Browsing by Subject "Tretinoin"

Now showing 1 - 3 of 3
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    Developmental exposure to pesticides that disrupt retinoic acid signaling causes persistent retinoid and behavioral dysfunction in zebrafish.
    (Toxicological sciences : an official journal of the Society of Toxicology, 2024-03) Hawkey, Andrew B; Shekey, Nathan; Dean, Cassandra; Asrat, Helina; Koburov, Reese; Holloway, Zade R; Kullman, Seth W; Levin, Edward D
    Early developmental exposure to environmental toxicants may play a role in the risk for developing autism. A variety of pesticides have direct effects on retinoic acid (RA) signaling and as RA signaling has important roles in neurodevelopment, such compounds may cause developmental neurotoxicity through an overlapping adverse outcome pathway. It is hypothesized that a pesticide's embryonic effects on retinoid function may correspond with neurobehavioral disruption later in development. In the current studies, we determined the effects of RA-acting pesticides on neurobehavioral development in zebrafish. Buprofezin and imazalil caused generalized hypoactivity in the larval motility test, whereas chlorothalonil and endosulfan I led to selective hypoactivity and hyperactivity, respectively. With buprofezin, chlorothalonil, and imazalil, hypoactivity and/or novel anxiety-like behaviors persisted in adulthood and buprofezin additionally decreased social attraction responses in adulthood. Endosulfan I did not produce significant adult behavioral effects. Using qPCR analyses of adult brain tissue, we observed treatment-induced alterations in RA synthesis or catabolic genes, indicating persistent changes in RA homeostasis. These changes were compound-specific, with respect to expression directionality, and potential patterns of homeostatic disruption. Results suggest the likely persistence of disruptions in RA signaling well into adulthood and may represent compensatory mechanisms following early life stage exposures. This study demonstrates that early developmental exposure to environmental toxicants that interfere with RA signaling causes short as well as long-term behavioral disruption in a well-established zebrafish behavioral model and expand upon the meaning of the RA adverse outcome pathway, indicating that observed effects likely correspond with the nature of underlying homeostatic effects.
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    Site-specific retinoic acid production in the brain of adult songbirds.
    (Neuron, 2000-08) Denisenko-Nehrbass, NI; Jarvis, E; Scharff, C; Nottebohm, F; Mello, CV
    The song system of songbirds, a set of brain nuclei necessary for song learning and production, has distinctive morphological and functional properties. Utilizing differential display, we searched for molecular components involved in song system regulation. We identified a cDNA (zRalDH) that encodes a class 1 aldehyde dehydrogenase. zRalDH was highly expressed in various song nuclei and synthesized retinoic acid efficiently. Brain areas expressing zRalDH generated retinoic acid. Within song nucleus HVC, only projection neurons not undergoing adult neurogenesis expressed zRalDH. Blocking zRalDH activity in the HVC of juveniles interfered with normal song development. Our results provide conclusive evidence for localized retinoic acid synthesis in an adult vertebrate brain and indicate that the retinoic acid-generating system plays a significant role in the maturation of a learned behavior.
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    Vulnerabilities in mIDH2 AML confer sensitivity to APL-like targeted combination therapy.
    (Cell research, 2019-06) Mugoni, Vera; Panella, Riccardo; Cheloni, Giulia; Chen, Ming; Pozdnyakova, Olga; Stroopinsky, Dina; Guarnerio, Jlenia; Monteleone, Emanuele; Lee, Jonathan David; Mendez, Lourdes; Menon, Archita Venugopal; Aster, Jon Christopher; Lane, Andrew A; Stone, Richard Maury; Galinsky, Ilene; Zamora, José Cervera; Lo-Coco, Francesco; Bhasin, Manoj Kumar; Avigan, David; Longo, Letizia; Clohessy, John Gerard; Pandolfi, Pier Paolo
    Although targeted therapies have proven effective and even curative in human leukaemia, resistance often ensues. IDH enzymes are mutated in ~20% of human AML, with targeted therapies under clinical evaluation. We here characterize leukaemia evolution from mutant IDH2 (mIDH2)-dependence to independence identifying key targetable vulnerabilities of mIDH2 leukaemia that are retained during evolution and progression from early to late stages. Mechanistically, we find that mIDH2 leukaemia are metastable and vulnerable at two distinct levels. On the one hand, they are characterized by oxidative and genotoxic stress, in spite of increased 1-carbon metabolism and glutathione levels. On the other hand, mIDH2 leukaemia display inhibition of LSD1 and a resulting transcriptional signature of all-trans retinoic acid (ATRA) sensitization, in spite of a state of suppressed ATRA signalling due to increased levels of PIN1. We further identify GSH/ROS and PIN1/LSD1 as critical nodes for leukaemia maintenance and the combination of ATRA and arsenic trioxide (ATO) as a key therapeutic modality to target these vulnerabilities. Strikingly, we demonstrate that the combination of ATRA and ATO proves to be a powerfully synergistic and effective therapy in a number of mouse and human mIDH1/2 leukemic models. Thus, our findings pave the way towards the treatment of a sizable fraction of human AMLs through targeted APL-like combinatorial therapies.