Immunomodulating effects of the anti-viral agent Silibinin in liver transplant patients with HCV recurrence

Background: Silibinin has been shown to have anti-HCV activity and immune-modulating properties by regulating dendritic cell (DC) function. DCs are antigen-presenting cells that, together with regulatory T cells (Treg), play a pivotal role in controlling alloimmune, as well as anti-HCV immune responses. Methods: Twelve liver transplant patients with HCV recurrence received iv infusion of Silibinin (iv-SIL) for 14 consecutive days. Using flow cytometry, before and at the end of treatment, we determined the frequencies of circulating myeloid (m) and plasmacytoid (p) DC and Treg and the expression of costimulatory/coregulatory molecules by the DC subsets and Treg. Statistical analysis was performed using the paired Student's t test and Pearson correlation test. Results: After iv-SIL treatment, we observed an elevated plasmacytoid dendritic cell (pDC)/myeloid dendritic cell (mDC) ratio, while pDC displayed lower HLA-DR and higher immunoglobulin-like transcript 4 (ILT4), CD39, and HLA-G expression compared to the pretreatment baseline. In addition, after iv-SIL, mDC showed increased inducible costimulator ligand (ICOSL) expression. No changes were detected in Treg frequency or programed death (PD)-1 expression by these cells. Moreover, several correlations between DC/Treg markers and clinical parameters were detected. Conclusions: This descriptive study, in liver transplant patients with HCV recurrence, reveals the impact of iv-SIL on DC and Treg. The changes observed in circulating pDC and mDC that have previously been associated with tolerogenic conditions shed new light on how iv-SIL may regulate anti-viral and alloimmunity. We have also observed multiple clinical correlations that could improve the clinical management of liver transplant patients and that deserve further analysis

Pharmacological modulation of mitochondrial calcium uniporter controls lung inflammation in cystic fibrosis

Mitochondria physically associate with the endoplasmic reticulum to coordinate interorganelle calcium transfer and regulate fundamental cellular processes, including inflammation. Deregulated endoplasmic reticulum–mitochondria cross-talk can occur in cystic fibrosis, contributing to hyperinflammation and disease progression. We demonstrate that Pseudomonasaeruginosainfection increases endoplasmic reticulum–mitochondria associations in cystic fibrosis bronchial cells by stabilizing VAPB-PTPIP51 (vesicle-associated membrane protein–associated protein B–protein tyrosine phosphatase interacting protein 51) tethers, affecting autophagy. Impaired autophagy induced mitochondrial unfolding protein response and NLRP3 inflammasome activation, contributing to hyperinflammation. The mechanism by which VAPB-PTPIP51 tethers regulate autophagy in cystic fibrosis involves calcium transfer via mitochondrial calcium uniporter. Mitochondrial calcium uniporter inhibition rectified autophagy and alleviated the inflammatory response in vitro and in vivo, resulting in a valid therapeutic strategy for cystic fibrosis pulmonary disease

SARS-CoV-2 infection in patients with inflammatory bowel disease: comparison between the first and second pandemic waves

In Italy, the incidence of SARS-CoV-2 infection peaked in April and November 2020, defining two pandemic waves of coronavirus disease 2019 (COVID-19). This study compared the characteristics and outcomes of patients with inflammatory bowel disease (IBD) and SARS-CoV-2 infections between pandemic waves.MethodsObservational longitudinal study of IBD patients with SARS-CoV-2 infection. Patients with established diagnoses of IBD and of SARS-CoV-2 infection were consecutively enrolled in two periods: (i) first wave, from 1 March 2020 to 31 May 2020; and (ii) second wave, from 15 September to 15 December 2020.ResultsWe enrolled 937 IBD patients (219 in the first wave, 718 in the second wave). Patients of the first wave were older (mean & PLUSMN; SD: 46.3 & PLUSMN; 16.2 vs. 44.1 & PLUSMN; 15.4 years, p = 0.06), more likely to have ulcerative colitis (58.0% vs. 44.4%, p < 0.001) and comorbidities (48.9% vs. 38.9%; p < 0.01), and more frequently residing in Northern Italy (73.1% vs. 46.0%, p < 0.001) than patients of the second wave. There were no significant differences between pandemic waves in sex (male: 54.3% vs. 53.3%, p = 0.82) or frequency of active IBD (44.3% vs. 39.0%, p = 0.18). The rates of negative outcomes were significantly higher in the first than second wave: pneumonia (27.8% vs. 11.7%, p < 0.001), hospital admission (27.4% vs. 9.7%, p < 0.001), ventilatory support (11.9% vs. 5.4%, p < 0.003) and death (5.5% vs. 1.8%, p < 0.007).ConclusionBetween the first and second SARS-CoV-2 pandemic waves, demographic, clinical and geographical features of IBD patients were different as were the symptoms and outcomes of infection. These differences are likely due to the different epidemiological situations and diagnostic possibilities between the two waves

