Sex hormone deprivation abolishes sex-specific differences in murine colon inflammation and related lipid mediator production.

Unresolved inflammation, due to unfavorable imbalances between pro-inflammatory and pro-resolving mediators, leads to chronic inflammatory pathologies that are often sex-biased and regulated by sex hormones, including inflammatory bowel disease. Lipid mediators (LM) produced from polyunsaturated fatty acids by various lipoxygenases (LOX) and cyclooxygenases govern all stages of inflammation, i.e.

Extended pleurectomy decortication and chemotherapy versus chemotherapy alone for pleural mesothelioma (MARS 2): a phase 3 randomised controlled trial.

Background: Extended pleurectomy decortication for complete macroscopic resection for pleural mesothelioma has never been evaluated in a randomised trial. The aim of this study was to compare outcomes after extended pleurectomy decortication plus chemotherapy versus chemotherapy alone.

Methods: MARS 2 was a phase 3, national, multicentre, open-label, parallel two-group, pragmatic, superiority randomised controlled trial conducted in the UK.

Cannabidiol acts as molecular switch in innate immune cells to promote the biosynthesis of inflammation-resolving lipid mediators.

Cannabinoids are phytochemicals from cannabis with anti-inflammatory actions in immune cells. Lipid mediators (LM), produced from polyunsaturated fatty acids (PUFA), are potent regulators of the immune response and impact all stages of inflammation. How cannabinoids influence LM biosynthetic networks is unknown.

Lung volume reduction surgery endobronchial valves: a randomised controlled trial.

Background: Lung volume reduction surgery (LVRS) and bronchoscopic lung volume reduction (BLVR) with endobronchial valves can improve outcomes in appropriately selected patients with emphysema. However, no direct comparison data exist to inform clinical decision making in people who appear suitable for both procedures. Our aim was to investigate whether LVRS produces superior health outcomes when compared with BLVR at 12 months.

Discovery and Optimization of Indoline-Based Compounds as Dual 5-LOX/sEH Inhibitors: and Anti-Inflammatory Characterization.

The design of multitarget drugs represents a promising strategy in medicinal chemistry and seems particularly suitable for the discovery of anti-inflammatory drugs. Here, we describe the identification of an indoline-based compound inhibiting both 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH). analysis of an in-house library identified nine compounds as potential 5-LOX inhibitors.

An Unusual Case of Postpartum Empyema.

We present the case of a 32-year-old woman with a left empyema and T12 osteomyelitis resulting from group B Streptococcus infection occurring 3 weeks after instrumental delivery of a healthy boy. Empyema is a rare complication of instrumental delivery, and this patient highlights the maternal risk resulting from group B Streptococcus bacteremia.

Shifting the Biosynthesis of Leukotrienes Toward Specialized Pro-Resolving Mediators by the 5-Lipoxygenase-Activating Protein (FLAP) Antagonist BRP-201.

Background And Purpose: Lipid mediators (LM) play crucial roles in the complex inflammation process with respect to initiation, maintenance, and resolution. Proinflammatory leukotrienes (LTs), generated by 5-lipoxygenase (LOX) and the 5-LOX-activating protein (FLAP), initiate and maintain inflammation while specialized pro-resolving mediators (SPMs) formed by various LOXs as key enzymes promote inflammation resolution and the return to homeostasis. Since 5-LOX also contributes to SPM biosynthesis, smart pharmacological manipulation of the 5-LOX pathway and accompanied activation of 12-/15-LOXs may accomplish suppression of LT formation but maintain or even elevate SPM formation.

Sex Hormone-Dependent Lipid Mediator Formation in Male and Female Mice During Peritonitis.

Sex differences in inflammation are obvious and contribute to divergences in the incidence and severity of inflammation-related diseases that frequently preponderate in women. Lipid mediators (LMs), mainly produced by lipoxygenase (LOX) and cyclooxygenase (COX) pathways from polyunsaturated fatty acids (PUFAs), regulate all stages of inflammation. Experimental and clinical studies revealed sex divergences for selected LM pathways without covering the entire LM spectrum, and only few studies have addressed the respective role of sex hormones.

