An epistatic mini-circuitry between the transcription factors Snail and HNF4a controls liver stem cell and hepatocyte features exhorting opposite regulation on stemness-inhibiting microRNAs

Preservation of the epithelial state involves the stable repression of EMT program while maintenance of the stem compartment requires the inhibition of differentiation processes. A simple and direct molecular mini-circuitry between master elements of these biological processes, may provide the best device to keep balanced such complex phenomena. In this work, we show that in hepatic stem cell Snail, a transcriptional repressor of the hepatocyte differentiation master gene HNF4, directly represses the expression of the epithelial microRNAs-200c and -34a, which in turn target several stem cell genes. Notably, in differentiated hepatocytes HNF4, previously identified as a transcriptional repressor of Snail, induces the microRNAs-34a and -200a, b, c that, when silenced, causes epithelial dedifferentiation and reacquisition of stem traits. Altogether these data unveiled Snail, HNF4 and microRNAs -200a, b, c and -34a as epistatic elements controlling hepatic stem cell maintenance/differentiation

Extracellular vesicle microRNAs contribute to the osteogenic inhibition of mesenchymal stem cells in multiple myeloma

Osteolytic bone disease is the major complication associated with the progression of multiple myeloma (MM). Recently, extracellular vesicles (EVs) have emerged as mediators of MM-associated bone disease by inhibiting the osteogenic differentiation of human mesenchymal stem cells (hMSCs). Here, we investigated a correlation between the EV-mediated osteogenic inhibition and MM vesicle content, focusing on miRNAs. By the use of a MicroRNA Card, we identified a pool of miRNAs, highly expressed in EVs, from MM cell line (MM1.S EVs), expression of which was confirmed in EVs from bone marrow (BM) plasma of patients affected by smoldering myeloma (SMM) and MM. Notably,we found that miR-129-5p, which targets different osteoblast (OBs) differentiation markers, is enriched in MM-EVs compared to SMM-EVs, thus suggesting a selective packaging correlated with pathological grade. We found that miR-129-5p can be transported to hMSCs by MM-EVs and, by the use of miRNA mimics, we investigated its role in recipient cells. Our data demonstrated that the increase of miR-129-5p levels in hMSCs under osteoblastic differentiation stimuli inhibited the expression of the transcription factor Sp1, previously described as a positive modulator of osteoblastic differentiation, and of its target the Alkaline phosphatase (ALPL), thus identifying miR-129-5p among the players of vesicle-mediated bone disease

Sull'antagonismo in vivo ed in vitro di Acremonium byssoides, endofita in Vitis vinifera, nei confronti di Plasmopara viticola

Lo studio dell\u2019interazione fra Acremonium byssoides, Vitis vinifera e Plasmopara viticola, condotto nell\u2019ultimo decennio, ha evidenziato in vitro e in vivo l\u2019attivit\ue0 antagonistica dell\u2019ifomicete, endofita negli organi verdi di alcune cultivars di vite, nei confronti del patogeno. In particolare, \ue8 stato accertato che sospensioni conidiche, filtrati colturali, estratti grezzi e metaboliti di A. byssoides riducono sensibilmente la germinazione delle spore agamiche e gamiche di P. viticola, limitando la produzione di propaguli. Inoltre, l\u2019uso di un microscopio laser confocale e l\u2019impiego di un\u2019opportuna tecnica di decolorazione dei tessuti fogliari, seguita da colorazione di contrasto, ha consentito di visualizzare l\u2019ifomicete, latente nelle nervature di foglie sane e iperparassita dell\u2019oomicete in foglie infette. In queste ultime, infatti, A. byssoides, dopo aver prodotto metaboliti secondari tossici per P. viticola, ne invade e degrada micelio, rami sporangiofori e spore gamiche. Tale attivit\ue0 antagonistica, determinando il contenimento sia della diffusione che della sopravvivenza del patogeno, pu\uf2 assumere, quindi, un ruolo rilevante nella definizione di strategie di difesa biologica contro la peronospora della vite

Rapamycin-loaded polymeric nanoparticles as an advanced formulation for macrophage targeting in atherosclerosis

