Archivio Istituzionale della Ricerca- Università del Piemonte Orientale
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Gliadin-dependent UPR induction directly triggers the expression of TG2 and pro-inflammatory cytokines, dysregulates intestinal permeability, and reduces CFTR expression in intestinal epithelial cells of celiac disease patients
Full text linkBackground: Celiac disease (CD) is an autoimmune disorder that primarily affects the gut of genetically predisposed individuals and is triggered by gliadin peptides (PT) produced by the digestion of gluten. Although inappropriate activation of the immune system is thought to be the main trigger of CD, the interaction between PT and intestinal epithelial cells (IECs) remains a key step. Recently, the possible involvement of ER stress in the pathogenesis of CD has been pointed out, although its role is still largely unclear. Therefore, discovering the molecular mechanism(s) activated in IECs exposed to PT represents a unique opportunity to better understand the disease and define new potential therapeutic targets. Methods: In this study we used three different experimental set-ups: intestinal biopsies from CD patients and non-CD control subjects, an in vitro model, based on human CaCo-2 cells, and an ex vivo model, based on our recently described mouse gut-ex-vivo system (GEVS), with the latter two systems were studied after stimulation with gliadin peptides (PT). To understand the signaling pathways involved we monitor the expression of a number of proteins by qPCR, Western blotting, IF, ELISA or a combination of tests. Specifically, we have analyzed the level of CD, ER stress, tissue permeability, and inflammation markers. Results: Indeed, our study demonstrated a prompt induction of the transcription factors ATF4, ATF6 and XBP1 in IECs upon PT exposure. Thus, the upregulation of TG2 and downregulation of CFTR were prevented by ER stress inhibition/buffering by a pharmacological chaperone, also leading to restored physiological expression of OCL, CLD-2 and CLD-15, while preventing the expression of IFNγ, IL-15 and IL-17 A. Conclusion: Overall, our analysis has highlighted the key role of ER stress in the pathogenesis of CD and identified the chemical chaperones as a new potential valuable therapeutic treatment for CD patients
A reliable, green and fast two-step solid-phase extraction methodology for the obtention of anthocyanin-rich extracts from different sources
No full textDuring the last few years, researchers have been focusing of strategies to recover and purify anthocyanins, from simple liquid-liquid extractions to more advanced supercritical CO2 extractions, however, with such a huge number of different sources, it’s extremely hard to get a simple and fast methodology that fits several sources, not only by the structural nature of the anthocyanins but also by the presence of specific groups of natural compounds. Using simple methodologies like solid-phase extraction resins combined with the use of green solvents, represents a powerful economical and efficient strategy. In this work, we tested several sources of structurally distinct anthocyanins, including purple basil, purple cabbage, purple sweet potato, butterfly pea flower, cornflower and wild pansy, in different resins, to assess their efficiency in the obtention of anthocyanin-pure extracts using acidified water-ethyl acetate-ethanol and water-ethyl acetate-methanol. The results showed us that the combination of Oasis HLB® resin followed by a cation-exchange SPE with DSC-MCAX® resulted in high-purity anthocyanin extracts for all the cases. Also, the overall efficiency of the greener approach water-ethyl acetateethanol did not compromise the efficacy of the system when compared to methanol, encouraging of this solvent rather than less environmentally friendly and more toxic alternatives
Bioaccessibility of phenolic compounds during simulated gastrointestinal digestion of black rice (Oryza sativa L., cv. Artemide)
