16 research outputs found
The emerging role and therapeutic implications of bacterial and parasitic deubiquitinating enzymes
Deubiquitinating enzymes (DUBs) are emerging as key factors for the infection of human cells by pathogens such as bacteria and parasites. In this review, we discuss the most recent studies on the role of deubiquitinase activity in exploiting and manipulating ubiquitin (Ub)-dependent host processes during infection. The studies discussed here highlight the importance of DUB host-pathogen research and underscore the therapeutic potential of inhibiting pathogen-specific DUB activity to prevent infectious diseases
Efficacy of Budesonide Orodispersible Tablets as Induction Therapy for Eosinophilic Esophagitis in a Randomized Placebo-Controlled Trial.
BACKGROUND & AIMS: Swallowed topical-acting corticosteroids are recommended as first-line therapy for eosinophilic esophagitis (EoE). Asthma medications not optimized for esophageal delivery are sometimes effective, although given off-label. We performed a randomized, placebo-controlled trial to assess the effectiveness and tolerability of a budesonide orodispersible tablet (BOT), which allows the drug to be delivered to the esophagus in adults with active EoE. METHODS: We performed a double-blind, parallel study of 88 adults with active EoE in Europe. Patients were randomly assigned to groups that received BOT (1 mg twice daily; n = 59) or placebo (n = 29) for 6 weeks. The primary end point was complete remission, based on clinical and histologic factors, including dysphagia and odynophagia severity ≤2 on a scale of 0-10 on each of the 7 days before the end of the double-blind phase and a peak eosinophil count <5 eosinophils/high power field. Patients who did not achieve complete remission at the end of the 6-week double-blind phase were offered 6 weeks of open-label treatment with BOT (1 mg twice daily). RESULTS: At 6 weeks, 58% of patients given BOT were in complete remission compared with no patients given placebo (P < .0001). The secondary end point of histologic remission was achieved by 93% of patients given BOT vs no patients given placebo (P < .0001). After 12 weeks, 85% of patients had achieved remission. Six-week and 12-week BOT administration were safe and well tolerated; 5% of patients who received BOT developed symptomatic, mild candida, which was easily treated with an oral antifungal agent. CONCLUSIONS: In a randomized trial of adults with active EoE, we found that budesonide oral tablets were significantly more effective than placebo in inducing clinical and histologic remission. Eudra-CT number 2014-001485-99; ClinicalTrials.gov ID NCT02434029
Pharmacological HIF-inhibition attenuates postoperative adhesion formation
Abstract Peritoneal adhesions represent a common complication of abdominal surgery, and tissue hypoxia is a main determinant in adhesion formation. Reliable therapeutic options to reduce peritoneal adhesions are scarce. We investigated whether the formation of postsurgical adhesions can be affected by pharmacological interference with hypoxia-inducible factors (HIFs). Mice were treated with a small molecule HIF-inhibitor, YC-1 (3-[5′-Hydroxymethyl-2′-furyl]-1-benzyl-indazole), or vehicle three days before and seven days after induction of peritoneal adhesions or, alternatively, once during induction of peritoneal adhesions. Pretreatment or single intraperitoneal lavage with YC-1 significantly reduced postoperative adhesion formation without prompting systemic adverse effects. Expression analyses of cytokines in peritoneal tissue and fluid and in vitro assays applying macrophages and peritoneal fibroblasts indicated that this effect was cooperatively mediated by various putatively HIF-1α-dependent mechanisms, comprising attenuated pro-inflammatory activation of macrophages, impaired recruitment and activation of peritoneal fibroblasts, mitigated epithelial-mesenchymal-transition (EMT), as well as enhanced fibrinolysis and impaired angiogenesis. Thus, this study identifies prevention of postsurgical peritoneal adhesions as a novel and promising field for the application of HIF inhibitors in clinical practice
Light-Dependent Control of Bacterial Expression at the mRNA Level
Sensory photoreceptors mediate numerous light-dependent
adaptations
across organisms. In optogenetics, photoreceptors achieve the reversible,
non-invasive, and spatiotemporally precise control by light of gene
expression and other cellular processes. The light-oxygen-voltage
receptor PAL binds to small RNA aptamers with sequence specificity
upon blue-light illumination. By embedding the responsive aptamer
in the ribosome-binding sequence of genes of interest, their expression
can be downregulated by light. We developed the pCrepusculo and pAurora
optogenetic systems that are based on PAL and allow to down- and upregulate,
respectively, bacterial gene expression using blue light. Both systems
are realized as compact, single plasmids that exhibit stringent blue-light
responses with low basal activity and up to several 10-fold dynamic
range. As PAL exerts light-dependent control at the RNA level, it
can be combined with other optogenetic circuits that control transcription
initiation. By integrating regulatory mechanisms operating at the
DNA and mRNA levels, optogenetic circuits with emergent properties
can thus be devised. As a case in point, the pEnumbra setup permits
to upregulate gene expression under moderate blue light whereas strong
blue light shuts off expression again. Beyond providing novel signal-responsive
expression systems for diverse applications in biotechnology and synthetic
biology, our work also illustrates how the light-dependent PAL-aptamer
interaction can be harnessed for the control and interrogation of
RNA-based processes