These results suggest that two key elements in AIDS dementia are massive productive viral infection, involving microglia, neurons, and astrocytes, and concomitant stimulation of cytokine transcription in the neighboring uninfected cells.

Fruit juice is one of the most easily accessible resources for the isolation of plant-derived vesicles. Here we found that micro- and nano-sized vesicles (MVs and NVs) from four Citrus species, C. sinensis, C. limon, C. paradisi and C. aurantium, specifically inhibit the proliferation of lung, skin and breast cancer cells, with no substantial effect on the growth of non-cancer cells. Cellular and molecular analyses demonstrate that grapefruit-derived vesicles cause cell cycle arrest at G2/M checkpoint associated with a reduced cyclins B1 and B2 expression levels and the upregulation of cell cycle inhibitor p21. Further data suggest the inhibition of Akt and ERK signalling, reduced intercellular cell adhesion molecule-1 and cathepsins expressions, and the presence of cleaved PARP-1, all associated with the observed changes at the cellular level. Gas chromatography-mass spectrometry-based metabolomics reveals distinct metabolite profiles for the juice and vesicle fractions. NVs exhibit a high relative amount of amino acids and organic acids whereas MVs and fruit juice are characterized by a high percentage of sugars and sugar derivatives. Grapefruit-derived NVs are in particular rich in alpha–hydroxy acids and leucine/isoleucine, myo-inositol and doconexent, while quininic acid was detected in MVs. Our findings reveal the metabolite signatures of grapefruit-derived vesicles and substantiate their potential use in new anticancer strategies.

Oral-facial-digital (OFD) type I syndrome is an X-linked dominant disease (MIM311200) characterized by malformations of oral cavity, face, and digits and by cystic kidneys. We previously identified OFD1, the gene responsible for this disorder, which encodes for a centrosomal protein with an unknown function. We now report that OFD1 localizes both to the primary cilium and to the nucleus. Moreover, we demonstrate that the OFD1 protein is able to self-associate and that this interaction is mediated by its coiled-coil rich region. Interestingly, we identify an OFD1-interacting protein RuvBl1, a protein belonging to the AAA ؉ -family of ATPases, which has been recently associated to cystic kidney in zebrafish and to ciliary assembly and function in Chlamydomonas reinhardtii. We also provide experimental evidence that OFD1, together with RuvBl1, is able to coimmunoprecipitate with subunits of the human TIP60 histone acetyltransferase (HAT) multisubunit complex. On the basis of these results, we hypothesize that OFD1 may be part of a multi-protein complex and could play different biological functions in the centrosome-primary cilium organelles as well as in the nuclear compartment. INTRODUCTIONOral-facial-digital syndromes (OFDs) are a heterogeneous group of developmental disorders for which nine different forms have been described. OFD type I (MIM311200) presents an X-linked dominant pattern of inheritance with lethality in males (Doege et al., 1964;Wettke Schäfer and Kantner, 1983). Affected females have malformations of oral cavity (cleft palate, lip and tongue, abnormal dentition, and hamartomas), face (hypertelorism and milia), and digits (syndactyly, brachydactyly, and polydactyly), with a highly variable severity even within the same family. Involvement of the CNS includes mental retardation, hydrocephalus, cerebellar anomalies, porencephaly, and agenesis of the corpus callosum (Towfighi et al., 1985;Odent et al., 1998). All these clinical features overlap with those reported in the other forms of OFDs. Among these, type 1 can be easily distinguished for the presence of cystic kidneys, with reports of patients in which the renal involvement completely dominates the clinical course of the disease (Connacher et al., 1987;Feather et al., 1997). We identified the gene, named OFD1, responsible for this genetic disorder, we showed that it is expressed during development and in adult tissues, in all the structures affected in this syndrome.The OFD1 gene encodes a 1011-amino acid protein that shares no sequence homologies with proteins having known function. Five predicted coiled coil domains (hereafter CC) occupy almost the entire length of the molecule (de Conciliis et al., 1998), whereas the N-terminal region shares a Lis1 homology motif (LisH) with over 100 eukaryotic intracellular proteins (Emes and Ponting, 2001). Data from the literature indicate that the alpha-helical CC, despite its simplicity, is a highly versatile folding motif found in proteins with different functions and is described to mediate subunit ol...

Plants produce different types of nano and micro-sized vesicles. Observed for the first time in the 60s, plant nano and microvesicles (PDVs) and their biological role have been inexplicably under investigated for a long time. Proteomic and metabolomic approaches revealed that PDVs carry numerous proteins with antifungal and antimicrobial activity, as well as bioactive metabolites with high pharmaceutical interest. PDVs have also been shown to be also involved in the intercellular transfer of small non-coding RNAs such as microRNAs, suggesting fascinating mechanisms of long-distance gene regulation and horizontal transfer of regulatory RNAs and inter-kingdom communications. High loading capacity, intrinsic biological activities, biocompatibility, and easy permeabilization in cell compartments make plant-derived vesicles excellent natural or bioengineered nanotools for biomedical applications. Growing evidence indicates that PDVs may exert anti-inflammatory, anti-oxidant, and anticancer activities in different in vitro and in vivo models. In addition, clinical trials are currently in progress to test the effectiveness of plant EVs in reducing insulin resistance and in preventing side effects of chemotherapy treatments. In this review, we concisely introduce PDVs, discuss shortly their most important biological and physiological roles in plants and provide clues on the use and the bioengineering of plant nano and microvesicles to develop innovative therapeutic tools in nanomedicine, able to encompass the current drawbacks in the delivery systems in nutraceutical and pharmaceutical technology. Finally, we predict that the advent of intense research efforts on PDVs may disclose new frontiers in plant biotechnology applied to nanomedicine.