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Absence of D147E mutation of CYP11B2 gene in hypertensive patients with increased corticosterone and aldosterone production.
No full textAbsence of D147E mutation of CYP11B2 gene in hypertensive patients with increased corticosterone and aldosterone production.
Mulatero P1, Glorioso N, Fallo F, Soro A, Morra di Cella S, Carra R, Filigheddu F, Veglio F.
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Abstract
OBJECTIVE:
11beta-Hydroxylase and aldosterone synthase are two highly homologous genes involved in different forms of human hypertension and in different animal models of hypertension. It has been shown that the conservative substitution D147E in the human CYP11B2 gene results in an increased production of corticosterone and aldosterone in vitro. A gene conversion between the CYP11B1 and CYP11B2 genes could be responsible for such a substitution.
METHODS:
In this study we investigated the presence of the mutation D147E of CYP11B2 in a group of 128 patients with primary aldosteronism, 68 patients with essential hypertension and increased corticosterone production and in 48 normal volunteers.
RESULTS AND CONCLUSIONS:
We did not identify any patient carrying this mutation, indicating that if it exists it is very rare and so has no relevance in determining the increased steroid excretion seen in some subtypes of human hypertension
Overnight dexamethasone suppression of cortisol is associated with radiocholesterol uptake patterns in adrenal incidentalomas
No full textComment - Is there a role for low doses of mitotane (o, p'-DDD) as adjuvant therapy in adrenocortical carcinoma?
No full textThe effects of mitotane and 1α,25-dihydroxyvitamin D3 on Wnt/beta-catenin signaling in human adrenocortical carcinoma cells
Full text linkPurpose: Mitotane is the only chemotherapeutic agent available for the treatment of adrenocortical carcinoma (ACC), however, the anti-neoplastic efficacy is limited due to several side-effects in vivo. There is, therefore, a need of exploring for new anti-tumoral agents which can be used either alone or in combination with mitotane. The active vitamin D metabolite 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) acts as an anti-proliferative agent in human cancer by inhibiting the Wnt/beta-catenin pathway through the vitamin D receptor (VDR). The aim of this study was to study the effects of mitotane and 1α,25(OH)2D3, individually or in combination, in an in vitro model with H295R ACC cells, and to elucidate the molecular events behind their effects involving the Wnt/beta-catenin signaling. Methods and results: Multiple concentrations of mitotane and 1α,25(OH)2D3, individually or in combination, were tested on H295R cells for 24–96 h, and the effects analysed by MTT. A reduction in cell growth was observed in a dose/time-dependent manner for both mitotane and 1α,25(OH)2D3. In addition, a combination of clinically sub-therapeutic concentrations of mitotane with 1α,25(OH)2D3, had an additive anti-proliferative effect (Combination Index = 1.02). In a wound healing assay, individual treatments of both mitotane and 1α,25(OH)2D3 reduced the migration ability of H295R cells, with the effect further enhanced on combining both the agents. Western blotting and qRT-PCR analysis showed a modulation of the Wnt/beta-catenin and VDR signaling pathways. Conclusion: Our results show an additive effect of mitotane and 1α,25(OH)2D3 on the inhibition of H295R ACC cell growth and viability, and suggest that molecular mechanisms of their effects involve a functional link between VDR and Wnt/beta-catenin pathways
Insulin signaling in adipose tissue of patients with primary aldosteronism.
No full textOBJECTIVE:
We studied phosphorylation of insulin-receptors substrate downstream molecules: 1) in the ex-vivo visceral adipose tissue (VAT) of patients with aldosterone-producing adenoma (APA) (no.=7) and non-functioning adenoma (NFA) (no.=7) undergoing laparoscopic adrenalectomy; 2) in aldosterone-treated sc adipocytes of subjects (no.=5) who requested abdominoplasty.
PATIENTS AND METHODS:
Western blotting was used to detect phosphorylation of Akt and extracellular signal-regulated kinase (ERK) 1/2 in VAT from APA and NFA patients, and in subcutaneous adipocytes pre-treated with different aldosterone concentrations. Phosphorylation of Akt and ERK1/2 was similar in VAT of patients with APA and NFA. Pre-treatment in adipocytes with both physiological (1 nM) and pharmacological (10 μM) doses of aldosterone did not affect basal or insulin-induced phosphorylation of Akt and ERK1/2.
CONCLUSIONS:
Our data give further evidence that insulin signaling in human VAT is not affected by primary aldosterone overproduction
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