Search

Type 1 and Type 2 diabetes mellitus (T1DM and T2DM) are caused by beta(β)-cell loss and functional impairment. Identification of mechanisms of β-cell death and therapeutic interventions to enhance β-cell survival are essential for prevention and treatment of diabetes. Oxidative stress is a common feature of both T1DM and T2DM; elevated biomarkers of oxidative stress are detected in blood, urine and tissues including pancreas of patients with DM. Islet transplantation is a promising treatment for diabetes. However, exposure to stress (chemical and mechanical) and ischemia-reperfusion during isolation and transplantation causes islet loss by generation of reactive oxygen species (ROS). Human intracellular antioxidant enzymes and related molecules are essential defenses against ROS. Antioxidant enzyme levels including superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX) have been shown to be low in islet cells. However, little is known about the expression and function of antioxidant enzymes within islet cell subsets. We evaluated the expression of the key antioxidant enzymes in β- and alpha(α)-cell and accessed effects of oxidative stress, islet isolation and transplantation on β/α-cell ratio and viability in human islets.Human pancreata from T1DM, T2DM and non-diabetic deceased donors were obtained and analyzed by confocal microscopy. Isolated islets were (I) transplanted in the renal sub-capsular space of streptozotocin-induced diabetic nude mice (in vivo bioassay), or (II) exposed to oxidative (H2O2) and nitrosative (NO donor) stress for 24 hrs in vitro. The ratio, % viability and death of β- and α-cells, and DNA damage (8OHdG) were measured.Catalase and GPX expression was much lower in β- than α-cells. The β/α-cell ratio fells significantly following islet isolation and transplantation. Exposure to oxidative stress caused a significantly lower survival and viability, with higher DNA damage in β- than α-cells. These findings identified the weakness of β-cell antioxidant capacity as a main cause of vulnerability to oxidative stress. Potential strategies to enhance β-cell antioxidant capacity might be effective in prevention/treatment of diabetes.

ObjectivesThe effects of glucocorticoid during culture on human islet cells have been controversial. Exendin-4 (EX) enhances the insulin secretion and significantly improves clinical outcomes in islet cell transplantation. In this study, we examined the effects of glucocorticoids and EX on human islet cells during pretransplant culture.MethodsMethylprednisolone (MP) and/or EX were added to the standard culture medium for clinical islet cell transplantation. Islets were cultured for 24 hours with 3 different conditions (control, no additives; MP alone; and MP + EX). β-Cell fractional viability, cellular composition, multiple cytokine/chemokine production, multiple phosphorylation proteins, and glucose-induced insulin secretion were evaluated.ResultsViable β-cell survival in MP and MP + EX group was significantly higher than in the control group. Exendin-4 prevented MP-induced reduction of insulin secretion. Methylprednisolone supplementation to the culture medium decreased cytokine and chemokine production. Moreover, extracellular signal-regulated kinase 1/2 phosphorylation was significantly increased by MP and MP + EX.ConclusionsGlucocorticoid supplementation into culture media significantly decreased the cytokine/chemokine production and increased the extracellular signal-regulated kinase 1/2 phosphorylation, resulting in the improvement of human β-cell survival. In addition, EX maintained the insulin secretion suppressed by MP. The supplementation of MP and EX together could be a useful strategy to create suitable human islets for transplantation.

Background and Aims: Critically ill patients with liver failure have high mortality. Besides the management of organ‐specific complications, liver transplantation constitutes a definitive treatment. However, clinicians may hesitate to introduce mechanical ventilation for patients on liver transplantation waitlists because of poor prognosis. This study investigated the outcomes of intensive care and ventilation support therapy effects in patients with liver failure. Methods: This single‐center study retrospectively enrolled 32 consecutive patients with liver failure who were admitted to the intensive care unit from January 2014 to December 2020. The medical records were reviewed and analyzed retrospectively for Acute Physiologic and Chronic Health Evaluation (APACHE)‐II. The model for end‐stage liver disease scores, 90‐day mortality, and survival was assessed using the Kaplan–Meier method. Results: The average patient age was 45.5 ± 20.1 years, and 53% of patients were women. On intensive care unit admission, APACHE‐II and model for end‐stage liver disease scores were 20 and 28, respectively. Among 13 patients considered for liver transplantation, 4 received transplants. Thirteen patients (40.6%) were intubated and mechanically ventilated in the intensive care unit. The 90‐day mortality rate of patients with and without mechanical ventilation in the intensive care unit (13, 61.5% vs. 19, 47.4%, p = 0.4905) was similar. APACHE‐II score >21 was an independent predictor of mechanical ventilation requirement in patients with liver failure during intensive care unit stay. Conclusion: Although critically ill patients with liver failure are at risk of multiorgan failure with poor outcomes, mechanical ventilation did not negatively affect the 90‐day mortality or performance rates of liver transplantation. Clinicians should consider mechanical ventilation‐based life support in critically ill patients with liver failure who are awaiting liver transplantation. Key points: What's known As critically ill patients with liver failure have high mortality, clinicians hesitate to introduce mechanical ventilation for patients on liver‐transplantation waitlists because of the poor prognosis. What's new We aimed to clarify the management and treatment outcomes of patients with liver failure, especially those who needed mechanical ventilation. What the clinical implications of this study are Mechanical ventilation‐based life support is not an adverse prognostic factor for critically ill patients with liver failure who are on a waitlist for liver transplantation. Therefore, clinicians should unhesitatingly provide mechanical ventilation‐based life support in this patient group. [ABSTRACT FROM AUTHOR]

Background: There is limited published information regarding the expression of mechanistic target of rapamycin (mTOR) in vessels that encapsulate tumor cluster (VETC)‐positive hepatocellular carcinoma (HCC). The mTOR inhibitor, everolimus, has been approved as an immunosuppressant for use in HCC patients after living donor liver transplantation (LDLT). Methods: Using a database of 214 patients who underwent LDLT for HCC, we examined the mTOR protein and angiopoietin‐2 (Ang‐2) in VETC‐positive HCC by immunohistochemical staining. The presence of VETC and mTOR expression were evaluated in both primary and recurrent HCC lesions. Results: Forty‐three of the 214 patients (20.1%) were VETC‐positive, and 29 of these 43 patients (67.4%) expressed mTOR. Relative Ang‐2 expression was significantly higher in the mTOR‐positive than in the mTOR‐negative group (p = 0.037). Thirty‐four of the 214 patients experienced HCC recurrence after LDLT; 20 of these were operable. The primary lesions of six of these 20 patients were VETC‐positive; five of these six patients also had VETC‐positive recurrent lesions (p < 0.001). The expression of mTOR was significantly higher in the VETC‐positive lesions (p = 0.0018). Conclusions: We showed that mTOR expression was higher in the VETC‐positive primary and recurrent lesions than in the VETC‐negative ones. [ABSTRACT FROM AUTHOR]

The article is a response to a letter from Drs. Daungsupawong and Wiwanitkit regarding a previously published article on the COVID-19 vaccine in liver transplant recipients. The authors reported that mRNA vaccines induce similar immune responses in liver transplant recipients as in healthy individuals and recommend that liver transplant recipients receive booster vaccinations. The study was conducted in Japan, where liver transplant recipients have good access to healthcare and have been receiving regular vaccinations and booster vaccinations every 6 months. The authors address concerns about the impact of pre-vaccination infections and the need for frequent measurement of antibody levels. They emphasize the importance of continued research on the prevention and treatment of COVID-19 in liver transplant recipients. [Extracted from the article]