Hydrogen peroxide stimulates nuclear import of the POU homeodomain protein Oct-1 and its repressive effect on the expression of Cdx-2

<p>Abstract</p> <p>Background</p> <p>The ubiquitously expressed POU homeodomain protein Oct-1 serves as a sensor for stress induced by irradiation. We found recently that in pancreatic and intestinal endocrine cells, Oct-1 also functions as a sensor for cyclic AMP (cAMP). The caudal homeobox gene Cdx-2 is a transactivator of proglucagon (gcg) and pro-insulin genes. Oct-1 binds to Cdx-2 promoter and represses its expression. cAMP elevation leads to increased nuclear exclusion of Oct-1, associated with reduced recruitment of nuclear co-repressors to the Cdx-2 promoter and increased Cdx-2 expression.</p> <p>Results</p> <p>We show in this study that inducing oxidative stress by hydrogen peroxide (H₂O₂) increased nuclear Oct-1 content in both pancreatic α and β cell lines, as well as in a battery of other cells. This increase was then attributed to accelerated nuclear import of Oct-1, assessed by Fluorescence Recovery After Photobleaching (FRAP) using green fluorescence protein (EGFP) tagged Oct-1 molecule. H₂O₂treatment was then shown to stimulate the activities of DNA-dependent protein kinase (DNA-PK) and c-jun N-terminal kinase (JNK). Finally, increased Oct-1 nuclear content upon H₂O₂treatment in a pancreatic α cell line was associated with reduced Cdx-2 and gcg mRNA expression.</p> <p>Conclusion</p> <p>These observations suggest that Oct-1 functions as a sensor for both metabolic and stress/survival signaling pathways via altering its nuclear-cytoplasmic shuttling.</p

An sTGC Prototype Readout System for ATLAS New-Small-Wheel Upgrade

This paper presents a readout system designed for testing the prototype of Small-Strip Thin Gap Chamber (sTGC), which is one of the main detector technologies used for ATLAS New-Small-Wheel Upgrade. This readout system aims at testing one full-size sTGC quadruplet with cosmic muon triggers

Scanning Test System Prototype of p/sFEB for the ATLAS Phase-I sTGC Trigger Upgrade

The Pad Front End Board (pFEB) and the Strip Front End Board (sFEB) are developed for the ATLAS Phase-I sTGC Trigger Upgrade. The pFEB is used to to gather and analyze pads trigger, and the sFEB is developed to accept the pad trigger to define the regions-of-interest for strips readout. The performance of p/sFEBs must be confirmed before they are mounted on the sTGC detector. We will present the scanning test system prototype which is designed according to the test requirements of the p/sFEB. In this test system prototype, a simulation signal board is developed to generate different types of signal to the p/sFEB. PC software and FPGA XADC cooperate to achieve the scan test of analog parameter

Curcumin Prevents High Fat Diet Induced Insulin Resistance and Obesity via Attenuating Lipogenesis in Liver and Inflammatory Pathway in Adipocytes

Background: Mechanisms underlying the attenuation of body weight gain and insulin resistance in response to high fat diet (HFD) by the curry compound curcumin need to be further explored. Although the attenuation of the inflammatory pathway is an accepted mechanism, a recent study suggested that curcumin stimulates Wnt signaling pathway and hence suppresses adipogenic differentiation. This is in contrast with the known repressive effect of curcumin on Wnt signaling in other cell lineages. Methodology and Principal Findings: We conducted the examination on low fat diet, or HFD fed C57BL/6J mice with or without curcumin intervention for 28 weeks. Curcumin significantly attenuated the effect of HFD on glucose disposal, body weight/fat gain, as well as the development of insulin resistance. No stimulatory effect on Wnt activation was observed in the mature fat tissue. In addition, curcumin did not stimulate Wnt signaling in vitro in primary rat adipocytes. Furthermore, curcumin inhibited lipogenic gene expression in the liver and blocked the effects of HFD on macrophage infiltration and the inflammatory pathway in the adipose tissue. Conclusions and Significance: We conclude that the beneficial effect of curcumin during HFD consumption is mediated by attenuating lipogenic gene expression in the liver and the inflammatory response in the adipose tissue, in the absence o

Current understanding and dispute on the function of the Wnt signaling pathway effector TCF7L2 in hepatic gluconeogenesis

AbstractApproximately 10 years ago, the Wnt signaling pathway effector TCF7L2 (=TCF-4) was recognized as a type 2 diabetes (T2D) risk gene through a genome wide association study (GWAS). As the correlation between TCF7L2 polymorphisms and T2D susceptibility has been reproducibly observed by numerous follow-up investigations among different ethnic groups, great efforts have been made to explore the function of TCF7L2 in metabolic organs including the pancreas, liver and adipose tissues. Although these explorations have enriched our general knowledge on the Wnt signaling cascade in metabolic homeostasis, studies conducted to date have also generated controversial suggestions. Here I will provide a brief review on the Wnt signaling pathway as well as the milestone GWAS discovery and the follow-up studies. I will then discuss the two different opinions on the correlation between TCF7L2 variants and T2D risk, a gain-of-function event versus a loss-of-function event. This will be followed by summarizing the relevant investigations on the metabolic function of hepatic TCF7L2 and presenting our view on the discrepancy and perspectives

Combined Oral Administration of GABA and DPP-4 Inhibitor Prevents Beta Cell Damage and Promotes Beta Cell Regeneration in Mice

