Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020440 (hypercapnia)
 7,939 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In newborn pigs, vasodilation in response to hypercapnia is dependent on prostaglandin (PG) H synthase. We investigated the contribution of activated oxygen by-products to hypercapnia-induced PGH synthase-dependent dilation of pial arteries and arterioles in anesthetized newborn pigs. Activated oxygen species were generated on the cerebral surface using xanthine oxidase and hypoxanthine. Catalase, H2O2, and iron or N-(2-mercaptopropionyl)-glycine (MPG) were used to separate effects of superoxide anion and hydroxyl radical. All the activated oxygen species tested caused vasodilation of both arteries and arterioles. Vasodilation to all activated oxygen species was largely reversible with only the hydroxyl radical encouraging combination of xanthine oxidase, hypoxanthine, H2O2, and FeCl3, causing significant dilation 20 min after removal of treatment. Cotreatment with MPG blocked this residual dilation. Neither pretreatment with the extracellular superoxide anion radical scavenger, superoxide dismutase (SOD), the intracellular superoxide anion radical scavenger, Tiron, the H2O2 scavenger, catalase, nor hydroxyl radical scavengers, dimethyl sulfoxide (DMSO) and MPG, altered vasodilation of pial arteries or arterioles in response to hypercapnia. Furthermore, the increase in cerebral prostanoid synthesis in response to hypercapnia was not affected by pretreatment with SOD, Tiron, catalase, DMSO, or MPG. We conclude that the progressively reduced forms of oxygen that would be produced during PGH synthase metabolism of arachidonic acid can dilate pial arteries and arterioles of newborn pigs. However, these activated oxygen species are not responsible for the vasodilation to hypercapnia in the newborn pig, suggesting that eicosanoids cause the dilation.
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PMID:Activated oxygen species do not mediate hypercapnia-induced cerebral vasodilation in newborn pigs. 187 61

Heterozygous in frame duplications of the PHOX2B gene, leading to polyalanine (polyAla) expansions ranging from +5 to +13 residues of a 20-alanine stretch, have been identified in the vast majority of patients affected with Congenital Central Hypoventilation Syndrome (CCHS), a rare neurocristopathy characterized by absence of adequate autonomic control of respiration with decreased sensitivity to hypoxia and hypercapnia. Ventilatory supports such as tracheostomy, nasal mask or diaphragm pacing represent the only options available for affected. We have already shown that the severity of the CCHS phenotype correlates with the length of polyAla expansions, ultimately leading to formation of toxic intracytoplasmic aggregates and impaired PHOX2B mediated transactivation of target gene promoters, such as DBH. At present, there is no specific treatment to reduce cell aggregates and to ameliorate patients' respiration. In this work, we have undertaken in vitro analyses aimed at assessing the effects of molecules on the cellular response to polyAla PHOX2B aggregates. In particular, we tested 17-AAG, ibuprofen, 4-PBA, curcumin, trehalose, congo red and chrysamine G for their ability to i) recover the nuclear localisation of polyAla expanded PHOX2B, ii) rescue of PHOX2B mediated transactivation of the DBH promoter, and iii) clearance of PHOX2B (+13 Ala) aggregates. Our data have suggested that 17-AAG and curcumin are effective in vitro in both rescuing the nuclear localization and transactivation activity of PHOX2B carrying the largest expansion of polyAla and promoting the clearance of aggregates of these mutant proteins inducing molecular mechanisms such as ubiquitin-proteasome (UPS), autophagy and heat shock protein (HSP) systems.
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PMID:In vitro drug treatments reduce the deleterious effects of aggregates containing polyAla expanded PHOX2B proteins. 2196 50