Persistent low-grade inflammation and premature ageing are hallmarks of the uremic phenotype and contribute to impaired health status, reduced quality of life, and premature mortality in chronic ...kidney disease (CKD). Because there is a huge global burden of disease due to CKD, treatment strategies targeting inflammation and premature ageing in CKD are of particular interest. Several distinct features of the uremic phenotype may represent potential treatment options to attenuate the risk of progression and poor outcome in CKD. The nuclear factor erythroid 2-related factor 2 (NRF2)-kelch-like erythroid cell-derived protein with CNC homology ECH-associated protein 1 (KEAP1) signaling pathway, the endocrine phosphate-fibroblast growth factor-23-klotho axis, increased cellular senescence, and impaired mitochondrial biogenesis are currently the most promising candidates, and different pharmaceutical compounds are already under evaluation. If studies in humans show beneficial effects, carefully phenotyped patients with CKD can benefit from them.
Background and Purpose
Tyrosine kinase inhibitors (TKI) used to treat chronic myeloid leukaemia (CML) have been associated with cardiovascular side effects, including reports of calcific aortic valve ...stenosis. The aim of this study was to establish the effects of first and second generation TKIs in aortic valve stenosis and to determine the associated molecular mechanisms.
Experimental Approach
Hyperlipidemic APOE*3Leiden.CETP transgenic mice were treated with nilotinib, imatinib or vehicle. Human valvular interstitial cells (VICs) were isolated and studied in vitro. Gene expression analysis was perfromed in aortic valves from 64 patients undergoing aortic valve replacement surgery.
Key Results
Nilotinib increased murine aortic valve thickness. Nilotinib, but not imatinib, promoted calcification and osteogenic activation and decreased autophagy in human VICs. Differential tyrosine kinase expression was detected between healthy and calcified valve tissue. Transcriptomic target identification revealed that the discoidin domain receptor DDR2, which is preferentially inhibited by nilotinib, was predominantly expressed in human aortic valves but markedly downregulated in calcified valve tissue. Nilotinib and selective DDR2 targeting in VICs induced a similar osteogenic activation, which was blunted by increasing the DDR2 ligand, collagen.
Conclusions and Implications
These findings suggest that inhibition of DDR2 by nilotinib promoted aortic valve thickening and VIC calcification, with possible translational implications for cardiovascular surveillance and possible personalized medicine in CML patients.
Proinflammatory bioactive lipid mediators and oxidative stress are increased in coronavirus disease 2019 (COVID-19). The randomized controlled single-blind trial COVID-Omega-F showed that intravenous ...omega-3 polyunsaturated fatty acids (n-3 PUFA) shifted the plasma lipid signature of COVID-19 towards increased proresolving precursor levels and decreased leukotoxin diols, associated with a beneficial immunodulatory response. The present study aimed to determine the effects of n-3 PUFA on the urinary oxylipidome and oxidative stress in COVID-19. From the COVID-Omega-F trial, 20 patients hospitalized for COVID-19 had available serial urinary samples collected at baseline, after 24-48 h, and after completing 5 days treatment with one daily intravenous infusion (2 mL/kg) of either placebo (NaCl; n = 10) or a lipid emulsion containing 10 g of n-3 PUFA per 100 mL (n = 10). Urinary eicosanoids and isoprostanes were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Erythrocytes obtained at the different time-points from n = 10 patients (n = 5 placebo and n = 5 n-3 PUFA) were used for determination of reactive oxygen species. Intravenous n-3 PUFA emulsion administration altered eicosanoid metabolites towards decreased levels for mediators of inflammation and thrombosis, and increased levels of the endothelial function mediator prostacyclin. Furthermore, non-enzymatic metabolism was skewed towards n-3 PUFA-derived metabolites with potential anti-inflammatory and pro-resolving effects. The oxidative stress marker 15-F2t-isoprostane was significantly lower in patients receiving n-3 PUFA treatment, who also exhibited significantly decreased erythrocyte oxidative stress compared with placebo-treated patients. These findings point to additional beneficial effects of intravenous n-3 PUFA emulsion treatment through a beneficial oxylipin profile and decreased oxidative stress in COVID-19.
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•COVID-Omega-F showed beneficial immunomodulatory effects in COVID-19.•Urinary fatty acid metabolites reflect the systemic lipid mediator biosynthesis.•Intravenous omega-3 fatty acids decreased urinary isoprostanes.•Erythrocte reactive oxygen species were lower in omega-3 compared with placebo.•Beneficial effects of n-3 PUFA on the oxylipidome and oxidate stress in COVID-19.
