Anti-Allergic Cromones Inhibit Histamine and Eicosanoid Release from Activated Human and Murine Mast Cells by Releasing Annexin A1

PMCID: PMC3601088This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Heme oxygenase-1 regulates cell proliferation via carbon monoxide-mediated inhibition of T-type Ca2+ channels

Induction of the antioxidant enzyme heme oxygenase-1 (HO-1) affords cellular protection and suppresses proliferation of vascular smooth muscle cells (VSMCs) associated with a variety of pathological cardiovascular conditions including myocardial infarction and vascular injury. However, the underlying mechanisms are not fully understood. Over-expression of Cav3.2 T-type Ca2+ channels in HEK293 cells raised basal [Ca2+]i and increased proliferation as compared with non-transfected cells. Proliferation and [Ca2+]i levels were reduced to levels seen in non-transfected cells either by induction of HO-1 or exposure of cells to the HO-1 product, carbon monoxide (CO) (applied as the CO releasing molecule, CORM-3). In the aortic VSMC line A7r5, proliferation was also inhibited by induction of HO-1 or by exposure of cells to CO, and patch-clamp recordings indicated that CO inhibited T-type (as well as L-type) Ca2+ currents in these cells. Finally, in human saphenous vein smooth muscle cells, proliferation was reduced by T-type channel inhibition or by HO-1 induction or CO exposure. The effects of T-type channel blockade and HO-1 induction were non-additive. Collectively, these data indicate that HO-1 regulates proliferation via CO-mediated inhibition of T-type Ca2+ channels. This signalling pathway provides a novel means by which proliferation of VSMCs (and other cells) may be regulated therapeutically

Proteomic Biomarkers for Acute Interstitial Lung Disease in Gefitinib-Treated Japanese Lung Cancer Patients

Interstitial lung disease (ILD) events have been reported in Japanese non-small-cell lung cancer (NSCLC) patients receiving EGFR tyrosine kinase inhibitors. We investigated proteomic biomarkers for mechanistic insights and improved prediction of ILD. Blood plasma was collected from 43 gefitinib-treated NSCLC patients developing acute ILD (confirmed by blinded diagnostic review) and 123 randomly selected controls in a nested case-control study within a pharmacoepidemiological cohort study in Japan. We generated ∼7 million tandem mass spectrometry (MS/MS) measurements with extensive quality control and validation, producing one of the largest proteomic lung cancer datasets to date, incorporating rigorous study design, phenotype definition, and evaluation of sample processing. After alignment, scaling, and measurement batch adjustment, we identified 41 peptide peaks representing 29 proteins best predicting ILD. Multivariate peptide, protein, and pathway modeling achieved ILD prediction comparable to previously identified clinical variables; combining the two provided some improvement. The acute phase response pathway was strongly represented (17 of 29 proteins, p = 1.0×10−25), suggesting a key role with potential utility as a marker for increased risk of acute ILD events. Validation by Western blotting showed correlation for identified proteins, confirming that robust results can be generated from an MS/MS platform implementing strict quality control

Non-Photochemical Quenching in Cryptophyte Alga Rhodomonas salina Is Located in Chlorophyll a/c Antennae

Photosynthesis uses light as a source of energy but its excess can result in production of harmful oxygen radicals. To avoid any resulting damage, phototrophic organisms can employ a process known as non-photochemical quenching (NPQ), where excess light energy is safely dissipated as heat. The mechanism(s) of NPQ vary among different phototrophs. Here, we describe a new type of NPQ in the organism Rhodomonas salina, an alga belonging to the cryptophytes, part of the chromalveolate supergroup. Cryptophytes are exceptional among photosynthetic chromalveolates as they use both chlorophyll a/c proteins and phycobiliproteins for light harvesting. All our data demonstrates that NPQ in cryptophytes differs significantly from other chromalveolates – e.g. diatoms and it is also unique in comparison to NPQ in green algae and in higher plants: (1) there is no light induced xanthophyll cycle; (2) NPQ resembles the fast and flexible energetic quenching (qE) of higher plants, including its fast recovery; (3) a direct antennae protonation is involved in NPQ, similar to that found in higher plants. Further, fluorescence spectroscopy and biochemical characterization of isolated photosynthetic complexes suggest that NPQ in R. salina occurs in the chlorophyll a/c antennae but not in phycobiliproteins. All these results demonstrate that NPQ in cryptophytes represents a novel class of effective and flexible non-photochemical quenching

