Neprilysin Is Required for Angiotensin-(1-7)'s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1-2)

Recent work has renewed interest in therapies targeting the renin-angiotensin system (RAS) to improve β-cell function in type 2 diabetes. Studies show that generation of angiotensin-(1–7) by ACE2 and its binding to the Mas receptor (MasR) improves glucose homeostasis, partly by enhancing glucose-stimulated insulin secretion (GSIS). Thus, islet ACE2 upregulation is viewed as a desirable therapeutic goal. Here, we show that, although endogenous islet ACE2 expression is sparse, its inhibition abrogates angiotensin-(1–7)–mediated GSIS. However, a more widely expressed islet peptidase, neprilysin, degrades angiotensin-(1–7) into several peptides. In neprilysin-deficient mouse islets, angiotensin-(1–7) and neprilysin-derived degradation products angiotensin-(1–4), angiotensin-(5–7), and angiotensin-(3–4) failed to enhance GSIS. Conversely, angiotensin-(1–2) enhanced GSIS in both neprilysin-deficient and wild-type islets. Rather than mediating this effect via activation of the G-protein–coupled receptor (GPCR) MasR, angiotensin-(1–2) was found to signal via another GPCR, namely GPCR family C group 6 member A (GPRC6A). In conclusion, in islets, intact angiotensin-(1–7) is not the primary mediator of beneficial effects ascribed to the ACE2/angiotensin-(1–7)/MasR axis. Our findings warrant caution for the concurrent use of angiotensin-(1–7) compounds and neprilysin inhibitors as therapies for diabetes

HoxA-11 and FOXO1A Cooperate to Regulate Decidual Prolactin Expression: Towards Inferring the Core Transcriptional Regulators of Decidual Genes

During the menstrual cycle, the ovarian steroid hormones estrogen and progesterone control a dramatic transcriptional reprogramming of endometrial stromal cells (ESCs) leading to a receptive state for blastocyst implantation and the establishment of pregnancy. A key marker gene of this decidualization process is the prolactin gene. Several transcriptional regulators have been identified that are essential for decidualization of ESCs, including the Hox genes HoxA-10 and HoxA-11, and the forkhead box gene FOXO1A. While previous studies have identified downstream target genes for HoxA-10 and FOXO1A, the role of HoxA-11 in decidualization has not been investigated. Here, we show that HoxA-11 is required for prolactin expression in decidualized ESC. While HoxA-11 alone is a repressor on the decidual prolactin promoter, it turns into an activator when combined with FOXO1A. Conversely, HoxA-10, which has been previously shown to associate with FOXO1A to upregulate decidual IGFBP-1 expression, is unable to upregulate PRL expression when co-expressed with FOXO1A. By co-immunoprecipitation and chromatin immunoprecipitation, we demonstrate physical association of HoxA-11 and FOXO1A, and binding of both factors to an enhancer region (−395 to −148 relative to the PRL transcriptional start site) of the decidual prolactin promoter. Because FOXO1A is induced upon decidualization, it serves to assemble a decidual-specific transcriptional complex including HoxA-11. These data highlight cooperativity between numerous transcription factors to upregulate PRL in differentiating ESC, and suggest that this core set of transcription factors physically and functionally interact to drive the expression of a gene battery upregulated in differentiated ESC. In addition, the functional non-equivalence of HoxA-11 and HoxA-10 with respect to PRL regulation suggests that these transcription factors regulate distinct sets of target genes during decidualization

Brown Planthopper (N. lugens Stal) Feeding Behaviour on Rice Germplasm as an Indicator of Resistance

BACKGROUND: The brown planthopper (BPH) Nilaparvata lugens (Stal) is a serious pest of rice in Asia. Development of novel control strategies can be facilitated by comparison of BPH feeding behaviour on varieties exhibiting natural genetic variation, and then elucidation of the underlying mechanisms of resistance. METHODOLOGY/PRINCIPAL FINDINGS: BPH feeding behaviour was compared on 12 rice varieties over a 12 h period using the electrical penetration graph (EPG) and honeydew clocks. Seven feeding behaviours (waveforms) were identified and could be classified into two phases. The first phase involved patterns of sieve element location including non penetration (NP), pathway (N1+N2+N3), xylem (N5) [21] and two new feeding waveforms, derailed stylet mechanics (N6) and cell penetration (N7). The second feeding phase consisted of salivation into the sieve element (N4-a) and sieve element sap ingestion (N4-b). Production of honeydew drops correlated with N4-b waveform patterns providing independent confirmation of this feeding behaviour. CONCLUSIONS/SIGNIFICANCE: Overall variation in feeding behaviour was highly correlated with previously published field resistance or susceptibility of the different rice varieties: BPH produced lower numbers of honeydew drops and had a shorter period of phloem feeding on resistant rice varieties, but there was no significant difference in the time to the first salivation (N4-b). These qualitative differences in behaviour suggest that resistance is caused by differences in sustained phloem ingestion, not by phloem location. Cluster analysis of the feeding and honeydew data split the 12 rice varieties into three groups: susceptible, moderately resistant and highly resistant. The screening methods that we have described uncover novel aspects of the resistance mechanism (or mechanisms) of rice to BPH and will in combination with molecular approaches allow identification and development of new control strategies

Chemical Biology Drug Sensitivity Screen Identifies Sunitinib as Synergistic Agent with Disulfiram in Prostate Cancer Cells

Peer reviewe

The effects of lifestyle interventions on (long-term) weight management, cardiometabolic risk and depressive symptoms in people with psychotic disorders:A meta-analysis

AIMS: The aim of this study was to estimate the effects of lifestyle interventions on bodyweight and other cardiometabolic risk factors in people with psychotic disorders. Additionally, the long-term effects on body weight and the effects on depressive symptoms were examined. MATERIAL AND METHODS: We searched four databases for randomized controlled trials (RCTs) that compared lifestyle interventions to control conditions in patients with psychotic disorders. Lifestyle interventions were aimed at weight loss or weight gain prevention, and the study outcomes included bodyweight or metabolic parameters. RESULTS: The search resulted in 25 RCTs -only 4 were considered high quality- showing an overall effect of lifestyle interventions on bodyweight (effect size (ES)  =  -0.63, p<0.0001). Lifestyle interventions were effective in both weight loss (ES =  -0.52, p<0.0001) and weight-gain-prevention (ES =  -0.84, p = 0.0002). There were significant long-term effects, two to six months post-intervention, for both weight-gain-prevention interventions (ES =  -0.85, p = 0.0002) and weight loss studies (ES =  -0.46, p = 0.02). Up to ten studies reported on cardiometabolic risk factors and showed that lifestyle interventions led to significant improvements in waist circumference, triglycerides, fasting glucose and insulin. No significant effects were found for blood pressure and cholesterol levels. Four studies reported on depressive symptoms and showed a significant effect (ES =  -0.95, p = 0.05). CONCLUSION: Lifestyle interventions are effective in treating and preventing obesity, and in reducing cardiometabolic risk factors. However, the quality of the studies leaves much to be desired