Modulation of the 5-Lipoxygenase Pathway by Chalcogen-Containing Inhibitors of Leukotriene A Hydrolase.

The 5-lipoxygenase (5-LOX) pathway gives rise to bioactive inflammatory lipid mediators, such as leukotrienes (LTs). 5-LOX carries out the oxygenation of arachidonic acid to the 5-hydroperoxy derivative and then to the leukotriene A epoxide which is converted to a chemotactic leukotriene B (LTB) by leukotriene A hydrolase (LTAH). In addition, LTAH possesses aminopeptidase activity to cleave the N-terminal proline of a pro-inflammatory tripeptide, prolyl-glycyl-proline (PGP).

The IRE1α Inhibitor KIRA6 Blocks Leukotriene Biosynthesis in Human Phagocytes.

The ER stress and Unfolded Protein Response (UPR) component inositol-requiring enzyme 1α (IRE1α) has been linked to inflammation and lipid mediator production. Here we report that the potent IRE1α inhibitor, KIRA6, blocks leukotriene biosynthesis in human phagocytes activated with lipopolysaccharide (LPS) plus N-formyl-methionyl-leucyl-phenylalanine (fMLP) or thapsigargin (Tg). The inhibition affects both leukotriene B (LTB) and cysteinyl leukotriene (cys-LTs) production at submicromolar concentration.

Human leukocytes selectively convert 4,5-epoxy-resolvin to resolvin D3, resolvin D4, and a cys-resolvin isomer.

Human phagocytes have key functions in the resolution of inflammation. Here, we assessed the role of the proposed 4,5-epoxy-resolvin intermediate in the biosynthesis of both resolvin D3 and resolvin D4. We found that human neutrophils converted this synthetic intermediate to resolvin D3 and resolvin D4.

Modulation of microRNA processing by 5-lipoxygenase.

The miRNA biogenesis is tightly regulated to avoid dysfunction and consequent disease development. Here, we describe modulation of miRNA processing as a novel noncanonical function of the 5-lipoxygenase (5-LO) enzyme in monocytic cells. In differentiated Mono Mac 6 (MM6) cells, we found an in situ interaction of 5-LO with Dicer, a key enzyme in miRNA biogenesis.

The identification of adverse events in hip fracture patients using the Global Trigger Tool: A prospective observational cohort study.

Introduction: Hip fracture is common in the elderly and is associated with high comorbidity, mortality and complication rates. There has been an increase in the investigation of healthcare-related adverse events (AEs) in some patient groups but there is limited knowledge about hip fracture patients. The aim was to explore the incidence, preventability and nature of AEs in hip fracture patients.

Dicer up-regulation by inhibition of specific proteolysis in differentiating monocytic cells.

Dicer is a ribonuclease III enzyme in biosynthesis of micro-RNAs (miRNAs). Here we describe a regulation of Dicer expression in monocytic cells, based on proteolysis. In undifferentiated Mono Mac 6 (MM6) cells, full-length Dicer was undetectable; only an ∼50-kDa fragment appeared in Western blots.

Exploring the incidence and nature of nursing-sensitive orthopaedic adverse events: A multicenter cohort study using Global Trigger Tool.

Background: For decades, patient safety has been recognized as a critical global healthcare issue. However, there is a gap of knowledge of all types of adverse events sensitive to nursing care within hospitals in general and within orthopaedic care specifically.

Objectives: The aim of this study is to explore the incidence and nature of nursing-sensitive adverse events following elective or acute hip arthroplasty at a national level.

Only 8% of major preventable adverse events after hip arthroplasty are filed as claims: a Swedish multi-center cohort study on 1,998 patients.

Background and purpose - Hip arthroplasty is one of the most performed surgeries in Sweden, and the rate of adverse events (AEs) is fairly high. All patients in publicly financed healthcare in Sweden are insured by the Mutual Insurance Company of Swedish County Councils (Löf). We assessed the proportion of patients that sustained a major preventable AE and filed an AE claim to Löf.

The influence of depression on patient-reported outcomes for hip-fracture patients 1 year after surgery: a prospective cohort study.

Background: Depression is common in elderly hip-fracture patients and together with cognitive impairment is associated with increased risk of mortality.

Aim: We aimed to examine the influence depression has on patient-reported outcome up to 1 year after acute hip fracture.

Methods: 162 hip-fracture patients participated in the prospective observational cohort study and were followed up at baseline, and 3 and 12 months using patient-reported outcome scores.

Validation of adverse events after hip arthroplasty: a Swedish multi-centre cohort study.

Objectives: Preventing adverse events (AEs) after orthopaedic surgery is a field with great room for improvement. A Swedish instrument for measuring AEs after hip arthroplasty based on administrative data from the national patient register is used by both the Swedish Hip Arthroplasty Register and the Swedish Association of Local Authorities and Regions. It has never been validated and its accuracy is unknown.

Exosomes and cells from lung cancer pleural exudates transform LTC4 to LTD4, promoting cell migration and survival via CysLT1.

Tumor-derived exosomes can modulate the cancer microenvironment and induce metastatic spread. Exosomes may carry enzymes for leukotriene (LT) biosynthesis, but the role of exosomal LTs has not been studied in cancer. We isolated exosomes and malignant cells from pleura exudates from 14 patients with non-small cell lung cancer.

