Upregulation of PCP4 in human aldosterone-producing adenomas fosters human adrenocortical tumor cell growth via AKT and AMPK pathway.

Primary aldosteronism (PA) is characterized by aldosterone hypersecretion and adrenal hyperplasia and ranks as one of the most common causes of secondary hypertension. However, the molecular mechanism involved in adrenal hyperplasia and tumorigenesis is largely unknown. Dysregulation of Purkinji cell protein 4 (PCP4) is involved in the development and progression of neoplasia and aldosterone secretion, but little is known about the effect of PCP4 on human adrenocortical tumorigenesis. We investigated the expression pattern of PCP4 in different adrenal tissues and studied whether PCP4 is involved in cell growth in human adrenal cell lines. The mRNA levels of PCP4 were measured by real-time PCR in tissues from aldosterone-producing adenomas (APAs), idiopathic hyperaldosteronism (IHA) tissues, and normal adrenal (NA) tissues. In vitro siRNA knockdown of PCP4 in NCI-H295R and SW13 cell lines was used to determine the effect of PCP4 on cellular growth. Our results show that the mRNA level of PCP4 is upregulated in APAs and IHA compared with that in NA. The PCP4 mRNA expression level was positively correlated with tumor size in APAs. Knockdown of PCP4 decreased cell proliferation. Flow cytometry analysis showed that PCP4 knockdown fosters apoptosis. Finally, PCP4 knockdown inhibited phosphorylation of AKT308 and AMPKThr172. Our data suggest that PCP4 may represent a key player in the development and pathophysiology of PA via targeting the AKT and AMPK signaling pathways and thus may be a promising therapeutic target for PA.

Endocrinal description of two Chinese Kennedy's disease pedigrees.

Kennedy's disease (KD), also known as X-linked spinal and bulbar muscular atrophy (SBMA), is caused by the expansion of cytosine-adenine-guanine (CAG) repeats in the first exon of the androgen receptor (AR) gene. KD is a late-onset neural-endocrinal disease that is characterized by the degeneration of motor neurons in the brainstem and spinal cord. In addition, partial androgen insensitivity is an important manifestation of KD. Here, we report two Chinese KD pedigrees that reveal the clinical and genetic manifestations and fully elaborate the endocrinal characteristics of KD patients. The proband in pedigree 1 was referred to an endocrinologist for gynaecomastia and sexual dysfunction. A gene analysis of this patient revealed that there were 53 CAG repeats in the AR gene. A family survey identified an additional two KD patients in pedigree 1. The proband in pedigree 2 was diagnosed by a neurologist and did not have gynaecomastia or sexual dysfunction. A family survey identified an additional subclinical patient, and both patients exhibited partial androgen insensitivity at a hormonal level. We therefore suggest that a family survey and hormone tests should be routinely performed in KD patients and that physicians should increase their understanding of the different symptoms of KD to achieve correct diagnoses in affected patients.

Effect of Saxagliptin on Circulating Endothelial Progenitor Cells and Endothelial Function in Newly Diagnosed Type 2 Diabetic Patients.

Endothelial dysfunction is associated with the risk of cardiovascular complications in diabetic patients. Endothelial progenitor cells (EPCs) and flow-mediated dilation (FMD) are common markers of endothelial function. In this study, we aim to investigate whether the DPP-4 inhibitor saxagliptin modulate EPCs number and FMD in newly diagnosed, treatment-naive type 2 diabetic patients. This was a controlled, randomized, open-label clinical trial. Saxagliptin group and metformin group consumed either saxagliptin 5 mg per day or metformin 1 500 mg per day respectively for 12 weeks. Changes of FMD and EPCs number after 12-week intervention were the primary endpoints. 31 patients were initially enrolled and randomized to saxagliptin group (n=16) and metformin group (n=15). 27 patients completed the trial (saxagliptin group n=14 and metformin group n=13), and 4 patients dropped out during the study. FMD and EPCs number increased significantly in both saxagliptin group and metformin group, and there was no significant difference between groups. 2-h postprandial plasma glucose, HbA1c and diastolic blood pressure improved significantly in both groups, and there was no significant difference between groups. Saxagliptin and metformin had comparable beneficial effects on endothelial function.

A new mutation in the CSB gene in a Chinese patient with mild Cockayne syndrome.

KEY CLINICAL MESSAGE: Cockayne syndrome (CS) is a rare autosomal recessive genetic disease characterized by growth failure and progressive neurological degeneration. Here we report a mild form of CS patient who was homozygous for the C526T transition resulting in a new nonsense mutation, which converts Arg176 to a stop codon.

Decreased LINE-1 methylation levels in aldosterone-producing adenoma.

PURPOSE: Abnormal global DNA methylation levels are associated with many diseases. In this study, we examined long interspersed nuclear elements-1 (LINE-1) methylation as a biomarker for abnormal global DNA methylation and aldosterone-producing adenoma (APA). METHODS: Tissues from 25 APA and 6 normal adrenal glands (NAs) were analyzed for LINE-1 methylation by real-time methylation-specific polymerase chain reaction. The estimated LINE-1 methylation level was then tested for correlation with the clinicopathologic parameters of APA patients. RESULTS: The methylation index (MI) level for LINE-1 was 0.91 in NA samples and 0.77 in APA samples (P < 0.001). For the APA samples, there were no statistical correlations between the MI level and various clinicopathologic parameters such as gender (P = 0.07). CONCLUSION: LINE-1 methylation is significantly lower in APA samples than in NA samples. LINE-1 methylation is not correlated with the clinical characteristics of APA.