Transcriptional co-repressor CtBP2 orchestrates epithelial-mesenchymal transition through a novel transcriptional holocomplex with OCT1.

The epithelial to mesenchymal transition (EMT) is a cell intrinsic program controlling cellular morphological and phenotypic remodeling in a wide range of biological processes. Despite the accumulating evidence, the transcriptional networks regulating EMT still remain to be elucidated. In this study, we demonstrate that C-terminal binding protein 2 (CtBP2), a critical transcriptional co-repressor harboring pyridine nucleotide sensing capability, orchestrates the EMT program at least in part through a novel transcriptional interaction with an octamer transcription factor, OCT1 (POU2F1, POU class 2 homeobox 1). We identified novel interactions of CtBP2 with several octamer transcription factors, and CtBP2 exhibits a direct interaction with OCT1 in particular. OCT1 accelerates the EMT program as reported, which is diminished by the mutation of the CtBP-binding motif in OCT1, suggesting OCT1 represses epithelial gene expression through recruiting the co-repressor CtBP2. In accordance with these findings, a canonical EMT activator transforming growth factor-ß (TGF-ß) promotes the formation of the CtBP2/OCT1 complex. Our observations illustrate the role of CtBP2 to orchestrate the EMT program through the interaction with OCT1 and highlight the potential of therapeutic exploitation of this new transcriptional system for a wide range of diseases.

Deciphering genetic signatures by whole exome sequencing in a case of co-prevalence of severe renal hypouricemia and diabetes with impaired insulin secretion.

BACKGROUND: Renal hypouricemia (RHUC) is a hereditary disorder where mutations in SLC22A12 gene and SLC2A9 gene cause RHUC type 1 (RHUC1) and RHUC type 2 (RHUC2), respectively. These genes regulate renal tubular reabsorption of urates while there exist other genes counterbalancing the net excretion of urates including ABCG2 and SLC17A1. Urate metabolism is tightly interconnected with glucose metabolism, and SLC2A9 gene may be involved in insulin secretion from pancreatic ß-cells. On the other hand, a myriad of genes are responsible for the impaired insulin secretion independently of urate metabolism. CASE PRESENTATION: We describe a 67 year-old Japanese man who manifested severe hypouricemia (0.7 mg/dl (3.8-7.0 mg/dl), 41.6 µmol/l (226-416 µmol/l)) and diabetes with impaired insulin secretion. His high urinary fractional excretion of urate (65.5%) and low urinary C-peptide excretion (25.7 µg/day) were compatible with the diagnosis of RHUC and impaired insulin secretion, respectively. Considering the fact that metabolic pathways regulating urates and glucose are closely interconnected, we attempted to delineate the genetic basis of the hypouricemia and the insulin secretion defect observed in this patient using whole exome sequencing. Intriguingly, we found homozygous Trp258* mutations in SLC22A12 gene causing RHUC1 while concurrent mutations reported to be associated with hyperuricemia were also discovered including ABCG2 (Gln141Lys) and SLC17A1 (Thr269Ile). SLC2A9, that also facilitates glucose transport, has been implicated to enhance insulin secretion, however, the non-synonymous mutations found in SLC2A9 gene of this patient were not dysfunctional variants. Therefore, we embarked on a search for causal mutations for his impaired insulin secretion, resulting in identification of multiple mutations in HNF1A gene (MODY3) as well as other genes that play roles in pancreatic ß-cells. Among them, the Leu80fs in the homeobox gene NKX6.1 was an unreported mutation. CONCLUSION: We found a case of RHUC1 carrying mutations in SLC22A12 gene accompanied with compensatory mutations associated with hyperuricemia, representing the first report showing coexistence of the mutations with opposed potential to regulate urate concentrations. On the other hand, independent gene mutations may be responsible for his impaired insulin secretion, which contains novel mutations in key genes in the pancreatic ß-cell functions that deserve further scrutiny.

Effectiveness of a Remote Monitoring-Based Home Training System for Preventing Frailty in Older Adults in Japan: A Preliminary Randomized Controlled Trial.