Controlling irregular migration: International human rights standards and the Hungarian legal framework

In the summer of 2015 Hungary constructed a 175 km long barbed-wire fence at its southern border with Serbia. New criminal offences and asylum procedures were introduced that limited access to refugee status determination and ignored agreed EU asylum policy, deterring and de facto preventing asylum seekers from entering Hungarian territory. This paper provides an analysis of these new measures, which criminalized asylum seekers, and the subsequent Hungarian policy in relation to the case law of the European Court of Human Rights – arguing that the Hungarian authorities excessively abused their discretion in implementing these new policies of immigration and border control

Effects of endothelin-1 on the rat isolated heart

This study shows that bolus injections of endothelin-1 (ET-1) (1-30 pmol) produce transient vasodilator and prolonged coronary vasoconstrictor actions. The initial effect on cardiac contractility was a positive inotropic action, but with repeated doses a negative inotropic action developed. Verapamil (0.1 microM) antagonized the vasoconstrictor action of Bay K 8644 but did not affect ET-1-induced vasoconstriction. In contrast, removal of extracellular calcium did block the vasoconstrictor action of ET-1. This suggests that vasoconstriction is due to activation of receptor-rather than potential-operated calcium channels. The ET-1-induced vasoconstriction was not due to the release of platelet-activating factor (PAF) or thromboxane A2 since it was not inhibited by WEB 2086 (0.5 microM), fluribiprofen (2 microM), or BW755C (7 microM). In addition, thromboxane B2 could not be detected in the effluent from the heart. The vasoconstrictor action of ET-1 was potentiated by passage of air through the coronary vascular bed, suggesting that an intact endothelium normally opposes this vasoconstrictor effect

Biodistribution and dosimetry of Tc-99m-RP527, a gastrin-releasing peptide (GRP) agonist for the visualization of GRP receptor-expressing malignancies

The aim of this study was to determine the human biodistribution and radiation dosimetry of Tc-99m-RP527, a promising radioligand for the visualization of gastrin-releasing peptide (GRP) receptor-expressing human malignancies. Methods: Whole-body scans were obtained up to 48 h after intravenous injection of 555 MBq Tc-99m-RP527 in each of 6 subjects. Blood samples were taken at various times up to 48 h after injection. Urine was collected up to 48 h after injection for calculation of renal clearance and whole-body clearance. Time-activity curves were generated for the thyroid, heart, breasts in women, testes in men, and liver by fitting the organ-specific geometric mean counts, obtained from regions of interest, on the respective images as a function of the time after injection. The MIRD formulation was applied to calculate the absorbed radiation dose for various organs. Results: The serial whole-body images showed rapid hepatobiliary excretion, resulting in low background and potentially high-contrast imaging of the thoracic region. Imaging of abdominal tumors may prove problematic, however, because of the extensive bowel activity. Tc-99m-RP527 was predominantly cleared by the kidneys and to a lesser extent by the gastrointestinal tract. The mean excretion in the urine (+/- SD) at 48 h after injection was 58.3 +/- 5.4 percentage of the injected activity corrected for decay to the time of injection. The highest absorbed doses were received by the excretory organs (i.e., the urinary bladder and gallbladder wall). The average effective dose of Tc-99m-RP527 was estimated to be 0.0095 mSv/MBq. Conclusion: The biodistribution of Tc-99m-RP527 revealed low lung, myocardial, and liver uptake, which allowed early imaging of the supradiaphragmatic region with a favorable dosimetry (including effective dose) for administered activities required for SPECT imaging