Epoxyeicosatrienoic Acids Research Articles

Levels of fatty acids in blood plasma in workers with vibration disease

Introduction. Changes in the levels of fatty acids (FA), reflecting the specifics of metabolic disorders in workers with vibration disease (VD), and persons with VD aggravated by metabolic syndrome (MS) have not been studied enough. Mass spectrometric study of the composition of FA in VD patients and cases suffered from VD in combination with MS seems justified, since these compounds can be included in the formation of disorders at the early stages of changes in health status under the influence of adverse factors, which will later establish significant prognostic indicators.
 Materials and methods. The levels of esterified and free forms of fatty acids: saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) in blood plasma, were determined on an Agilent 7890A/5975C gas chromatograph.
 Results. The FA composition was studied in the surveyed cohort of people in vibration-hazardous occupations with a diagnosis of VD and VD+MS established in the clinic. Significant shifts in the FA levels were established, in VD + MS patients there was an increase in the concentrations of myristic, pentadecanoic, palmitic, margaric, stearic acids and ΣSFA when compared with VD patients. For all MUFAs and for ΣMUFA, large values were observed for the VD + MS group (p<0.001 to 0.027). For PUFAs, significant differences were noted in relation to the level of: α-linolenic, eicosatrienoic and eicosapentaenoic acids ω-3, total ω-3 PUFAs, linoleic, γ-linolenic and dihomo-γ-linolenic acids ω-6, total ω-6 PUFAs and total all PUFAs.
 Limitations. The results apply to sixty six vibration-hazardous occupations surveyed. The influence of experience and dietary preferences on the FA composition in blood plasma has not been studied.
 Conclusion. A study of the quantitative FA indicators in the blood plasma showed the total indicators of saturated, monounsaturated and polyunsaturated fatty acids in persons with VD+MS to be higher than in VD patients by 1.36, 1.33 and 1.12 times, respectively.

Glimepiride, a novel soluble epoxide hydrolase inhibitor, protects against heart failure via increasing epoxyeicosatrienoic acids

BackgroundEpoxyeicosatrienoic acids (EETs), which exert multiple endogenous protective effects, are hydrolyzed into less active dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). However, commercial drugs related to EETs or sEH are not yet in clinical use. MethodsFirstly, the plasma concentration of EETs and DHETs of 316 patients with heart failure (HF) were detected and quantitated by liquid chromatography-tandem mass spectrometry. Then, transverse aortic constriction (TAC)-induced HF was introduced in cardiomyocyte-specific Ephx2−/− mice. Moreover, Western blot, real-time PCR, luciferase reporter, ChIP assays were employed to explore the underlying mechanism. Finally, multiple sEH inhibitors were designed, synthesized, and validated in vitro and in vivo. ResultsThe ratios of DHETs/EETs were increased in the plasma from patients with HF. Meanwhile, the expression of sEH was upregulated in the heart of patients and mice with HF, especially in cardiomyocytes. Cardiomyocyte-specific Ephx2−/− mice ameliorated cardiac dysfunction induced by TAC. Consistently, Ephx2 knockdown protected Angiotensin II (AngII)-treated cardiomyocytes via increasing EETs in vitro. Mechanistically, AngII could enhance the expression of transcript factor Krüppel-like factor 15 (KLF15), which in turn upregulated sEH. Importantly, glimepiride was identified as a novel sEH inhibitor, which benefited from the elevated EETs during HF. ConclusionsGlimepiride attenuates HF in mice in part by increasing EETs.Clinical trial identifier:NCT03461107 (https://clinicaltrials.gov).