This study examined whether SUKUBARA®, a remotely managed training system that we developed, could improve skeletal muscle mass and muscle strength in community-dwelling older adults. SUKUBARA® is a composite exercise program that combines lower-load resistance training and balance exercises. Participants were instructed to exercise while watching individually assigned videos on YouTube, such that the research administrators could verify the viewing records of each participant. Fifteen participants (69 ± 4 years) were randomly assigned to the intervention (eight participants; the RT group) or the control group (seven participants; the CO group). The primary endpoint was a change in fat-free mass (FFM; kg), whereas the secondary endpoints included a change in knee extension strength (KES; Nm/kg). Correlation analyses were conducted to examine the relationship between FFM and KES. During the 12-week intervention period, significant differences were observed between the RT and CO groups in the changes in FFM (0.5 ± 0.5 vs. -0.1 ± 0.5) and KES (0.20 ± 0.22 vs. 0.02 ± 0.13), and significant positive correlations were found between the changes. Thus, SUKUBARA®-based interventions have the potential to improve muscle hypertrophy and enhance muscle strength among community-dwelling older adults. Thus, SUKUBARA® -based interventions show promise in improving muscle hypertrophy and enhance muscle strength among community-dwelling older adults. However, appropriately powered future research is needed to replicate these findings.

A case of early-onset diabetes with impaired insulin secretion carrying a PAX6 gene Gln135* mutation.

Summary: A paired homeodomain transcription factor, PAX6 (paired-box 6), is essential for the development and differentiation of pancreatic endocrine cells as well as ocular cells. Despite the impairment of insulin secretion observed in PAX6-deficient mice, evidence implicating causal association between PAX6 gene mutations and monogenic forms of human diabetes is limited. We herein describe a 33-year-old Japanese woman with congenital aniridia who was referred to our hospital because of her uncontrolled diabetes with elevated hemoglobin A1c (13.1%) and blood glucose (32.5 mmol/L) levels. Our biochemical analysis revealed that her insulin secretory capacity was modestly impaired as represented by decreased 24-h urinary C-peptide levels (38.0 µg/day), primarily explaining her diabetes. Intriguingly, there was a trend toward a reduction in her serum glucagon levels as well. Based on the well-recognized association of PAX6 gene mutations with congenital aniridia, we screened the whole PAX6 coding sequence, leading to an identification of a heterozygous Gln135* mutation. We tested our idea that this mutation may at least in part explain the impaired insulin secretion observed in this patient. In cultured pancreatic ß-cells, exogenous expression of the PAX6 Gln135* mutant produced a truncated protein that lacked the transcriptional activity to induce insulin gene expression. Our observation together with preceding reports support the recent attempt to include PAX6 in the growing list of genes causally responsible for monogenic diabetes. In addition, since most cases of congenital aniridia carry PAX6 mutations, we may need to pay more attention to blood glucose levels in these patients. Learning points: PAX6 Gln135* mutation may be causally associated not only with congenital aniridia but also with diabetes. Blood glucose levels may deserve more attention in cases of congenital aniridia with PAX6 mutations. Our case supports the recent attempt to include PAX6 in the list of MODY genes, and Gln135* may be pathogenic.

Effects of Branched-Chain Amino Acids on Skeletal Muscle, Glycemic Control, and Neuropsychological Performance in Elderly Persons with Type 2 Diabetes Mellitus: An Exploratory Randomized Controlled Trial.

Although branched-chain amino acids (BCAA) are known to stimulate myofibrillar protein synthesis and affect insulin signaling and kynurenine metabolism (the latter being a metabolite of tryptophan associated with depression and dementia), the effects of BCAA supplementation on type 2 diabetes (T2D) are not clear. Therefore, a 24-week, prospective randomized open blinded-endpoint trial was conducted to evaluate the effects of supplementation of 8 g of BCAA or 7.5 g of soy protein on skeletal muscle and glycemic control as well as adverse events in elderly individuals with T2D. Thirty-six participants were randomly assigned to the BCAA group (n = 21) and the soy protein group (n = 15). Skeletal muscle mass and HbA1c, which were primary endpoints, did not change over time or differ between groups. However, knee extension muscle strength was significantly increased in the soy protein group and showed a tendency to increase in the BCAA group. Homeostasis model assessment for insulin resistance did not significantly change during the trial. Depressive symptoms were significantly improved in the BCAA group but the difference between groups was not significant. Results suggested that BCAA supplementation may not affect skeletal muscle mass and glycemic control and may improve depressive symptoms in elderly individuals with T2D.