Background and Purpose
Microsomal PGE synthase‐1 (mPGES‐1), the inducible synthase that catalyses the terminal step in PGE2 biosynthesis, is of high interest as therapeutic target to treat ...inflammation. Inhibition of mPGES‐1 is suggested to be safer than traditional NSAIDs, and recent data demonstrate anti‐constrictive effects on vascular tone, indicating new therapeutic opportunities. However, there is a lack of potent mPGES‐1 inhibitors lacking interspecies differences for conducting in vivo studies in relevant preclinical disease models.
Experimental Approach
Potency was determined based on the reduction of PGE2 formation in recombinant enzyme assays, cellular assay, human whole blood assay, and air pouch mouse model. Anti‐inflammatory properties were assessed by acute paw swelling in a paw oedema rat model. Effect on vascular tone was determined with human ex vivo wire myography.
Key Results
We report five new mPGES‐1 inhibitors (named 934, 117, 118, 322, and 323) that selectively inhibit recombinant human and rat mPGES‐1 with IC50 values of 10–29 and 67–250 nM respectively. The compounds inhibited PGE2 production in a cellular assay (IC50 values 0.15–0.82 μM) and in a human whole blood assay (IC50 values 3.3–8.7 μM). Moreover, the compounds blocked PGE2 formation in an air pouch mouse model and reduced acute paw swelling in a paw oedema rat model. Human ex vivo wire myography analysis showed reduced adrenergic vasoconstriction after incubation with the compounds.
Conclusion and Implications
These mPGES‐1 inhibitors can be used as refined tools in further investigations of the role of mPGES‐1 in inflammation and microvascular disease.
Prostaglandins (PGD2, PGE2, PGF2α), prostacyclin (PGI2), and thromboxane A2 (TXA2) together form the prostanoid family of lipid mediators. As autacoids, these five primary prostanoids propagate ...intercellular signals and are involved in many physiological processes. Furthermore, alterations in their biosynthesis accompany a wide range of pathological conditions, which leads to substantially increased local levels during disease. Primary prostanoids are chemically instable and rapidly metabolized. Their metabolites are more stable, integrate the local production on a systemic level, and their analysis in various biological matrices yields valuable information under different pathological settings. Therefore, prostanoid metabolites may be used as diagnostic, predictive, or prognostic biomarkers in human disease. Although their potential as biomarkers is great and extensive research has identified major prostanoid metabolites that serve as target analytes in different biofluids, the number of studies that correlate prostanoid metabolite levels to disease outcome is still limited. We review the metabolism of primary prostanoids in humans, summarize the levels of prostanoid metabolites in healthy subjects, and highlight existing biomarker studies. Since analysis of prostanoid metabolites is challenging because of ongoing metabolism and limited half-lives, an emphasis of this review lies on the reliable measurement and interpretation of obtained levels.
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). SARS-CoV-2 triggers an immune response with local inflammation in the lung, ...which may extend to a systemic hyperinflammatory reaction. Excessive inflammation has been reported in severe cases with respiratory failure and cardiovascular complications. In addition to the release of cytokines, referred to as cytokine release syndrome or "cytokine storm," increased pro-inflammatory lipid mediators derived from the omega-6 polyunsaturated fatty acid (PUFA) arachidonic acid may cause an "eicosanoid storm," which contributes to the uncontrolled systemic inflammation. Specialized pro-resolving mediators, which are derived from omega-3 PUFA, limit inflammatory reactions by an active process called resolution of inflammation. Here, the rationale for omega-3 PUFA supplementation in COVID-19 patients is presented along with a brief overview of the study protocol for the trial "Resolving Inflammatory Storm in COVID-19 Patients by Omega-3 Polyunsaturated Fatty Acids - A single-blind, randomized, placebo-controlled feasibility study" (COVID-Omega-F). EudraCT: 2020-002293-28; clinicaltrials.gov: NCT04647604.
Potent antithrombotic therapy has significantly improved prognosis for patients with acute myocardial infarction (AMI), however, at a price of increased bleeding risk. Chronic gastric infection with ...Helicobacter pylori (Hp) commonly causes upper gastrointestinal bleeding and is proposed as a risk factor for subsequent bleeding post AMI. The prevalence of active Hp in a current AMI population and the feasibility of Hp screening as part of routine clinical care are unclear.
To determine the prevalence of active Hp infection in a contemporary AMI cohort and to establish the feasibility of Hp diagnosis as part of routine clinical MI care.
Multicenter, prospective cohort study.