No full textBlack rice can be defined as a natural functional food, due to its high content of antioxidant polyphenols, particularly anthocyanins and phenolic acids. The objective of this study was to assess the fate of the main phenolic compounds in cooked black rice through in vitro digestion, defining both their soluble and insoluble fractions at the different digestive phases. The digestion significantly impacted the stability of the molecules, more specifically anthocyanins, which tend to be stable up to the gastric level and then degrade during the intestinal phase; after gastrointestinal digestion the total recovery of cyanidin-3-O-glucoside, the most abundant anthocyanin, was 52.4 %. On the other hand, bioaccessibility of free phenolic acids progressively increases up to the intestinal phase, with a total recovery of protocatechuic acid, the most represented phenolic acid in free form, of 84.3 %. Finally bound phenolic acids were not significantly released during the digestive phases
Right ventricular strain predicts outcome in patients receiving sacubitril/valsartan: A sub-analysis of DISCOVER-ARNI
No full textAimsAngiotensin receptor/neprilysin inhibitors (ARNI) have emerged as a pivotal medical treatment considerably improving the clinical outcome of patients with heart failure and reduced ejection fraction (HFrEF). Identifying individuals who stand to benefit the most from ARNI could markedly enhance patient management strategies. The aim of this sub-analysis of DISCOVER-ARNI register was to evaluate the prospective prognostic significance of speckle tracking echocardiography (STE) parameters in patients undergoing ARNI therapy.Methods and resultsDISCOVER-ARNI multicentre Italian register retrospectively enrolled 341 patients with HFrEF referred for treatment with ARNI. These patients underwent clinical, biohumuoral, and echocardiographic assessment at baseline. Subsequently, among those with available right ventricular STE data, a prospective long-term follow-up was conducted by telephone interview or on-site visits. The primary endpoint encompassed a composite of outcomes, including all-cause or cardiovascular mortality, heart failure hospitalization, heart transplantation, and left ventricular assist device (LVAD) implantation. Overall, 136 HFrEF patients were included in this sub-analysis (mean age 65 +/- 10 years, 82% male). The mean follow-up was 40 +/- 18 months, during which 32 patients reached the primary endpoint (14 deaths of which 10 due to cardiovascular reasons, 22 hospitalization, 3 heart transplantation, 1 LVAD implantation). Baseline assessment revealed that patients with events had higher LV volumes and EF (LV end-diastolic volume 212 +/- 65 vs.174 +/- 57 mL, P = 0.002; LV end-systolic volume 156 +/- 52 vs. 122 +/- 49 mL, P = 0.001; LV EF = 26 +/- 5 vs. 29 +/- 5 mL, P = 0.006, respectively), lower but preserved tricuspid annular plane systolic excursion (TAPSE, 17 +/- 3 vs.19 +/- 3, P = 0.008), and higher systolic pulmonary artery pressures (38 +/- 11 vs. 31 +/- 8 mmHg, P = 0.001) compared to those who did not experience events. LV, left atrial (LA), and free wall right ventricular longitudinal strain (fwRVLS) were reduced in patients with events (-7 +/- 2 vs. -8 +/- 2%, P = 0.002; 11 +/- 3 vs. 15 +/- 7%, P = 0.001 and -15 +/- 5 vs. -22 +/- 5%, P = 0.007, respectively). Employing Cox proportional hazard model including LVEF, TAPSE, RVFAC, LV strain, LA strain, and fwRVLS, the latest emerged as the sole independent predictor of the combined endpoint (hazard ratio = 1.15 [1.05;1.26], P = 0.002). Receiver operating characteristic (ROC) curves determined that fwRVLS = -20% was the optimal cut-off for predicting the combined endpoint (area under curve [AUC] = 0.70). This threshold was used for constructing Kaplan-Meier survival curves, demonstrating effective risk stratification of fwRVLS over long-term follow-up for the primary endpoint.ConclusionsfwRVLS by STE holds promise as a valuable parameter to assess response to ARNI therapy in terms of overall survival, heart failure hospitalizations, heart transplantation, or LVAD implantation
Biological pathways and mechanisms linking COPD and cardiovascular disease
No full textCardiovascular disease (CVD) still poses a significant risk for morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). For a long time, among functional parameters, only the forced expiratory volume in 1 s (FEV1) has been considered as predictive of cardiovascular (CV) mortality especially in elderly patients in fact, there is evidence that reductions in lung function indices can increase the risk of ischaemic heart diseases and cerebrovascular diseases, independently from other risk factors. Now, there is considerable evidence suggesting that hypoxemia, systemic inflammation, oxidative stress and hyperinflation may lead to an early sub-clinical CV involvement in patients affected by COPD. Ageing in itself impacts specific aspects of the CV