Recently, rapamycin (Rapa) represents a potential drug treatment to induce regression of atherosclerotic plaques; however, its use requires site-specific accumulation in the vessels involved in the formation of the plaques to avoid the systemic effects resulting from its indiscriminate biodistribution. In this work, a stable pharmaceutical formulation for Rapa was realized as a dried powder to be dispersed extemporaneously before administration. The latter was constituted by man-nitol (Man) as an excipient and a Rapa-loaded polymeric nanoparticle carrier. These nanoparticles were obtained by nanoprecipitation and using as a starting polymeric material a polycaprolactone (PCL)/α,β-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) graft copolymer. To obtain nanoparti-cles targeted to macrophages, an oxidized phospholipid with a high affinity for the CD36 receptor of macrophages, the 1-(palmitoyl)-2-(5-keto-6-octene-dioyl) phosphatidylcholine (KOdia-PC), was added to the starting organic phase. The chemical–physical and technological characterization of the obtained nanoparticles demonstrated that: both the drug loading (DL%) and the entrapment efficiency (EE%) entrapped drug are high; the entrapped drug is in the amorphous state, protected from degradation and slowly released from the polymeric matrix; and the KOdia-PC is on the nanoparticle surface (KP-Nano). The biological characterization demonstrated that both systems are quickly internalized by macrophages while maintaining the activity of the drug. In vitro studies demonstrated that the effect of KP-Nano Rapa-loaded, in reducing the amount of the Phospo-Ser757-ULK1 protein through the inhibition of the mammalian target of rapamycin (mTOR), is comparable to that of the free drug

The association between dyslipidemia and lethality of suicide attempts: A case-control study

Evidence supports the existence of an association between dyslipidemia, psychiatric disorders, and suicide risk due to the effects of altered lipid profiles on serotoninergic neuron membranes. The aim of this study was to investigate the differences in c-reactive protein (CRP), thyroid functioning, total cholesterol, high lipoprotein density cholesterol (HDL-c), low-lipoprotein density cholesterol (LDL-c), and triglycerides (TG) serum levels in low lethality (LLSA) vs. high lethality suicide attempters (HLSA) within 24 h fromthe suicide attempt and inpatients who never attempted suicide (NAS). After attempting suicide, subjects were admitted to the emergency ward of the IRCCS Ospedale Policlinico San Martino and later to the section of Psychiatry from 1st August 2013 to 31st July 2018. Socio-demographic and clinical characteristics, serum lipids profile, CRP, and thyroid functioning were collected. The sample consisted of 133 individuals with a HLSA, 299 subjects with LLSA, and 200 patients NAS. HLSA subjects were more likely to be males and diagnosed as having a bipolar disorder. Furthermore, HLSA subgroup showed significantly lower total cholesterol and LDL-c levels and higher CRP serum levels compared to LLSA and control group, respectively. LLSA subgroup showed higher HDL-c levels compared to HLSA subgroup (no differences between HLSA and control group were observed). Additionally, the control group reported higher triglycerides levels compared to patients admitted to psychiatric ward for a suicide attempt. Only male gender, having a diagnosis of bipolar disorder, lower total cholesterol, and higher CRP serum levels predicted HLSA. Investigating the relation between dyslipidemia and the severity of suicide attempts may contribute to reveal the complex determinants underlying at-risk behaviors such as suicide, thus playing a relevant role in the possible prevention of this disabling phenomenon

The Relationship Between Bullying Victimization and Perpetration and Non-suicidal Self-injury: A Systematic Review

Experience of bullying may be a significant risk factor for non-suicidal self-injury (NSSI). This study had three aims: to systematically investigate the association between bullying and NSSI, analyze the possible mechanisms underlying the two phenomena, and evaluate any differences between bullying victimization and bullying perpetration with respect to NSSI. A systematic search about the association between bullying victimization and perpetration and NSSI was conducted using specific databases (PubMed, Scopus, Science Direct). The following keywords were used in all database searches: "bullying" AND "NSSI" OR "peer victimization" and NSSI. The searches in PubMed, Scopus and Science Direct revealed a total of 88 articles about bullying or peer victimization and NSSI. However, only 29 met our inclusion criteria and were used for the present review. Overall, all studies examined victimization; four studies also evaluated the effects of perpetration and one included bully-victims. According to the main findings, both being a victim of bullying and perpetrating bullying may increase the risk of adverse psychological outcomes in terms of NSSI and suicidality in the short and the long run. To the best of our knowledge, this is the first review to systematically evaluate the relation between bullying victimization/perpetration and NSSI. The main results support a positive association. Future research should evaluate the possible role of specific mediators/moderators of the association between experience of bullying and NSSI

