Clinical Perspectives of Urocortin and Related Agents for the Treatment of Cardiovascular Disease

The effects of corticotropin-releasing hormone, also known as corticotropin-releasing factor (CRF), on the cardiovascular system have been intensively researched since its discovery. Moreover, the actions of urocortin (Ucn) I on the cardiovascular system have also been intensively scrutinized following the cloning and identification of its receptor, CRF receptor type 2 (CRFR2), in peripheral tissues including the heart. Given the cardioprotective actions of CRFR2 ligands, the clinical potential of not only Ucn I but also Ucn II and III, which were later identified as more specific ligands for CRFR2, has received considerable attention from researchers. In addition, recent work has indicated that CRF type 1 receptor may be also involved in cardioprotection against ischemic/reperfusion injury. Here we provide a historical overview of research on Ucn I and related agents, their effects on the cardiovascular system, and the clinical potential of the use of such agents to treat cardiovascular diseases

Combination of Real-Value Smell and Metaphor Expression Aids Yeast Detection

Background: Smell provides important information about the quality of food and drink. Most well-known for their expertise in wine tasting, sommeliers sniff out the aroma of wine and describe them using beautiful metaphors. In contrast, electronic noses, devices that mimic our olfactory recognition system, also detect smells using their sensors but describe them using electronic signals. These devices have been used to judge the freshness of food or detect the presence of pathogenic microorganisms. However, unlike information from gas chromatography, it is difficult to compare odour information collected by these devices because they are made for smelling specific smells and their data are relative intensities. Methodology: Here, we demonstrate the use of an absolute-value description method using known smell metaphors, and early detection of yeast using the method. Conclusions: This technique may help distinguishing microbial-contamination of food products earlier, or improvement o

Detection of Thyroid Carcinoma Antigen with Quantum Dots and Monoclonal IgM Antibody (JT-95) System

High-intensity fluorescent nanoparticles, quantum dots (QDs), have been applied to a wide range of biological studies and medical studies by taking advantage of their fluorescent properties. On the other hand, we have reported the specificity of JT-95 monoclonal IgM antibody, which recognizes the antigen of thyroid carcinomas. Here we show that the combination of QDs and JT-95 monoclonal antibody was applicable to Western blotting analysis, ELISA-like system, and fluorescent microscopic analysis of SW1736 thyroid carcinoma cell line. We have opened up the possibility that antibodies for higher specific recognition, even IgM, are applicable to the detection system with QDs

Amino Acid Synthesis in a Supercritical Carbon Dioxide - Water System

Mars is a CO2-abundant planet, whereas early Earth is thought to be also CO2-abundant. In addition, water was also discovered on Mars in 2008. From the facts and theory, we assumed that soda fountains were present on both planets, and this affected amino acid synthesis. Here, using a supercritical CO2/liquid H2O (10:1) system which mimicked crust soda fountains, we demonstrate production of amino acids from hydroxylamine (nitrogen source) and keto acids (oxylic acid sources). In this research, several amino acids were detected with an amino acid analyzer. Moreover, alanine polymers were detected with LC-MS. Our research lights up a new pathway in the study of life’s origin

Tetrahydrouridine Inhibits Cell Proliferation through Cell Cycle Regulation Regardless of Cytidine Deaminase Expression Levels

Tetrahydrouridine (THU) is a well characterized and potent inhibitor of cytidine deaminase (CDA). Highly expressed CDA catalyzes and inactivates cytidine analogues, ultimately contributing to increased gemcitabine resistance. Therefore, a combination therapy of THU and gemcitabine is considered to be a potential and promising treatment for tumors with highly expressed CDA. In this study, we found that THU has an alternative mechanism for inhibiting cell growth which is independent of CDA expression. Three different carcinoma cell lines (MIAPaCa-2, H441, and H1299) exhibited decreased cell proliferation after sole administration of THU, while being unaffected by knocking down CDA. To investigate the mechanism of THU-induced cell growth inhibition, cell cycle analysis using flow cytometry was performed. This analysis revealed that THU caused an increased rate of G1-phase occurrence while S-phase occurrence was diminished. Similarly, Ki-67 staining further supported that THU reduces cell proliferation. We also found that THU regulates cell cycle progression at the G1/S checkpoint by suppressing E2F1. As a result, a combination regimen of THU and gemcitabine might be a more effective therapy than previously believed for pancreatic carcinoma since THU works as a CDA inhibitor, as well as an inhibitor of cell growth in some types of pancreatic carcinoma cells

Non-canonical NFKB signaling endows suppressive function through FOXP3-dependent regulatory T cell program

