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Dimethyl fumarate

George Vavougios, Sotirios G Zarogiannis, Triantafylos Doskas
Recent research has outlined that Dimethyl Fumarate (DMF) functions as a gene regulator via multiple pathways, critical among which is the NRF2 cytoprotective cascade. PARK7/DJ-1 is a multifunctional protein that acts as a redox sensor and effector of multiple cytoprotective pathways, including NRF2. Specifically, it prevents the association of NRF2 with its inhibitor KEAP1, allowing NRF2 to enter the nucleus and mediate cytoprotective and antioxidant cascades. It is our hypothesis that while the NRF2-KEAP1 inhibitory complex is reported the main pharmacological target for DMF's NRF dependent functions, no study to date has explored the effects of DMF on DJ-1's expression, and vice-versa, the possibility of a regulatory inadequacy in the upstream, oxidant-responsive DJ-1 activator of the NRF2 cascade...
February 26, 2018: Multiple Sclerosis and related Disorders
Stanley L Cohan, Harold Moses, Jonathan Calkwood, Carlo Tornatore, Chris LaGanke, Kyle E Smoot, Venkata Meka, Macaulay Okwuokenye, Christophe Hotermans, Jason P Mendoza, Monica K Mann, Leslie A Meltzer
BACKGROUND: Delayed-release dimethyl fumarate (DMF) may be a therapeutic option for patients with relapsing-remitting multiple sclerosis (RRMS) who are treated with natalizumab and require a change in therapy. However, there is limited information regarding predictors of favorable treatment outcomes in patients switching from natalizumab to DMF. Clinical practices and sequencing protocols vary. Herein, we present the clinical results, including annualized relapse rate (ARR) and risk of relapse, of a phase 4 retrospective observational study of patients with RRMS who switched from natalizumab to DMF in a community practice setting (STRATEGY)...
February 26, 2018: Multiple Sclerosis and related Disorders
Mariko Kita, Robert J Fox, Ralf Gold, Gavin Giovannoni, J Theodore Phillips, Sujata P Sarda, Jessica Kong, Vissia Viglietta, Sarah I Sheikh, Macaulay Okwuokenye, Ludwig Kappos
No abstract text is available yet for this article.
March 7, 2018: Clinical Therapeutics
Nathaniel Edward Bennett Saidu, Marie Bretagne, Audrey Lupo Mansuet, Pierre-Alexandre Just, Karen Leroy, Olivier Cerles, Sandrine Chouzenoux, Carole Nicco, Diane Damotte, Marco Alifano, Bruno Borghese, François Goldwasser, Frédéric Batteux, Jérôme Alexandre
KRAS mutation, one of the most common molecular alterations observed in adult carcinomas, was reported to activate the anti-oxidant program driven by the transcription factor NRF2 (Nuclear factor-erythroid 2-related factor 2). We previously observed that the antitumoral effect of Dimethyl fumarate (DMF) is dependent of NRF2 pathway inhibition. We used in vitro methods to examine the effect of DMF on cell death and the activation of the NRF2/DJ-1 antioxidant pathway. We report here that DMF is preferentially cytotoxic against KRAS mutated cancer cells...
February 6, 2018: Oncotarget
Antonio Cuadrado, Gina Manda, Ahmed Hassan, María José Alcaraz, Coral Barbas, Andreas Daiber, Pietro Ghezzi, Rafael León, Manuela G López, Baldo Oliva, Marta Pajares, Ana I Rojo, Natalia Robledinos-Antón, Angela M Valverde, Emre Guney, Harald H H W Schmidt
Systems medicine has a mechanism-based rather than a symptom- or organ-based approach to disease and identifies therapeutic targets in a nonhypothesis-driven manner. In this work, we apply this to transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) by cross-validating its position in a protein-protein interaction network (the NRF2 interactome) functionally linked to cytoprotection in low-grade stress, chronic inflammation, metabolic alterations, and reactive oxygen species formation. Multiscale network analysis of these molecular profiles suggests alterations of NRF2 expression and activity as a common mechanism in a subnetwork of diseases (the NRF2 diseasome)...
April 2018: Pharmacological Reviews
Jacqueline Nicholas, Aaron Boster, Ning Wu, Wei-Shi Yeh, Monica Fay, Jon Kendter, Ming-Yi Huang, Andrew Lee
BACKGROUND: Data on comparative healthcare resource utilization and costs associated with the newer oral disease-modifying therapies (DMTs) for managing relapsing-remitting multiple sclerosis (MS) in routine clinical practice are limited. The purpose of this study was to estimate healthcare resource utilization, costs, and relapse rates in the year after initiating treatment with dimethyl fumarate (DMF), interferon (IFN)-β, glatiramer acetate (GA), teriflunomide, or fingolimod in routine clinical practice for patients with MS who did not receive a DMT in the previous year...
