Autophagy-related protein LC3 and Beclin-1 in the first trimester of pregnancy

Autophagy is a degradation process that acts in response to environmental stressors. Recently, autophagy has been detected in normal term, preeclamptic and intrauterine growth-restricted placentas. The object of this work was to investigate the presence of autophagy in first trimester voluntary interruption of pregnancy placental villi by the expression of autophagy-related proteins, light chain 3 (LC3), and Beclin-1. In first trimester placental villi laser scanning confocal microscopy (LSCM) analysis revealed LC3 and Beclin-1 immunoreactivity prevalently located in villous cytotrophoblasts. Using LSCM, LC3, and Beclin-1 were localized to the cytoplasm of the trophoblast layer in human full-term placentas. Beclin-1 expression and LC3 activation were confirmed by western blotting. These data emphasize that autophagy activation is different among cytotrophoblasts and syncytiotrophoblasts depending on the gestational age and thus we speculate that autophagy might play a prosurvival role throughout human pregnancy

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Morphology demonstrates similar autophagy alterations in neurodegeneration and brain tumors.

Malignant glioma are the most malignant brain tumors. Frequent genetic alterations involve PTEN (Phosphatase homolog deleted on chromosome Tensin and Ten), a lipid phosphatase that after mutation is not able to convert phosphatidylinositol (3,4,5)-triphosphate (PIP3) into phosphatidylinositol (4,5)-bisphosphate (PIP2) and thereby inhibiting AKT, which in turn activates the apoptotic factors, mutations of p53 and retinoblastoma, both responsible of controlling the phase transition G1 / S of cell cycle under physiological conditions and prevent the replication of DNA when the cell is altered. Recently a dramatic uptake of the amino acid glutamine was reported in malignant glioma. This amino acid produces a marked inhibition of the autophagy pathway. Consistently, autophagy is defective in human glioblastoma similar to neurodegeneration. Autophagy is the main clearing system to remove damaged or potentially harmful organelles and misfolded proteins. Autophagy progresses through several stages: (i) the phagophore (ii) the autophagosome (iii) the amphisomes; (iv) the autophagolysosome and (v) the autophagoproteasome. The last stages involves the fusion of amphisome with lysosome which originates autophagolysosome that contains the elements to be removed and lytic enzymes necessary for this degradation process, while the autophagoproteasome derives from the fusion with component of the proteasome. The autophagy machinery can be measured by several specific markers such as beclin1 and LC3, the occurrence of stagnant autophagy vacuoles. In the present study we characterized the consistency and relevance of autophagy failure in glioblastoma by using human cell lines, primary human cell cultures and in vivo human glioblastoma cells implanted in the brain of nude mice. In baseline conditions we observed in cells obtained from surgery of human patients a marked inhibition of the autophagy pathway. This was associated with an increase in autophagy substrates overlapping with neurodegenerative disorders. In keeping with the ongoing autophagy inhibition we found that activation of the autophagy pathway reduced cell proliferation and promoted cell differentiation dose-dependently in vitro while the systemic administration of a powerful autophagy activator reduced the volume of brain tumor in vivo by 96.6%. These data indicate a relevant role of autophagy failure in glioblastoma and suggest potential approaches to contrast tumor growth

[The efficacy of slow-release diltiazem in the treatment of stable angina of effort: a comparison between diltiazem and placebo].

The efficacy of a new slow release (SR) diltiazem preparation was assessed in 10 patients with stable effort angina. A double-blind, placebo controlled, randomized, crossover protocol was carried out comparing the effects of diltiazem 60 mg tid and diltiazem SR 120 mg bid on clinical and ergometric parameters. Exercise test was carried out 3 and 12 hours after the last dose of diltiazem or diltiazem SR respectively. Both drug preparations reduced the incidence of positive test, increased the exercise time and the time of onset of ischemic ST depression. The beneficial effects of the drugs appeared to be due to a reduction in myocardial oxygen consumption at the same workload as shown by the lesser value of pressure rate product at submaximal exercise. In conclusion, diltiazem SR at 12 hours after the last administration has the same effectiveness of diltiazem 60 mg at 3 hours

IL-1beta-511 and IL-1RN*2 polymorphisms in inflammatory bowel disease: An Italian population study and meta-analysis of European studies.

Several studies have tried to find possible associations between genetic polymorphisms and inflammatory bowel disease prevalence and/or phenotype. Our objectives were to test the frequency and phenotypic association of two polymorphisms of the interleukin-1 pathway, IL-1beta-511 and IL-1RN*2, in inflammatory bowel disease patients and controls from an Italian population, and to compare our data with previously published similar studies in Europe.We screened 290 inflammatory bowel disease patients (178 ulcerative colitis and 112 Crohn's disease) and 106 controls for IL-1beta-511 and IL-1RN*2 polymorphisms by polymerase chain reaction (PCR)-based methods. The prevalence of the IL-1beta-511 and IL-1RN*2 polymorphisms in European inflammatory bowel disease patients was calculated by a meta-analysis of previously published studies using the Mantel-Haenszel method.No correlation between the IL-1 polymorphisms and inflammatory bowel disease prevalence was found in our study population. Crohn's disease patients with the IL-1beta-511 mutation had a higher rate of complicated disease. A trend for an association between the IL-1RN*2 mutation and a higher risk for inflammatory bowel disease has been found only in studies with Northern European populations.The IL-1beta-511 mutation can be associated with complex disease behaviour in Italian Crohn's disease patients. The IL-1RN*2 mutation may play a role in Northern European people with inflammatory bowel disease