Evaluation of the cardiotoxicity potential of bisphenol analogues in human induced pluripotent stem cells derived cardiomyocytes.

The importance of evaluating the cardiotoxicity potential of common chemicals as well as new drugs is increasing as a result of the development of animal alternative test methods using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Bisphenol A (BPA), which is used as a main material in plastics, is known as an endocrine-disrupting chemical, and recently reported to cause cardiotoxicity through inhibition of ion channels in CMs even with acute exposure. Accordingly, the need for the development of alternatives to BPA has been highlighted, and structural analogues including bisphenol AF, C, E, F, and S have been developed. However, cardiotoxicity data for analogues of bisphenol are not well known. In this study, in order to evaluate the cardiotoxicity potential of analogues, including BPA, a survival test of hiPSC-CMs and a dual-cardiotoxicity evaluation based on a multi-electrode array were performed. Acute exposure to all bisphenol analogues did not affect survival rate, but spike amplitude, beat period, and field potential duration were decreased in a dose-dependent manner in most of the bisphenols except bisphenol S. In addition, bisphenols, except for bisphenol S, reduced the contractile force of hiPSC-CMs and resulted in beating arrest at high doses. Taken together, it can be suggested that the developed bisphenol analogues could cause cardiotoxicity even with acute exposure, and it is considered that the application of the MEA-based dual-cardiotoxicity evaluation method can be an effective help in the development of safe alternatives.

Promotion of maturation of human pluripotent stem cell-derived cardiomyocytes via treatment with the peroxisome proliferator-activated receptor alpha agonist Fenofibrate.

As research on in vitro cardiotoxicity assessment and cardiac disease modeling becomes more important, the demand for human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is increasing. However, it has been reported that differentiated hPSC-CMs are in a physiologically immature state compared to in vivo adult CMs. Since immaturity of hPSC-CMs can lead to poor drug response and loss of acquired heart disease modeling, various approaches have been attempted to promote maturation of CMs. Here, we confirm that peroxisome proliferator-activated receptor alpha (PPARα), one of the representative mechanisms of CM metabolism and cardioprotective effect also affects maturation of CMs. To upregulate PPARα expression, we treated hPSC-CMs with fenofibrate (Feno), a PPARα agonist used in clinical hyperlipidemia treatment, and demonstrated that the structure, mitochondria-mediated metabolism, and electrophysiology-based functions of hPSC-CMs were all mature. Furthermore, as a result of multi electrode array (MEA)-based cardiotoxicity evaluation between control and Feno groups according to treatment with arrhythmia-inducing drugs, drug response was similar in a dose-dependent manner. However, main parameters such as field potential duration, beat period, and spike amplitude were different between the 2 groups. Overall, these results emphasize that applying matured hPSC-CMs to the field of preclinical cardiotoxicity evaluation, which has become an essential procedure for new drug development, is necessary.

Genetic analyses of the chimeric CYP11B1/CYP11B2 gene in a Korean family with glucocorticoid-remediable aldosteronism.

Glucocorticoid-remediable aldosteronism (GRA) is an autosomal-dominant inheritable form of hyperaldosteronism with early onset hypertension. GRA is caused by unequal crossing-over of the steroid 11 beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes. As a result of chimeric gene duplication, aldosterone is ectopically synthesized in the adrenal zona fasciculata under the control of adrenocorticotropin. Here, we describe three cases of GRA in a Korean family. The proband-a 21-yr-old female-was incidentally found to have high blood pressure (170/108 mmHg). Her 46-yr-old father had been treated twice for cerebral hemorrhage at the ages of 29 and 39 yr. Her 15-yr-old brother had a 2-yr history of hypertension; however, he was never treated. Their laboratory test results showed normokalemia, hyporeninemia, hyperaldosteronism, and a high plasma aldosterone concentration-to-plasma renin activity ratio. Normal saline loading failed to suppress aldosterone secretion. However, dexamethasone administration effectively suppressed their plasma aldosterone concentrations. Following genetic analyses with PCR and direct sequencing to document the chimeric gene and crossover site, respectively, we identified CYP11B1/CYP11B2 and determined the breakpoint of unequal crossover to be located between intron 2 of CYP11B1 and exon 3 of CYP11B2.

Characteristics of nonvariceal upper gastrointestinal hemorrhage in patients with chronic kidney disease.

AIM: To evaluate the clinical characteristics of nonvariceal upper gastrointestinal hemorrhage (NGIH) in patients with chronic kidney disease (CKD). METHODS: From 2003 to 2010, a total of 72 CKD patients (male n = 52, 72.2%; female n = 20, 27.8%) who had undergone endoscopic treatments for NGIH were retrospectively identified. Clinical findings, endoscopic features, prognosis, rebleeding risk factors, and mortality-related factors were evaluated. The characteristics of the patients and rebleeding-related data were recorded for the following variables: gender, age, alcohol use and smoking history, past hemorrhage history, endoscopic findings (the cause, location, and size of the hemorrhage and the hemorrhagic state), therapeutic options for endoscopy, endoscopist experience, clinical outcomes, and mortality. RESULTS: The average size of the hemorrhagic site was 13.7 ± 10.2 mm, and the most common hemorrhagic site in the stomach was the antrum (n = 21, 43.8%). The most frequent method of hemostasis was combination therapy (n = 32, 44.4%). The incidence of rebleeding was 37.5% (n = 27), and 16.7% (n = 12) of patients expired due to hemorrhage. In a multivariate analysis of the risk factors for rebleeding, alcoholism (OR = 11.19, P = 0.02), the experience of endoscopists (OR = 0.56, P = 0.03), and combination endoscopic therapy (OR = 0.06, P = 0.01) compared with monotherapy were significantly related to rebleeding after endoscopic therapy. In a risk analysis of mortality after endoscopic therapy, only rebleeding was related to mortality (OR = 7.1, P = 0.02). CONCLUSION: Intensive combined endoscopic treatments by experienced endoscopists are necessary for the treatment of NGIH in patients with CKD, especially when a patient is an alcoholic.

Bone mineral density in prediabetic men.

BACKGROUND: There are many studies regarding the effects of insulin on bone metabolism and changes in bone mineral density (BMD) in the setting of diabetes. The effect of prediabetes on BMD is not known. METHODS: A total of 802 men participated in the Korea Rural Genomic Cohort Study (in Geumsan County). According to the results of an oral glucose tolerance test, subjects were classified into normal, prediabetic, and diabetic categories. One hundred twenty-four subjects diagnosed with type 2 diabetes were excluded, leaving 678 subjects for the study inclusion. BMD was estimated with a quantitative ultrasonometer. RESULTS: The average BMD T scores of normal and prediabetic subjects were -1.34 ± 1.42 and -1.33 ± 1.30, respectively; there was no significant difference in the BMD T scores between these groups. The BMD T score was inversely associated with age and positively correlated with body weight, body mass index, total cholesterol, low density lipoprotein cholesterol, and HbA1c. On multiple linear regression analysis, low density lipoprotein cholesterol was the only statistically significant variable for prediabetes (ß = 0.007, P = 0.005). On the stepwise regression analysis, age (ß = -0.026, P < 0.001), the body mass index (ß = 0.079, P < 0.001), and low density lipoprotein cholesterol (ß = 0.004, P = 0.016) were significant variables for prediabetes. CONCLUSIONS: There was no significant difference in the BMD T score between the normal and prediabetic subjects. Further studies are needed regarding the association of fracture risk and changes in BMD with the development of overt diabetes.