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Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total, n= 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2(aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2similarly to CADM1mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of CADM1cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production.

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Aldosterone production is stimulated by activation of calcium signaling in aldosterone-producing adenomas (APAs), and epigenetic factors such as DNA methylation may be associated with the expression of genes involved in aldosterone regulation.

Brown fat dissipates energy as heat and protects against obesity. Here, we identified nuclear factor I-A (NFIA) as a transcriptional regulator of brown fat by a genome-wide open chromatin analysis of murine brown and white fat followed by motif analysis of brown-fat-specific open chromatin regions. NFIA and the master transcriptional regulator of adipogenesis, PPARγ, co-localize at the brown-fat-specific enhancers. Moreover, the binding of NFIA precedes and facilitates the binding of PPARγ, leading to increased chromatin accessibility and active transcription. Introduction of NFIA into myoblasts results in brown adipocyte differentiation. Conversely, the brown fat of NFIA-knockout mice displays impaired expression of the brown-fat-specific genes and reciprocal elevation of muscle genes. Finally, expression of NFIA and the brown-fat-specific genes is positively correlated in human brown fat. These results indicate that NFIA activates the cell-type-specific enhancers and facilitates the binding of PPARγ to control the brown fat gene program.

Heteroarene sind reaktiv genug: Bi‐, Ter‐ und Quaterheteroaryle wurden durch nucleophile aromatische Substitutionen (SNAr) unter Indiumkatalyse erhalten. Damit gelang erstmals die katalytische Verknüpfung von zwei Heteroarylsubstraten ohne aktivierende Gruppen durch SNAr‐Substitution (siehe Schema; El=Elektrophil, In‐Kat.=In(OTf)3oder In(ONf)3, Nu=Nucleophil).

Unique performance: Bi‐, ter‐, and quater‐heteroaryls have been prepared under indium catalysis by nucleophilic aromatic substitution (SNAr). This is the first example of catalytic heteroaryl–heteroaryl bond formation based on SNAr between two heteroaryl substrates without needing activating groups to enhance their reactivity (see scheme; El=electrophile, In=In(OTf)3or In(ONf)3, Nu=nucleophile).

We recently demonstrated that SA13353, a transient receptor potential vanilloid 1 (TRPV1) agonist, reduced the severity of the symptoms of kidney injury, arthritis, and encephalomyelitis in disease models. Here, we investigated the effects of orally administered SA13353 on leukocyte infiltration in lipopolysaccharide (LPS)-induced acute lung injury and ovalbumin-induced allergic airway inflammation. In LPS-induced lung injury, SA13353 attenuated neutrophil infiltration and the increase of TNF-αand CINC-1 levels. In allergic airway inflammation, SA13353 tended to inhibit leukocyte infiltration and attenuated the increase of IL-4 and IL-12p40. These results suggest that somatosensory TRPV1 may play an anti-inflammatory role in lung inflammation.

Abstract: A 61-year-old man with hypertension and diabetes was referred for the evaluation of multiple bilateral adrenal tumors. While Cushingoid features were not apparent, an elevated cortisol level in response to a low-dose dexamethasone suppression test (187.7 nmol/l), an elevated urinary cortisol level (170.9 nmol/day), and a weak response to a cosyntropin-releasing hormone (CRH) provocation test were observed. Furthermore, the serum cortisol level increased in response to a posture test or isoproterenol infusion. Accordingly, the patient was diagnosed as having ACTH-independent macronodular adrenal hyperplasia (AIMAH) with subclinical Cushing’s syndrome associated with the aberrant expression of β-adrenergic receptors. After 2 months of propranolol therapy, the serum cortisol responses to a posture test and isoproterenol infusion, the cortisol level in response to a low-dose dexamethasone suppression test (102.1 nmol/l), and the urinary cortisol level (165.9 nmol/day) all normalized. While the suppression of cortisol secretion was sustained for 24 months, glucose metabolism and adrenal size were unaffected. To our knowledge, this is the first report of AIMAH accompanied by subclinical Cushing’s syndrome associated with the aberrant expression of β-adrenergic receptors. Furthermore, propranolol inhibited cortisol hypersecretion in the present case. Additional cases or controlled studies are needed to determine the potential effect of propranolol on metabolic disorders and adrenal size in patients with AIMAH.

Adrenal insufficiency is a life-threatening disorder. In the treatment of adrenal insufficiency, it is essential to administer the optimal medication at the optimal dose. Glucocorticoids are the main therapeutic approach in all forms of adrenal insufficiency. The recommended protocol for maintenance therapy is 15 – 25 mg of hydrocortisone, divided into two or three separate doses. Patients with primary adrenal insufficiency generally receive mineralocorticoid replacement comprised of fludrocortisone 0.05 – 0.2 mg/day. Recently, dehydroepiandrosterone has been proposed as a new therapeutic approach, despite the lack of strong evidence for beneficial effects. Additional glucocorticoid supplementation should be administered in stressful states. During critical illness, inadequate or no temporary increase in the dose of the replacement glucocorticoid can lead to acute adrenal failure. When acute adrenal failure occurs, it becomes necessary to administer intravenous hydrocortisone.

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In most cases, In(O‐Tf)3is found to be the optimal catalyst.