March 2018: PharmacoEconomics open
Na-Ri Shin, Woorim Kang, Euon Jung Tak, Dong-Wook Hyun, Pil Soo Kim, Hyun Sik Kim, June-Young Lee, Hojun Sung, Tae Woong Whon, Jin-Woo Bae
A strictly anaerobic, Gram-stain-positive, non-motile and coccoid- or oval-shaped bacterium, designated strain KB1T , was isolated from a faecal sample of a patient with diverticulitis in South Korea. Degeneracies in the 16S rRNA gene sequence of strain KB1T were resolved by cloning, which yielded five different sequences with heterogeneity. Phylogenetic analysis based on the 16S rRNA gene sequences showed that strain KB1T formed a monophyletic branch with species in the genus Blautia, with highest sequence similarity to the type strain of Blautia producta (97...
February 9, 2018: International Journal of Systematic and Evolutionary Microbiology
Elizabeth A Mills, Yang Mao-Draayer
The increased use of newer potent immunomodulatory therapies for multiple sclerosis (MS), including natalizumab, fingolimod, and dimethyl fumarate, has expanded the patient population at risk for developing progressive multifocal leukoencephalopathy (PML). These MS therapies shift the profile of lymphocytes within the central nervous system (CNS) leading to increased anti-inflammatory subsets and decreased immunosurveillance. Similar to MS, PML is a demyelinating disease of the CNS, but it is caused by the JC virus...
2018: Frontiers in Immunology
Ewa Krzystanek, Przemyslawa Jarosz-Chobot
BACKGROUND: Dimethyl fumarate (DMF) is approved for use in patients with relapsing-remitting multiple sclerosis (MS). Its mechanism of action is still not well understood, but besides the immunological pathways in MS, it may also affect the metabolism of normally functioning internal organs, tissues and cells. CASE PRESENTATION: We report on the case of 29-year-old woman with satisfactorily-controlled type 1 diabetes (T1D), who was diagnosed as having MS. After administration of DMF she experienced intense, adverse gastro-intestinal reactions together with ketonuria up to 160 mg/dL...
February 7, 2018: Multiple Sclerosis and related Disorders
Irena Majkutewicz, Ewelina Kurowska, Magdalena Podlacha, Dorota Myślińska, Beata Grembecka, Jan Ruciński, Karolina Pierzynowska, Danuta Wrona
We previously demonstrated that dimethyl fumarate (DMF), an anti-oxidative and immunosuppresive compound, prevents intracerebroventricular (ICV) streptozotocin-induced disruption of spatial memory and neurodegeneration in 4-month-old rats. The present study evaluated the influence of age on DMF's therapeutic effect. Aged rats (22-months-old, n=40) were provided rodent chow containing DMF (0.4%) and given ICV injections of streptozotocin (STZ) or vehicle (Sham) on days 2 and 4. Spatial memory was evaluated using the Morris water maze (MWM) on days 14-21...
February 14, 2018: Brain Research
Neha Singh, Sheekha Vijayanti, Lekha Saha
Epilepsy is a complex, chronic neurological disorder characterized by increased and abnormal synchronization of neuronal electrical activity, which is manifested as seizures. It is associated with many comorbid conditions such as depression, anxiety, sleep disorder, psychiatric disorder etc. which consequently causes higher mortality rate. The understanding of its cellular and molecular mechanism is partial, because of which it remains an ongoing health problem, despite the increasing availability of newer antiepileptic drugs...
February 15, 2018: International Journal of Neuroscience
Tingting Wang, Lingling Liu, Xuyong Chen, Yuqing Shen, Gaojian Lian, Nilay Shah, Andrew M Davidoff, Jun Yang, Ruoning Wang
Heightened aerobic glycolysis and glutaminolysis are characteristic metabolic phenotypes in cancer cells. Neuroblastoma (NBL), a devastating pediatric cancer, is featured by frequent genomic amplification of MYCN, a member of the Myc oncogene family that is primarily expressed in the early stage of embryonic development and required for neural crest development. Here we report that an enriched glutaminolysis gene signature is associated with MYCN amplification in children with NBL. The partial knockdown of MYCN suppresses glutaminolysis in NBL cells...
February 14, 2018: Cell Death & Disease
Oliver Oey, Padmashree Rao, Magdalena Luciuk, Carly Mannix, Natasha M Rogers, Priyanka Sagar, Annette Wong, Gopala Rangan
Dimethyl fumarate is an FDA-approved oral immunomodulatory drug with anti-inflammatory properties that induces the upregulation of the anti-oxidant transcription factor, nuclear factor erythroid-derived factor 2. The aim of this study was to determine the efficacy of dimethyl fumarate on interstitial inflammation and renal cyst growth in a preclinical model of nephronophthisis. Four-week-old female Lewis polycystic kidney disease (a genetic ortholog of human nephronophthisis-9) rats received vehicle (V), 10 mg/kg (D10) or 30 mg/kg (D30) ( n = 8-9 each) dimethyl fumarate in drinking water for eight weeks...
