The activation of the transcription factor NF-E2-related factor 2 (Nrf2) maintains cellular homeostasis in response to oxidative stress by the regulation of multiple cytoprotective genes. Without stressors, the activity of Nrf2 is inhibited by its interaction with the Keap1 (kelch-like ECH-associated protein 1). Here, we describe (3S)-1-[4-[(2,3,5,6-tetramethylphenyl) sulfonylamino]-1-naphthyl]pyrrolidine-3-carboxylic acid (RA839), a small molecule that binds noncovalently to the Nrf2-interacting kelch domain of Keap1 with a K d of ϳ6 M, as demonstrated by x-ray co-crystallization and isothermal titration calorimetry. Whole genome DNA arrays showed that at 10 M RA839 significantly regulated 105 probe sets in bone marrow-derived macrophages. Canonical pathway mapping of these probe sets revealed an activation of pathways linked with Nrf2 signaling. These pathways were also activated after the activation of Nrf2 by the silencing of Keap1 expression. RA839 regulated only two genes in Nrf2 knock-out macrophages. Similar to the activation of Nrf2 by either silencing of Keap1 expression or by the reactive compound 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester (CDDO-Me), RA839 prevented the induction of both inducible nitric-oxide synthase expression and nitric oxide release in response to lipopolysaccharides in macrophages. In mice, RA839 acutely induced Nrf2 target gene expression in liver. RA839 is a selective inhibitor of the Keap1/Nrf2 interaction and a useful tool compound to study the biology of Nrf2.The transcription factor NF-E2-related factor 2 (Nrf2) 2 is a promising target for the treatment of oxidative and inflammatory stress-related disorders, such as neurodegenerative and microvascular diseases (1-5). Nrf2 regulates the expression of several cytoprotective anti-oxidative and anti-inflammatory proteins by binding to the cis-acting antioxidant response element (ARE) within gene promoters. Nrf2 itself is regulated by the kelch-like ECH-associated protein 1 (Keap1), which is a substrate recognition subunit for a cullin3-based ubiquitin E3 ligase and functions as a sensor for oxidative and electrophilic stress. Structural elements of the Keap1 protein include the C-terminal Nrf2-binding kelch domain, the intervening region, and the broad complex-Tramtrack-Bric-a-Brac domain. Keap1 binds as a dimer via its two Kelch domains to one molecule of Nrf2, specifically to the high affinity ETGE and the low affinity DLG motives at the N terminus of Nrf2. Without stressors, this leads to the ubiquitinylation and subsequent proteolytic degradation of the transcription factor. In the presence of oxidative or electrophilic stress, cysteine residues within the intervening region and broad complex-Tramtrack-Bric-a-Brac domain of Keap1 become modified. According to the hinge and latch model, this weakens the interaction between Keap1 and the DLG motif of Nrf2 but does not lead to a release of Nrf2 (6, 7). The conformation cycling model postulates a stabilization of the Keap1/Nrf2 interaction by the Keap1 modifica...

Purpose The abdomen is the second most common source of sepsis and is associated with unacceptably high morbidity and mortality. Recently, the essential definitions of sepsis and septic shock were updated (Third International Consensus Definitions for Sepsis and Septic Shock, Sepsis-3) and modified. The purpose of this review is to provide an overview of the changes introduced by Sepsis-3 and the current state of the art regarding the treatment of abdominal sepsis. Results While Sepsis-1/2 focused on detecting systemic inflammation as a response to infection, Sepsis-3 defines sepsis as a lifethreatening organ dysfunction caused by a dysregulated host response to infection. The Surviving Sepsis Campaign (SSC) guideline, which was updated in 2016, recommends rapid diagnosis and initiating standardized therapy. New diagnostic tools, the establishment of antibiotic stewardship programs, and a host of new-generation antibiotics are new landmark changes in the sepsis literature of the last few years. Although the Bold^surgical source control consisting of debridement, removal of infected devices, drainage of purulent cavities, and decompression of the abdominal cavity is the gold standard of surgical care, the timing of gastrointestinal reconstruction and closure of the abdominal cavity (Bdamage control surgery^) are discussed intensively in the literature. The SSC guidelines provide evidence-based sepsis therapy. Nevertheless, treating critically ill intensive care patients requires individualized, continuous daily re-evaluation and flexible therapeutic strategies, which can be best discussed in the interdisciplinary rounds of experienced surgeons and intensive care medicals.

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Despite many efforts, the mortality of patients with ACS remains unacceptably high. Permanent clinical education and surgical trials will be necessary to improve the outcome of our critically ill surgical patients.

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During the last two decades, the number of international migrants worldwide has constantly risen. In this context, crosscultural dimensions of psychological disorders receive increased attention, especially depression, anxiety and post-traumatic stress disorders among the migrant population. In this paper we propose a theoretical framework for the understanding of migrant mental health. This framework combines elements from Berry ' s acculturation model and Antonovsky ' s salutogenic theory. The former illustrates the main factors that affect an individual ' s adaptation in a new cultural context. The term acculturative stress denotes unresolved problems resulting from intercultural contact that cannot be overcome easily by simply adjusting or assimilating. The latter specifi es the relationship between culturally associated stress and mental health more distinctive, introducing the concepts of generalized resistance resources and sense of coherence that determine mental health outcomes of migrants during acculturative stress periods. Specifi cally, we provide an integrative framework of acculturation and salutogenesis that helps to integrate inconsistent fi ndings in the migrant mental health literature. The current paper focuses on the effect of resource factors for positive mental health outcomes in the migrant population and summarises some implications for future research activities.

Perceived work strain is related to nicotine dependence in this general adult population.

The therapeutic success of peptidic GLP-1 receptor agonists for treatment of type 2 diabetes mellitus (T2DM) motivated our search for orally bioavailable small molecules that can activate the GLP-1 receptor (GLP-1R) as a well-validated target for T2DM. Here, the discovery and characterization of a potent and selective positive allosteric modulator (PAM) for GLP-1R based on a 3,4,5,6-tetrahydro-1H-1,5-epiminoazocino­[4,5-b]­indole scaffold is reported. Optimization of this series from HTS was supported by a GLP-1R ligand binding model. Biological in vitro testing revealed favorable ADME and pharmacological profiles for the best compound 19. Characterization by in vivo pharmacokinetic and pharmacological studies demonstrated that 19 activates GLP-1R as positive allosteric modulator (PAM) in the presence of the much less active endogenous degradation product GLP1(9–36)­NH2 of the potent endogenous ligand GLP-1(7–36)­NH2. While these data suggest the potential of small molecule GLP-1R PAMs for T2DM treatment, further optimization is still required towards a clinical candidate.