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)

Necroptosis is a form of regulated necrosis that can be activated by ligands of death receptors and stimuli that induce the expression of death receptor ligands under apoptotic deficient conditions. Activation of necroptosis by ligands of death receptors requires the kinase activity of RIP1, which mediates the activation of RIP3 and MLKL, two critical downstream mediators of necroptosis. Blocking the kinase activity of RIP1, a key druggable target in the necroptosis pathway, by necrostatins inhibits the activation of necroptosis and allows cell survival and proliferation in the presence of death receptor ligands. The activation of necroptosis is modulated by different forms of ubiquitination, including K63, linear and K48 ubiquitination, as well as phosphorylation of RIP1, RIP3 and MLKL. Necroptosis is suppressed by caspase-8/FADD-mediated apoptosis. Deficiency in caspase-8 and FADD leads to embryonic lethality, tissue degeneration and inflammation which can be suppressed by inhibition of RIP1 kinase and RIP3. On the other hand, the lack of RIP3 kinase activity leads to early embryonic lethality which can be suppressed by the loss of caspase-8, suggesting that although the kinase activity of RIP3 is involved in mediating necroptosis, the basal activity of RIP3 kinase may be required for suppressing caspase-8 mediated apoptosis. Necroptosis as well as RIP1- and RIP3-mediated inflammatory response have been implicated in mediating multiple human diseases including TNF-mediated hypothermia and systemic inflammation, ischemic reperfusion injury, neurodegeneration, Gaucher's disease, progressive atherosclerotic lesions, etc. Targeting RIP1 kinase may provide therapeutic benefits for the treatment of human diseases characterized by necrosis and inflammation.
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PMID:Necroptosis in health and diseases. 2508 83

The aims of this study were (1) to behaviorally phenotype rats at different ages for both cognitive performance and affect, (2) to evaluate the possible beneficial effects of 8-OH-DPAT (a 5-HT1A receptor agonist) treatments on improving age-related behavioral deficits, and (3) to uncover putative key brain targets (e.g., Fas-associated protein with death domain [FADD] and related partners) that might contribute to the observed age-related behavioral changes. The principal results showed that acute, but not repeated, 8-OH-DPAT treatments improved age-related deficits in cognitive performance and affect while induced hypothermia. Moreover, multifunctional FADD protein decreased with age specifically in the hippocampus (as compared to the prefrontal cortex) and was further decreased following acute 8-OH-DPAT. The major conclusions indicate a parallelism between the beneficial effects observed following acute 8-OH-DPAT on improving the negative consequences of aging on cognition and affect, together with the acute induction of hypothermia and hippocampal FADD regulation. Because these effects were not observed following repeated treatment (i.e., observed tolerance to acute hypothermia), the results suggest 5-HT1A receptors desensitization and/or the activation of compensatory adaptive mechanisms.
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PMID:Improved age-related deficits in cognitive performance and affective-like behavior following acute, but not repeated, 8-OH-DPAT treatments in rats: regulation of hippocampal FADD. 3013 65