system, including reduced beta-adrenergic responsiveness, increased vagal tone and myocardial and vascular stiffness, endothelial dysfunction, diminished arterial baroreflex and compromised diastolic function. The complex involved interactions include ageing mechanisms as well as multiple known and unknown (e.g. genetic) risk factors. CVDs are leading causes of mortality in individuals with impaired lung function and the two entities commonly coexist with poor outcomes in patients experiencing both conditions. However, the precise mechanisms responsible for this association remain largely unknown. In this narrative review, we summarize current knowledge regarding the co-occurrence of COPD and CVD focusing on the shared biological pathways and biological mechanisms involved in these conditions
Venetoclax therapy in chronic lymphocytic leukaemia patients relapsed after allogeneic haematopoietic stem cell transplantation
No full textAllogeneic hematopoietic stem cell transplantation (alloHSCT) remains an option for young and fit chronic lymphocytic leukaemia (CLL) patients with high-risk disease features. However, allotransplanted patients are generally excluded from clinical trials, making data regarding the use of venetoclax after alloHSCT extremely rare. We report data from 7 CLL patients who received venetoclax after alloHSCT among 53 Italian centers. These patients underwent alloHSCT between 2006 and 2021 after failing chemoimmunotherapy (7/7), ibrutinib (5/7) and/or idelalisib (1/7). Of note, 3/7 patients had already received venetoclax-based therapy before alloHSCT. Post-allo HSCT venetoclax treatment resulted safe, with adverse events not different from what reported in clinical trials. Importantly, no meaningful impact on graft versus host disease (GvHD) course was observed: 4/7 patients with pre-existing chronic GvHD had no exacerbation after venetoclax start, and only one patient developed GvHD during venetoclax therapy, that was managed as per standard clinical practice. Concerning efficacy, 5/7 patients presented a clinical response to venetoclax, with two patients achieving an undetectable minimal residual disease. To our knowledge, this is the largest reported series of CLL patients treated with venetoclax after alloHSCT. In these heavily pretreated and high-risk patients, previous alloHSCT did not compromise the feasibility of venetoclax therapy, that lacked unexpected toxicities and did not exacerbate GvHD
Intertemporal Mahalanobis distance matching for heterogeneous-treatment-effect evaluations of air-pollution-abatement policies
No full textThis paper develops a novel Intertemporal Mahalanobis-Distance Matching (IMDM) model for evaluating air-pollution-abatement interventions, such as limited-traffic and congestion-charge zones, bans of fossil-fuel traffic and switches to low-emission public transportation. These policies have a strong potential for heterogeneous impacts based on prevailing daily meteorological conditions, determining different average baseline pollution levels, and they pose quite unique causal impact identification conditions. Under these conditions, our IMDM model offers a number of relevant advantages with respect to the existing alternatives. An empirical analysis on data from the covid-19-lockdown traffic abatement in Northwestern Italy illustrates the applicability of the model and shows the policy-relevance of the heterogeneous impacts
La valutazione delle politiche attive del lavoro: attuazione, effetti occupazionali, meccanismi.
No full textLe politiche attive per il lavoro si propongono di rimuovere gli ostacoli all’accesso all’occupazione ricorrendo ad un mix di strumenti: servizi di orientamento, formazione, incentivi, varie forme di accompagnamento e inserimento protetto. Questo libro ripercorre la genesi e lo sviluppo di queste politiche al livello internazionale e italiano, caratterizzati da un rilevante ruolo delle Regioni e dei fondi europei. Concentra poi l’attenzione su come le politiche attive del lavoro si possono valutare, presentando e discutendo l’esperienza della Regione Piemonte che si è caratterizzata per un approccio misto in grado di combinare l’analisi del processo di attuazione, la stima degli effetti occupazionali e l’approfondimento dei meccanismi al livello micro. Le conclusioni avanzano alcune riflessioni sullo stato dell’arte delle politiche attive del lavoro nel nostro Paese e sul contributo che la valutazione può offrire allo sviluppo delle politiche