Regulatory Mechanism of Skeletal Muscle Glucose Transport by Phenolic Acids

Type 2 diabetes mellitus (T2DM) is one of the most severe public health problems in the world. In recent years, evidences show a commonness of utilization of alternative medicines such as phytomedicine for the treatment of T2DM. Phenolic acids are the most common compounds in non-flavonoid group of phenolic compounds and have been suggested to have a potential to lower the risk of T2DM. Skeletal muscle is the major organ that contributes to the pathophysiology of T2DM. Studies have shown that several phenolic acids (caffeic acid, chlorogenic acid, gallic acid, salicylic acid, p-coumaric acid, ferulic acid, sinapic acid) have antidiabetic effects, and these compounds have been implicated in the regulation of skeletal muscle glucose metabolism, especially glucose transport. Glucose transport is a major regulatory step for whole-body glucose disposal, and the glucose transport processes are regulated mainly through two different systems: insulin-dependent and insulin-independent mechanism. In this chapter, we reviewed recent experimental evidences linking phenolic acids to glucose metabolism focusing on insulin-dependent and insulin-independent glucose transport systems and the upstream signaling events in skeletal muscle

Autocrine/paracrine role of adrenomedullin in cultured endothelial and mesangial cells

Autocrine/paracrine role of adrenomedullin in cultured endothelial and mesangial cells. Adrenomedullin (AM), a potent vasorelaxant and natriuretic peptide isolated from human pheochromocytoma, is present in the kidney and secreted from endothelial cells (EC) and vascular smooth muscle cells (VSMC), but the functional role of AM is still unclear. To clarify the significance of AM as a local regulator, we investigated its secretion and action in cultured cells, and examined the effects of neutralization using a specific monoclonal antibody against AM. The prepared antibody directed against the ring structure showed a high affinity for human and rat AM. Using radioimmunoassay with this antibody, we found significant secretion from cultured rat mesangial cells (MC) of a 6-kDa mature form of AM as seen from EC and VSMC. The addition of AM into cultured cells dose-dependently increased cAMP production and potently inhibited PDGF-stimulated thymidine incorporation. Pretreatment with the monoclonal antibody completely abolished cAMP increase induced by exogenous AM. Moreover, antibody neutralization of endogenously secreted AM in cultured EC, but not in MC or VSMC, markedly (by ∼70%) reduced basal cAMP production and significantly (1.7-fold) enhanced DNA synthesis. These results indicate that AM, acting as an autocrine/paracrine regulator, exerts an antiproliferative action on EC and MC, and suggest its role as a local modulator of endothelial and mesangial function

Autocrine/paracrine role of adrenomedullin in cultured endothelial and mesangial cells

Autocrine/paracrine role of adrenomedullin in cultured endothelial and mesangial cells. Adrenomedullin (AM), a potent vasorelaxant and natriuretic peptide isolated from human pheochromocytoma, is present in the kidney and secreted from endothelial cells (EC) and vascular smooth muscle cells (VSMC), but the functional role of AM is still unclear. To clarify the significance of AM as a local regulator, we investigated its secretion and action in cultured cells, and examined the effects of neutralization using a specific monoclonal antibody against AM. The prepared antibody directed against the ring structure showed a high affinity for human and rat AM. Using radioimmunoassay with this antibody, we found significant secretion from cultured rat mesangial cells (MC) of a 6-kDa mature form of AM as seen from EC and VSMC. The addition of AM into cultured cells dose-dependently increased cAMP production and potently inhibited PDGF-stimulated thymidine incorporation. Pretreatment with the monoclonal antibody completely abolished cAMP increase induced by exogenous AM. Moreover, antibody neutralization of endogenously secreted AM in cultured EC, but not in MC or VSMC, markedly (by ∼70%) reduced basal cAMP production and significantly (1.7-fold) enhanced DNA synthesis. These results indicate that AM, acting as an autocrine/paracrine regulator, exerts an antiproliferative action on EC and MC, and suggest its role as a local modulator of endothelial and mesangial function

