Ghrelin inhibits insulin secretion through the AMPK–UCP2 pathway in β cells

AbstractGhrelin inhibits insulin secretion partly via induction of IA-2β. However, the orexigenic effect of ghrelin is mediated by the AMP-activated protein kinase (AMPK)–uncoupling protein 2 (UCP2) pathway. Here, we demonstrate that ghrelin’s inhibitory effect on insulin secretion also occurs through the AMPK-UCP2 pathway. Ghrelin increased AMPK phosphorylation and UCP2 mRNA expression in MIN6 insulinoma cells. Overexpression or downregulation of UCP2 attenuated or enhanced insulin secretion, respectively. Furthermore, AMPK activator had a similar effect to ghrelin on UCP2 and insulin secretion in MIN6 cells. In conclusion, ghrelin’s inhibitory effect on insulin secretion is partly mediated by the AMPK-UCP2 pathway, which is independent of the IA-2β pathway

Am80, a retinoic acid receptor agonist, activates the cardiomyocyte cell cycle and enhances engraftment in the heart

ヒトiPS細胞由来心筋細胞の生着能改善に向けた新しい方法. 京都大学プレスリリース. 2023-07-14.Am80, a retinoic acid receptor agonist, activates cell cycle in induced cardiomyocytes and enhances heart tissue engraftment. 京都大学プレスリリース. 2023-07-14.Human induced pluripotent stem cell-derived (hiPSC) cardiomyocytes are a promising source for regenerative therapy. To realize this therapy, however, their engraftment potential after their injection into the host heart should be improved. Here, we established an efficient method to analyze the cell cycle activity of hiPSC cardiomyocytes using a fluorescence ubiquitination-based cell cycle indicator (FUCCI) system. In vitro high-throughput screening using FUCCI identified a retinoic acid receptor (RAR) agonist, Am80, as an effective cell cycle activator in hiPSC cardiomyocytes. The transplantation of hiPSC cardiomyocytes treated with Am80 before the injection significantly enhanced the engraftment in damaged mouse heart for 6 months. Finally, we revealed that the activation of endogenous Wnt pathways through both RARA and RARB underlies the Am80-mediated cell cycle activation. Collectively, this study highlights an efficient method to activate cell cycle in hiPSC cardiomyocytes by Am80 as a means to increase the graft size after cell transplantation into a damaged heart

Influence of contrast media dose and osmolality on the diagnostic performance of contrast fractional flow reserve

Background—Contrast fractional flow reserve (cFFR) is a method for assessing functional significance of coronary stenoses, which is more accurate than resting indices and does not require adenosine. However, contrast media volume and osmolality may affect the degree of hyperemia and therefore diagnostic performance. Methods and Results—cFFR, instantaneous wave–free ratio, distal pressure/aortic pressure at rest, and FFR were measured in 763 patients from 12 centers. We compared the diagnostic performance of cFFR between patients receiving low or iso-osmolality contrast (n=574 versus 189) and low or high contrast volume (n=341 versus 422) using FFR≤0.80 as a reference standard. The sensitivity, specificity, and overall accuracy of cFFR for the low versus iso-osmolality groups were 73%, 93%, and 85% versus 87%, 90%, and 89%, and for the low versus high contrast volume groups were 69%, 99%, and 83% versus 82%, 93%, and 88%. By receiver operating characteristics (ROC) analysis, cFFR provided better diagnostic performance than resting indices regardless of contrast osmolality and volume (P<0.001 for all groups). There was no significant difference between the area under the curve of cFFR in the low- and iso-osmolality groups (0.938 versus 0.957; P=0.40) and in the low- and high-volume groups (0.939 versus 0.949; P=0.61). Multivariable logistic regression analysis showed that neither contrast osmolality nor volume affected the overall accuracy of cFFR; however, both affected the sensitivity and specificity. Conclusions—The overall accuracy of cFFR is greater than instantaneous wave–free ratio and distal pressure/aortic pressure and not significantly affected by contrast volume and osmolality. However, contrast volume and osmolality do affect the sensitivity and specificity of cFFR

Electronic Structures of Aromatic Cluster Ions

Yamada Conference XLIII on Structures and Dynamics of Clusters, 1995年5月10日-13日, 下田(静岡

Electronic Structures of Aromatic Cluster Ions

The photodissociation spectra are observed for cluster ions of several aromatic molecules including benzene, toluene, and phenol. Benzene cluster ions, (C6H6)n+ with n = 3-6, retain spectroscopic features characteristic of (C6H6)2+, suggesting that the positive charge is carried by a dimer subunit in (C6H6)n+. The spectrum of (benzene-toluene)+ shows charge resonance bands, which are commonly seen in homo-dimer ions. The resonance interaction is also important in the hetero-dimer ion, despite the difference in the ionization potentials between the two components. Phenol dimer ion exhibits no strong charge resonance band, although it is a homo-dimer ion. Owing to the geometrical constraint of an O-H・・・O hydrogen bond, the two aromatic rings cannot be in a parallel configuration suitable for the resonance interaction