January 1, 2018: Experimental Biology and Medicine
Irene Eriksson, Joris Komen, Fredrik Piehl, Rickard E Malmström, Björn Wettermark, Mia von Euler
PURPOSE: The purpose of this study is to describe the utilization of disease-modifying treatments (DMTs) in relapsing-remitting multiple sclerosis (MS) and assess the impact of both the introduction of new drugs and treatment recommendations (local recommendation on rituximab use issued at the largest MS clinic in Stockholm and regional Drug and Therapeutics Committee (DTC) recommendation on how dimethyl fumarate should be used). METHODS: Interrupted time series analyses using monthly data on all MS patients treated with DMTs in the Stockholm County, Sweden, from January 2011 to December 2017...
February 10, 2018: European Journal of Clinical Pharmacology
(no author information available yet)
[This corrects the article on p. e432 in vol. 5, PMID: 29296636.].
March 2018: Neurology® Neuroimmunology & Neuroinflammation
Elizabeth A Mills, Magdalena A Ogrodnik, Andrew Plave, Yang Mao-Draayer
Dimethyl fumarate (DMF) is an effective treatment option for relapsing-remitting multiple sclerosis (MS), but its therapeutic mechanism of action has not been fully elucidated. A better understanding of its mechanism will allow for the development of assays to monitor its clinical efficacy and safety in patients, as well as guide the development of the next generation of therapies for MS. In order to build the foundation for determining its mechanism, we reviewed the manner in which DMF alters lymphocyte subsets in MS patients, its impact on clinical efficacy and safety, as well as its molecular effects in cellular and animal models...
2018: Frontiers in Neurology
Xinyue Hu, Mohanraj Rajesh, Jian Zhang, Shanshan Zhou, Shudong Wang, Jian Sun, Yi Tan, Yang Zheng, Lu Cai
Oxidative stress and inflammation play key roles in the development of diabetic cardiomyopathy (DCM). Dimethyl fumarate (DMF), an FDA approved medicine for relapsing multiple sclerosis, has manifested its antioxidant and anti-inflammatory function mostly in the central nervous system. In this study, we investigated whether DMF could attenuate the development of DCM. Type 1 diabetes mouse model was established using multiple low-dose streptozotocin, and the diabetic mice were treated with DMF (10 mg/kg body weight) for 3 months...
February 2, 2018: Toxicology Letters
Qing Lin, Peng An, Tracey M Lewandowski
The BODIPY-linked bithiophene-tetrazoles were designed and synthesized for bioorthogonal photoclick reactions in vitro and in vivo. The reactivity of these tetrazoles toward dimethyl fumarate was found to depend on BODIPY attachment site, with the meta-linked BODIPY-tetrazole being the most reactive. The resulting BODIPY-pyrazolines showed drastically reduced BODIPY fluorescence. Interestingly, the BODIPY fluorescence recovered after treatment with hydrogen peroxide, which was attributed to the conversion from the pyrazoline to the pyrazole...
January 31, 2018: Chembiochem: a European Journal of Chemical Biology
Mohammed Selman, Paula Ou, Christopher Rousso, Anabel Bergeron, Ramya Krishnan, Larissa Pikor, Andrew Chen, Brian A Keller, Carolina Ilkow, John C Bell, Jean-Simon Diallo
Resistance to oncolytic virotherapy is frequently associated with failure of tumor cells to get infected by the virus. Dimethyl fumarate (DMF), a common treatment for psoriasis and multiple sclerosis, also has anticancer properties. We show that DMF and various fumaric and maleic acid esters (FMAEs) enhance viral infection of cancer cell lines as well as human tumor biopsies with several oncolytic viruses (OVs), improving therapeutic outcomes in resistant syngeneic and xenograft tumor models. This results in durable responses, even in models otherwise refractory to OV and drug monotherapies...
January 24, 2018: Science Translational Medicine
Giovanna Casili, Michela Campolo, Irene Paterniti, Marika Lanza, Alessia Filippone, Salvatore Cuzzocrea, Emanuela Esposito
TBI is a serious neuropathology that causes secondary injury mechanisms, including dynamic interplay between ischemic, inflammatory and cytotoxic processes. Fumaric acid esters (FAEs) showed beneficial effects in preclinical models of neuroinflammation and toxic oxidative stress, so the aim of the present work was to evaluate the potential beneficial effects of dimethyl fumarate (DMF), the most pharmacologically effective molecules among the FAEs, in a mouse model of TBI induced by controlled cortical impact (CCI)...
January 23, 2018: Journal of Neurotrauma
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