Polystyrene nanoplastics affect the human ubiquitin structure and ubiquitination in cells: a high-resolution study.

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.

Role of cytosolic calcium-dependent phospholipase A2 in Alzheimer's disease pathogenesis.

Phospholipases (PLA2s) are a superfamily of enzymes characterized by the ability to specifically hydrolyze the sn-2 ester bond of phospholipids generating arachidonic acid, utilized in inflammatory responses, and lysophospholipids involved in the control of cell membrane remodeling and fluidity. PLA2s have been so far considered a crucial element in the etiopathogenesis of several neurological diseases such as cerebral ischemia, multiple sclerosis, Parkinson's disease, and Alzheimer's disease (AD). In AD, the role of beta-amyloid (Aß) fragments is well established although still more elusive are the molecular events of the cascade that from the Aß accumulation leads to neurodegeneration with its clinical manifestations. However, it is well known that inflammation and alteration of lipid metabolism are common features of AD brains. Findings obtained from in vitro studies, animal models, and human brain imaging analysis point towards cPLA2 as a key molecule in the onset and maintenance of the neurodegenerative mechanism(s) of AD. In this review, we have focused on the molecular and biological evidence of the involvement of cPLA2s in the pathogenesis of AD. An insight into the molecular mechanism(s) underlying the action and the regulation of cPLA2 is of tremendous interest in the pharmaceutical and biotechnology industry in developing selective and potent inhibitors able to modulate the onset and/or the outcome of AD.

A novel mechanism of action for statins against diabetes-induced oxidative stress.

AIMS/HYPOTHESIS: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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.

Impaired insulin-like growth factor I vasorelaxant effects in hypertension.

Insulin-like growth factor I (IGF-I) can be considered a factor potentially involved in arterial hypertension not only for its growth-promoting features but also for its effects on vascular tone. Nevertheless, the actions of the hormone on vascular reactivity are still unexplored in hypertension. Therefore, the vasodilation induced by increasing doses of IGF-I and the modulation of norepinephrine vasoconstriction induced by low levels of the hormone were tested on aortic rings of spontaneously hypertensive and normotensive rats. The results indicate that the vasodilation evoked by IGF-I is impaired in hypertensive rats (Delta% of maximal vasorelaxation, 30+/-1 versus 41+/-1; P<0.01), and after the removal of endothelium or the inhibition of endothelial NO synthase, the vasodilation evoked by the hormone was blunted in both rat strains and became similar between hypertensive and normotensive rats (Delta% of maximal vasorelaxation, 21+/-1 versus 20+/-1; P=NS). Moreover, IGF-I does not show any effect on norepinephrine vasoconstriction in hypertensive rats, and this alteration may depend on the lack of sensitizing effect exerted by IGF-I on alpha(2)-adrenergic-evoked NO vasorelaxation. The defect in IGF-I vascular action is also present in young spontaneously hypertensive rats (age 5 weeks). In conclusion, our data demonstrate that IGF-I vasorelaxant properties are impaired in spontaneously hypertensive rats, suggesting that such defect may play a causative or permissive role in the development of hypertensive conditions.

Anticuerpos asimétricos: el arma de protección antigénica en la respuesta inmune regulada por Th2 / Asymmetric antibodies: the antigen protective arm in a Th2-regulated immune response

Está bien aceptado que, durante el embarazo, las infecciones por micro organismos extracelulares y los procesos alérgicos -aparte de otras condiciones-, los adultos inmunocompetentes montan respuestas inmunitarias Th2 que implican un aumento de la producción de anticuerpos. Considerando que los anticuerpos son capaces de activar mecanismos inmunitarios efectores tales como la fijación de complemento, el aclaramiento de antígenos y la fagocitosis, un simple desvío de las citocinas implicadas en ese cambio podrían no explicar completamente fenómenos tales como la supervivencia fetal y la cronicidad de ciertas infecciones. Hace unos veinte años que comenzamos nuestras investigaciones sobre anticuerpos asimétricamente glicosilados. Así probamos que la presencia de un carbohidrato extra en una de las regiones Fab de la molécula de IgG, afecta a la interacción con el antígeno y determina su univalencia característica y sus propiedades bloqueantes. En el presente estudio, revisaremos las principales propiedades de este tipo de anticuerpos y reportaremos nuestros hallazgos en distintos procesos fisiopatológicos. (AU)