Two university hospitals in Stockholm, Sweden.
Patients admitted for AMI between November 6, 2019 and April 4, 2020. After written informed consent, Hp diagnostics was performed with a bedside urea breath test (Diabact, Mayoly Spindler) incorporated into routine care during the hospitalization period.
Positive test for Hp infection.
The primary outcome was the prevalence of Hp infection. Secondary aims included predictive factors in patient characteristics and outcomes which were obtained from linkage with national registries. Predefined subgroup analyses included stratification for proton pump inhibitor use and infarct type.
Three hundred and ten consecutive AMI patients (median age 67; 23% female; 41% ST-elevation MI STEMI) were enrolled. Overall, the Hp prevalence was 20% (95%CI, 15.5-24.7). Hp positive status was significantly more common in smokers compared with nonsmokers (36% vs 21%, respectively; P < .05) and in patients presenting with STEMI compared with Non-STEMI (26% vs 15%, respectively; P = .02). The latter observation remained significant after multivariable adjustment. After exclusion of 97 subjects with current proton pump inhibitor use, the Hp prevalence was 24% (95%CI, 18.9-31.0).
Active Hp infection is common in a contemporary AMI population and may represent a modifiable risk factor for upper gastrointestinal bleeding, which has been hitherto disregarded. Hp screening as part of clinical routine during AMI hospitalization was feasible. A future randomized trial is needed to determine whether routine Hp screening and subsequent eradication therapy reduces bleeding complications and improves prognosis.
Question: Is Helicobacter pylori (Hp) infection sufficiently common in patients with acute myocardial infarction (AMI) to consider systematic screening, and can Hp diagnostics be performed during AMI hospitalization?
Findings: In this multicenter prospective cohort study of 310 consecutive AMI patients, Hp infection was established in at least 20% of patients. Infected patients were significantly more likely to be active smokers and to present with ST-elevation MI.
Meaning: Hp screening as part of clinical routine during AMI hospitalization was feasible. Given the high Hp prevalence detected, Hp diagnostics and eradication to reduce bleeding complications and to improve prognosis after AMI should be further investigated.
Dear Editor, COVID-Omega-F (“Resolving inflammatory storm in COVID-19 patients by Omega-3 Polyunsaturated fatty acids”) is a randomized controlled trial on intravenous (i.v.) omega-3 (n-3) ...polyunstaurated fatty acids (PUFA) treatment of coronavirus disease 2019 (COVID-19).1 We here report that COVID-Omega-F met its primary endpoint of changes in inflammatory biomarkers for white blood cell counts and lipid metabolites, and we also present exploratory studies of the underlying mechanisms. The n-3 PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) decrease C-reactive protein (CRP) in COVID-19.2,3 I.v. n-3 PUFA reduces hyperinflammation in other critical infectious conditions4 but has not previously been studied in COVID-19, and the mechanisms involved remain unknown. ...this proof-of-concept trial points to possible additive beneficial effects of n-3 PUFA treatment in COVID-19 on top of current treatment recommendations, in particular for vulnerable older COVID-19 patients with multiple comorbidities, which tolerated and responded to n-3 PUFA treatment.
Resolvin D2 (RvD2) and its G protein-coupled receptor (GPR) 18 detected in human coronary atherosclerosis. RvD2 injections reduced murine atherosclerosis, but not in the presence of the GPR18 ...antagonist O-1918. Illustration created with BioRender.com
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Chronic inflammation in atherosclerosis reflects a failure in the resolution of inflammation. Pro-resolving lipid mediators derived from omega-3 fatty acids reduce the development of atherosclerosis in murine models. The aim of the present study was to decipher the role of the specialized proresolving mediator (SPM) resolvin D2 (RvD2) in atherosclerosis and its signaling through the G-protein coupled receptor (GPR) 18. The ligand and receptor were detected in human coronary arteries in relation to the presence of atherosclerotic lesions and its cellular components. Importantly, RvD2 levels were significantly higher in atherosclerotic compared with healthy human coronary arteries. Furthermore, apolipoprotein E (ApoE) deficient hyperlipidemic mice were treated with either RvD2 or vehicle in the absence and presence of the GPR18 antagonist O-1918. RvD2 significantly reduced atherosclerosis, necrotic core area, and pro-inflammatory macrophage marker expression. RvD2 in addition enhanced macrophage phagocytosis. The beneficial effects of RvD2 were not observed in the presence of O-1918. Taken together, these results provide evidence of atheroprotective pro-resolving signalling through the RvD2-GPR18 axis.
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