Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020672 (hypothermia)
 17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of a retinoid X receptor (RXR) to heterodimerize with many nuclear receptors, including LXR, PPAR, NGF1B and RAR, underscores its pivotal role within the nuclear receptor superfamily. Among these heterodimers, PPAR:RXR is considered an important signalling mediator of both PPAR ligands, such as fatty acids, and 9-cis retinoic acid (9-cis RA), an RXR ligand. In contrast, the existence of an RXR/9-cis RA signalling pathway independent of PPAR or any other dimerization partner remains disputed. Using in vivo chromatin immunoprecipitation, we now show that RXR homodimers can selectively bind to functional PPREs and induce transactivation. At the molecular level, this pathway requires stabilization of the homodimer-DNA complexes through ligand-dependent interaction with the coactivator SRC1 or TIF2. This pathway operates both in the absence and in the presence of PPAR, as assessed in cells carrying inactivating mutations in PPAR genes and in wild-type cells. In addition, this signalling pathway via PPREs is fully functional and can rescue the severe hypothermia phenotype observed in fasted PPARalpha-/- mice. These observations have important pharmacological implications for the development of new rexinoid-based treatments.
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PMID:In vivo activation of PPAR target genes by RXR homodimers. 1510 26

The process by which the periderm transitions to stratified epidermis with the establishment of the skin barrier is unknown. Understanding the cellular and molecular processes involved is crucial for the treatment of human pathologies, where abnormal skin development and barrier dysfunction are associated with hypothermia and perinatal dehydration. For the first time, we demonstrate that retinoic acid (RA) levels are important for periderm desquamation, embryonic skin differentiation and barrier formation. Although excess exogenous RA has been known to have teratogenic effects, little is known about the consequences of elevated endogenous retinoids in skin during embryogenesis. Absence of cytochrome P450, family 26, subfamily b, polypeptide 1 (Cyp26b1), a retinoic-acid-degrading enzyme, results in aberrant epidermal differentiation and filaggrin expression, defective cornified envelopes and skin barrier formation, in conjunction with peridermal retention. We show that these alterations are RA dependent because administration of exogenous RA in vivo and to organotypic skin cultures phenocopy Cyp26b1(-/-) skin abnormalities. Furthermore, utilizing the Flaky tail (Ft/Ft) mice, a mouse model for human ichthyosis, characterized by mutations in the filaggrin gene, we establish that proper differentiation and barrier formation is a prerequisite for periderm sloughing. These results are important in understanding pathologies associated with abnormal embryonic skin development and barrier dysfunction.
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PMID:Increased retinoic acid levels through ablation of Cyp26b1 determine the processes of embryonic skin barrier formation and peridermal development. 2236 55

We investigated the protective effects of remote postconditioning (RPC) in the lungs of rats with deep hypothermia ischemia/reperfusion (I/R) injury and the role of nuclear factor E2-related factor 2 (Nrf2) signaling in this process. Forty-nine rats were randomly divided into a sham control group, deep hypothermia I/R group, RPC group, I/R+all-trans retinoic acid (ATRA) group, I/R+RPC+ATRA group, I/R+tert-butylhydroquinone (tBHQ) group, and I/R+RPC+tBHQ group. Real-time polymerase chain reaction and Western blot analysis were used to examine Nrf2 mRNA and protein expression, respectively. Compared with the sham control group, Nrf2 expression, malondialdehyde (MDA) content, and the wet/dry weight (W/D) ratio were significantly increased in the I/R group, while superoxide dismutase (SOD) activity was significantly decreased. Pulmonary Nrf2 expression and SOD activity was significantly increased, and MDA content and the W/D ratio were significantly decreased in the RPC group compared with the I/R group. Compared with the I/R group, MDA and W/D ratio significantly decreased and SOD activity remarkably increased in I/R+tBHQ group. After ATRA intervention in the I/R+ATRA group, MDA content and W/D ratio increased and SOD activity decreased compared to the I/R group. MDA content and W/D ratio in the RPC+tBHQ group significantly decreased and SOD activity increased compared with in the RPC group (P < 0.01). In the RPC+ATRA group, MDA content and W/D ratio decreased while SOD activity increased compared with the RPC group (P < 0.01). RPC alleviated deep hypothermia I/R injury; the Nrf2 signaling pathway may be involved in the protective effects induced by RPC.
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PMID:Role of Nrf2 signal pathway in rats with deep hypothermia ischemia/reperfusion injury undergoing remote postconditioning. 2572 83