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Quercetin AND Dasatinib

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https://www.readbyqxmd.com/read/28273655/new-agents-that-target-senescent-cells-the-flavone-fisetin-and-the-bcl-xl-inhibitors-a1331852-and-a1155463
#1
Yi Zhu, Ewald J Doornebal, Tamar Pirtskhalava, Nino Giorgadze, Mark Wentworth, Heike Fuhrmann-Stroissnigg, Laura J Niedernhofer, Paul D Robbins, Tamara Tchkonia, James L Kirkland
Senescent cells accumulate with aging and at sites of pathology in multiple chronic diseases. Senolytics are drugs that selectively promote apoptosis of senescent cells by temporarily disabling the pro-survival pathways that enable senescent cells to resist the pro-apoptotic, pro-inflammatory factors that they themselves secrete. Reducing senescent cell burden by genetic approaches or by administering senolytics delays or alleviates multiple age- and disease-related adverse phenotypes in preclinical models...
March 8, 2017: Aging
https://www.readbyqxmd.com/read/28230051/cellular-senescence-mediates-fibrotic-pulmonary-disease
#2
Marissa J Schafer, Thomas A White, Koji Iijima, Andrew J Haak, Giovanni Ligresti, Elizabeth J Atkinson, Ann L Oberg, Jodie Birch, Hanna Salmonowicz, Yi Zhu, Daniel L Mazula, Robert W Brooks, Heike Fuhrmann-Stroissnigg, Tamar Pirtskhalava, Y S Prakash, Tamara Tchkonia, Paul D Robbins, Marie Christine Aubry, João F Passos, James L Kirkland, Daniel J Tschumperlin, Hirohito Kita, Nathan K LeBrasseur
Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by interstitial remodelling, leading to compromised lung function. Cellular senescence markers are detectable within IPF lung tissue and senescent cell deletion rejuvenates pulmonary health in aged mice. Whether and how senescent cells regulate IPF or if their removal may be an efficacious intervention strategy is unknown. Here we demonstrate elevated abundance of senescence biomarkers in IPF lung, with p16 expression increasing with disease severity...
February 23, 2017: Nature Communications
https://www.readbyqxmd.com/read/26864908/chronic-senolytic-treatment-alleviates-established-vasomotor-dysfunction-in-aged-or-atherosclerotic-mice
#3
Carolyn M Roos, Bin Zhang, Allyson K Palmer, Mikolaj B Ogrodnik, Tamar Pirtskhalava, Nassir M Thalji, Michael Hagler, Diana Jurk, Leslie A Smith, Grace Casaclang-Verzosa, Yi Zhu, Marissa J Schafer, Tamara Tchkonia, James L Kirkland, Jordan D Miller
While reports suggest a single dose of senolytics may improve vasomotor function, the structural and functional impact of long-term senolytic treatment is unknown. To determine whether long-term senolytic treatment improves vasomotor function, vascular stiffness, and intimal plaque size and composition in aged or hypercholesterolemic mice with established disease. Senolytic treatment (intermittent treatment with Dasatinib + Quercetin via oral gavage) resulted in significant reductions in senescent cell markers (TAF(+) cells) in the medial layer of aorta from aged and hypercholesterolemic mice, but not in intimal atherosclerotic plaques...
October 2016: Aging Cell
https://www.readbyqxmd.com/read/26711051/identification-of-a-novel-senolytic-agent-navitoclax-targeting-the-bcl-2-family-of-anti-apoptotic-factors
#4
Yi Zhu, Tamara Tchkonia, Heike Fuhrmann-Stroissnigg, Haiming M Dai, Yuanyuan Y Ling, Michael B Stout, Tamar Pirtskhalava, Nino Giorgadze, Kurt O Johnson, Cory B Giles, Jonathan D Wren, Laura J Niedernhofer, Paul D Robbins, James L Kirkland
Clearing senescent cells extends healthspan in mice. Using a hypothesis-driven bioinformatics-based approach, we recently identified pro-survival pathways in human senescent cells that contribute to their resistance to apoptosis. This led to identification of dasatinib (D) and quercetin (Q) as senolytics, agents that target some of these pathways and induce apoptosis preferentially in senescent cells. Among other pro-survival regulators identified was Bcl-xl. Here, we tested whether the Bcl-2 family inhibitors, navitoclax (N) and TW-37 (T), are senolytic...
June 2016: Aging Cell
https://www.readbyqxmd.com/read/25754370/the-achilles-heel-of-senescent-cells-from-transcriptome-to-senolytic-drugs
#5
Yi Zhu, Tamara Tchkonia, Tamar Pirtskhalava, Adam C Gower, Husheng Ding, Nino Giorgadze, Allyson K Palmer, Yuji Ikeno, Gene B Hubbard, Marc Lenburg, Steven P O'Hara, Nicholas F LaRusso, Jordan D Miller, Carolyn M Roos, Grace C Verzosa, Nathan K LeBrasseur, Jonathan D Wren, Joshua N Farr, Sundeep Khosla, Michael B Stout, Sara J McGowan, Heike Fuhrmann-Stroissnigg, Aditi U Gurkar, Jing Zhao, Debora Colangelo, Akaitz Dorronsoro, Yuan Yuan Ling, Amira S Barghouthy, Diana C Navarro, Tokio Sano, Paul D Robbins, Laura J Niedernhofer, James L Kirkland
The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis...
August 2015: Aging Cell
https://www.readbyqxmd.com/read/25418056/ingredients-in-fruit-juices-interact-with-dasatinib-through-inhibition-of-bcrp-a-new-mechanism-of-beverage-drug-interaction
#6
COMPARATIVE STUDY
Brett Fleisher, Jesse Unum, Jie Shao, Guohua An
Small molecule tyrosine kinase inhibitors (TKIs) are a group of highly novel and target-specific anticancer drugs. Recently, most TKIs are found to be substrates of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). However, little information is available regarding the Pgp- or BCRP-mediated interaction of TKIs with coadministered drugs/food/beverage. Our objective was to evaluate the effect of the major ingredients of grapefruit juice (GFJ), orange juice (OJ), apple juice (AJ), and green tea on P-gp and BCRP-mediated dasatinib efflux...
January 2015: Journal of Pharmaceutical Sciences
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