Impact of Preharvest Ethephon Foliar Spray on the Postharvest Fatty Acid Profile and Dietary Indicators of Macadamia Nuts

The use of ethephon, designed to stimulate nut detachment, initiates the release of ethylene, a well-established regulator of postharvest shelf-life in various agricultural products. This study aimed to assess the impact of ethephon application on individual fatty acids and dietary indicators in two macadamia nut cultivars, namely ‘788’ and ‘Beaumont,’ during postharvest storage. Nuts that naturally abscised and those detached through ethephon treatment were divided into two groups: the ethylene-treated group (ED) and the control group (CD). Nuts were stored at 25 °C and sampled at 0, 36, and 72 days for fatty profile analysis. Our findings indicated a significant increase in stearic acid content in ED nuts (24,622 µg/g) compared to CD nuts (16,764 µg/g) at the end of the storage period for the ‘Beaumont’ cultivar. Additionally, unsaturated fatty acids (USFAs), such as eicosatrienoic acid + erucic acid (C20:3n3 + C22:1) and eicosatrienoic acid + alpha-linolenic acid (C20:1 + C18:3n3), were notably reduced. Hierarchical clustering analysis revealed positive correlations between ethylene treatment and saturated fatty acids (SFAs) in both ‘Beaumont’ (0.78) and ‘788’ (0.80) cultivars. This also coincided with an increase in atherogenic indices, thrombogenic index, and saturation index and a decrease in the hypocholesterolemic/hypercholesterolemic ratio and arachidonic acid (C20:4n6) within the ED group of the ‘Beaumont’ cultivar, collectively potentially impacting nutritional quality negatively. Furthermore, our findings indicated that the PUFA:SFA ratio was higher in CD (0.51) compared to ED (0.45) on day 72 for the ‘Beaumont’ cultivar, revealing differences in fatty acid compositions between the two treatment groups. Conversely, for ‘788’, both ED and CD had a PUFA:SFA ratio below 0.45, indicating an increased risk of cardiovascular diseases. These results suggest that ethephon treatment increases SFA levels and reduces USFA levels in the ‘Beaumont’ cultivar, while the response to ethylene varies between the two cultivars. Thus, the study provides insight into the significant role of modifying ethephon treatment methods and careful cultivar selection in the attainment of optimal nutritional value and shelf-life of macadamia nuts.

Arachidonic acid metabolism in health and disease.

Arachidonic acid (AA), an n-6 essential fatty acid, is a major component of mammalian cells and can be released by phospholipase A2. Accumulating evidence indicates that AA plays essential biochemical roles, as it is the direct precursor of bioactive lipid metabolites of eicosanoids such as prostaglandins, leukotrienes, and epoxyeicosatrienoic acid obtained from three distinct enzymatic metabolic pathways: the cyclooxygenase pathway, lipoxygenase pathway, and cytochrome P450 pathway. AA metabolism is involved not only in cell differentiation, tissue development, and organ function but also in the progression of diseases, such as hepatic fibrosis, neurodegeneration, obesity, diabetes, and cancers. These eicosanoids are generally considered proinflammatory molecules, as they can trigger oxidative stress and stimulate the immune response. Therefore, interventions in AA metabolic pathways are effective ways to manage inflammatory-related diseases in the clinic. Currently, inhibitors targeting enzymes related to AA metabolic pathways are an important area of drug discovery. Moreover, many advances have also been made in clinical studies of AA metabolic inhibitors in combination with chemotherapy and immunotherapy. Herein, we review the discovery of AA and focus on AA metabolism in relation to health and diseases. Furthermore, inhibitors targeting AA metabolism are summarized, and potential clinical applications are discussed.

Red Blood Cell Fatty Acid Profiles Are Significantly Altered in South Australian Mild Cognitive Impairment and Alzheimer's Disease Cases Compared to Matched Controls.