Regulation of Multicolor Fluorescence Changes Found in Donor-acceptor-type Mechanochromic Fluorescent Dyes.

The regulation of multicolor fluorescence changes in mechanochromic fluorescence (MCF) remains a challenging task. Herein, we report the regulation of MCF using a donor-acceptor structure. Two crystal polymorphs, BTD-pCHO(O) and BTD-pCHO(R) produced by the introduction of formyl groups to an MCF dye, respond to a mechanical stimulus, allowing a three-color fluorescence change. Specifically, the orange-colored fluorescence of the metastable BTD-pCHO(O) polymorph changed to a deep-red color in the amorphous-like state to finally give a red color in the stable BTD-pCHO(R) polymorph. This change occurred by mechanical grinding followed by vapor fuming. The two different crystal packing patterns were selectively regulated by the electronic effect of the introduced functional groups. The two types of selectively formed crystals in BTD(F)-pCHO bearing fluorine atoms, and BTD(OMe)-pCHO bearing methoxy groups, respond to mechanical grinding, allowing for the regulation of multicolor MCL from a three-color change to two different types of two-color changes.

Meso-unsubstituted iron corrole in hemoproteins: remarkable differences in effects on peroxidase activities between myoglobin and horseradish peroxidase.

Myoglobin (Mb) and horseradish peroxidase (HRP) were both reconstituted with a meso-unsubstituted iron corrole and their electronic configurations and peroxidase activities were investigated. The appearance of the 540 nm band upon incorporation of the iron corrole into apoMb indicates axial coordination by the proximal histidine imidazole in the Mb heme pocket. Based on (1)H NMR measurements using the Evans method, the total magnetic susceptibility of the iron corrole reconstituted Mb was evaluated to be S = 3/2. In contrast, although a band does not appear in the vicinity of 540 nm during reconstitution of the iron corrole into the matrix of HRP, a spectrum similar to that of the iron corrole reconstituted Mb is observed upon the addition of dithionite. This observation suggests that the oxidation state of the corrole iron in the reconstituted HRP can be assigned as +4. The catalytic activities of both proteins toward guaiacol oxidation are quite different; the iron corrole reconstituted HRP decelerates H(2)O(2)-dependent oxidation of guaiacol, while the same reaction catalyzed by iron corrole reconstituted Mb has the opposite effect and accelerates the reaction. This finding can be attributed to the difference in the oxidation states of the corrole iron when these proteins are in the resting state.

Pancreaticoduodenal artery aneurysm associated with coeliac artery occlusion from an aortic intramural hematoma.

Pancreaticoduodenal artery aneurysms are a rare type of visceral artery aneurysm, whose rupture is associated with high mortality. These aneurysms are of particular interest because local haemodynamic change caused by coeliac artery obstruction plays an important role in their development. However, the pathophysiological mechanism of coeliac artery obstruction is not completely understood. Pressure from the median arcuate ligament is most frequently reported cause. Although it is well-known that stenosis or occlusion of the visceral vessels may be caused by aortic syndrome, reports of pancreaticoduodenal artery aneurysm associated with coeliac artery occlusion due to aortic syndrome are extremely rare. Our case indicates a new aetiology for a pancreaticoduodenal artery aneurysm and demonstrates the rapid deterioration of the patient affected.

Protracted anaphylaxis developed after peginterferon α-2a administration for chronic hepatitis C.

Peginterferon is a key drug used to treat chronic viral hepatitis that is known for causing various side effects. Side effects occurring immediately after administration include headache, nausea, and influenza-like symptoms, such as fever and joint pain. However, reports of anaphylactic shock are extremely rare. Here we report a patient with protracted anaphylaxis who suffered shock symptoms after peginterferon α-2a administration for chronic hepatitis C. Although the patient improved temporarily with shock treatment, symptoms of anaphylaxis recurred. As peginterferon is often administered on an outpatient basis, it is important to recognize life-threatening side effects that may develop in a protracted manner.