Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Acute Valproate Exposure Induces Mitochondrial Biogenesis and Autophagy with FOXO3a Modulation in SH-SY5Y Cells

Valproic acid (VPA) is an antiepileptic drug found to induce mitochondrial dysfunction and autophagy in cancer cell lines. We treated the SH-SY5Y cell line with various concentrations of VPA (1, 5, and 10 mM). The treatment decreased cell viability, ATP production, and mitochondrial membrane potential and increased reactive oxygen species production. In addition, the mitochondrial DNA copy number increased after VPA treatment in a dose-dependent manner. Western blotting showed that the levels of mitochondrial biogenesis-related proteins (PGC-1α, TFAM, and COX4) increased, though estrogen-related receptor expression decreased after VPA treatment. Further, VPA treatment increased the total and acetylated FOXO3a protein levels. Although SIRT1 expression was decreased, SIRT3 expression was increased, which regulated FOXO3 acetylation in the mitochondria. Furthermore, VPA treatment induced autophagy via increased LC3-II levels and decreased p62 expression and mTOR phosphorylation. We suggest that VPA treatment induces mitochondrial biogenesis and autophagy via changes in FOXO3a expression and posttranslational modification in the SH-SY5Y cell line

Prenatal Trimethyltin Exposure Induces Long-Term DNA Methylation Changes in the Male Mouse Hippocampus

Trimethyltin (TMT) is an irreversible neurotoxicant. Because prenatal TMT exposure has been reported to induce behavioral changes, this study was conducted to observe gender differences and epigenetic changes using a mouse model. In behavioral testing of offspring at 5 weeks of age, the total times spent in the center, corner, or border zones in the male prenatal TMT-exposed mice were less than those of control unexposed mice in the open-field test. Female TMT-exposed mice scored lower on total numbers of arm entries and percentages of alternations than controls in the Y-maze test with lower body weight. We found that only TMT-exposed males had fewer copies of mtDNA in the hippocampus and prefrontal cortex region than controls. Additional epigenetic changes, including increased 5-methyl cytosine/5-hydroxymethyl cytosine levels in the male TMT hippocampus, were observed. After methylation binding domain (MBD) sequencing, multiple signaling pathways related to metabolism and neurodevelopment, including FoxO signaling, were identified by pathway analysis for differentially methylated regions (DMRs). Increased FOXO3 and decreased ASCL1 expression were also observed in male TMT hippocampi. This study suggests that sex differences and epigenetics should be more carefully considered in prenatal toxicology studies

Neonatal Exposure to Valproate Induces Long-Term Alterations in Steroid Hormone Levels in the Brain Cortex of Prepubertal Rats

Valproic acid (VPA) is a known drug for treating epilepsy and mood disorders; however, it is not recommended for pregnant women because of its possible teratogenicity. VPA affects neurotransmission and gene expression through epigenetic mechanisms by acting as a histone deacetylase inhibitor and has been used to establish animal models of autism spectrum disorder (ASD). However, studies on the long-term effects of early exposure to VPA on glucocorticoid and neurosteroid synthesis in the brain are lacking. Therefore, this study aimed to investigate the long-term changes in metabolic alterations and gene expression regulation according to sex, using metabolic steroid profiling data from cerebral cortex samples of rats four weeks after VPA exposure (400 mg/kg). In neonatal VPA-exposed models, estradiol levels decreased, and cytochrome P450 19A1 gene (Cyp19a1) expression was reduced in the prepubertal male cortex. Progesterone and allopregnanolone levels decreased, and 3β-hydroxysteroid dehydrogenase 1 gene (Hsd3b1) expression was also downregulated in the prepubertal female cortex. Furthermore, cortisol levels increased, and mRNA expression of the nuclear receptor subfamily 3 group C member 1 gene (Nr3c1) was downregulated in the cortices of both sexes. Unlike the neonatal VPA-exposed models, although a decrease in progestin and estradiol levels was observed in females and males, respectively, no differences were observed in cortisol levels in the cortex tissues of 8-week-old adult rats administered VPA for four weeks. These results indicate that early environmental chemical exposure induces long-term neurosteroid metabolic effects in the brain, with differences according to sex

Does siwonhan-mat represent delicious in Korean foods?

