Deficiency of Soluble Epoxide Hydrolase Protects Cardiac Function Impaired by LPS-Induced Acute Inflammation

Lipopolysaccharide (LPS) is a bacterial wall endotoxin producing many pathophysiological conditions including myocardial inflammation leading to cardiotoxicity. Linoleic acid (18:2n6, LA) is an essential n-6 PUFA which is converted to arachidonic acid (20:4n6, AA) by desaturation and elongation via enzyme systems within the body. Biological transformation of PUFA through CYP-mediated hydroxylation, epoxidation, and allylic oxidation produces lipid mediators, which may be subsequently hydrolyzed to corresponding diol metabolites by soluble epoxide hydrolase (sEH). In the current study, we investigate whether inhibition of sEH, which alters the PUFA metabolite profile, can influence LPS induced cardiotoxicity and mitochondrial function. Our data demonstrate that deletion of soluble epoxide hydrolase provides protective effects against LPS-induced cardiotoxicity by maintaining mitochondrial function. There was a marked alteration in the cardiac metabolite profile with notable increases in sEH-derived vicinal diols, 9,10- and 12,13-dihydroxyoctadecenoic acid (DiHOME) in WT hearts following LPS administration, which was absent in sEH null mice. We found that DiHOMEs triggered pronounced mitochondrial structural abnormalities, which also contributed to the development of extensive mitochondrial dysfunction in cardiac cells. Accumulation of DiHOMEs may represent an intermediate mechanism through which LPS-induced acute inflammation triggers deleterious alterations in the myocardium in vivo and cardiac cells in vitro. This study reveals novel research exploring the contribution of DiHOMEs in the progression of adverse inflammatory responses toward cardiac function in vitro and in vivo

A Case of Ciprofloxacin-Induced QT Prolongation and Torsade de Pointes

Prolongation of the QT interval is a recognized adverse effect of fluoroquinolone antibiotics. This effect on ventricular repolarization can potentially lead to life-threatening arrhythmias such as Torsade de pointes. Torsade de pointes is a polymorphic form of ventricular tachycardia identified by twisting of the QRS axis around an isoelectric point. We report a case of torsade de pointes induced by ciprofloxacin treatment. The patient experienced an acquired QT interval prolongation followed by Torsade de pointes arrhythmia with ciprofloxacin administration for ileostomy closure surgery and unfortunately expired

Genetic Deletion or Pharmacological Inhibition of Soluble Epoxide Hydrolase Ameliorates Cardiac Ischemia/Reperfusion Injury by Attenuating NLRP3 Inflammasome Activation

Activation of the nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome cascade has a role in the pathogenesis of ischemia/reperfusion (IR) injury. There is growing evidence indicating cytochrome p450 (CYP450)-derived metabolites of n-3 and n-6 polyunsaturated fatty acids (PUFAs) possess both adverse and protective effects in the heart. CYP-derived epoxy metabolites are rapidly hydrolyzed by the soluble epoxide hydrolase (sEH). The current study hypothesized that the cardioprotective effects of inhibiting sEH involves limiting activation of the NLRP3 inflammasome. Isolated hearts from young wild-type (WT) and sEH null mice were perfused in the Langendorff mode with either vehicle or the specific sEH inhibitor t-AUCB. Improved post-ischemic functional recovery and better mitochondrial respiration were observed in both sEH null hearts or WT hearts perfused with t-AUCB. Inhibition of sEH markedly attenuated the activation of the NLRP3 inflammasome complex and limited the mitochondrial localization of the fission protein dynamin-related protein-1 (Drp-1) triggered by IR injury. Cardioprotective effects stemming from the inhibition of sEH included preserved activities of both cytosolic thioredoxin (Trx)-1 and mitochondrial Trx-2 antioxidant enzymes. Together, these data demonstrate that inhibiting sEH imparts cardioprotection against IR injury via maintaining post-ischemic mitochondrial function and attenuating a detrimental innate inflammatory response

Mitochondrial Dysfunction and Inflammaging in Heart Failure: Novel Roles of CYP-Derived Epoxylipids

Age-associated changes leading to a decline in cardiac structure and function contribute to the increased susceptibility and incidence of cardiovascular diseases (CVD) in elderly individuals. Indeed, age is considered a risk factor for heart failure and serves as an important predictor for poor prognosis in elderly individuals. Effects stemming from chronic, low-grade inflammation, inflammaging, are considered important determinants in cardiac health; however, our understanding of the mechanisms involved remains unresolved. A steady decline in mitochondrial function is recognized as an important biological consequence found in the aging heart which contributes to the development of heart failure. Dysfunctional mitochondria contribute to increased cellular stress and an innate immune response by activating the NLRP-3 inflammasomes, which have a role in inflammaging and age-related CVD pathogenesis. Emerging evidence suggests a protective role for CYP450 epoxygenase metabolites of N-3 and N-6 polyunsaturated fatty acids (PUFA), epoxylipids, which modulate various aspects of the immune system and protect mitochondria. In this article, we provide insight into the potential roles N-3 and N-6 PUFA have modulating mitochondria, inflammaging and heart failure

A Survey of Linezolid Prescription Before and After Protocol Implementation in a Teaching Hospital

Background: Linezolid has been recognized as a safe and effective medicine against a wide variety of Gram-positive pathogens. Purpose: The primary objective of this study was to assess utilization appropriateness of linezolid and explore the efficiency of protocol intervention to proceed to rational drug usage. Method: The project was conducted in a referral teaching hospital from September 2015 to January 2017 in two phases. In the first step, a six-month survey was performed to evaluate the prescribing appropriateness of linezolid. Patients receiving linezolid were identified using hospital IT system and the medical charts were analyzed based on accurate indications and duration of linezolid prescription. Subsequently, a restrictive protocol was developed and communicated after a consensus by Drug and Therapeutics Committee in May 2016. After introduction of the protocol, an active daily surveillance of patients was done by hospital pharmacists. The appropriateness of linezolid utilization and infectious consultations were compared before and after protocol implementation. Results: In the first phase of the study, the indication of linezolid was appropriate in 56.2% of cases and improved considerably to 68.6% (P value: 0.04) after protocol enforcement. Furthermore the duration of the linezolid consumption was correct in 66.6% of patients, increasing to 88.5% after protocol introduction (P value 0.07). In the first step, 56.9% of linezolid prescriptions were based on infectious disease consultation which enhanced remarkably to 87.5% in the second step (P value 0.001), while, 65.5% and 73.8% of these consultations were appropriate in the study surveys respectively. Conclusion: The protocol intervention could improve appropriate prescribing of linezolid in the hospital setting. However, ongoing audit studies are recommended to maintain the rational prescription of linezolid