The role of seasonality and photoperiod on the lethality of suicide attempts: A case-control study

Background: The risk factors related to suicidal behaviors are complex and not yet fully known. Several studies underline how suicide results from the combination of psycho-social, biological, cultural, and environmental factors. The aim of this study was to investigate the potential role of seasonality and photoperiod on high-lethality suicide attempts (HLSA) compared with low-lethality suicide attempts (LLSA) in a sample of psychiatric inpatients. Methods: After attempting suicide, subjects were admitted in the emergency/psychiatric ward of the IRCCS Ospedale Policlinico San Martino from 1st August 2013 to 31st July 2018. Socio-demographic and clinical characteristics were collected. Results: The sample consisted of four hundred thirty-two individuals admitted for suicide attempt. One hundred thirty-three subjects (30.8%) of the sample committed a HLSA. The HLSA group peaked in the months with a higher sunlight exposure (June and July). Bivariate correlation analyses between seasonality/photoperiod in the whole sample and HLSA were positively associated with summer and highest solar intensity period. Limitations: Data were limited to a single hospital, patients’ seasonal environment, meteorological variables and psychological factors. In addition, the presence of acute life-events fostering the suicidal crisis has not been investigated. Conclusions: The current study provides a novel perspective on the questions surrounding the impact of seasonality and daylight exposure on lethality of suicide attempts. further studies are needed to provide deeper understandings on the delicate molecular network that links suicide behaviors, seasonality and daylight in order to develop more effective prevention and treatment strategies in the future

Restoration of peripheral blood natural killer and B cell levels in patients affected by rheumatoid and psoriatic arthritis during etanercept treatment

Etanercept (ETN) is an anti-tumour necrosis factor (TNF)-α agent used in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Few studies focused on the effects of anti-TNF-α on peripheral blood cells. We aimed to evaluate peripheral blood cells in RA and PsA patients during ETN treatment and to explore their relationships with disease activity. RA (n = 82) and PsA (n = 32) patients who started ETN were included into the study and evaluated prospectively before the beginning of ETN therapy and after 14, 22, 54 and 102 weeks. Patients were studied in terms of disease activity score on 28 joints (DAS28), clinical response and laboratory findings. Natural killer (NK) cells, B cells and T cells were characterized by immunophenotyping. Both the RA and the PsA patients showed reduced NK and B cell count before ETN treatment compared with controls. A negative correlation was demonstrated between DAS28 and B cell count in RA patients at baseline. Sustained significant increase of NK and B cells up to normal levels was observed in RA and PsA patients along ETN treatment. Increase of NK cell count was associated with a good-moderate clinical response to ETN in both RA and PsA patients. During ETN treatment peripheral blood NK and B cells levels were restored in RA and PsA patients. Correlations between NK and B cells with disease activity were observed, suggesting that those effects could be mediated by ETN treatment.Etanercept (ETN) is an anti-tumour necrosis factor (TNF)-α agent used in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Few studies focused on the effects of anti-TNF-α on peripheral blood cells. We aimed to evaluate peripheral blood cells in RA and PsA patients during ETN treatment and to explore their relationships with disease activity. RA (n = 82) and PsA (n = 32) patients who started ETN were included into the study and evaluated prospectively before the beginning of ETN therapy and after 14, 22, 54 and 102 weeks. Patients were studied in terms of disease activity score on 28 joints (DAS28), clinical response and laboratory findings. Natural killer (NK) cells, B cells and T cells were characterized by immunophenotyping. Both the RA and the PsA patients showed reduced NK and B cell count before ETN treatment compared with controls. A negative correlation was demonstrated between DAS28 and B cell count in RA patients at baseline. Sustained significant increase of NK and B cells up to normal levels was observed in RA and PsA patients along ETN treatment. Increase of NK cell count was associated with a good-moderate clinical response to ETN in both RA and PsA patients. During ETN treatment peripheral blood NK and B cells levels were restored in RA and PsA patients. Correlations between NK and B cells with disease activity were observed, suggesting that those effects could be mediated by ETN treatment

