FR167653 improves renal recovery and decreases inflammation and fibrosis after renal ischemia reperfusion injury

ObjectiveAcute tubular necrosis (ATN) secondary to induced warm ischemia (WI) results in inflammatory and delayed fibrotic processes and remains a common clinical problem with serious consequences. Because tumor necrosis factor-α (TNF-α) is a prominent proinflammatory factor implicated in the pathophysiology of acute renal ischemia reperfusion injury (IRI), we hypothesized that FR167653 (FR), a potent inhibitor of TNF-α and interleukin-1β production, may reduce IRI.MethodsIRI was induced in male pigs by bilateral clamping of the renal pedicle for 90 minutes (WI90), or unilateral renal clamping (90 minutes) after contralateral nephrectomy (1/2N×90), or unilateral renal clamping without contralateral nephrectomy (WIuni90). FR was administered intravenously 60 minutes before WI (1 mg/kg/h), during WI, and continuously for 3 hours (1 mg/kg/h) during reperfusion in treated groups (FRWI90, FR1/2N×90, or FRWIuni90). Blood and urine samples were collected between day 1 and 3 months after reperfusion for assessment of renal function. Kidneys were excised and renal tissues were collected at 3 months for morphologic and inflammation evaluation and protein analysis. Experimental groups were compared with sham operated (control) and heminephrectomized (Unif) groups without renal ischemia.ResultsThree WI90 animals (43%) and five 1/2N×90 (70%) were euthanized and necropsied at day 7 because of no urine production or poor conditions. Mortality was significantly improved after FR treatment. Survival was 100% in the control, Unif, WIuni90, and FR groups. In Unif groups, FR significantly reduced renal failure and bilateral renal ischemia (P < .05). At 3 months, proteinuria was significantly reduced in FR-treated groups (P < .01). Inflammatory cells count was also dramatically diminished in FR-treated pigs (P < .01 for CD3-positive cells). The second aspect of transient ischemia is the fibrotic process determined at 3 months. FR treatment was characterized by a reduction of renal fibrosis, particularly in Unif groups. TNF-α protein expression was diminished in FR-treated groups.ConclusionThis is the first evidence that FR reduced the early and long-term effect of WI in the severe ischemia model. This effect was particularly marked against fibrosis and inflammation, which would contribute to deterioration of a patient's renal function.Clinical RelevanceAcute ischemia of the kidney is common in the setting of renal artery or aortic surgery. Deterioration in renal function is a common cause of morbidity in patients treated surgically for juxtarenal and suprarenal abdominal aortic aneurysms. FR167653 represents a useful therapeutic approach to prevent renal damage in a planned period of warm ischemia and during suprarenal aortic surgery

Prognostic impact of vitamin B6 metabolism in lung cancer

Patients with non-small cell lung cancer (NSCLC) are routinely treated with cytotoxic agents such as cisplatin. Through a genome-wide siRNA-based screen, we identified vitamin B6 metabolism as a central regulator of cisplatin responses in vitro and in vivo. By aggravating a bioenergetic catastrophe that involves the depletion of intracellular glutathione, vitamin B6 exacerbates cisplatin-mediated DNA damage, thus sensitizing a large panel of cancer cell lines to apoptosis. Moreover, vitamin B6 sensitizes cancer cells to apoptosis induction by distinct types of physical and chemical stress, including multiple chemotherapeutics. This effect requires pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. In line with a general role of vitamin B6 in stress responses, low PDXK expression levels were found to be associated with poor disease outcome in two independent cohorts of patients with NSCLC. These results indicate that PDXK expression levels constitute a biomarker for risk stratification among patients with NSCLC.publishedVersio

Ferrofluides - Nanoparticules superparamagnétiques

On sait bien sûr que toute matière présente des propriétés magnétiques, mais les liquides ne peuvent avoir qu'une sensibilité extrêmement faible au champ magnétique. Les liquides sont généralement diamagnétiques car les liaisons moléculaires ne laissent pas d'électrons non appairés. En pratique le champ magnétique n'a pas d'effet macroscopique sensible sur un liquide sauf dans des cas très particulier comme lorsque que l'on dispose d'un aimant capable de produire un champ important avec un gradient très fort. Un ferrofluide n'est donc pas à proprement parler un liquide magnétique mais une dispersion colloïdale de nanoparticules magnétiques dans un liquide porteur. Dans la mesure où les particules sont ferromagnétiques (ou ferrimagnétiques), le fluide est alors sensible à un champ magnétique externe. Son comportement dépend de l'équilibre entre les interactions magnétiques, les forces de Van der Wall (et éventuellement electrostatiques) et la tension superficielle. En raison de la taille nanométrique des particules (autour de 10 nm), l'effet de l'agitation thermique joue un rôle très important dans les propriétés magnétiques des ferrofluides. Les ferrofluides obéissent à la loi du paramagnétisme de Langevin, mais avec une aimantation beaucoup plus sensible au champ que dans un paramagnétique classique puisque c'est non pas un spin qui réagit au champ, mais l'ensemble des spins de chaque particule. On dit alors qu'il est superparamagnétique. Cette combinaison des propriétés rhéologiques des liquides et magnétique des particule, confère au ferrofluides des propriétés et une gamme inédite de comportements macroscopiques sous l'effet d'un champ qui permet des applications originales. Les ferrofluides n'existent pas à l'état naturel, il faut donc les synthétiser. On s'emploiera donc à produire des nanoparticules métalliques (principalement Fe) ou d'oxydes (magnétite) en s'attachant à éviter leur agglomération et la sédimentation pour garantir la stabilité de la suspension colloïdale

Ammonia survey of cold massive clumps discovered in the inner galactic disk with ATLASGAL

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Molecular fingerprints of an unbiased sample of Galactic massive star forming clumps

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Molecular fingerprints of an unbiased sample of Galactic massive star forming clumps II.

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Ammonia survey of cold massive clumps discovered in the inner galactic disk with ATLASGAL

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Ammonia survey of cold massive clumps discovered in the inner galactic disk with ATLASGAL

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Molecular fingerprints of an unbiased sample of Galactic massive star forming clumps

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