Systematic review with meta-analysis: de novo non-alcoholic fatty liver disease in liver-transplanted patients

Background: De novo non-alcoholic fatty liver disease (NAFLD) in liver-transplanted patients for cirrhosis not due to non-alcoholic steatohepatitis (NASH) is becoming a growing phenomenon. Aims: We performed a systematic review and evaluated the prevalence of this event and possible associated factors. Methods: A literature search in medical databases (PubMed, MEDLINE/OVIDSP, Science Direct and EMBASE) was performed in March 2017. Relevant publications were identified in most important databases. We estimated the pooled prevalence of NAFLD and NASH in patients with liver transplant. The data have been expressed as proportions/percentages, and 95% confidence intervals (CI) were calculated, using the inverse variance method. Odd ratios (OR) and 95% confidence intervals (95% CI) were estimated. Results: Twelve studies were selected, enrolling 2166 subjects overall undergoing post-liver transplant biopsy. The pooled weighted prevalence of de novo NAFLD was 26% (95% CI 20%-31%). The pooled weighted prevalence of NASH was 2% (95% CI 0%-3%). The highest prevalences of de novo NAFLD were found for patients transplanted for alcoholic cirrhosis (37%) and cryptogenic cirrhosis (35%) and for patients taking tacrolimus (26%). Tacrolimus showed a risk of NAFLD similar to ciclosporin (OR&nbsp;=&nbsp;1.02, 95% CI 0.3-3.51). Conclusions: Patients undergoing liver transplant are more prone to experience diabetes, hypertension or dyslipidaemia, and NAFLD may be an important element in this context. In this study, we show how the prevalence of NASH tends to remain significant and similar to the general population. Moreover, this study suggests a possible association with specific transplant indications. Further studies are required to confirm these findings

Olmesartan Associated Enteropathy: Usefulness of Video Capsule Endoscopy in a Case With Doubtful Upper Endoscopic/Histological Picture

BACKGROUND: Olmesartan, an antihypertensive drug, may be associated with a severe "sprue-like enteropathy". OBJECTIVES: To report a case of Olmesartan enteropathy demonstrated by video capsule endoscopy distally from the second duodenum along with the whole small bowel before and after drug withdrawal. CASE PRESENTATION: A 81-years-old man was referred for asthenia, chronic watery diarrhea and anasarca (ascites, pleural effusion and edemas of superior and inferior limb). The only comorbidity was hypertension treated with Olmesartan. All causes of infective and inflammatory chronic diarrhea were investigated and excluded. Upper endoscopy was normal; histological examination of the second portion of the duodenum showed moderate and patchy infiltration of lymphocytes at mucosal and intra-epithelial level with intermittent partial villous atrophy. The possibility of adverse drug reaction, estimated by Naranjo scale, showed a score of 7, indicating a strong probability. Olmesartan was then withdrawn. However, because of severe clinical general condition, we preferred to corroborate our diagnostic work-up by a non-invasive investigation, i.e. video capsule endoscopy, which showed jejunal and ileal mucosal alterations (mosaic pattern, diffuse hyperemia, severe edema, consequent apparent reduced lumen, diffuse thickening of intestinal folds, multiple erosions, patchy lymphangectasia). After 14 days, the resolution of anasarcatic state and hydroelectrolytic imbalances was observed. Nine months later, small-bowel video-capsule demonstrated mild mucosal hyperaemia and mosaic pattern. CONCLUSION: Our case could give new insights in the field of Olmesartan associated enteropathy by highlighting the possibility of distally main lesion location and, therefore, the usefulness of video capsule endoscopy in the presence of doubtful diagnostic features

