High glucose-induced apoptosis in human coronary artery endothelial cells involves up-regulation of death receptors

<p>Abstract</p> <p>Background</p> <p>High glucose can induce apoptosis in vascular endothelial cells, which may contribute to the development of vascular complications in diabetes. We evaluated the role of the death receptor pathway of apoptotic signaling in high glucose-induced apoptosis in human coronary artery endothelial cells (HCAECs).</p> <p>Methods</p> <p>HCAECs were treated with media containing 5.6, 11.1, and 16.7 mM of glucose for 24 h in the presence or absence of tumor necrosis factor (TNF)-α. For detection of apoptosis, DNA fragmentation assay was used. HCAEC expression of death receptors were analyzed by the PCR and flow cytometry methods. Also, using immunohistochemical techniques, coronary expression of death receptors was assessed in streptozotocin-nicotinamide-induced type 2 diabetic mice.</p> <p>Results</p> <p>Exposure of HCAECs to high glucose resulted in a significant increase in TNF-R1 and Fas expression, compared with normal glucose. High glucose increased TNF-α production by HCAECs and exogenous TNF-α up-regulated TNF-R1 and Fas expression in HCAECs. High glucose-induced up-regulation of TNF-R1 and Fas expression was undetectable in the presence of TNF-α. Treatment with TNF-R1 neutralizing peptides significantly inhibited high glucose-induced endothelial cell apoptosis. Type 2 diabetic mice displayed appreciable expression of TNF-R1 and Fas in coronary vessels.</p> <p>Conclusions</p> <p>In association with increased TNF-α levels, the death receptors, TNF-R1 and Fas, are up-regulated in HCAECs under high glucose conditions, which could in turn play a role in high glucose-induced endothelial cell apoptosis.</p

Distinct Effects of Ketone Bodies on Down-Regulation of Cell Surface Insulin Receptor and Insulin Receptor Substrate-1 Phosphorylation in Adrenal Chromaffin Cells

ABSTRACT Treatment (м24 h) of cultured bovine adrenal chromaffin cells with ketoacidosis-related concentrations (м3 mM) of acetoacetate (but not ␤-hydroxybutyrate, acetone, and acidic medium) caused a time-and concentration-dependent reduction of cell surface 125 I-insulin binding by ϳ38%, with no change in the K d value. The reduction of 125 I-insulin binding returned to control nontreated level at 24 h after the washout of acetoacetate-treated cells. Acetoacetate did not increase the internalization rate of cell surface insulin receptor (IR), as measured in the presence of brefeldin A, an inhibitor of cell surface vesicular exit from the trans-Golgi network. Acetoacetate (10 mM for 24 h) lowered cellular levels of the immunoreactive IR precursor molecule (ϳ190 kDa) and IR by 22 and 28%, respectively. Acetoacetate decreased IR mRNA levels by ϳ23% as early as 6 h, producing their maximum plateau reduction at 12 and 24 h. The half-life of IR mRNA was shortened by acetoacetate from 13.6 to 9.5 h. Immunoprecipitation followed by immunoblot analysis revealed that insulin-induced (100 nM for 10 min) tyrosine-phosphorylation of insulin receptor substrate-1 (IRS-1) was attenuated by 56% in acetoacetate-treated cells, with no change in IRS-1 level. These results suggest that chronic treatment with acetoacetate selectively down-regulated the density of cell surface functional IR via lowering IR mRNA levels and IR synthesis, thereby retarding insulin-induced activation of IRS-1

Quantum critical behavior of the hyperkagome magnet Mn3CoSi

β-Mn-type family alloys Mn3TX (T = Co, Rh, and Ir; X = Si and Ge) have a three-dimensional antiferromagnetic (AF) corner-shared triangular network, i.e., the hyperkagome lattice. The antiferromagnet Mn3RhSi shows magnetic short-range order over a wide temperature range of approximately 500 K above the Néel temperature TN of 190 K. In this family of compounds, as the lattice parameter decreases, the long-range magnetic ordering temperature decreases. Mn3CoSi has the smallest lattice parameter and the lowest TN in the family. The quantum critical point (QCP) from AF to the quantum paramagnetic state is expected near a cubic lattice parameter of 6.15 Å. Although the Néel temperature of Mn3CoSi is only 140 K, the emergence of the quantum critical behavior in Mn3CoSi is discussed. We study how the magnetic short-range order appears in Mn3CoSi by using neutron scattering, μSR, and bulk characterization such as specific heat capacity. According to the results, the neutron scattering intensity of the magnetic short-range order in Mn3CoSi does not change much at low temperatures from that of Mn3RhSi, although the μSR short-range order temperature of Mn3CoSi is largely suppressed to 240 K from that of Mn3RhSi. Correspondingly, the volume fraction of the magnetic short-range order regions, as shown by the initial asymmetry drop ratio of μSR above TN, also becomes small. Instead, the electronic-specific heat coefficient γ of Mn3CoSi is the largest in this Mn3T Si system, possibly due to the low-energy spin fluctuation near the quantum critical point

The effects of the photoperiod-insensitive alleles, se13, hd1 and ghd7, on yield components in rice.