SILVERRUSH. III. Deep Optical and Near-Infrared Spectroscopy for Lya and UV-Nebular Lines of Bright Lya Emitters at z=6-7

We present Lya and UV-nebular emission line properties of bright Lya emitters (LAEs) at z=6-7 with a luminosity of log L_Lya/[erg s-1] = 43-44 identified in the 21-deg2 area of the SILVERRUSH early sample developed with the Subaru Hyper Suprime-Cam (HSC) survey data. Our optical spectroscopy newly confirm 21 bright LAEs with clear Lya emission, and contribute to make a spectroscopic sample of 96 LAEs at z=6-7 in SILVERRUSH. From the spectroscopic sample, we select 7 remarkable LAEs as bright as Himiko and CR7 objects, and perform deep Keck/MOSFIRE and Subaru/nuMOIRCS near-infrared spectroscopy reaching the 3sigma-flux limit of ~ 2x10^{-18} erg s-1 for the UV-nebular emission lines of He II1640, C IV1548,1550, and O III]1661,1666. Except for one tentative detection of C IV, we find no strong UV-nebular lines down to the flux limit, placing the upper limits of the rest-frame equivalent widths (EW_0) of ~2-4 A for He II, C IV, and O III] lines. Here we also investigate the VLT/X-SHOOTER spectrum of CR7 whose 6 sigma detection of He II is claimed by Sobral et al. Although two individuals and the ESO-archive service carefully re-analyze the X-SHOOTER data that are used in the study of Sobral et al., no He II signal of CR7 is detected, supportive of weak UV-nebular lines of the bright LAEs even for CR7. Spectral properties of these bright LAEs are thus clearly different from those of faint dropouts at z~7 that have strong UV-nebular lines shown in the various studies. Comparing these bright LAEs and the faint dropouts, we find anti-correlations between the UV-nebular line EW_0 and UV-continuum luminosity, which are similar to those found at z~2-3.Comment: 26 pages, 12 figures. Accepted for publication in PASJ special issu

Transcriptional Regulation of an Evolutionary Conserved Intergenic Region of CDT2-INTS7

In the mammalian genome, a substantial number of gene pairs (approximately 10%) are arranged head-to-head on opposite strands within 1,000 base pairs, and separated by a bidirectional promoter(s) that generally drives the co-expression of both genes and results in functional coupling. The significance of unique genomic configuration remains elusive.Here we report on the identification of an intergenic region of non-homologous genes, CDT2, a regulator of DNA replication, and an integrator complex subunit 7 (INTS7), an interactor of the largest subunit of RNA polymerase II. The CDT2-INTS7 intergenic region is 246 and 245 base pairs long in human and mouse respectively and is evolutionary well-conserved among several mammalian species. By measuring the luciferase activity in A549 cells, the intergenic human sequence was shown to be able to drive the reporter gene expression in either direction and notably, among transcription factors E2F, E2F1 approximately E2F4, but not E2F5 and E2F6, this sequence clearly up-regulated the reporter gene expression exclusively in the direction of the CDT2 gene. In contrast, B-Myb, c-Myb, and p53 down-regulated the reporter gene expression in the transcriptional direction of the INTS7 gene. Overexpression of E2F1 by adenoviral-mediated gene transfer resulted in an increased CDT2, but not INTS7, mRNA level. Real-time polymerase transcription (RT-PCR) analyses of the expression pattern for CDT2 and INTS7 mRNA in human adult and fetal tissues and cell lines revealed that transcription of these two genes are asymmetrically regulated. Moreover, the abundance of mRNA between mouse and rat tissues was similar, but these patterns were quite different from the results obtained from human tissues.These findings add a unique example and help to understand the mechanistic insights into the regulation of gene expression through an evolutionary conserved intergenic region of the mammalian genome