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Humans are estimated to consume several grams per week of nanoplastics (NPs) through exposure to a variety of contamination sources. Nonetheless, the effects of these polymeric particles on living systems are still mostly unknown. Here, by means of CD, NMR and TEM analyses, we describe at an atomic resolution the interaction of ubiquitin with polystyrene NPs (PS-NPs), showing how a hard protein corona is formed. Moreover, we report that in human HeLa cells exposure to PS-NPs leads to a sensible reduction of ubiquitination. Our study overall indicates that PS-NPs cause significant structural effects on ubiquitin, thereby influencing one of the key metabolic processes at the base of cell viability.

Mutations in Progranulin (PGRN) gene have been genetically associated with fronto-temporal dementia (FTD), although the neurobiology of this secreted glycoprotein is still unclear. We identified three familial cases having a rare +5 deletion in exon six of PGRN gene (g.101349_101355delCTGCTGT) as causative of frameshift mutation. This mutation is not considered frequent and already described in two apparently sporadic case of FTD only, but never associated with familial cases. Our patients showed also heterogeneous clinical phenotypes, such as behavioral variant (bv-FTD) in men and primary progressive aphasia (PPA) in women. Quantitative RT-PCR of PGRN gene expression in WBC shows an unusual increasing of expression, while protein analyses of plasma concentration detected a PGRN protein deficiency. Using allele-specific PCR mutation-primers (ARMS), this mutation was searched in three hundreds healthy controls matched by age, sex and geographic regions and no deletion was ever found. The findings provide convincing evidence of the putative role of PGRN in the genetic etiology of FTD and show a link between FTD and ex 6-del PGRN mutations, which probably are more frequent than previously considered. The described mutation express two different gender linked phenotypes bv-FTD in men and PPA in women. Although we believe that this is the product of a founder effect, we yet cannot prove at this stage. Our findings imply that PGRN is essential for neuronal survival and even partial loss of PGRN eventually leads to neurodegeneration.

Atorvastatin exerts beneficial vascular effects in diabetes, but the underlying mechanisms are yet to be elucidated. The aim of the present study was to determine whether Rac-1 is involved in the effect of atorvastatin on oxidative stress and vascular dysfunction. Using human aortic endothelial cells (HAECs) we evaluated the effect of high glucose levels on peroxide production by dihydrodichlorofluorescein and on Rac-1 activity using immunocytochemistry to detect Rac-1 translocation to the membrane. We evaluated vascular function, peroxide production by dihydroethidium and NADPH oxidase activity in vessels from atorvastatin-treated mice. Rac-1 activity was also assessed, both by immunoprecipitation of the Rac–p21-activated kinase complex and by analysis of Rac-1 translocation to the membrane. These experiments were also conducted in vessels infected with an adenoviral vector carrying a constitutively active mutant of Rac-1. In HAECs exposed to high glucose levels, atorvastatin prevented oxidative stress, and this protection was associated with impaired Rac-1 activation. This effect was also observed in a murine model of diabetes mellitus. More importantly, the addition of geranylgeranyl pyrophosphate (GGPP) blocked the effects of atorvastatin in both glucose-exposed HAECs and diabetic vessels. Atorvastatin failed to afford protection against vascular abnormalities in the presence of a constitutively active mutant of Rac-1. The results of this study demonstrate that the vascular antioxidant effect of atorvastatin in diabetes is mediated through inhibition of Rac-1 via a reduction in GGPP. Thus, selective Rac-1 inhibition should be considered in the design of novel pharmacological strategies to reduce the impact of diabetes mellitus on vascular function.