Is autophagy the key mechanism by which the sphingolipid rheostat controls the cell fate decision?

Sphingolipids are major constituents of biological membrane and some of them behave as second messengers involved in the cell fate decision. Ceramide and sphingosine 1-phosphate (S1P) constitute a rheostat system in which ceramide promotes cell death and S1P increases cell survival. We have shown that both sphingolipids are able to trigger autophagy with opposing outcomes on cell survival. Here we discuss and speculate on the diverging functions of the autophagic pathways induced by ceramide and S1P, respectively

Cefiderocol- Compared to Colistin-Based Regimens for the Treatment of Severe Infections Caused by Carbapenem-Resistant Acinetobacter baumannii

Cefiderocol may represent a therapeutic option for carbapenem-resistant Acinetobacter baumannii (CRAB) infections, but clinical data are limited. This is an observational retrospective study conducted in the University Hospital of Pisa including consecutive patients with CRAB infections (January 2020 to August 2021). Patients were divided in two study groups according to the antibiotic treatment received: cefiderocol- and colistin-containing regimens. The primary outcome was the 30-day mortality. A Cox regression analysis was performed to identify factors independently associated with 30-day mortality. A propensity score analysis using inverse probability of treatment weighting (IFTW) was also performed. A total of 124 patients were included: 47 (37.9%) received cefiderocol, while 77 (62.1%) colistin-containing regimens. Overall, 79 (63.7%) patients had a bloodstream infection (BSI), 35 (285%) a ventilator-associated pneumonia NAP) and 10 (8.1%) other infections. Thirty-day mortality was higher in patients receiving colistin- compared to those who received cefiderocol-containing regimens (55.8% versus 34%, P = 0.018). This difference was confirmed in patients with BSI, but not in those with VAR On multivariable analysis, septic shock, SOFA score, and age were independently associated with 30-day mortality, while cefiderocol therapy was protective in an IPTW analysis (Hazard ratio 0.44, 95% confidence interval 0.22-0.66, P < 0.001). Nephrotoxicity was more common in the colistin group. Microbiological failure occurred in 17.4% of patients receiving cefiderocol versus 6.8% of those receiving colistin (P = 0.079). Among 8 cases in the cefiderocol group who experienced microbiological failure, 4 (50%) developed resistance to cefiderocol. Cefiderocol represents a promising therapeutic option in patients with severe CRAB infections. Randomized clinical trial in this specific patient population should confirm our findings

Disruption of Retinoic Acid Receptor Alpha Reveals the Growth Promoter Face of Retinoic Acid

Retinoic acid (RA), the bioactive derivative of Vitamin A, by epigenetically controlling transcription through the RA-receptors (RARs), exerts a potent antiproliferative effect on human cells. However, a number of studies show that RA can also promote cell survival and growth. In the course of one of our studies we observed that disruption of RA-receptor alpha, RARalpha, abrogates the RA-mediated growth-inhibitory effects and unmasks the growth-promoting face of RA (Ren et al., Mol. Cell. Biol., 2005, 25:10591). The objective of this study was to investigate whether RA can differentially govern cell growth, in the presence and absence of RARalpha, through differential regulation of the "rheostat" comprising ceramide (CER), the sphingolipid with growth-inhibitory activity, and sphingosine-1-phosphate (S1P), the sphingolipid with prosurvival activity.We found that functional inhibition of endogenous RARalpha in breast cancer cells by using either RARalpha specific antagonists or a dominant negative RARalpha mutant hampers on one hand the RA-induced upregulation of neutral sphingomyelinase (nSMase)-mediated CER synthesis, and on the other hand the RA-induced downregulation of sphingosine kinase 1, SK1, pivotal for S1P synthesis. In association with RA inability to regulate the sphingolipid rheostat, cells not only survive, but also grow more in response to RA both in vitro and in vivo. By combining genetic, pharmacological and biochemical approaches, we mechanistically demonstrated that RA-induced growth is, at least in part, due to non-RAR-mediated activation of the SK1-S1P signaling.In the presence of functional RARalpha, RA inhibits cell growth by concertedly, and inversely, modulating the CER and S1P synthetic pathways. In the absence of a functional RARalpha, RA-in a non-RAR-mediated fashion-promotes cell growth by activating the prosurvival S1P signaling. These two distinct, yet integrated processes apparently concur to the growth-promoter effects of RA

