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Soluble epoxide hydrolase (sEH) is an emerging therapeutic target in a number of diseases that have inflammation as a common underlying cause. sEH limits tissue levels of cytochrome P450 (CYP) epoxides derived from omega-6 and omega-3 polyunsaturated fatty acids (PUFA) by converting these antiinflammatory mediators into their less active diols. Here, we explored the metabolic effects of a sEH inhibitor (t-TUCB) in fat-1 mice with transgenic expression of an omega-3 desaturase capable of enriching tissues with endogenous omega-3 PUFA. These mice exhibited increased CYP1A1, CYP2E1, and CYP2U1 expression and abundant levels of the omega-3-derived epoxides 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic (19,20-EDP) in insulin-sensitive tissues, especially liver, as determined by LC-ESI-MS/MS. In obese fat-1 mice, t-TUCB raised hepatic 17,18-EEQ and 19,20-EDP levels and reinforced the omega-3-dependent reduction observed in tissue inflammation and lipid peroxidation. t-TUCB also produced a more intense antisteatotic action in obese fat-1 mice, as revealed by magnetic resonance spectroscopy. Notably, t-TUCB skewed macrophage polarization toward an antiinflammatory M2 phenotype and expanded the interscapular brown adipose tissue volume. Moreover, t-TUCB restored hepatic levels of Atg12-Atg5 and LC3-II conjugates and reduced p62 expression, indicating up-regulation of hepatic autophagy. t-TUCB consistently reduced endoplasmic reticulum stress demonstrated by the attenuation of IRE-1α and eIF2α phosphorylation. These actions were recapitulated in vitro in palmitate-primed hepatocytes and adipocytes incubated with 19,20-EDP or 17,18-EEQ. Relatively similar but less pronounced actions were observed with the omega-6 epoxide, 14,15-EET, and nonoxidized DHA. Together, these findings identify omega-3 epoxides as important regulators of inflammation and autophagy in insulin-sensitive tissues and postulate sEH as a druggable target in metabolic diseases.

Introduction: The Spanish Haematology and Haemotherapy Society organizes peripheral blood smear review scheme, focused on the evaluation of diagnostic proficiency of participants by blood cell morphology analysis. The objective was to evaluate the efficacy of this scheme as an educational tool to improve the diagnostic proficiency of the participants. Methods: During 2011‐2019, 54 peripheral blood smears, alongside with patient details such as age, sex, blood cell counts and relevant clinical information, were sent to an average of 125 ± 13 laboratories per year. A number of 44 shipments were selected to analyse whether successive surveys of the same disease may lead to an improvement in the diagnostic success rate proposed by the laboratories. Participants were asked to select the most relevant morphological abnormalities, alongside the diagnostic orientation. Agreement of participant responses with RR was evaluated. Results: Spanish laboratories showed a diagnostic proficiency greater than 80% in acute myeloid leukaemia, including acute promyelocytic leukaemia, mature B‐cell neoplasms (hairy cell leukaemia and splenic marginal zone lymphoma), chronic myeloid leukaemia, sickle cell disease, Bernard‐Soulier syndrome and infectious mononucleosis. It was important to note the significant improvement over the time in the successive shipments of the same disease, with a 31% and 13% increase in their diagnostic orientation success rate for acute myeloid leukaemia and acute promyelocytic leukaemia cases, respectively, 15% for mantle cell lymphoma and 6% for sickle cell disease. Conclusions: The present study provides evidence that peripheral blood smear review scheme can be a valid educational tool to improve the clinical pathologist skills in blood morphology and haematological diagnosis. [ABSTRACT FROM AUTHOR]

The prototypic proinflammatory cytokine IL‐1β plays a central role in innate immunity and inflammatory disorders. The formation of mature IL‐1β from an inactive pro‐IL‐1β precursor is produced via nonconventional multiprotein complexes called the inflammasomes, of which the most common is the nucleotide‐binding domain leucine‐rich repeat‐containing protein 3 (NLRP3) inflammasome composed by NLRP3, (ASC) apoptosis‐associated speck‐like protein containing a caspase activation and recruitment domain (CARD), and caspase‐1. Specialized proresolving mediators (SPMs) promote resolution of inflammation, which is an essential process to maintain host health. SPMs prevent excessive inflammation by terminating the inflammatory response and returning to tissue homeostasis without immunosupression. This study tested the hypothesis that modulation of the NLRP3 inflammasome in macrophages is one mechanism involved in the SPM‐regulated processes during resolution. Our findings demonstrate that the SPM resolvin D2 (RvD2) suppressed the expression of pro‐IL‐1β and reduced the secretion of mature IL‐1β in bone marrow‐derived macrophages challenged with LPS+ATP (classical NLRP3 inflammasome model) or LPS+palmitate (lipotoxic model). Similar findings were observed in thioglycolate‐elicited peritoneal macrophages, in which RvD2 remarkably reduced ASC oligomerization, inflammasome assembly, and caspase‐1 activity. In vivo, in a self‐resolving zymosan A‐induced peritonitis model, RvD2 blocked the NLRP3 inflammasome leading to reduced release of IL‐1β into the exudates, repression of osteopontin, and MCP‐1 expression and induction of M2 markers of resolution (i.e., CD206 and arginase‐1) in peritoneal macrophages. RvD2 inhibitory actions were receptor mediated and were abrogated by a selective GPR18 antagonist. Together, these findings support the hypothesis that SPMs have the ability to inhibit the priming and to expedite the deactivation of the NLRP3 inflammasome in macrophages during the resolution process. Resolvin D2 modulates the NLRP3 inflammasome and the production of IL‐1β in macrophages during resolution of inflammation. [ABSTRACT FROM AUTHOR]

Objective: Systemic inflammation predisposes acutely decompensated (AD) cirrhosis to the development of acute-on-chronic liver failure (ACLF). Supportive treatment can improve AD patients, becoming recompensated. Little is known about the outcome of patients recompensated after AD. We hypothesise that different inflammasome activation is involved in ACLF development in compensated and recompensated patients., Design: 249 patients with cirrhosis, divided into compensated and recompensated (previous AD), were followed prospectively for fatal ACLF development. Two external cohorts (n=327) (recompensation, AD and ACLF) were included. Inflammasome-driving interleukins (ILs), IL-1α (caspase-4/11-dependent) and IL-1β (caspase-1-dependent), were measured. In rats, bile duct ligation-induced cirrhosis and lipopolysaccharide exposition were used to induce AD and subsequent recompensation. IL-1α and IL-1β levels and upstream/downstream gene expression were measured., Results: Patients developing ACLF showed higher baseline levels of ILs. Recompensated patients and patients with detectable ILs had higher rates of ACLF development than compensated patients. Baseline CLIF-C (European Foundation for the study of chronic liver failure consortium) AD, albumin and IL-1α were independent predictors of ACLF development in compensated and CLIF-C AD and IL-1β in recompensated patients. Compensated rats showed higher IL-1α gene expression and recompensated rats higher IL-1β levels with higher hepatic gene expression. Higher IL-1β detection rates in recompensated patients developing ACLF and higher IL-1α and IL-1β detection rates in patients with ACLF were confirmed in the two external cohorts., Conclusion: Previous AD is an important risk factor for fatal ACLF development and possibly linked with inflammasome activation. Animal models confirmed the results showing a link between ACLF development and IL-1α in compensated cirrhosis and IL-1β in recompensated cirrhosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)