Inhibition of S6K1 accounts partially for the anti-inflammatory effects of the arginase inhibitor L-norvaline

<p>Abstract</p> <p>Background</p> <p>Pharmacological inhibition of endothelial arginase-II has been shown to improve endothelial nitric oxide synthase (eNOS) function and reduce atherogenesis in animal models. We investigated whether the endothelial arginase II is involved in inflammatory responses in endothelial cells.</p> <p>Methods</p> <p>Human endothelial cells were isolated from umbilical veins and stimulated with TNFα (10 ng/ml) for 4 hours. Endothelial expression of the inflammatory molecules i.e. vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin were assessed by immunoblotting.</p> <p>Results</p> <p>The induction of the expression of endothelial VCAM-1, ICAM-1 and E-selectin by TNFα was concentration-dependently reduced by incubation of the endothelial cells with the arginase inhibitor L-norvaline. However, inhibition of arginase by another arginase inhibitor S-(2-boronoethyl)-L-cysteine (BEC) had no effects. To confirm the role of arginase-II (the prominent isoform expressed in HUVECs) in the inflammatory responses, adenoviral mediated siRNA silencing of arginase-II knocked down the arginase II protein level, but did not inhibit the up-regulation of the adhesion molecules. Moreover, the inhibitory effect of L-norvaline was not reversed by the NOS inhibitor L-NAME and L-norvaline did not interfere with TNFα-induced activation of NF-κB, JNK, p38mapk, while it inhibited p70s6k (S6K1) activity. Silencing S6K1 prevented up-regulation of E-selectin, but not that of VCAM-1 or ICAM-1 induced by TNFα.</p> <p>Conclusion</p> <p>The arginase inhibitor L-norvaline exhibits anti-inflammatory effects independently of inhibition of arginase in human endothelial cells. The anti-inflammatory properties of L-norvaline are partially attributable to its ability to inhibit S6K1.</p

Nem todas as pericardites são idiopáticas

Apresenta-se um caso clínico de pericardite por Mycobacterium tuberculosis, que condicionou um estado de pré-tamponamento cardíaco. Apesar dos progressos dos últimos anos, Portugal continua a ser o único país da Europa Ocidental com uma taxa intermédia de infeção por Mycobacterium tuberculosis. A infeção é adquirida por via respiratória e pode disseminar- se e instalar-se em qualquer órgão durante a primoinfeção ou em outra qualquer altura em que haja imunodepressão do indivíduo. O atingimento pleural é o mais comum e o pericárdico é raro, representando apenas 1-2% dos doentes com tuberculose. No presente caso clínico torna-se evidente a importância de uma abordagem sistematizada e holística dos doentes com pericardite durante a sua investigação etiológica.We report an interesting case of tuberculous pericarditis that evolved to a cardiac pre-tamponade. Portugal is still the only country in Western Europe with an intermediate rate of Mycobacterium tuberculosis infection. The infection is acquired by inhalation and can disseminate to any body organ during primary infection or at any other time where there is immunodepression of the patient. Pleural involvement is the most common and pericardial involvement is rare with just 1-2% of the patients with pulmonary tuberculosis. In this clinical case we evidence the importance of a systematized approach to these patients during the etiological investigatio

Opposing and uncoupling effects of mTOR and S6K1 in the regulation of endothelial tissue factor expression

Rapamycin has been reported to enhance tissue factor (TF) expression. The present study investigated roles of mammalian target of rapamycin (mTOR) and its downstream S6K1 in this process. We showed here that, consistent with rapamycin, knocking-down mTOR enhanced thrombin-induced TF mRNA and protein levels, whereas silencing S6K1 mitigated up-regulation of TF protein but not TF mRNA level. The enhanced TF protein level upon mTOR-silencing was further augmented by over-expression of a constitutively active S6K1 mutant and reduced by blocking RhoA, p38mapk or NF-κB. The results reveal an opposing and uncoupling effect of mTOR and S6K1 in regulating TF expression

Nem todas as pericardites são idiopáticas

Apresenta-se um caso clínico de pericardite por Mycobacterium tuberculosis, que condicionou um estado de pré-tamponamento cardíaco. Apesar dos progressos dos últimos anos, Portugal continua a ser o único país da Europa Ocidental com uma taxa intermédia de infeção por Mycobacterium tuberculosis. A infeção é adquirida por via respiratória e pode disseminar-se e instalar-se em qualquer órgão durante a primoinfeção ou em outra qualquer altura em que haja imunodepressão do indivíduo. O atingimento pleural é o mais comum e o pericárdico é raro, representando apenas 1-2% dos doentes com tuberculose. No presente caso clínico torna-se evidente a importância de uma abordagem sistematizada e holística dos doentes com pericardite durante a sua investigação etiológica

The hexosamine biosynthesis inhibitor azaserine prevents endothelial inflammation and dysfunction under hyperglycemic condition through antioxidant effects