One-year effectiveness and safety of ustekinumab in ulcerative colitis: a multicenter real-world study from Italy

Background: Efficacy and safety of ustekinumab for the treatment of ulcerative colitis (UC) has been demonstrated in clinical trials, but few real-world data are available so far. The aim of this study was to assess effectiveness and safety of ustekinumab in a cohort of refractory UC patients. Methods: Data of patients with moderate to severe UC treated with ustekinumab were retrospectively collected. Primary endpoint was steroid-free clinical remission at weeks 24 and 52 of therapy. Secondary endpoints were treatment response, endoscopic remission, treatment persistence at 12&nbsp;months and safety. Results: A total of 68 patients [males 63%; median (range) age 42 (16–72) years] were included. Almost all patients (97%) were biologics experienced. At weeks 24 and 52, 31% and 50% of patients achieved steroid-free clinical remission, 84% and 82% had clinical response, respectively. At the end of follow-up, there was a significant reduction of pMS from baseline (p&nbsp;&lt;&nbsp;0.001) and of steroid use (p&nbsp;&lt;&nbsp;0.001). At week 52, 22% of the available endoscopies (18/38) showed mucosal healing. The probability to persist in therapy at week 52 was 87%. Only one adverse event occurred. Conclusions: Data from our real-life cohort of refractory UC patients suggest satisfactory effectiveness and a good safety of ustekinumab

Beneficial effects of recombinant CER-001 high-density lipoprotein infusion in sepsis: results from a bench to bedside translational research project

Background: Sepsis is characterized by a dysregulated immune response and metabolic alterations, including decreased high-density lipoprotein cholesterol (HDL-C) levels. HDL exhibits beneficial properties, such as lipopolysaccharides (LPS) scavenging, exerting anti-inflammatory effects and providing endothelial protection. We investigated the effects of CER-001, an engineered HDL-mimetic, in a swine model of LPS-induced acute kidney injury (AKI) and a Phase 2a clinical trial, aiming to better understand its molecular basis in systemic inflammation and renal function. Methods: We carried out a translational approach to study the effects of HDL administration on sepsis. Sterile systemic inflammation was induced in pigs by LPS infusion. Animals were randomized into LPS (n = 6), CER20 (single dose of CER-001 20&nbsp;mg/kg; n = 6), and CER20 × 2 (two doses of CER-001 20&nbsp;mg/kg; n = 6) groups. Survival rate, endothelial dysfunction biomarkers, pro-inflammatory mediators, LPS, and apolipoprotein A-I (ApoA-I) levels were assessed. Renal and liver histology and biochemistry were analyzed. Subsequently, we performed an open-label, randomized, dose-ranging (Phase 2a) study included 20 patients with sepsis due to intra-abdominal infection or urosepsis, randomized into Group A (conventional treatment, n = 5), Group B (CER-001 5&nbsp;mg/kg BID, n = 5), Group C (CER-001 10&nbsp;mg/kg BID, n = 5), and Group D (CER-001 20&nbsp;mg/kg BID, n = 5). Primary outcomes were safety and efficacy in preventing AKI onset and severity; secondary outcomes include changes in inflammatory and endothelial dysfunction markers. Results: CER-001 increased median survival, reduced inflammatory mediators, complement activation, and endothelial dysfunction in endotoxemic pigs. It enhanced LPS elimination through the bile and preserved liver and renal parenchyma. In the clinical study, CER-001 was well-tolerated with no serious adverse events related to study treatment. Rapid ApoA-I normalization was associated with enhanced LPS removal and immunomodulation with improvement of clinical outcomes, independently of the type and gravity of the sepsis. CER-001-treated patients had reduced risk for the onset and progression to severe AKI (stage 2 or 3) and, in a subset of critically ill patients, a reduced need for organ support and shorter ICU length of stay. Conclusions: CER-001 shows promise as a therapeutic strategy for sepsis management, improving outcomes and mitigating inflammation and organ damage. Trial registration: The study was approved by the Agenzia Italiana del Farmaco (AIFA) and by the Local Ethic Committee (N° EUDRACT 2020–004202-60, Protocol CER-001- SEP_AKI_01) and was added to the EU Clinical Trials Register on January 13, 2021