Le potenzialità della filiera foresta-legno in Sicilia

Dalla seconda metà del secolo scorso il patrimonio forestale della Sicilia è aumentato in termini di superficie. L’aumento recente è stato favorito dai processi di rinaturalizzazione degli ex coltivi e dei pascoli e dalla disponibilità di fondi europei per i rimboschimenti e l’arboricoltura da legno, insieme all’adozione di nuove politiche rivolte alla sostenibilità ambientale. Tuttavia, tale incremento della risorsa nella maggior parte dei casi non è stato un affiancato da uno sviluppo delle politiche e delle azioni mirate a promuovere la gestione forestale, tantomeno la valorizzazione dei prodotti legnosi e non. Tale carenza di politiche efficaci nel contesto italiano, in particolare l’applicazione nel territorio siciliano, dove il tasso di produzione interna di legno è tra i più bassi in Europa, si è verificata non solo riguardo la produzione ma anche la tutela dell’assetto idrogeologico e la difesa del territorio. L’anello più debole della filiera legno in Sicilia è quello che riguarda le prime fasi della catena produttiva, dalla gestione della risorsa forestale stessa ai settori delle utilizzazioni e della prima trasformazione. Ciò è dovuto principalmente alla carenza di infrastrutture e in particolare di un’adeguata viabilità forestale, ma anche al limitato valore qualitativo degli attuali prodotti e alla domanda di materia prima legnosa nettamente superiore rispetto all’offerta interna, oltre alla presenza di una elevata e stabile offerta estera di materiale spesso qualitativamente superiore importato a prezzi competitivi. Inoltre la filiera foresta-legno in Sicilia presenta fondamentalmente un grave deficit nell’organizzazione e nel coordinamento fra i diversi segmenti che la compongono, caratterizzati da gradi di sviluppo diversi. Tuttavia, la filiera produttiva legata alla risorsa legno, presenta importanti opportunità di crescita e sviluppo dal punto di vista produttivo e occupazionale, sia a monte che a valle della filiera stessa, motivo per cui si dovrebbe intervenire sulla pianificazione e gestione delle stesse, al fine di incentivare l’utilizzo della materia prima locale ed al contempo informare i protagonisti del settore dei vantaggi economici che possono trarre da tali possibilità. Scopo del presente lavoro è quello di analizzare il consumo e le potenzialità del legno in Sicilia attraverso indagini di settore e territoriali. La raccolta dei dati è stata effettuata tramite la consultazione di dati ISTAT, Camera di Commercio e associazioni di categoria, tra cui FederLegno. Sono state analizzati i dati disponibili sui consumi regionali di legno e l’identificazione e distribuzione sul territorio siciliano di aziende di utilizzazione e trasformazione del legno. Nonostante la scarsa rappresentatività dei dati e la difficoltà nel reperimento degli stessi è stato delineato un quadro generale del settore relativo all’utilizzazione, al commercio e alla trasformazione del legno in Sicilia

Inhibitory Effect of Aureobasidin A on Toxoplasma gondii

The apicomplexan parasite Toxoplasma gondii is a leading opportunistic pathogen associated with AIDS and congenital birth defects. Due to the need for identifying new parasite-specific treatments, the possibility of targeting sphingolipid biosynthesis in the parasite was investigated. Aureobasidin A, an inhibitor of the enzyme synthesizing the sphingolipid inositol phosphorylceramide, which is present in fungi, plants, and some protozoa but absent in mammalian cells, was found to block in vitro T. gondii replication without affecting host cell metabolism. Aureobasidin A treatment did not induce tachyzoite to bradyzoite stage conversion in T. gondii but resulted in a loss of intracellular structures and vacuolization within the parasite. In addition, aureobasidin A inhibited sphingolipid synthesis in T. gondii. Sphingolipid biosynthetic pathways may therefore be considered targets for the development of anti-T. gondii agents

Is autophagy the key mechanism by which the sphingolipid rheostat controls the cell fate decision?

Sphingolipids are major constituents of biological membrane and some of them behave as second messengers involved in the cell fate decision. Ceramide and sphingosine 1-phosphate (S1P) constitute a rheostat system in which ceramide promotes cell death and S1P increases cell survival. We have shown that both sphingolipids are able to trigger autophagy with opposing outcomes on cell survival. Here we discuss and speculate on the diverging functions of the autophagic pathways induced by ceramide and S1P, respectively