γ-aminobutyric acid (GABA) or glucagon-like peptide-1 based drugs, such as sitagliptin (a dipeptidyl peptidase-4 inhibitor), were shown to induce beta cell regenerative effects in various diabetic mouse models. We propose that their combined administration can bring forth an additive therapeutic effect. We tested this hypothesis in a multiple low-dose streptozotocin (STZ)-induced beta cell injury mouse model (MDSD). Male C57BL/6J mice were assigned randomly into four groups: non-treatment diabetic control, GABA, sitagliptin, or GABA plus sitagliptin. Oral drug administration was initiated 1 week before STZ injection and maintained for 6 weeks. GABA or sitagliptin administration decreased ambient blood glucose levels and improved the glucose excursion rate. This was associated with elevated plasma insulin and reduced plasma glucagon levels. Importantly, combined use of GABA and sitagliptin significantly enhanced these effects as compared with each of the monotherapies. An additive effect on reducing water consumption was also observed. Immunohistochemical analyses revealed that combined GABA and sitagliptin therapy was superior in increasing beta cell mass, associated with increased small-size islet numbers, Ki67+ and PDX-1+ beta cell counts; and reduced Tunel+ beta cell counts. Thus, beta cell proliferation was increased, whereas apoptosis was reduced. We also noticed a suppressive effect of GABA or sitagliptin on alpha cell mass, which was not significantly altered by combining the two agents. Although either GABA or sitagliptin administration delays the onset of MDSD, our study indicates that combined use of them produces superior therapeutic outcomes. This is likely due to an amelioration of beta cell proliferation and a decrease of beta cell apoptosis

The involvement of the wnt signaling pathway and TCF7L2 in diabetes mellitus: The current understanding, dispute, and perspective

Abstract The Wnt signaling pathway was initially discovered for its role in tumorigenesis and the development of Drosophila and other eukaryotic organisms. The key effector of this pathway, the bipartite transcription factor β-cat/TCF, is formed by free β-catenin (β-cat) and a TCF protein, including TCF7L2. Extensive recent investigations have highlighted the role of the Wnt signaling pathway in metabolic homeostasis and its implication in diabetes and other metabolic diseases. Genome-wide association studies have shown that several key components of the Wnt signaling pathway are implicated in metabolic homeostasis and the development of type 2 diabetes (T2D). Despite controversial observations regarding the role of Wnt signaling in the development and function of pancreatic islets, the discovery of the association between certain single nucleotide polymorphisms of TCF7L2 and T2D susceptibility has fueled great efforts to explore the role of Wnt signaling in the function of pancreatic β-cells and glucose homeostasis. Here we have introduced our basic understanding of the canonical Wnt signaling pathway, summarized our current knowledge on its implication in metabolic homeostasis and T2D, discussed the work on TCF7L2 as a T2D susceptibility gene, and presented the controversial role of Wnt signaling and TCF7L2 in pancreatic islets as well as their potential metabolic function in other organs. We then expanded our view into the crosstalk among Wnt, insulin and FOXO signaling cascades, which further illustrates the complexity of the Wnt signaling pathway in metabolic homeostasis. Finally, we have presented our perspectives

Short‐term semaglutide treatment improves FGF21 responsiveness in primary hepatocytes isolated from high fat diet challenged mice

Abstract Metabolic functions of GLP‐1 and its analogues have been extensively investigated. In addition to acting as an incretin and reducing body weight, we and others have suggested the existence of GLP‐1/fibroblast growth factor 21 (FGF21) axis in which liver mediates certain functions of GLP‐1 receptor agonists. In a more recent study, we found with surprise that four‐week treatment with liraglutide but not semaglutide stimulated hepatic FGF21 expression in HFD‐challenged mice. We wondered whether semaglutide can also improve FGF21 sensitivity or responsiveness and hence triggers the feedback loop in attenuating its stimulation on hepatic FGF21 expression after a long‐term treatment. Here, we assessed effect of daily semaglutide treatment in HFD‐fed mice for 7 days. HFD challenge attenuated effect of FGF21 treatment on its downstream events in mouse primary hepatocytes, which can be restored by 7‐day semaglutide treatment. In mouse liver, 7‐day semaglutide treatment stimulated FGF21 as well as genes that encode its receptor (FGFR1) and the obligatory co‐receptor (KLB), and a battery of genes that are involved in lipid homeostasis. In epididymal fat tissue, expressions of a battery genes including Klb affected by HFD challenge were reversed by 7‐day semaglutide treatment. We suggest that semaglutide treatment improves FGF21 sensitivity which is attenuated by HFD challenge

An evaluation of the accuracy of toric intraocular lens power calculation based on measured total corneal refractive power

Purpose: To evaluate a method using measured values of total corneal refractive power (TCRP) for a manufacturer's online calculator by comparing it with the Barrett toric calculator (BTC) and Kane toric calculator (KTC) combined with simulated keratometry values (SimK). Methods: This was a retrospective case series. Patient records were reviewed to identify the patients who had biometry with the IOL Master 700 and Pentacam recorded before toric IOL implantation and refractive follow-up data after implantation. The predicted error in residual astigmatism was calculated by vector analysis according to the calculation methods and the measurements used. Results: A total of 70 eyes of 56 patients were included. The mean absolute astigmatism prediction errors were 0.6 ± 0.32, 0.59 ± 0.35, and 0.61 ± 0.35 D for the ATCTCRP, BTCSimK, and KTCSimK calculators, respectively (P = 0.934), and the centroid of the prediction errors were 0.3 D @ 178°, 0.11 D @ 102°, and 0.09 D @ 147°, respectively (P = 0.23). In the with-the-rule subgroup, the centroid of the prediction error was 0.34 D @ 176° for ATCTCRP and was the highest among the three calculation methods (P = 0.046). Conclusion: The ATCTCRP, BTCSimK, and KTCSimK calculators had similar performance with regards to their astigmatism prediction accuracy. The ATCTCRP calculator combined with 4.0-mm apex/ring readings of TCRP was slightly intended to result in against-the-rule residual astigmatism