Nutritional imbalances have been associated with a higher risk for cognitive impairment. This study determined the red blood cell (RBC) fatty acid profile of newly diagnosed mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients compared to age and gender-matched controls. There was a significant increase in palmitic acid (p < 0.00001) for both MCI and AD groups. Saturated fatty acids were significantly elevated in the MCI group, including stearic acid (p = 0.0001), arachidic acid (p = 0.003), behenic acid (p = 0.0002), tricosanoic acid (p = 0.007) and lignoceric acid (p = 0.001). n-6 polyunsaturated fatty acids (PUFAs) were significantly reduced in MCI, including linoleic acid (p = 0.001), γ-linolenic acid (p = 0.03), eicosatrienoic acid (p = 0.009) and arachidonic acid (p < 0.00004). The n-3 PUFAs, α-linolenic acid and docosahexaenoic acid, were both significantly reduced in MCI and AD (p = 0.0005 and p = 0.00003). A positive correlation was evident between the Mini-Mental State Examination score and nervonic acid in MCI (r = 0.54, p = 0.01) and a negative correlation with γ-linolenic acid in AD (r = -0.43, p = 0.05). Differences in fatty acid profiles may prove useful as potential biomarkers reflecting increased risk for dementia.

Fatty acid binding proteins are novel modulators of synaptic epoxyeicosatrienoic acid signaling in the brain

Fatty acid binding proteins (FABPs) govern intracellular lipid transport to cytosolic organelles and nuclear receptors. More recently, FABP5 has emerged as a key regulator of synaptic endocannabinoid signaling, suggesting that FABPs may broadly regulate the signaling of neuroactive lipids in the brain. Herein, we demonstrate that brain-expressed FABPs (FABP3, FABP5, and FABP7) interact with epoxyeicosatrienoic acids (EETs) and the peroxisome proliferator-activated receptor gamma agonist 15-deoxy-Δ12,14-Prostaglandin J2 (15d-PGJ2). Among these lipids, EETs displayed highest affinities for FABP3 and FABP5, and 11,12-EET was identified as the preferred FABP ligand. Similarly, 15d-PGJ2 interacted with FABP3 and FABP5 while binding to FABP7 was markedly lower. Molecular modeling revealed unique binding interactions of the ligands within the FABP binding pockets and highlighted major contributions of van der Waals clashes and acyl chain solvent exposure in dictating FABP affinity and specificity. Functional studies demonstrated that endogenous EETs gate the strength of CA1 hippocampal glutamate synapses and that this function was impaired following FABP inhibition. As such, the present study reveals that FABPs control EET-mediated synaptic gating, thereby expanding the functional roles of this protein family in regulating neuronal lipid signaling.

Epoxyeicosatrienoic Acids Prevent Cardiac Dysfunction in Viral Myocarditis via Interferon Type I Signaling.

Myocarditis is a challenging inflammatory disease of the heart, and better understanding of its pathogenesis is needed to develop specific drug therapies. Epoxyeicosatrienoic acids (EETs), active molecules synthesized by CYP (cytochrome P450) enzymes from arachidonic acids and hydrolyzed to less active dihydroxyeicosatrienoic acids by sEH (soluble epoxide hydrolase), have been attributed anti-inflammatory activity. Here, we investigated whether EETs have immunomodulatory activity and exert protective effects on coxsackie B3 virus-induced myocarditis. Viral infection altered eicosanoid epoxide and diol levels in both patients with myocarditis and in the murine heart and correlated with the increased expression and activity of sEH after coxsackie B3 virus infection. Administration of a sEH inhibitor prevented coxsackie B3 virus-induced cardiac dysfunction and inflammatory infiltration. Importantly, EET/sEH inhibitor treatment attenuated viral infection or improved viral resistance by activating type I IFN (interferon) signaling. At the molecular level, EETs enhanced the interaction between GSK3β (glycogen synthase kinase-3 beta) and TBK1 (TANK-binding kinase 1) to promote IFN-β production. Our findings revealed that EETs and sEH inhibitors prevent the progress of coxsackie B3 virus-induced myocarditis, particularly by promoting viral resistance by increasing IFN production.

Eicosanoid-Regulated Myeloid ENaC and Isolevuglandin Formation in Human Salt-Sensitive Hypertension.

