دورية أكاديمية
أعرض في EDS

Ribonucleotide reductase inhibition improves the symptoms of a Caenorhabditis elegans model of Alzheimer's disease.

التفاصيل البيبلوغرافية
العنوان: Ribonucleotide reductase inhibition improves the symptoms of a Caenorhabditis elegans model of Alzheimer's disease.
المؤلفون: Brokate-Llanos AM; Centro Andaluz de Biologia del Desarrollo, University Pablo de Olavide-CISC-Junta de Andalucía, Ctra Utrera Km 1, Sevilla 41013, Spain., Sanchez-Ibañez M; Department of Surgery, Immunology and Biochemistry, School of Medicine, University of Malaga, Boulevar Louis Pasteur s/n, Málaga 29010, Spain., Pérez-Jiménez MM; Centro Andaluz de Biologia del Desarrollo, University Pablo de Olavide-CISC-Junta de Andalucía, Ctra Utrera Km 1, Sevilla 41013, Spain., Monje-Moreno JM; Centro Andaluz de Biologia del Desarrollo, University Pablo de Olavide-CISC-Junta de Andalucía, Ctra Utrera Km 1, Sevilla 41013, Spain., Gómez-Marín C; Centro Andaluz de Biologia del Desarrollo, University Pablo de Olavide-CISC-Junta de Andalucía, Ctra Utrera Km 1, Sevilla 41013, Spain., Caro C; Andalusian Centre for Nanomedicine and Biotechnology (Junta de Andalucía-Universidad de Málaga), BIONAND, Málaga 29590, Spain., Vivar-Rios C; Department of Surgery, Immunology and Biochemistry, School of Medicine, University of Malaga, Boulevar Louis Pasteur s/n, Málaga 29010, Spain., Moreno-Mateos MA; Centro Andaluz de Biologia del Desarrollo, University Pablo de Olavide-CISC-Junta de Andalucía, Ctra Utrera Km 1, Sevilla 41013, Spain., García-Martín ML; Andalusian Centre for Nanomedicine and Biotechnology (Junta de Andalucía-Universidad de Málaga), BIONAND, Málaga 29590, Spain., Muñoz MJ; Centro Andaluz de Biologia del Desarrollo, University Pablo de Olavide-CISC-Junta de Andalucía, Ctra Utrera Km 1, Sevilla 41013, Spain., Royo JL; Department of Surgery, Immunology and Biochemistry, School of Medicine, University of Malaga, Boulevar Louis Pasteur s/n, Málaga 29010, Spain.
المصدر: G3 (Bethesda, Md.) [G3 (Bethesda)] 2024 May 07; Vol. 14 (5).
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: Oxford University Press Country of Publication: England NLM ID: 101566598 Publication Model: Print Cited Medium: Internet ISSN: 2160-1836 (Electronic) Linking ISSN: 21601836 NLM ISO Abbreviation: G3 (Bethesda) Subsets: MEDLINE
أسماء مطبوعة: Publication: 2021- : [Oxford] : Oxford University Press
Original Publication: Bethesda, MD : Genetics Society of America, 2011-
مواضيع طبية MeSH: Caenorhabditis elegans*/drug effects , Alzheimer Disease*/drug therapy , Disease Models, Animal* , Deoxycytidine*/analogs & derivatives , Deoxycytidine*/pharmacology , Deoxycytidine*/therapeutic use, Animals ; Amyloid beta-Peptides/metabolism ; Humans ; Gemcitabine ; Ribonucleoside Diphosphate Reductase/genetics ; Ribonucleotide Reductases/antagonists & inhibitors ; Ribonucleotide Reductases/metabolism ; Adenosine Triphosphate/metabolism ; Caenorhabditis elegans Proteins/metabolism ; Caenorhabditis elegans Proteins/genetics ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/therapeutic use ; RNA Interference
مستخلص: Alzheimer's disease is the main cause of aging-associated dementia, for which there is no effective treatment. In this work, we reanalyze the information of a previous genome wide association study, using a new pipeline design to identify novel potential drugs. With this approach, ribonucleoside-diphosphate reductase gene (RRM2B) emerged as a candidate target and its inhibitor, 2', 2'-difluoro 2'deoxycytidine (gemcitabine), as a potential pharmaceutical drug against Alzheimer's disease. We functionally verified the effect of inhibiting the RRM2B homolog, rnr-2, in an Alzheimer's model of Caenorhabditis elegans, which accumulates human Aβ1-42 peptide to an irreversible paralysis. RNA interference against rnr-2 and also treatment with 200 ng/ml of gemcitabine, showed an improvement of the phenotype. Gemcitabine treatment increased the intracellular ATP level 3.03 times, which may point to its mechanism of action. Gemcitabine has been extensively used in humans for cancer treatment but at higher concentrations. The 200 ng/ml concentration did not exert a significant effect over cell cycle, or affected cell viability when assayed in the microglia N13 cell line. Thus, the inhibitory drug of the RRM2B activity could be of potential use to treat Alzheimer's disease and particularly gemcitabine might be considered as a promising candidate to be repurposed for its treatment.
Competing Interests: Conflicts of interest AMBL, MSI, CV, JLR, and MJM signed as authors of a patent application P201830955. The other authors declare no conflicts of interest.
(© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)
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معلومات مُعتمدة: P40 OD010440 United States OD NIH HHS
فهرسة مساهمة: Keywords: Caenorhabditis elegans; Alzheimer; RRM2B; gemcitabine
المشرفين على المادة: 0W860991D6 (Deoxycytidine)
0 (Amyloid beta-Peptides)
0 (Gemcitabine)
EC 1.17.4.1 (Ribonucleoside Diphosphate Reductase)
EC 1.17.4.- (Ribonucleotide Reductases)
8L70Q75FXE (Adenosine Triphosphate)
0 (Caenorhabditis elegans Proteins)
0 (Enzyme Inhibitors)
تواريخ الأحداث: Date Created: 20240227 Date Completed: 20240507 Latest Revision: 20240603
رمز التحديث: 20240603
مُعرف محوري في PubMed: PMC11075554
DOI: 10.1093/g3journal/jkae040
PMID: 38412549
قاعدة البيانات: MEDLINE
الوصف
تدمد:2160-1836
DOI:10.1093/g3journal/jkae040