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Balducci, C.

Publications and source records attributed to Balducci, C..

2 recordsLinked to original sources
bioRxiv2020

A2E induces the transactivation of RARs, PPARs and RXRs and its effects are counteracted by norbixin in retinal pigment epithelium cells in vitro

N-retinylidene-N-retinylethanolamine (A2E) plays a central role in age-related macular degeneration (AMD) by inducing apoptosis, angiogenesis and inflammation. It has been proposed that A2E effects are mediated at least partly via the retinoic acid receptor (RAR)-. Here we show that A2E binds and transactivates not only RARs, but also peroxisome proliferator-activated receptors (PPARs) and retinoid X receptors (RXRs). Norbixin, which protects retinal pigment epithelium (RPE) cells against apoptosis induced by combined blue light illumination and A2E exposure, is also a ligand of these nuclear receptors (NRs) but does not induce their transactivation. Norbixin inhibits RXRs and PPARs but enhances RARs transactivation induced by A2E. Norbixin also inhibits PPAR-{gamma} transactivation induced by its high affinity ligand troglitazone. Photoprotection of RPE cells by norbixin correlates with maintained levels of the antiapoptotic B-cell lymphoma 2 (Bcl2) protein. Moreover, norbixin reduces protein kinase B (AKT) phosphorylation, NF-{kappa}B and activator protein 1 (AP-1) transactivation, and the mRNA expression of the inflammatory interleukins (IL) 6 and 8 and of vascular endothelial growth factor (VEGF) that are enhanced by A2E. By contrast, norbixin increases matrix metalloproteinase 9 (MMP9) and C-C motif chemokine ligand 2 (CCL2) mRNA expression but has neither effect on extracellular signal-regulated kinase (ERK) phosphorylation, nor on IL-18 mRNA expression in response to A2E. Altogether, we show for the first time that A2E deleterious biological effects appear to be mediated through RARs, PPARs and RXRs. Moreover, we report that the modulation of these NRs by norbixin may open new avenues for the treatment of AMD.

cell biology↗
bioRxiv2020

Deletion of calcineurin from astrocytes reproduces proteome signature of Alzheimer's disease and epilepsy and predisposes to seizures

In astrocytes, calcineurin (CaN) is involved in neuroinflammation and gliosis, while its role in healthy CNS or in early neuro-pathogenesis is poorly understood. Here we report that in astroglial CaN KO (ACN-KO) mice, at one month of age, proteome is deranged in hippocampus and cerebellum. Bioinformatic analysis reveals association with Alzheimers disease (AD) and epilepsy. We found significant overlap with the proteome of an AD mouse model and of human subjects with drug-resistant epilepsy. In Barnes maze ACN-KO mice learned the task but adopted serial search strategy. Strikingly, from five months of age ACN-KO mice develop spontaneous seizures with an inflammatory signature of epileptic brains. These results suggest that astroglial CaN KO impairs hippocampal connectivity, produces proteome features of neurological disorders and predisposes mice to seizures. We suggest that astroglial CaN may serve as a novel Ca2+-sensitive switch which regulates protein expression and homeostasis in the CNS.

neuroscience↗