Background: Koreans believe that there is another sense experienced throughout the body when eating, in addition to smell and taste. This taste, siwonhan-mat, describes a sensation within the body, including the tongue, stomach, and intestines, when consuming food. Siwonhan-mat is often considered to be synonymous with deliciousness among Koreans. In this paper, determining factors of siwonhan-mat are explored in terms of kan (levels of salinity) and taste. Two representative dishes of siwonhan-mat, kongnamul-kuk (bean sprout soup) and hwangtaebuko-kuk (pollock soup), are used in this study. Sensory evaluation tests were performed in order to understand the relationship between siwonhan-mat and levels of salinity and taste. Methods: Different versions of kongnamul-kuk and hwangtaebuko-kuk were created with either of two types of seasoning (salt or soy sauce) and varying levels of salinity (1%, 2%, 3%, and 4%). The temperature of the kuk was set to 80°C, and varieties of kuk were randomly assigned to participants. The first group of participants rated siwonhan-mat in the kuk. The participants were 30 individuals in their 40s and 50s, as it is presumed that this age group would be more familiar with siwonhan-mat. 9 pt hedonic scale was used in the experiment. Another group of 30 participants was composed of people in their 20s and 30s, who were assumed to be less familiar with siwonhan-mat as compared to the first group. This group also rated deliciousness of the kuk using a similar procedure. Results: This research was conducted to allow better understanding of siwonhan-mat, a sensation of taste experienced by Koreans, in relation to levels of salinity and taste. The results suggest that types of seasoning and levels of salinity are determining factors of siwonhan-mat. For kongnamul-kuk, 2% salinity earned the highest score in both the salt and soy sauce seasoning conditions. As for buko-kuk, 3% salinity with soy sauce was preferred. Ratings of deliciousness were correlated with ratings of siwonhan-mat, suggesting that siwonhan-mat may be a core element of pleasant taste in kuk and tang. Conclusion: Balancing kan is a determining factor of siwonhan-mat in Korean cuisine. Particularly, a strong association between siwonhan-mat and deliciousness was found in kuk and tang, suggesting the importance of siwonhan-mat in experiencing the best flavor in Korean food

Development of a Korean Fracture Risk Score (KFRS) for Predicting Osteoporotic Fracture Risk: Analysis of Data from the Korean National Health Insurance Service.

Asian-specific prediction models for estimating individual risk of osteoporotic fractures are rare. We developed a Korean fracture risk prediction model using clinical risk factors and assessed validity of the final model.A total of 718,306 Korean men and women aged 50-90 years were followed for 7 years in a national system-based cohort study. In total, 50% of the subjects were assigned randomly to the development dataset and 50% were assigned to the validation dataset. Clinical risk factors for osteoporotic fracture were assessed at the biennial health check. Data on osteoporotic fractures during the follow-up period were identified by ICD-10 codes and the nationwide database of the National Health Insurance Service (NHIS).During the follow-up period, 19,840 osteoporotic fractures were reported (4,889 in men and 14,951 in women) in the development dataset. The assessment tool called the Korean Fracture Risk Score (KFRS) is comprised of a set of nine variables, including age, body mass index, recent fragility fracture, current smoking, high alcohol intake, lack of regular exercise, recent use of oral glucocorticoid, rheumatoid arthritis, and other causes of secondary osteoporosis. The KFRS predicted osteoporotic fractures over the 7 years. This score was validated using an independent dataset. A close relationship with overall fracture rate was observed when we compared the mean predicted scores after applying the KFRS with the observed risks after 7 years within each 10th of predicted risk.We developed a Korean specific prediction model for osteoporotic fractures. The KFRS was able to predict risk of fracture in the primary population without bone mineral density testing and is therefore suitable for use in both clinical setting and self-assessment. The website is available at http://www.nhis.or.kr