Ethoxy acetalated dextran-based nanocarriers accomplish efficient inhibition of leukotriene formation by a novel FLAP antagonist in human leukocytes and blood.

Leukotrienes are pro-inflammatory lipid mediators generated by 5-lipoxygenase aided by the 5-lipoxygenase-activating protein (FLAP). BRP-201, a novel benzimidazole-based FLAP antagonist, inhibits leukotriene biosynthesis in isolated leukocytes. However, like other FLAP antagonists, BRP-201 fails to effectively suppress leukotriene formation in blood, which limits its therapeutic value.

Exploration of Long-Chain Vitamin E Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5-LOX Inhibitor that Limits Inflammation.

Endogenous long-chain metabolites of vitamin E (LCMs) mediate immune functions by targeting 5-lipoxygenase (5-LOX) and increasing the systemic concentrations of resolvin E3, a specialized proresolving lipid mediator. SAR studies on semisynthesized analogues highlight α-amplexichromanol (), which allosterically inhibits 5-LOX, being considerably more potent than endogenous LCMs in human primary immune cells and blood. Other enzymes within lipid mediator biosynthesis were not substantially inhibited, except for microsomal prostaglandin E synthase-1.

From Vietnamese plants to a biflavonoid that relieves inflammation by triggering the lipid mediator class switch to resolution.

Chronic inflammation results from excessive pro-inflammatory signaling and the failure to resolve the inflammatory reaction. Lipid mediators orchestrate both the initiation and resolution of inflammation. Switching from pro-inflammatory to pro-resolving lipid mediator biosynthesis is considered as efficient strategy to relieve chronic inflammation, though drug candidates exhibiting such features are unknown.

Anti-inflammatory celastrol promotes a switch from leukotriene biosynthesis to formation of specialized pro-resolving lipid mediators.

The pentacyclic triterpenoid quinone methide celastrol (CS) from Tripterygium wilfordii Hook. F. effectively ameliorates inflammation with potential as therapeutics for inflammatory diseases.

Staphylococcus aureus-Derived α-Hemolysin Evokes Generation of Specialized Pro-resolving Mediators Promoting Inflammation Resolution.

Underlying mechanisms of how infectious inflammation is resolved by the host are incompletely understood. One hallmark of inflammation resolution is the activation of specialized pro-resolving mediators (SPMs) that enhance bacterial clearance and promote tissue repair. Here, we reveal α-hemolysin (Hla) from Staphylococcus aureus as a potent elicitor of SPM biosynthesis in human M2-like macrophages and in the mouse peritoneum through selective activation of host 15-lipoxygenase-1 (15-LOX-1).

5α-dihydrotestosterone abrogates sex bias in asthma like features in the mouse.

Androgen levels inversely correlate with the incidence, susceptibility and severity of asthma. However, whether male sex hormones such as 5α-dihydrotestosterone (DHT) have beneficial effects on asthma symptoms and/or could affect asthma susceptibility have not been investigated. DHT administration to female mice, during the sensitization phase, abrogates the sex bias in bronchial hyperreactivity.

Ectonucleoside Triphosphate Diphosphohydrolase-1/CD39 Affects the Response to ADP of Female Rat Platelets.

There is evidence that an imbalance of extracellular purine levels may be associated with increased cardiovascular risk. Platelets play a pivotal role in vascular homeostasis and thrombosis and are important source of purine nucleotides and nucleosides. Hydrolysis of nucleotides ATP and ADP is regulated by two ectonucleotidases, triphosphate diphosphohydrolase-1 (NTPDase-1/CD39) and ecto-5'-nucleotidase (ecto-5'-NT/CD73).

Vacuolar (H)-ATPase Critically Regulates Specialized Proresolving Mediator Pathways in Human M2-like Monocyte-Derived Macrophages and Has a Crucial Role in Resolution of Inflammation.

Alternative (M2)-polarized macrophages possess high capacities to produce specialized proresolving mediators (SPM; i.e., resolvins, protectins, and maresins) that play key roles in resolution of inflammation and tissue regeneration.

Novel benzoxanthene lignans that favorably modulate lipid mediator biosynthesis: A promising pharmacological strategy for anti-inflammatory therapy.