The mechanisms by which salt increases blood pressure in people with salt sensitivity remain unclear. Our previous studies found that high sodium enters antigen-presenting cells (APCs) via the epithelial sodium channel and leads to the production of isolevuglandins and hypertension. In the current mechanistic clinical study, we hypothesized that epithelial sodium channel-dependent isolevuglandin-adduct formation in APCs is regulated by epoxyeicosatrienoic acids (EETs) and leads to salt-sensitive hypertension in humans. Salt sensitivity was assessed in 19 hypertensive subjects using an inpatient salt loading and depletion protocol. Isolevuglandin-adduct accumulation in APCs was analyzed using flow cytometry. Gene expression in APCs was analyzed using cellular indexing of transcriptomes and epitopes by sequencing analysis of blood mononuclear cells. Plasma and urine EETs were measured using liquid chromatography-mass spectrometry. Baseline isolevuglandin+ APCs correlated with higher salt-sensitivity index. Isolevuglandin+ APCs significantly decreased from salt loading to depletion with an increasing salt-sensitivity index. We observed that human APCs express the epithelial sodium channel δ subunit, SGK1 (salt-sensing kinase serum/glucocorticoid kinase 1), and cytochrome P450 2S1. We found a direct correlation between baseline urinary 14,15 EET and salt-sensitivity index, whereas changes in urinary 14,15 EET negatively correlated with isolevuglandin+ monocytes from salt loading to depletion. Coincubation with 14,15 EET inhibited high-salt-induced increase in isolevuglandin+ APC. Isolevuglandin formation in APCs responds to acute changes in salt intake in salt-sensitive but not salt-resistant people with hypertension, and this may be regulated by renal 14,15 EET. Baseline levels of isolevuglandin+ APCs or urinary 14,15 EET may provide diagnostic tools for salt sensitivity without a protocol of salt loading.

Abstract P418: Antigen-presenting Cell-specific MAP-kinase Signaling Contributes To Inflammation And Salt-sensitivity Of Blood Pressure In Humans

Salt-sensitivity of blood pressure (SSBP) is defined by the changes in blood pressure in concert with salt intake/depletion. SSBP affects 50 percent of hypertensive and 25 percent of normotensive individuals and is an independent risk for stroke and cardiovascular death in both groups. We recently found that phosphorylation of STAT3 and SMAD3 in antigen-presenting cells plays an important role in developing SSBP. We hypothesized that mitogen-activated protein kinases (MAPKs) signaling plays an important role in activating/phosphorylating JAK-STAT-SMAD and contributes to salt-sensitivity of blood pressure. We isolated monocytes from eleven healthy individuals and treated them with either normal salt (NS) or high salt (HS) and performed bulk-RNA-sequencing. The bulk-RNA transcriptomic data analysis suggested that out of 21 members of the MAPK family, eighteen were upregulated (1.7-fold) in monocytes exposed to high salt. Among these, MAPK7 (NS:818.18±54.96; HS:1473.18±151.50) and MAPKAPK2 (NS:3977.81±286.67; HS:6222.63±440.32) were significantly upregulated. In additional experiments, we enrolled eleven hypertensive patients and phenotyped them for salt-sensitivity using a rapid salt-load and depletion inpatient protocol. Blood was collected at baseline, after salt loading, and depletion, and CITE-Seq was performed on isolated PBMCs. The data analysis showed that MAPK7 and MAPKAPK2 expressions mirror the blood pressure changes following salt loading and depletion in salt-sensitive but not in salt-resistant patients. Moreover, we found a positive correlation between MAPKAPK2 expression and the pulse pressure ((PP) r=0.52, p=0.033) after salt-load. Epoxyeicosatrienoic acid (EET) has been shown to activate MAPKs resulting in inhibiting ENAC activity. The data showed a strong positive correlation between MAPK7 expression and levels of EETs in plasma (r=0.70, p=0.036), and urine (r=0.68, p=0.045) after salt-load. These results from bulk-RNA and single-cell CITE-Seq data indicate that MAPKs play an important role in human SSBP.

