Browsing by Subject "statins"

Now showing 1 - 3 of 3
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    Classic and targeted anti-leukaemic agents interfere with the cholesterol biogenesis metagene in acute myeloid leukaemia: Therapeutic implications
    (Wiley, 2020-05-25) Chen, Fangli; Wu, Xue; Niculite, Cristina; Gilca, Marilena; Petrusca, Daniela; Rogozea, Adriana; Rice, Susan; Guo, Bin; Griffin, Shawn; Calin, George A.; Boswell, H. Scott; Konig, Heiko; Medicine, School of Medicine
    Despite significant advances in deciphering the molecular landscape of acute myeloid leukaemia (AML), therapeutic outcomes of this haematological malignancy have only modestly improved over the past decades. Drug resistance and disease recurrence almost invariably occur, highlighting the need for a deeper understanding of these processes. While low O2 compartments, such as bone marrow (BM) niches, are well‐recognized hosts of drug‐resistant leukaemic cells, standard in vitro studies are routinely performed under supra‐physiologic (21% O2, ambient air) conditions, which limits clinical translatability. We hereby identify molecular pathways enriched in AML cells that survive acute challenges with classic or targeted therapeutic agents. Experiments took into account variations in O2 tension encountered by leukaemic cells in clinical settings. Integrated RNA and protein profiles revealed that lipid biosynthesis, and particularly the cholesterol biogenesis branch, is a particularly therapy‐induced vulnerability in AML cells under low O2 states. We also demonstrate that the impact of the cytotoxic agent cytarabine is selectively enhanced by a high‐potency statin. The cholesterol biosynthesis programme is amenable to additional translational opportunities within the expanding AML therapeutic landscape. Our findings support the further investigation of higher‐potency statin (eg rosuvastatin)–based combination therapies to enhance targeting residual AML cells that reside in low O2 environments.
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    New aspects of cellular cholesterol regulation on blood glucose control- review and perspective on the impact of statin medications on metabolic health
    (2017-01-01) Grice, Brian A.; Elmendorf, Jeffrey S.; Cellular and Integrative Physiology, School of Medicine
    Cholesterol is an essential component of cell membranes, and during the past several years, diabetes researchers have found that membrane cholesterol levels in adipocytes, skeletal muscle fibers and pancreatic beta cells influence insulin action and insulin secretion. Consequently, it is thought that dysregulated cell cholesterol homeostasis could represent a determinant of type 2 diabetes (T2D). Recent clinical findings compellingly add to this notion by finding increased T2D susceptibility in individuals with alterations in a variety of cholesterol metabolism genes. While it remains imperfectly understood how statins influence glucose metabolism, the fact that they display an influence on blood glucose levels and diabetes susceptibility seems to intensify the emerging importance of understanding cellular cholesterol in glucose metabolism. Taking this into account, this review first presents cell system and animal model findings that demonstrate the negative impact of cellular cholesterol accumulation or diminution on insulin action and insulin secretion. With this framework, a description of how changes in cholesterol metabolism genes are associated with T2D susceptibility will be presented. In addition, the connection between statins and T2D risk will be reviewed with expanded information on pitavastatin, a newer statin medication that displays actions favoring metabolic health
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    Statin use and non-melanoma skin cancer risk: a meta-analysis of randomized controlled trials and observational studies
    (Impact Journals, 2017-08-08) Yang, Keming; Marley, Andrew; Tang, Huilin; Song, Yiqing; Tang, Jean Y.; Han, Jiali; Epidemiology, School of Public Health
    Background Existing evidence of the association between statin use and non-melanoma skin cancer (NMSC) risk has been inconsistent. Objective To maximize statistical power to synthesize prospective evidence on this relationship. Materials and Methods PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrial.gov were systematically searched up to December 11, 2016. A random-effects meta-analysis was conducted to calculate summary estimates. Results Our meta-analysis of 14 randomized controlled trials (RCTs) including 63,157 subjects showed no significant association between statin use and NMSC risk (RR = 1.09, 95%CI = 0.85–1.39). However, meta-analysis of four observational studies including 1,528,215 participants showed significantly increased risk of NMSC among statin users compared to non-users (RR = 1.11, 95%CI = 1.02–1.22). Furthermore, ever using lipophilic statins (RR = 1.14, 95%CI = 1.04–1.24) or lower-potency statins (RR = 1.14, 95%CI = 1.03–1.26), as well as usage of any statin longer than one year (RR = 1.14, 95%CI = 1.09–1.18) were significantly associated with increased NMSC risk based on observational studies. Conclusions Evidence from observational studies supported an association between statin use and increased NMSC risk. This finding should be interpreted with caution due to modest number of included studies, possible between-study heterogeneity and inherent limitations of observational studies.