Lipid mediators (LM) encompass pro-inflammatory prostaglandins (PG) and leukotrienes (LT) but also specialized pro-resolving mediators (SPM) which display pivotal bioactivities in health and disease. Pharmacological intervention with inflammatory disorders such as osteoarthritis and rheumatoid arthritis commonly employs anti-inflammatory drugs that can suppress PG and LT formation, which however, possess limited effectiveness and side effects. Here, we report on the discovery and characterization of the two novel benzoxanthene lignans 1 and 2 that modulate select LM biosynthetic enzymes enabling the switch from pro-inflammatory LT to SPM biosynthesis as potential pharmacological strategy to intervene with inflammation.

Leukotriene-mediated sex dimorphism in murine asthma-like features during allergen sensitization.

The incidence and severity of asthma preponderate in women versus men. Leukotrienes (LTs) are lipid mediators involved in asthma pathogenesis, and sex disparities in LT biosynthesis and anti-LT pharmacology in inflammation have recently emerged. Here, we report on sex dimorphism in LT production during allergen sensitization and its correlation to lung function.

Extended pleurectomy decortication: the current role.

Extended pleurectomy/decortication (EPD) has been formally defined but there remain technical areas of debate between practitioners. This is partly attributable to the relative rarity of this operation which is largely confined to a small number of specialist centres. Nevertheless, there is a widespread acceptance that extended pleurectomy/decortication (P/D) is a realistic and favourable alternative to extrapleural pneumonectomy.

Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase.

Systemic vitamin E metabolites have been proposed as signaling molecules, but their physiological role is unknown. Here we show, by library screening of potential human vitamin E metabolites, that long-chain ω-carboxylates are potent allosteric inhibitors of 5-lipoxygenase, a key enzyme in the biosynthesis of chemoattractant and vasoactive leukotrienes. 13-((2R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (α-T-13'-COOH) can be synthesized from α-tocopherol in a human liver-on-chip, and is detected in human and mouse plasma at concentrations (8-49 nM) that inhibit 5-lipoxygenase in human leukocytes.

Discovery of a benzenesulfonamide-based dual inhibitor of microsomal prostaglandin E synthase-1 and 5-lipoxygenase that favorably modulates lipid mediator biosynthesis in inflammation.

Leukotrienes (LTs) and prostaglandin (PG)E, produced by 5-lipoxygenase (5-LO) and microsomal prostaglandin E synthase-1 (mPGES-1), respectively, are key players in inflammation, and pharmacological suppression of these lipid mediators (LM) represents a strategy to intervene with inflammatory disorders. Previous studies revealed that the benzenesulfonamide scaffold displays efficient 5-LO-inhibitory properties. Here, we structurally optimized benzenesulfonamides which led to an N-phenylbenzenesulfonamide derivative (compound 47) with potent inhibitory activities (IC = 2.

Technetium and methylene blue guided pulmonary nodules resections: preliminary British experience.

Background: Subcentimetre pulmonary nodules can be challenging to locate either during video-assisted thoracoscopic surgery (VATS) or by open techniques. In an era of increasing computed tomography scan availability the number of nodules that are identified that are suspicious for malignancy is rising, and thoracic surgeons require a reliable method to locate these nodules intraoperatively.

Methods: Our aim was to evaluate, for the first time in the UK, resection of pulmonary nodules using radioactive dye labelling.

Perspective on uniportal thoracic surgery: where do we stand and what is the future.

Uniportal video assisted thoracic surgery (U-VATS) is undoubtedly one of the recent most significant innovation in the field of pulmonary resection. The concept of a single incision, minimally invasive, thoracic procedure moved its first step in the late 90'. In more recent years we had several reports of uniportal surgery for major lung resection, complex surgery and also awake major pulmonary surgery.

Pulmonary metastasectomy in uterine malignancy: outcomes and prognostic factors.

Metastatic uterine cancer is a form of systemic disease. As for other solid tumours, it is advocated by some authors that in selected patients, lung metastasectomy may play a role in long-term disease control. The practice of lung metastasectomy is however open to criticism as there is lack of convincing evidence, and over-encouraging outcomes may be attributed to intrinsic selection bias.