MicroRNA-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiac myocytes

GLUT4 shows decreased levels in failing human adult hearts. We speculated that GLUT4 expression in cardiac muscle may be fine-tuned by microRNAs. Forced expression of miR-133 decreased GLUT4 expression and reduced insulin-mediated glucose uptake in cardiomyocytes. A computational miRNA target prediction algorithm showed that KLF15 is one of the targets of miR-133. It was confirmed that over-expression of miR-133 reduced the protein level of KLF15, which reduced the level of the downstream target GLUT4. Cardiac myocytes infected with lenti-decoy, in which the 3′UTR with tandem sequences complementary to miR-133 was linked to the luciferase reporter gene, had decreased miR-133 levels and increased levels of GLUT4. The expression levels of KLF15 and GLUT4 were decreased at the left ventricular hypertrophy and congestive heart failure stage in a rat model. The present results indicated that miR-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiomyocytes

Defining the latent phase of labour: is it important?

Background and rationale. The latent phase of labour is recognised as a period of uncertainty for women and midwives. There is evidence from the literature of considerable variation in labour definitions and practice. Stimulated by discussion at an international maternity research conference, the authors set out to explore opinions regarding the need for labour-stage definitions.  Aim. To identify health professionals’ views on the need for a definition of the onset and the end of the latent phase of labour.  Methods. This was an opportunistic, semi-structured, online survey of attendees at a maternity care research conference, which included midwives, other clinicians, academics, advocates and user representatives. Attendees (approximately 100) were invited to participate through a single email invitation sent by the conference committee and containing a link to the survey. Consent was sought on the landing page. Ethical approval was obtained from Bournemouth University’s research ethics committee. Quantitative questions were analysed using simple descriptive statistics using IBM SPSS Statistics Version 24. Open questions were analysed using content analysis and where participants gave a more detailed answer, these were analysed using a thematic approach.  Findings. Participants in the survey (n=21) came from 12 countries. Most of the participants thought that there was a need to define the onset of the latent phase (n=15, 71%). Common characteristics were cited, but the main theme in the open comments referred to the importance of women’s perceptions of labour onset. Most participants (n = 18, 86%) thought that there was a need to define the end of the latent phase. This was felt necessary because current practice within facilities is usually dictated by a definition. The characteristics suggested were also not unexpected and there was some consensus; but the degree of cervical dilatation that signified the end of the latent phase varied among participants. There was significant debate about whether a prolonged latent phase was important; for example, was it associated with adverse consequences. Most participants thought it was important (n=15, 71%), but comments indicated that the reasons for this were complex. Themes included the value that women attached to knowing the duration of labour and the need to support women in the latent phase.  Implications for practice. The findings from this small, opportunistic survey reflect the current debate within the maternal health community regarding the latent phase of labour. There is a need for more clarity around latent phase labour (in terms of both the definition and the support offered) if midwives are to provide care that is both woman centred and evidence-based. The findings will inform the development of a larger survey to explore attitudes towards labour definitions

Functional regulation of the DNA damage-recognition factor DDB2 by ubiquitination and interaction with xeroderma pigmentosum group C protein

In mammalian nucleotide excision repair, the DDB1-DDB2 complex recognizes UV-induced DNA photolesions and facilitates recruitment of the XPC complex. Upon binding to damaged DNA, the Cullin 4 ubiquitin ligase associated with DDB1-DDB2 is activated and ubiquitinates DDB2 and XPC. The structurally disordered N-terminal tail of DDB2 contains seven lysines identified as major sites for ubiquitination that target the protein for proteasomal degradation; however, the precise biological functions of these modifications remained unknown. By exogenous expression of mutant DDB2 proteins in normal human fibroblasts, here we show that the N-terminal tail of DDB2 is involved in regulation of cellular responses to UV. By striking contrast with behaviors of exogenous DDB2, the endogenous DDB2 protein was stabilized even after UV irradiation as a function of the XPC expression level. Furthermore, XPC competitively suppressed ubiquitination of DDB2 in vitro, and this effect was significantly promoted by centrin-2, which augments the DNA damage-recognition activity of XPC. Based on these findings, we propose that in cells exposed to UV, DDB2 is protected by XPC from ubiquitination and degradation in a stochastic manner; thus XPC allows DDB2 to initiate multiple rounds of repair events, thereby contributing to the persistence of cellular DNA repair capacit