Flowering time is closely associated with grain yield in rice (Oryza sativa L.). In temperate regions, seasonal changes in day length (known as the photoperiod) are an important environmental cue for floral initiation. The timing of flowering is important not only for successful reproduction, but also for determining the ideal balance between vegetative growth and reproductive growth duration. Recent molecular genetics studies have revealed key flowering time genes responsible for photoperiod sensitivity. In this study, we investigated the effect of three recessive photoperiod-insensitive alleles, se13, hd1 and ghd7, on yield components in rice under Ehd1-deficient genetic background conditions to ensure vegetative growth of each line. We found that se13-bearing plants had fewer panicles, hd1-bearing plants showed decreased grain-filling percentage, and ghd7-bearing plants appeared to have fewer grains per panicle and fewer secondary branches. Our results indicate that the pleiotropic effects of photoperiod-insensitive genes on yield components are independent of short vegetative growth. This will provide critical information which can be used to create photoperiod-insensitive varieties that can be adapted to a wide range of latitudes

Neurodegenerative evidence in mice brains with cecal ligation and puncture-induced sepsis: preventive effect of the free radical scavenger edaravone.

Sepsis is a major clinical challenge and septic encephalopathy is its nasty complication. The pathogenesis and underlying mechanisms of septic encephalopathy are not well understood. This study sought to fully characterize sepsis-associated biochemical and histopathological changes in brains of mice after cecal ligation and puncture, regarded as a highly clinically relevant animal model of polymicrobial sepsis. Real-time PCR analysis showed that gene expression levels of proinflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, were significantly up-regulated in brain tissues from septic mice, but to a much lesser extent when compared with those in peripheral tissues such as lungs. Blood-brain barrier (BBB) permeability was significantly increased in septic mice, as determined by the measurement of sodium fluorescein and Evans blue content. Sepsis resulted in increases in NADPH oxidase activity and expression of p47(phox) and p67(phox) and up-regulation of inducible nitric oxide (NO) synthase in brains, indicating that superoxide, produced by NADPH oxidase, reacts with NO to form peroxynitrite, that maybe lead to the loss of BBB integrity. Light and electron microscopic examination of septic mouse brain showed serious neuronal degeneration, as indicated by hyperchromatic, shrunken, pyknotic, and electron-dense neurons. These histopathological changes were prevented by treatment with the free radical scavenger edaravone. Together, these results suggest that sepsis can lead to rapid neurodegenerative changes in brains via free radical species production and possibly subsequent injury to the BBB. We may also provide a potentially useful therapeutic tool for treating septic encephalopathy

Beneficial Effects of Combined Use of Extracorporeal Membrane Oxygenation and Hypothermic Machine Perfusion in Porcine Donors after Cardiac Death for Liver Transplantation

Grafts from donors after cardiac death (DCD) have greatly contributed to expanding the donor organ pool. This study aimed to determine the benefits of subnormothermic extracorporeal membrane oxygenation (ECMO) and hypothermic machine perfusion (HMP) in a porcine model of DCD liver. Female domestic crossbred Large Yorkshire and Landrace pigs weighing approximately 20 kg were used. The abdominal aorta and inferior vena cava were cannulated and connected to an ECMO circuit for in situ perfusion of the abdominal organs at 22 °C for 60 min, 45 min after cardiac death. The pigs were divided into the cold storage (CS) group (n = 3), where liver grafts were preserved at 4 °C, and the HMP group (n = 3), where liver grafts were preserved by HMP at 8–10 °C. After 4 h of preservation, liver function was evaluated using an isolated liver reperfusion model for 2 h. Although the difference was insignificant, the liver effluent enzyme levels in the HMP group were lower than those in the CS group. Furthermore, morphological findings showed fewer injured hepatocytes in the HMP group than in the CS group. The combined use of in situ subnormothermic ECMO and HMP was beneficial for the functional improvement of DCD liver grafts

The effects of phytochrome-mediated light signals on the developmental acquisition of photoperiod sensitivity in rice.

Plants commonly rely on photoperiodism to control flowering time. Rice development before floral initiation is divided into two successive phases: the basic vegetative growth phase (BVP, photoperiod-insensitive phase) and the photoperiod-sensitive phase (PSP). The mechanism responsible for the transition of rice plants into their photoperiod-sensitive state remains elusive. Here, we show that se13, a mutation detected in the extremely early flowering mutant X61 is a nonsense mutant gene of OsHY2, which encodes phytochromobilin (PΦB) synthase, as evidenced by spectrometric and photomorphogenic analyses. We demonstrated that some flowering time and circadian clock genes harbor different expression profiles in BVP as opposed to PSP, and that this phenomenon is chiefly caused by different phytochrome-mediated light signal requirements: in BVP, phytochrome-mediated light signals directly suppress Ehd2, while in PSP, phytochrome-mediated light signals activate Hd1 and Ghd7 expression through the circadian clock genes' expression. These findings indicate that light receptivity through the phytochromes is different between two distinct developmental phases corresponding to the BVP and PSP in the rice flowering process. Our results suggest that these differences might be involved in the acquisition of photoperiod sensitivity in rice