Hexosamine biosynthetic pathway (HBP) accounts for some cardiovascular adverse effects of hyperglycemia. We investigated whether the HBP inhibitor azaserine protects against hyperglycemia-induced endothelial damage dependently of HBP. Human endothelial cells isolated from umbilical veins were exposed either to a high (30.5 mmol/l) or low concentration of glucose (5.5 mmol/l) for 4 days, followed by a stimulation with TNF-α (1 ng/ml, 24 h). The blockade of the rate-limiting enzyme glutamine:fructose-6-phosphate amidotransferase inhibited HBP flux and oxidative stress (generation of superoxide and peroxynitrite) under the hyperglycemic condition and prevented the synergistic stimulation of VCAM-1 and ICAM-1 expression by hyperglycemia and TNF-α. In the cells cultured under a low-glucose condition when no increased HBP flux occurred, azaserine enhanced the manganese-superoxide dismutase (MnSOD) protein level and also inhibited the oxidative stress and the expression of VCAM-1 and ICAM-1 in response to TNF-α. Moreover, the polyphenol resveratrol inhibited the oxidative stress and adhesion molecule expression and did not decrease the HBP flux under the hyperglycemia condition. In addition, in isolated rat aortas exposed to hyperglycemic buffer for 5 h when no significant HBP flux occurred, azaserine upregulated the MnSOD protein level and prevented decreased endothelium-dependent relaxations to acetylcholine. In conclusion, hyperglycemia independently increases oxidative stress and HBP flux, amplifies endothelial inflammation, and impairs endothelial function mainly through oxidative stress and not the HBP pathway. Azaserine protects against hyperglycemic endothelial damage through its antioxidant effect independently of inhibiting HBP pathway

Mutation of the circadian clock gene Per2 alters vascular endothelial function

Background— The circadian clock regulates biological processes including cardiovascular function and metabolism. In the present study, we investigated the role of the circadian clock gene Period2 (Per2) in endothelial function in a mouse model. Methods and Results— Compared with the wild-type littermates, mice with Per2 mutation exhibited impaired endothelium-dependent relaxations to acetylcholine in aortic rings suspended in organ chambers. During transition from the inactive to active phase, this response was further increased in the wild-type mice but further decreased in the Per2 mutants. The endothelial dysfunction in the Per2 mutants was also observed with ionomycin, which was improved by the cyclooxygenase inhibitor indomethacin. No changes in the expression of endothelial acetylcholine-M₃ receptor or endothelial nitric oxide synthase protein but increased cyclooxygenase-1 (not cyclooxygenase-2) protein levels were observed in the aortas of the Per2 mutants. Compared with Per2 mutants, a greater endothelium-dependent relaxation to ATP was observed in the wild-type mice, which was reduced by indomethacin. In quiescent aortic rings, ATP caused greater endothelium-dependent contractions in the Per2 mutants than in the wild-type mice, contractions that were abolished by indomethacin. The endothelial dysfunction in the Per2 mutant mice is not associated with hypertension or dyslipidemia. Conclusions— Mutation in the Per2 gene in mice is associated with aortic endothelial dysfunction involving decreased production of NO and vasodilatory prostaglandin(s) and increased release of cyclooxygenase-1–derived vasoconstrictor(s). The results suggest an important role of the Per2 gene in maintenance of normal cardiovascular functions

ESPRESSO: the Echelle spectrograph for rocky exoplanets and stable spectroscopic observations

International audienceESPRESSO, the Echelle SPectrograph for Rocky Exoplanets and Stable Spectroscopic Observations, will combine the efficiency of modern echelle spectrograph design with extreme radial-velocity precision. It will be installed on ESO's VLT in order to achieve a gain of two magnitudes with respect to its predecessor HARPS, and the instrumental radialvelocity precision will be improved to reach cm/s level. Thanks to its characteristics and the ability of combining incoherently the light of 4 large telescopes, ESPRESSO will offer new possibilities in various fields of astronomy. The main scientific objectives will be the search and characterization of rocky exoplanets in the habitable zone of quiet, nearby G to M-dwarfs, and the analysis of the variability of fundamental physical constants. We will present the ambitious scientific objectives, the capabilities of ESPRESSO, and the technical solutions of this challenging project

Delayed colorectal cancer care during covid-19 pandemic (decor-19). Global perspective from an international survey

Background The widespread nature of coronavirus disease 2019 (COVID-19) has been unprecedented. We sought to analyze its global impact with a survey on colorectal cancer (CRC) care during the pandemic. Methods The impact of COVID-19 on preoperative assessment, elective surgery, and postoperative management of CRC patients was explored by a 35-item survey, which was distributed worldwide to members of surgical societies with an interest in CRC care. Respondents were divided into two comparator groups: 1) ‘delay’ group: CRC care affected by the pandemic; 2) ‘no delay’ group: unaltered CRC practice. Results A total of 1,051 respondents from 84 countries completed the survey. No substantial differences in demographics were found between the ‘delay’ (745, 70.9%) and ‘no delay’ (306, 29.1%) groups. Suspension of multidisciplinary team meetings, staff members quarantined or relocated to COVID-19 units, units fully dedicated to COVID-19 care, personal protective equipment not readily available were factors significantly associated to delays in endoscopy, radiology, surgery, histopathology and prolonged chemoradiation therapy-to-surgery intervals. In the ‘delay’ group, 48.9% of respondents reported a change in the initial surgical plan and 26.3% reported a shift from elective to urgent operations. Recovery of CRC care was associated with the status of the outbreak. Practicing in COVID-free units, no change in operative slots and staff members not relocated to COVID-19 units were statistically associated with unaltered CRC care in the ‘no delay’ group, while the geographical distribution was not. Conclusions Global changes in diagnostic and therapeutic CRC practices were evident. Changes were associated with differences in health-care delivery systems, hospital’s preparedness, resources availability, and local COVID-19 prevalence rather than geographical factors. Strategic planning is required to optimize CRC care