Dichotomous role of pancreatic HUWE1/MULE/ARF-BP1 in modulating beta cell apoptosis in mice under physiological and genotoxic conditions

Aims/hypothesis

Diabetes mellitus represents a significant burden on the health of the global population. Both type 1 and type 2 diabetes share a common feature of a reduction in functional beta cell mass. A newly discovered ubiquitination molecule HECT, UBA and WWE domain containing 1, E3 ubiquitin protein ligase (HUWE1 [also known as MULE or ARF-BP1]) is a critical regulator of p53-dependent apoptosis. However, its role in islet homeostasis is not entirely clear.

Methods

We generated mice with pancreas-specific deletion of Huwe1 using a Cre-loxP recombination system driven by the Pdx1 promoter (Pdx1cre ⁺ Huwe1 ^fl/fl) to assess the in vivo role of HUWE1 in the pancreas.

Results

Targeted deletion of Huwe1 in the pancreas preferentially activated p53-mediated beta cell apoptosis, leading to reduced beta cell mass and diminished insulin exocytosis. These defects were aggravated by ageing, with progressive further decline in insulin secretion and glucose homeostasis in older mice. Intriguingly, Huwe1 deletion provided protection against genotoxicity, such that Pdx1cre ⁺ Huwe1 ^fl/fl mice were resistant to multiple-low-dose-streptozotocin-induced beta cell apoptosis and diabetes.

Conclusion/interpretation

HUWE1 expression in the pancreas is essential in determining beta cell mass. Furthermore, HUWE1 demonstrated divergent roles in regulating beta cell apoptosis depending on physiological or genotoxic conditions.     

Expression of Toll-Like Receptors 2 and 3 on Esophageal Epithelial Cell Lines and on Eosinophils During Esophagitis

Background  

The chronic disease eosinophilic esophagitis may be mediated by the innate immune system. Activation of toll-like receptors (TLRs) in other tissues is known to initiate eosinophil infiltration, thus TLRs may be a potential mediator of esophageal eosinophilia. Little is known about TLRs in the esophagus.     

Effects of aging and propofol on the cardiovascular component of the autonomic nervous system

Study ObjectivesTo determine the combined effects of aging and propofol on autonomic nervous system activity using heart rate variability (HRV) analysis.DesignProspective, two-parallel group, repeated-measures study.SettingOperating room of an academic hospital.PatientsASA physical status 1, 2, and 3 patients, including 14 young (< 65 yrs) and 14 elderly (> 65 yrs) patients. All patients were scheduled for general surgical procedures with general anesthesia.InterventionsEach patient received two successive propofol doses during induction (0.5 mg/kg and 1.5 mg/kg) with a time interval allowing the return of Bispectral Index (BIS) to awake values.MeasurementsPrimary outcomes were HRV parameters, which included normalized power spectral density at low frequency (LFnorm) and high frequency (HFnorm) bands and the ratio LF/HF. Secondary outcomes were BIS values, blood pressure, heart rate, respiratory rate, and body temperature.Main ResultsThe interaction of age and propofol dose level was significant [multivariate analysis of variance, F (3,74) = 4.72, P = 0.005], representing a combined effect of age and propofol dose level on the mean HRV parameters. Propofol induction decreased the HFnorm component and enhanced LFnorm and LF/HF in the younger group, but had no significant effect in the older group. Such an effect was not associated with a significant difference in systolic blood pressure (SBP) decrements between the younger and older groups. Within each group, propofol caused significant decreases in SBP compared with preinduction values. Heart rate did not change significantly during propofol administration between groups or within groups.ConclusionsPropofol and aging act in synergy to depress the activity of the cardiovascular component of the autonomic nervous system. However, a compensatory increase in sympathetic outflow was seen in young patients. Such counterbalance was not observed in the older group.     

Pharmacokinetic evaluation of besifovir for the treatment of HBV infection

Introduction: Besifovir (LB80380) is a relatively new oral acyclic nucleotide phosphonate. We reviewed the pharmacokinetic characteristics of LB80380 and discussed its role in the treatment of chronic hepatitis B infection.

Areas covered: LB80380 is a prodrug of LB80331 and LB80317. It is rapidly absorbed when taken orally. Escalating doses of besifovir produce linear increase of the plasma concentration. Doses above 60mg are effective for inhibiting HBV in human. Using 60mg as an example, the maximal concentration of LB80331 in plasma is 397 ng/mL. The time required to reach maximal concentration in plasma and elimination half-life are 2.0 and 3.0 h, respectively. Besifovir and its metabolites are mainly excreted via the kidneys. Its antiviral efficacy is non-inferior to ETV 0.5mg daily. It is generally safe in terms of renal and bone toxicity. The most common adverse event is carnitine depletion which affects almost all patients on besifovir requiring carnitine supplementation.

Expert opinion: Besifovir demonstrated predictable pharmacokinetic characteristics in human subjects. Few clinical studies on besifovir have been conducted. More data are expected particularly for special populations. The adverse events upon long term exposure should be monitored. Large scale head-to-head trials comparing besifovir with existing NA, especially tenofovir alafenamide, should be conducted.