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| 2. |
- Faux, Noel G, et al.
(författare)
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PBT2 Rapidly Improves Cognition in Alzheimer's Disease : Additional Phase II Analyses
- 2010
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 20:2, s. 509-516
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Tidskriftsartikel (refereegranskat)abstract
- PBT2 is a copper/zinc ionophore that rapidly restores cognition in mouse models of Alzheimer's disease (AD). A recent Phase IIa double-blind, randomized, placebo-controlled trial found that the 250 mg dose of PBT2 was well-tolerated, significantly lowered cerebrospinal fluid (CSF) levels of amyloid-beta_{42}, and significantly improved executive function on a Neuro-psychological Test Battery (NTB) within 12 weeks of treatment in patients with AD. In the post-hoc analysis reported here, the cognitive, blood marker, and CSF neurochemistry outcomes from the trial were subjected to further analysis. Ranking the responses to treatment after 12 weeks with placebo, PBT2 50 mg, and PBT2 250 mg revealed that the proportions of patients showing improvement on NTB Composite or Executive Factor z-scores were significantly greater in the PBT2 250 mg group than in the placebo group. Receiver-operator characteristic analyses revealed that the probability of an improver at any level coming from the PBT2 250 mg group was significantly greater, compared to placebo, for Composite z-scores (Area Under the Curve [AUC] =0.76, p=0.0007), Executive Factor z-scores (AUC =0.93, p=1.3 x 10;{-9}), and near-significant for the ADAS-cog (AUC =0.72, p=0.056). There were no correlations between changes in CSF amyloid-beta or tau species and cognitive changes. These findings further encourage larger-scale testing of PBT2 for AD.
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| 3. |
- James, M. O., et al.
(författare)
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Properties and regional expression of a CYP3A-like protein in channel catfish intestine
- 2005
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Ingår i: Aquatic Toxicology. - : Elsevier BV. - 0166-445X. ; 72:4, s. 361-371
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Tidskriftsartikel (refereegranskat)abstract
- Biotransformation in the intestine may influence the bioavailability and toxicity of ingested xenobiotics. The objective of this study was to examine the expression and catalytic properties of a constitutive cytochrome P450 (CYP) 3A-like protein along the intestine of channel catfish, Ictalurus punctatus. Fish were maintained on commercial chow or nutritionally complete semi-purified diets. Polyclonal antibodies generated against rainbow trout CYP3A proteins reacted strongly with catfish washed intestinal microsomes on Western blots showing a major protein band with MW of 59 kDa. In catfish maintained on a standard chow diet, the expression of this protein was higher in the proximal segment (0.101 ± 0.031 units/mg protein, mean ± S.D., n = 4) than in the distal part (0.032 ± 0.023 units/mg protein). Microsomal testosterone 6β-hydroxylation activity was monitored as the catalytic indicator of CYP3A, and was higher in proximal than distal catfish intestine (263 ± 80.3 and 88.6 ± 15.6 pmol/min/mg protein for proximal and distal, respectively, mean S.D., n = 4). CYP3A protein levels and testosterone 6β-hydroxylation activities were lower in microsomes from the proximal segment of intestine from catfish maintained on a semi-purified diet, compared with commercial chow, but again the proximal intestine had higher CYP3A and 6β-hydroxylase activities than distal intestine. Testosterone 6β-hydroxylase activities in all samples correlated with the CYP3A protein levels, r(2) = 0.8. Testosterone 6β-hydroxylation was inhibited by specific CYP3A inhibitors, ketoconazole (IC50 = 0.02 μ M) and erythromycin (IC50 = 41 μ M), as well as general CYP inhibitors, metyrapone (IC50 = 2.8 μ M) and SKF-525A (IC50 = 25 μ M). There was evidence for the involvement of CYP3A in the mono-oxygenation of benzo(a)pyrene and of (-)-benzo(a)pyrene-7,8-dihydrodiol in intestinal microsomes from catfish maintained on the semi-purified diet. Mono-oxygenation of both substrates was increased in a concentration-dependent manner by in vitro addition of a-naphthoflavone. Benzo(a)pyrene hydroxylase activities were higher in proximal than in distal intestine; 3.72 ± 0.77 pmol/min/mg protein, mean ± S.D., n = 5 and 1.45 ± 0.42 in these respective segments. The results of this study strongly suggest that CYP3A is important in the first pass metabolism of dietary xenobiotics in untreated fish. © 2005 Elsevier B.V. All rights reserved.
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| 4. |
- Trendafilova, Teodora, et al.
(författare)
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Sodium-calcium exchanger-3 regulates pain “wind-up” : From human psychophysics to spinal mechanisms
- 2022
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Ingår i: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 110:16, s. 2571-2587.e13
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Tidskriftsartikel (refereegranskat)abstract
- Repeated application of noxious stimuli leads to a progressively increased pain perception; this temporal summation is enhanced in and predictive of clinical pain disorders. Its electrophysiological correlate is “wind-up,” in which dorsal horn spinal neurons increase their response to repeated nociceptor stimulation. To understand the genetic basis of temporal summation, we undertook a GWAS of wind-up in healthy human volunteers and found significant association with SLC8A3 encoding sodium-calcium exchanger type 3 (NCX3). NCX3 was expressed in mouse dorsal horn neurons, and mice lacking NCX3 showed normal, acute pain but hypersensitivity to the second phase of the formalin test and chronic constriction injury. Dorsal horn neurons lacking NCX3 showed increased intracellular calcium following repetitive stimulation, slowed calcium clearance, and increased wind-up. Moreover, virally mediated enhanced spinal expression of NCX3 reduced central sensitization. Our study highlights Ca2+ efflux as a pathway underlying temporal summation and persistent pain, which may be amenable to therapeutic targeting.
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