Antiphospholipid reactivity against cardiolipin metabolites occurring during endothelial cell apoptosis.

We have recently shown that cardiolipin (CL) and its metabolites move from mitochondria to other cellular membranes during death receptor-mediated apoptosis. In this study, we investigate the immunoreactivity to CL derivatives occurring during endothelial apoptosis in patients with antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). We compared the serum immunoreactivity to CL with that of its derivatives monolysocardiolipin (MCL), dilysocardiolipin (DCL), and hydrocardiolipin (HCL) by means of both enzyme-linked immunosorbent assay and thin-layer chromatography (TLC) immunostaining. In addition, we investigated the composition of phospholipid extracts from the plasma membrane of apoptotic endothelial cells and the binding of patients' sera to the surface of the same cells by using high-performance TLC and immunofluorescence analysis. The average reactivity to MCL was comparable with that of CL and significantly higher than that for DCL and HCL in patients studied, both in the presence or in the absence of beta2-glycoprotein I. Of relevance for the pathogenic role of these autoantibodies, immunoglobulin G from patients' sera showed an increased focal reactivity with the plasma membrane of endothelial cells undergoing apoptosis. Interestingly, the phospholipid analysis of these light membrane fractions showed an accumulation of both CL and MCL. Our results demonstrated that a critical number of acyl chains in CL derivatives is important for the binding of antiphospholipid antibodies and that MCL is an antigenic target with immunoreactivity comparable with CL in APS and SLE. Our finding also suggests a link between apoptotic perturbation of CL metabolism and the production of these antibodies

Preliminary results of citraves™ effects on low density lipoprotein cholesterol and waist circumference in healthy subjects after 12 weeks: A pilot open-label study

Appropriate monitoring and control of modifiable risk factors, such as the level of lowdensity lipoprotein cholesterol (LDL-C) and other types of dyslipidemia, have an important role in the prevention of cardiovascular diseases (CVD). Recently, various nutraceuticals with lipid-lowering effects have gained attention. In addition to the plant-derived bioactive compounds, recent studies suggested that plant cells are able to release small lipoproteic structures named extracellular vesicles (EVs). The interaction between EVs and mammalian cells could lead to beneficial effects through anti-inflammatory and antioxidant activities. The present study aimed to assess the safety of the new patented plant-based product citraVes™, containing extracellular vesicles (EVs) from Citrus limon (L.) Osbeck juice, and to investigate its ability to modulate different CV risk factors in healthy subjects. A cohort of 20 healthy volunteers was recruited in a prospective open-label study. All participants received the supplement in a spray-dried formulation at a stable dose of 1000 mg/day for 3 months. Anthropometric and hematobiochemical parameters were analyzed at the baseline and after the follow-up period of 1 and 3 months. We observed that the supplement has an effect on two key factors of cardiometabolic risk in healthy subjects. A significant change in waist circumference was found in women after 4 (85.4 [79.9, 91.0] cm, p < 0.005) and 12 (85.0 [80.0, 90.0] cm, p < 0.0005) weeks, when compared to the baseline value (87.6 [81.7, 93.6] cm). No difference was found in men (baseline: 100.3 [95.4, 105.2] cm; 4 weeks: 102.0 [95.7, 108.3] cm; 12 weeks: 100.0 [95.3, 104.7] cm). The level of LDL-C was significantly lower at 12 weeks versus 4 weeks (p = 0.0064). Our study evaluated, for the first time, the effects of a natural product containing plant-derived EVs on modifiable risk factors in healthy volunteers. The results support the use of EV extracts to manage cardiometabolic risk factors successfully