28473889/filling-the-gap-in-cns-drug-development-evaluation-of-the-role-of-drug-repurposing
#19
A Caban, K Pisarczyk, K Kopacz, A Kapuśniak, M Toumi, C Rémuzat, A Kornfeld
Background and objective: Background and objective: Drug repurposing has been considered a cost-effective and reduced-risk strategy for developing new drugs. Little is known and documented regarding the efficiency of repurposing strategies in drug development. The objective of this article is to assess the extent and meaning of this process in the CNS area. Methods: In order to identify repurposed drugs that target the CNS, an extensive search was performed. For each identified case, its initial and target indication, development status and the type of repurposing strategy (repositioning, reformulation or both) was recorded...
2017: Journal of Market Access & Health Policy
https://www.readbyqxmd.com/read/28472495/c-spade-a-web-tool-for-interactive-analysis-and-visualization-of-drug-screening-experiments-through-compound-specific-bioactivity-dendrograms
#20
Balaguru Ravikumar, Zaid Alam, Gopal Peddinti, Tero Aittokallio
The advent of polypharmacology paradigm in drug discovery calls for novel chemoinformatic tools for analyzing compounds' multi-targeting activities. Such tools should provide an intuitive representation of the chemical space through capturing and visualizing underlying patterns of compound similarities linked to their polypharmacological effects. Most of the existing compound-centric chemoinformatics tools lack interactive options and user interfaces that are critical for the real-time needs of chemical biologists carrying out compound screening experiments...
May 4, 2017: Nucleic Acids Research
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