Cholesterol impairment contributes to neuroserpin aggregation

Intraneural accumulation of misfolded proteins is a common feature of several neurodegenerative pathologies including Alzheimer's and Parkinson's diseases, and Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB). FENIB is a rare disease due to a point mutation in neuroserpin which accelerates protein aggregation in the endoplasmic reticulum (ER). Here we show that cholesterol depletion induced either by prolonged exposure to statins or by inhibiting the sterol regulatory binding-element protein (SREBP) pathway also enhances aggregation of neuroserpin proteins. These findings can be explained considering a computational model of protein aggregation under non-equilibrium conditions, where a decrease in the rate of protein clearance improves aggregation. Decreasing cholesterol in cell membranes affects their biophysical properties, including their ability to form the vesicles needed for protein clearance, as we illustrate by a simple mathematical model. Taken together, these results suggest that cholesterol reduction induces neuroserpin aggregation, even in absence of specific neuroserpin mutations. The new mechanism we uncover could be relevant also for other neurodegenerative diseases associated with protein aggregation.Comment: 7 figure

BIOLOGICAL AND CLINICAL RELEVANCE OF MIRNA EXPRESSION SIGNATURES IN PRIMARY PLASMA CELL LEUKEMIA

Purpose: Plasma cell leukemia (PCL) is a very aggressive and rare hematological malignancy that can be distinguished into primary (pPCL), originating de novo, or secondary (sPCL), arising as a leukemic transformation of multiple myeloma (MM). Genomic and clinical differences between pPCL and MM have been demonstrated, mainly based on retrospective studies. This study was aimed at investigating the involvement of miRNAs in pPCL and their possible relationship with higher tumor aggressiveness. Experimental design: MiRNA expression profiles were analyzed in highly-purified malignant plasma cells from 18 pPCL cases included in a prospective clinical trial. MiRNA expression patterns were evaluated in comparison with a representative series of multiple myeloma (MM) patients, in relation to the most recurrent chromosomal abnormalities (as assessed by fluorescence in situ hybridization and single nucleotide polymorphism-array analysis), and in association with clinical outcome. MiRNA expression was also integrated with gene expression profiles and computational prediction of miRNA target genes in pPCL and MM samples in order to identify putative target genes of deregulated miRNAs. The functional role of a few identified miRNAs in plasma cell dyscrasia pathogenesis was explored by transfection of synthetic pre/anti-miRNAs in multiple myeloma cell lines. Results: We identified a series of deregulated miRNAs in pPCL (42 up- and 41 down-regulated) in comparison with MM. Some of them, based on their reported functions or putative target genes computed by integrative analysis, might have a role in the pathobiology of pPCL, such as miR-21, that was found to promote in vitro growth of MM cell lines. As regards chromosomal aberrations, the expression of some miRNAs mapped to hot-spot altered regions was associated with DNA copy number of the corresponding genomic loci; furthermore, TP53 deletion, a frequent cytogenetic lesion in our pPCL cohort, was found associated with a trend of down-regulation of miR-34a, whose tumor suppressor activity was demonstrated for the first time also in the context of MM. Finally, four miRNAs (miR-497, miR-106b, miR-181a* and miR-181b) were identified having expression levels correlated with treatment response, and four (miR-92a, miR-330-3p, miR-22, and miR-146a) with clinical outcome. Conclusions: Overall, this study provides insights into the possible contribution of miRNAs in the pathogenesis of pPCL and suggests targets for future therapeutic investigations

Is premature birth an environmental sensitivity factor? A scoping review protocol

Introduction Globally, around 10% of children are born preterm and are more at risk of negative developmental outcomes. However, empirical evidences and theoretical reasoning also suggest that premature birth can be a susceptibility factor, increasing sensitivity to the environment for better and for worse. Because available findings are controversial, with the current scoping review we will explore if, based on the available literature, preterm birth can be seen as an environmental sensitivity (ES) factor. In doing so, we will consider a series of moderating variables, including the level of prematurity, the type of environment and the outcome investigated. Methodological aspects, as the type of measures used and study design, will be considered. Methods and analysis The scoping review will be conducted following the Joanna Briggs Institute Methodology guidelines. The report will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist. We will perform the search between 15 January 2022 and 1 February 2022. Data will be chartered by independent reviewers. Ethics and dissemination Ethical approval is not required, as primary data will not be collected. This scoping review will be the first to explore whether prematurity is associated with an increased ES. This review can have important implications for tailoring prevention and intervention programmes. Results will be published in a peer-reviewed journal

Barley beta-glucan promotes MnSOD expression and enhances angiogenesis under oxidative microenvironment

Manganese superoxide dismutase (MnSOD), a foremost antioxidant enzyme, plays a key role in angiogenesis. Barley-derived (1.3) β-d-glucan (β-d-glucan) is a natural water-soluble polysaccharide with antioxidant properties. To explore the effects of β-d-glucan on MnSOD-related angiogenesis under oxidative stress, we tested epigenetic mechanisms underlying modulation of MnSOD level in human umbilical vein endothelial cells (HUVECs) and angiogenesis in vitro and in vivo. Long-term treatment of HUVECs with 3% w/v β-d-glucan significantly increased the level of MnSOD by 200% ± 2% compared to control and by 50% ± 4% compared to untreated H2O2-stressed cells. β-d-glucan-treated HUVECs displayed greater angiogenic ability. In vivo, 24 hrs-treatment with 3% w/v β-d-glucan rescued vasculogenesis in Tg (kdrl: EGFP) s843Tg zebrafish embryos exposed to oxidative microenvironment. HUVECs overexpressing MnSOD demonstrated an increased activity of endothelial nitric oxide synthase (eNOS), reduced load of superoxide anion (O2-) and an increased survival under oxidative stress. In addition, β-d-glucan prevented the rise of hypoxia inducible factor (HIF)1-α under oxidative stress. The level of histone H4 acetylation was significantly increased by β-d-glucan. Increasing histone acetylation by sodium butyrate, an inhibitor of class I histone deacetylases (HDACs I), did not activate MnSOD-related angiogenesis and did not impair β-d-glucan effects. In conclusion, 3% w/v β-d-glucan activates endothelial expression of MnSOD independent of histone acetylation level, thereby leading to adequate removal of O2-, cell survival and angiogenic response to oxidative stress. The identification of dietary β-d-glucan as activator of MnSOD-related angiogenesis might lead to the development of nutritional approaches for the prevention of ischemic remodelling and heart failure