Regulatory T cells (Tregs) play a central role in modulating adaptive immune responses in humans and mice. The precise biological role of non-canonical nuclear factor ‘κ-light-chain-enhancer’ of activated B cells (NFKB) signaling in human Tregs has yet to be fully elucidated. To gain insight into this process, a Treg-like cell line (MT-2) was genetically modified using CRISPR/Cas9. Interestingly, NFKB2 knockout MT-2 cells exhibited downregulation of FOXP3, while NFKB1 knockout did not. Additionally, mRNA expression of FOXP3-dependent molecules was significantly reduced in NFKB2 knockout MT-2 cells. To better understand the functional role of the NFKB signaling, the NFKB1/NFKB2 loci of human primary Tregs were genetically edited using CRISPR/Cas9. Similar to MT-2 cells, NFKB2 knockout human Tregs displayed significantly reduced FOXP3 expression. Furthermore, NFKB2 knockout human Tregs showed downregulation of FOXP3-dependent molecules and a diminished suppressive function compared to wild-type and NFKB1 knockout Tregs. These findings indicate that non-canonical NFKB signaling maintains a Treg-like phenotype and suppressive function in human Tregs through the FOXP3-dependent regulatory T cell program

Enhancement of Chemosensitivity to Fluoropyrimidines by Retroviral Transduction of Thymidine Phosphorylase cDNA: an in vitro and in vivo Study

Thymidine phospholyrase (TP) is an essential enzyme in activating 5’-deoxy-5-fluorocytidine (5’- DFUR) into 5-fluorouracil (5-FU) and for the conversion of 5-FU into 5-fluoro-2’-deoxyuridine. The purpose of this study was to examine the therapeutic efficacy of the retroviral vector-mediated TP gene in the sensitivity to fluoropyrimidines, 5-FU and its prodrugs, 5’-DFUR and capecitabine, in MC38 murine colon adenocarcinoma cells in vitro and in vivo. After retroviral infection with or without human TP cDNA, we obtained MC38 cells having the stable expression of TP (MC38-TP) and control-vector transfected cells (MC38-Neo). There was no significant difference in the doubling time in vitro and tumor growth rate in vivo among parental MC38 cells (MC38-P), MC38- Neo and MC38-TP, demonstrating that the TP gene was not directly toxic. The in vitro study showed significant increases in sensitivities to 5-FU, 5’-DFUR and capecitabine in MC38-TP cells. The 50% growth inhibitory concentration (IC50) of MC38-TP cells to 5-FU, 5’-DFUR and capecitabine, respectively, was about 10-fold, 800-fold and 40-fold higher than that of MC38-P cells and MC38-Neo cells. The in vivo study showed significant increases in sensitivities to 5-FU, 5’- DFUR and capecitabine in MC38-TP tumors. There was no significant difference in the sensitivities to 5-FU, 5’-DFUR and capecitabine between MC38 and MC38-Neo tumors. The tumor-cure rate in MC38-TP tumors treated with capecitabine was 100% and that treated with 5’-DFUR was 63%. In conclusion, our results demonstrate that the stable expression of TP gene by using recombinant retroviral vector could dramatically increase the anticancer effect of fluoropyrimidines

Improving the Performance of an Electronic Nose by Wine Aroma Training to Distinguish between Drip Coffee and Canned Coffee

Coffee aroma, with more than 600 components, is considered as one of the most complex food aromas. Although electronic noses have been successfully used for objective analysis and differentiation of total coffee aromas, it is difficult to use them to describe the specific features of coffee aroma (i.e., the type of smell). This is because data obtained by electronic noses are generally based on electrical resistance/current and samples are distinguished by principal component analysis. In this paper, we present an electronic nose that is capable of learning the wine related aromas using the aroma kit “Le Nez du Vin,” and the potential to describe coffee aroma in a similar manner comparable to how wine experts describe wine aroma. The results of our investigation showed that the aromas of three drip coffees were more similar to those of pine and honey in the aroma kit than to the aromas of three canned coffees. Conversely, the aromas of canned coffees were more similar to the kit coffee aroma. In addition, the aromatic patterns of coffees were different from those of green tea and red wine. Although further study is required to fit the data to human olfaction, the presented method and the use of vocabularies in aroma kits promise to enhance objective discrimination and description of aromas by electronic noses

Suppression of Aldosterone Synthesis and Secretion by Channel Antagonists

Aldosterone, a specific mineralocorticoid receptor (MR) agonist and a key player in the development of hypertension, is synthesized as a final product of renin-angiotensin-aldosterone system. Hypertension can be generally treated by negating the effects of angiotensin II through the use of angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin II type 1 receptor antagonists (ARBs). However, the efficacy of angiotensin II blockade by such drugs is sometimes diminished by the so-called “aldosterone breakthrough” effect, by which ACE-Is or ARBs (renin-angiotensin system (RAS) inhibitors) gradually lose their effectiveness against hypertension due to the overproduction of aldosterone, known as primary aldosteronism. Although MR antagonists are used to antagonize the effects of aldosterone, these drugs may, however, give rise to life-threatening adverse actions, such as hyperkalemia, particularly when used in conjunction with RAS inhibitors. Recently, several groups have reported that some dihydropyridine Ca2+ channel blockers (CCBs) have inhibitory actions on aldosterone production in in vitro and in the clinical setting. Therefore, the use of such dihydropyridine CCBs to treat aldosterone-related hypertension may prove beneficial to circumvent such therapeutic problems. In this paper, we discuss the mechanism of action of CCBs on aldosterone production and clinical perspectives for CCB use to inhibit MR activity in hypertensive patients