Anti-vitamin K drugs are widely used as anticoagulant in human thromboembolic diseases. Similar compounds have also been used as rodenticides to control rodent population since 1950s. Massive use of ...first generation anticoagulants, especially warfarin, has lead to the development of genetic resistances in rodents. Similar resistances have been reported in human. In both cases, polymorphisms in VKORC1 (Vitamin K epoxide reductase subunit 1), the subunit 1 of the VKOR (Vitamin K epoxide reductase) complex, were involved. In rats (
Rattus norvegicus), the Y139F mutation confers a high degree of resistance to warfarin. Little is known about the
in vitro consequences of Y139F mutation on inhibitory effect of different anticoagulants available. A warfarin-susceptible and a warfarin-resistant Y139F strain of wild rats (
Rattus norvegicus) are maintained in enclosures of the Lyon College of Veterinary Medicine (France). Using liver microsomes from susceptible or resistant rats, we studied inhibition parameters by warfarin (
K
i
=
0.72
±
0.1
μM; 29
±
4.1
μM), chlorophacinone (
K
i
=
0.08
±
0.01
μM; 1.6
±
0.1
μM), diphacinone (
K
i
=
0.07
±
0.01
μM; 5.0
±
0.8
μM), coumachlor (
K
i
=
0.12
±
0.02
μM; 1.9
±
0.2
μM), coumatetralyl (
K
i
=
0.13
±
0.02
μM; 3.1
±
0.4
μM), difenacoum (
K
i
=
0.07
±
0.01
μM; 0.26
±
0.02
μM), bromadiolone (
K
i
=
0.13
±
0.02
μM; 0.91
±
0.07
μM), and brodifacoum (
K
i
=
0.04
±
0.01
μM; 0.09
±
0.01
μM) on VKOR activity. Analysis of the results leads us to highlight different anticoagulant structural elements, which influence inhibition parameters in both susceptible and Y139F resistant rats.
The regulation of gene expression by thyroid hormone (T3) involves binding of the hormone to nuclear receptors thyroid hormone receptor (TR) acting as T3-dependent transcription factors encoded by ...TRalpha (NR1A1) and TRbeta (NR1A2) genes. Several TRalpha variants have already been characterized, but only some of them display T3 binding activity. In this study, we have identified another transcript, TRalpha-DeltaE6, produced by alternative splicing with microexon 6b instead of exon 6. This splicing leads to the synthesis of a protein devoid of a hinge domain. The TRalpha-DeltaE6 transcript is detected in all mouse tissues tested. Although TRalpha-DeltaE6 did not bind DNA, its expression induced a TRalpha1 sequestration in the cytoplasm. Functional studies demonstrated that TRalpha-DeltaE6 inhibits the transcriptional activity of TRalpha1 and retinoic X receptor-alpha, but not of retinoic acid receptor-alpha. We also found that TRalpha-DeltaE6 efficiently decreased the ability of TRalpha to inhibit MyoD transcriptional activity during myoblast proliferation. Consequently, when overexpressed in myoblasts, it stimulated terminal differentiation. We suggest that this novel TRalpha variant may act as down regulator of overall T3 receptor activity, including its ability to repress MyoD transcriptional activity during myoblast proliferation.
The importance of mitochondrial activity has recently been extended to the regulation of developmental processes. Numerous pathologies associated with organelle's dysfunctions emphasize their ...physiological importance. However, regulation of mitochondrial genome transcription, a key element for organelle's function, remains poorly understood. After characterization in the organelle of a truncated form of the triiodothyronine nuclear receptor (p43), a T3-dependent transcription factor of the mitochondrial genome, our purpose was to search for other mitochondrial receptors involved in the regulation of organelle transcription. We show that a 44 kDa protein related to RXR alpha (mt-RXR), another nuclear receptor, is located in the mitochondrial matrix. We found that mt-RXR is produced after cytosolic or intramitochondrial enzymatic cleavage of the RXR alpha nuclear receptor. After mitochondrial import and binding to specific sequences of the organelle genome, mt-RXR induces a ligand-dependent increase in mitochondrial RNA levels. mt-RXR physically interacts with p43 and acts alone or through a heterodimerical complex activated by 9-cis-retinoic acid and T3 to increase RNA levels. These data indicate that hormonal regulation of mitochondrial transcription occurs through pathways similar to those that take place in the nucleus and open a new way to better understand hormone and vitamin action at the cellular level.
The clinical efficacy and safety of imidapril were evaluated in dogs that presented with mild to severe congestive heart failure (New York Heart Association stage II to IV) by comparing the success ...rate of imidapril with a positive control by a non-inferiority approach. This good, clinical practice compliant, multicentre study (EFFIC study) enrolled 142 client-owned dogs and was conducted in 20 locations in France, Belgium and Germany. Dogs of various breed, age and weight were included in the study. These dogs were randomised into two groups that were treated for 84 days with either the test product, imidapril, or the positive control, benazepril, and followed up in parallel over this period. Both treatments were administered at a dose of 0·25 mg/kg once a day with the possibility of doubling this dose to 0·5 mg/kg if considered necessary from a clinical point of view. In addition, concomitant treatment was given to dogs presenting with pulmonary oedema and/or ascites, supraventricular tachyarrhythmia and/or dilated cardiomyopathy. The evolution of the New York Heart Association stage and the "functional signs" score were evaluated as primary efficacy criteria. The success rate in the imidapril group was 66 compared with 68 per cent in the benazepril group. Regarding safety, 35 dogs in each group experienced at least one adverse event. Nine dogs in each group experienced at least one serious adverse event. The difference between these results was not statistically significant. Imidapril is as efficacious and safe as the reference product, benazepril.
The importance of mitochondrial activity has recently been extended to the regulation of developmental processes. Numerous pathologies associated with organelle's dysfunctions emphasize their ...physiological importance. However, regulation of mitochondrial genome transcription, a key element for organelle's function, remains poorly understood. After characterization in the organelle of a truncated form of the triiodothyronine nuclear receptor (p43), a T3-dependent transcription factor of the mitochondrial genome, our purpose was to search for other mitochondrial receptors involved in the regulation of organelle transcription. We show that a 44 kDa protein related to RXRalpha (mt-RXR), another nuclear receptor, is located in the mitochondrial matrix. We found that mt-RXR is produced after cytosolic or intramitochondrial enzymatic cleavage of the RXRalpha nuclear receptor. After mitochondrial import and binding to specific sequences of the organelle genome, mt-RXR induces a ligand-dependent increase in mitochondrial RNA levels. mt-RXR physically interacts with p43 and acts alone or through a heterodimerical complex activated by 9-cis-retinoic acid and T3 to increase RNA levels. These data indicate that hormonal regulation of mitochondrial transcription occurs through pathways similar to those that take place in the nucleus and open a new way to better understand hormone and vitamin action at the cellular level.
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