Lazaroid Treatment Prevents Death of Cultured Rat Embryonic Mesencephalic Neurons Following Glutathione Depletion

Abstract: Reactive oxygen species are believed to play a crucial role in situations where dopamine neurons die, such as in Parkinson's disease or during intracerebral transplantation of embryonic mesencephalic tissue. The present study was designed to address the question whether, and to what extent, the glutathione redox system is important for the viability of rat embryonic dopamine neurons in vitro. Furthermore, we studied whether the lazaroid U-83836E, a 2-methylaminochroman that inhibits lipid peroxidation, affects the survival of cultured mesencephalic neurons subjected to experimentally induced glutathione depletion. Glutathione depletion was achieved by exposing dissociated mesencephalic cell cultures to l -buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, at four different concentrations (1, 10, 100, and 1,000 µ M ). Dopamine neuron survival was significantly reduced by 65–94% in a concentration-dependent manner by 10–1,000 µ M BSO. The neurotoxic effects of BSO were almost completely prevented by supplementing the culture medium with 0.3 µ M U-83836E. As assessed by HPLC analysis, BSO treatment was associated with a marked reduction of cellular glutathione content, and this depletion was not altered by the presence of U-83836E. We conclude that in the present insult model of severe glutathione depletion, the lazaroid can afford efficient neuroprotection that does not seem to be mediated by a direct interaction with BSO or glutathione, but rather via an independent pathway.     

fs(1)K10, a germline-dependent female sterile mutation causing abnormal chorion morphology inDrosophila melanogaster

Summary Females homozygous for a newly isolated mutation induced by ethyl methane sulphonate,fs(1)K10, lay abnormally shaped eggs in which the dorsal appendages of the chorion are enlarged and fused ventrally. The eggs are usually not fertilized and development is never normal beyond the blastoderm stage. The mutant was mapped to the tip of the X-chromosome with a meiotic position of 1–0.5 and a cytological location between 2B17 and 3A3. Using germ line mosaics constructed by transplantation of pole cells, it was shown that the abnormal morphology and the sterility are obtained only when the germ line is homozygous for the mutant.     

Familial malignant mesothelioma: A population-based study in Central Italy (1980–2012)

Malignant mesothelioma is a sporadic cancer linked to asbestos exposure. Its occurrence among blood relatives (familial mesothelioma) may point to genetic susceptibility or shared exposures. The burden of the familial disease is unknown. The aims of the study were to assess at population level the proportion of familial mesotheliomas among all mesotheliomas and to investigate the family history of cancer among relatives of mesothelioma cases. We actively searched familial clusters based on a mesothelioma registry from central Italy (5.5 million people, 10% of the Italian population) of the National Mesothelioma Register network (ReNaM) as well as a pathology-based archive. Among 997 incident mesotheliomas recorded in a 32-year-period (1980–2012), we detected 13 clusters and 34 familial cases, accounting for 3.4% of all mesotheliomas. The most common clusters where those with affected siblings and unaffected parents. Asbestos exposure was occupational (n = 7 clusters), household (n = 2), environmental (n = 1), or not attributable for insufficient information (n = 3). There were 25 additional cancers in nine families. Some were cancer sites for which there is sufficient evidence (lung and larynx) or limited evidence (stomach and colon) of causal association with asbestos. The results suggest potential genetic recessive effects in mesothelioma that interact with asbestos exposure, but it is not possible to estimate the specific proportion attributable to each of these components.     

Proteomic profiles of human lung adeno and squamous cell carcinoma using super‐SILAC and label‐free quantification approaches

Nonsmall cell lung cancer (NSCLC) accounts for 85% of lung cancers, and is subdivided into two major histological subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SCC). There is an unmet need to further subdivide NSCLC according to distinctive molecular features that may be associated with responsiveness to therapies. Four primary tumor‐derived xenograft proteomes (two‐each ADC and SCC) were quantitatively compared by using a super‐SILAC labeling approach together with ultrahigh‐resolution MS. Proteins highly differentially expressed in the two subtypes were identified, including 30 that were validated in an independent cohort of 12 NSCLC primary tumor‐derived xenograft tumors whose proteomes were quantified by an alternative, label‐free shotgun MS methodology. The 30‐protein signature contains metabolism enzymes including phosphoglycerate dehydrogenase, which is more highly expressed in SCC, as well as a comprehensive set of cytokeratins and other components of the epithelial barrier, which is therefore distinctly different between ADC and SCC. These results demonstrate the utility of the super‐SILAC method for the characterization of primary tissues, and compatibility with datasets derived from different MS‐based platforms. The validation of proteome signatures of NSCLC subtypes supports the further development and application of MS‐based quantitative proteomics as a basis for precision classifications and treatments of tumors. All MS data have been deposited in the ProteomeXchange with identifier PXD000438 ( http://proteomecentral.proteomexchange.org/dataset/PXD000438 ).     

Emerging role of autophagy in kidney function,diseases and aging

Autophagy is a highly conserved process that degrades cellular long-lived proteins and organelles. Accumulating evidence indicates that autophagy plays a critical role in kidney maintenance, diseases and aging. Ischemic, toxic, immunological, and oxidative insults can cause an induction of autophagy in renal epithelial cells modifying the course of various kidney diseases. This review summarizes recent insights on the role of autophagy in kidney physiology and diseases alluding to possible novel intervention strategies for treating specific kidney disorders by modifying autophagy.     

Role of Sulfur Dioxide in Acute Lung Injury Following Limb Ischemia/Reperfusion in Rats

Sulfur dioxide (SO₂) is naturally synthesized by glutamate‐oxaloacetate transaminase (GOT) from l ‐cysteine in mammalian cells. We aim to investigate the role of SO₂ in inflammation in acute lung injury (ALI) following limb ischemia/reperfusion (I/R). Male Wistar rats were subjected to limb I/R and were injected with saline, GOT inhibitor hydroxamate (HDX, 0.47 mmol/kg), or the SO₂ donor Na₂SO₃/NaHSO₃ (0.54 mmol/kg/0.18 mmol/kg). Compared with the sham operation, the plasma SO₂ levels were significantly decreased by limb I/R treatment. In addition, SO₂ concentration and GOT activity in the lung tissue were also reduced in ALI. The occurrence of ALI following limb I/R can be prevented by Na₂SO₃/NaHSO₃ treatment, whereas it can be significantly aggravated by HDX. The plasma IL‐1β, IL‐6, and IL‐10 levels were consistent with myeloperoxidase activity and inflammation in lung tissue. In conclusion, our data suggest that downregulation of endogenous SO₂ production might be involved in pathogenesis of ALI following limb I/R in rats. © 2013 Wiley Periodicals, Inc. J BiochemMol Toxicol 27:389‐397, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/jbt.21492     

Role of epithelial mesenchymal transition (EMT) in chronic obstructive pulmonary disease (COPD)

Small airway fibrosis is the main contributor to physiological airway dysfunction in COPD. One potential mechanism contributing to small airway fibrosis is epithelial mesenchymal transition (EMT). When associated with angiogenesis (so called EMT-Type-3) it may well also be the link with the development of cancer, which is closely associated with COPD and predominantly in large airways. In a recent study published in Respiratory Research, Qin Wang and colleagues investigated the role of urokinase plasminogen activator receptor (uPAR) in EMT in small airway epithelium of COPD patients. However, there are some issues with the paper which we wish to comment on.