Tissue-specific activation of mitogen-activated protein kinases for expression of transthyretin by phenylalanine and its metabolite, phenylpyruvic acid

Phenylketonuria is an autosomal recessive disorder caused by a deficiency of phenylalanine hydroxylase. Transthyretin has been implicated as an indicator of nutritional status in phenylketonuria patients. In this study, we report that phenylalanine and its metabolite, phenylpyruvic acid, affect MAPK, changing transthyretin expression in a cell- and tissue-specific manner. Treatment of HepG2 cells with phenylalanine or phenylpyruvic acid decreased transcription of the TTR gene and decreased the transcriptional activity of the TTR promoter site, which was partly mediated through HNF4α. Decreased levels of p38 MAPK were detected in the liver of phenylketonuria-affected mice compared with wild-type mice. In contrast, treatment with phenylalanine increased transthyretin expression and induced ERK1/2 activation in PC-12 cells; ERK1/2 activation was also elevated in the brainstem of phenylketonuria-affected mice. These findings may explain between-tissue differences in gene expression, including Ttr gene expression, in the phenylketonuria mouse model

Association between a TGFbeta1 promoter polymorphism and rhinosinusitis in aspirin-intolerant asthmatic patients

BACKGROUND: Rhinosinusitis is highly associated with aspirin-intolerant asthma (AIA). The risk of aspirin intolerance is higher in people with rhinosinusitis than in those without it. Recently, the role of transforming growth factor beta1 (TGFbeta1) in the pathogenesis of chronic rhinosinusitis has come under investigation. The goal of this study was to evaluate the association of TGFbeta1 gene polymorphism with an AIA phenotype in the Korean population. METHODS: A promoter polymorphism of the TGFbeta1 gene, TGFbeta1-509C>T, and a coding polymorphism (L10P), were genotyped in 203 patients with AIA, 324 patients with aspirin-tolerant asthma (ATA), and 456 normal controls (NC). Serum TGFbeta1 levels were determined by ELISA. RESULTS: The TGFbeta1-509C>T polymorphism was not significantly associated with the AIA phenotype; however, a significant association with the prevalence of rhinosinusitis in AIA (P=0.012), but not in ATA (P>0.05), was observed. When stratified by the presence of rhinosinusitis, the frequency of T allele carriers (CT or TT genotype) of TGFbeta1-509C>T was significantly higher in AIA (87.1%) compared to ATA (52.9%, P<0.001, OR=6.0, 95% CI=3.3-11.1). In addition, AIA patients carrying the TGFbeta1-509T allele showed a lower serum TGFbeta1 level compared to AIA patients carrying the TGFbeta1-509 CC genotype, especially when stratified by the presence of rhinosinusitis (P=0.002). CONCLUSION: Our results show that the TGFbeta1 polymorphisms are not associated with the AIA phenotype in the Korean population, but may contribute to the development of the AIA phenotype with rhinosinusitis

Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial

Auteurs : the PRECISION investigatorsInternational audienceBackground Resistant hypertension is associated with increased cardiovascular risk. The endothelin pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically, thereby leaving this relevant pathophysiological pathway unopposed with currently available drugs. The aim of the study was to assess the blood pressure lowering efficacy of the dual endothelin antagonist aprocitentan in patients with resistant hypertension. Methods PRECISION was a multicentre, blinded, randomised, parallel-group, phase 3 study, which was done in hospitals or research centres in Europe, North America, Asia, and Australia. Patients were eligible for randomisation if their sitting systolic blood pressure was 140 mm Hg or higher despite taking standardised background therapy consisting of three antihypertensive drugs, including a diuretic. The study consisted of three sequential parts: part 1 was the 4-week double-blind, randomised, and placebo-controlled part, in which patients received aprocitentan 12•5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio; part 2 was a 32-week single (patient)-blind part, in which all patients received aprocitentan 25 mg; and part 3 was a 12-week double-blind, randomised, and placebo-controlled withdrawal part, in which patients were re-randomised to aprocitentan 25 mg or placebo in a 1:1 ratio. The primary and key secondary endpoints were changes in unattended office systolic blood pressure from baseline to week 4 and from withdrawal baseline to week 40, respectively. Secondary endpoints included 24-h ambulatory blood pressure changes. The study is registered on ClinicalTrials.gov, NCT03541174. Findings The PRECISION study was done from June 18, 2018, to April 25, 2022. 1965 individuals were screened and 730 were randomly assigned. Of these 730 patients, 704 (96%) completed part 1 of the study; of these, 613 (87%) completed part 2 and, of these, 577 (94%) completed part 3 of the study. The least square mean (SE) change in office systolic blood pressure at 4 weeks was-15•3 (SE 0•9) mm Hg for aprocitentan 12•5 mg,-15•2 (0•9) mm Hg for aprocitentan 25 mg, and-11•5 (0•9) mm Hg for placebo, for a difference versus placebo of-3•8 (1•3) mm Hg (97•5% CI-6•8 to-0•8, p=0•0042) and-3•7 (1•3) mm Hg (-6•7 to-0•8; p=0•0046), respectively. The respective difference for 24 h ambulatory systolic blood pressure was-4•2 mm Hg (95% CI-6•2 to-2•1) and-5•9 mm Hg (-7•9 to-3•8). After 4 weeks of withdrawal, office systolic blood pressure significantly increased with placebo versus aprocitentan (5•8 mm Hg, 95% CI 3•7 to 7•9, p<0•0001). The most frequent adverse event was mild-to-moderate oedema or fluid retention, occurring in 9%, 18%, and 2% for patients receiving aprocitentan 12•5 mg, 25 mg, and placebo, during the 4-week double-blind part, respectively. This event led to discontinuation in seven patients treated with aprocitentan. During the trial, a total of 11 treatment-emergent deaths occurred, none of which were regarded by the investigators to be related to study treatment. Interpretation In patients with resistant hypertension, aprocitentan was well tolerated and superior to placebo in lowering blood pressure at week 4 with a sustained effect at week 40