Cysteinyl leukotriene receptor 1 antagonism prevents experimental abdominal aortic aneurysm.

Cysteinyl-leukotrienes (cys-LTs) are 5-lipoxygenase-derived lipid mediators involved in the pathogenesis and progression of inflammatory disorders, in particular asthma. We have previously found evidence linking these mediators to increased levels of proteolytic enzymes in tissue specimens of human abdominal aortic aneurysm (AAA). Here we show that antagonism of the CysLT1 receptor by montelukast, an established antiasthma drug, protects against a strong aorta dilatation (>50% increase = aneurysm) in a mouse model of CaCl-induced AAA at a dose comparable to human medical practice.

Capturing LTA hydrolase in action: Insights to the chemistry and dynamics of chemotactic LTB synthesis.

Human leukotriene (LT) A hydrolase/aminopeptidase (LTAH) is a bifunctional enzyme that converts the highly unstable epoxide intermediate LTA into LTB, a potent leukocyte activating agent, while the aminopeptidase activity cleaves and inactivates the chemotactic tripeptide Pro-Gly-Pro. Here, we describe high-resolution crystal structures of LTAH complexed with LTA, providing the structural underpinnings of the enzyme's unique epoxide hydrolase (EH) activity, involving Zn, Y383, E271, D375, and two catalytic waters. The structures reveal that a single catalytic water is involved in both catalytic activities of LTAH, alternating between epoxide ring opening and peptide bond hydrolysis, assisted by E271 and E296, respectively.

Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males.

Proinflammatory leukotrienes (LTs) are produced by 5-lipoxygenase (5-LO) aided by 5-LO-activating protein (FLAP). LT biosynthesis inhibitors are currently under clinical investigation as treatments for respiratory and cardiovascular diseases. Here, we have revealed a sex bias in the efficiency of clinically relevant LT biosynthesis inhibitors, showing that their effects are superior in females.

GM-CSF- and M-CSF-primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures.

M1 and M2 activated macrophages (Mϕs) have different roles in inflammation. Because pathogens may first encounter resting cells, we investigated lipid mediator profiles prior to full activation. Human monocytes were differentiated with granulocyte Mϕ colony-stimulating factor (GM-CSF) or Mϕ colony-stimulating factor (M-CSF), which are known to prime toward M1 or M2 phenotypes, respectively.

Normal gastric emptying time of a carbohydrate-rich drink in elderly patients with acute hip fracture: a pilot study.

Background: Guidelines for fasting in elderly patients with acute hip fracture are the same as for other trauma patients, and longer than for elective patients. The reason is assumed stress-induced delayed gastric emptying with possible risk of pulmonary aspiration. Prolonged fasting in elderly patients may have serious negative metabolic consequences.

Waiting time to surgery is correlated with an increased risk of serious adverse events during hospital stay in patients with hip-fracture: A cohort study.

Background: Hip fractures are common in the elderly and are associated with a high adverse event and mortality rate. Time to surgery is one of the major modifiable risk factors influencing adverse outcomes in hip-fracture patients. National guidelines and recommendations have been introduced which advocate specific time frames in which surgery should be performed i.

Pulmonary epithelial cancer cells and their exosomes metabolize myeloid cell-derived leukotriene C4 to leukotriene D4.

Leukotrienes (LTs) play major roles in lung immune responses, and LTD4 is the most potent agonist for cysteinyl LT1, leading to bronchoconstriction and tissue remodeling. Here, we studied LT crosstalk between myeloid cells and pulmonary epithelial cells. Monocytic cells (Mono Mac 6 cell line, primary dendritic cells) and eosinophils produced primarily LTC4 In coincubations of these myeloid cells and epithelial cells, LTD4 became a prominent product.

A dynamic Asp-Arg interaction is essential for catalysis in microsomal prostaglandin E2 synthase.

Microsomal prostaglandin E2 synthase type 1 (mPGES-1) is responsible for the formation of the potent lipid mediator prostaglandin E2 under proinflammatory conditions, and this enzyme has received considerable attention as a drug target. Recently, a high-resolution crystal structure of human mPGES-1 was presented, with Ser-127 being proposed as the hydrogen-bond donor stabilizing thiolate anion formation within the cofactor, glutathione (GSH). We have combined site-directed mutagenesis and activity assays with a structural dynamics analysis to probe the functional roles of such putative catalytic residues.

Sex effects on short-term complications after hip fracture: a prospective cohort study.

Objectives: To evaluate potential sex differences and other factors associated with complications within 4 months after a hip fracture.

Methods: A total of 1,915 patients ≥65 years (480 men) with hip fracture were consecutively included in a prospective multicenter cohort study. A review of medical records and patient interviews according to a study protocol based on the Standardized Audit of Hip Fractures in Europe (SAHFE, RIKSHÖFT) was performed.

Design and Synthesis of Novel Arylketo-containing P1-P3 Linked Macro-cyclic BACE-1 Inhibitors.

A series of arylketo-containing P1-P3 linked macrocyclic BACE-1 inhibitors were designed, synthesized, and compared with compounds with a previously known and extensively studied corresponding P2 isophthalamide moiety with the aim to improve on permeability whilst retaining the enzyme- and cell-based activities. Several inhibitors displayed substantial increases in Caco-2 cell-based permeability compared to earlier synthesized inhibitors and notably also with retained activities, showing that this approach might yield BACE-1 inhibitors with improved properties.