P13-13: CYP2C19-mediated production of epoxyeicosatrienoic acids would facilitate M2 macrophage polarization through PPAR gamma activation

P13-13: CYP2C19-mediated production of epoxyeicosatrienoic acids would facilitate M2 macrophage polarization through PPAR gamma activation

In Silico Modeling and Structural Analysis of Soluble Epoxide Hydrolase Inhibitors for Enhanced Therapeutic Design.

Human soluble epoxide hydrolase (sEH), a dual-functioning homodimeric enzyme with hydrolase and phosphatase activities, is known for its pivotal role in the hydrolysis of epoxyeicosatrienoic acids. Inhibitors targeting sEH have shown promising potential in the treatment of various life-threatening diseases. In this study, we employed a range of in silico modeling approaches to investigate a diverse dataset of structurally distinct sEH inhibitors. Our primary aim was to develop predictive and validated models while gaining insights into the structural requirements necessary for achieving higher inhibitory potential. To accomplish this, we initially calculated molecular descriptors using nine different descriptor-calculating tools, coupled with stochastic and non-stochastic feature selection strategies, to identify the most statistically significant linear 2D-QSAR model. The resulting model highlighted the critical roles played by topological characteristics, 2D pharmacophore features, and specific physicochemical properties in enhancing inhibitory potential. In addition to conventional 2D-QSAR modeling, we implemented the Transformer-CNN methodology to develop QSAR models, enabling us to obtain structural interpretations based on the Layer-wise Relevance Propagation (LRP) algorithm. Moreover, a comprehensive 3D-QSAR analysis provided additional insights into the structural requirements of these compounds as potent sEH inhibitors. To validate the findings from the QSAR modeling studies, we performed molecular dynamics (MD) simulations using selected compounds from the dataset. The simulation results offered crucial insights into receptor-ligand interactions, supporting the predictions obtained from the QSAR models. Collectively, our work serves as an essential guideline for the rational design of novel sEH inhibitors with enhanced therapeutic potential. Importantly, all the in silico studies were performed using open-access tools to ensure reproducibility and accessibility.

Panax quinquefolius saponins combined with dual antiplatelet therapy enhanced platelet inhibition with alleviated gastric injury via regulating eicosanoids metabolism

BackgroundPanax quinquefolius saponin (PQS) was shown beneficial against platelet adhesion and for gastroprotection. This study aimed to investigate the integrated efficacy of PQS with dual antiplatelet therapy (DAPT) on platelet aggregation, myocardial infarction (MI) expansion and gastric injury in a rat model of acute MI (AMI) and to explore the mechanism regarding arachidonic acid (AA)-derived eicosanoids metabolism.MethodsWistar rats were subjected to left coronary artery occlusion to induce AMI model followed by treatment with DAPT, PQS or the combined therapy. Platelet aggregation was measured by light transmission aggregometry. Infarct size, myocardial histopathology was evaluated by TTC and H&E staining, respectively. Gastric mucosal injury was examined by scanning electron microscope (SEM). A comprehensive eicosanoids profile in plasma and gastric mucosa was characterized by liquid chromatography-mass spectrometer-based lipidomic analysis.ResultsPQS+DAPT further decreased platelet aggregation, lessened infarction and attenuated cardiac injury compared with DAPT. Plasma lipidomic analysis revealed significantly increased synthesis of epoxyeicosatrienoic acid (EET) and prostaglandin (PG) I2 (potent inhibitors for platelet adhesion and aggregation) while markedly decreased thromboxane (TX) A2 (an agonist for platelet activation and thrombosis) by PQS+DAPT, relative to DAPT. DAPT induced overt gastric mucosal damage, which was attenuated by PQS co-administration. Mucosal gastroprotective PGs (PGE2, PGD2 and PGI2) were consistently increased after supplementation of PQS+DAPT.ConclusionsCollectively, PQS+DAPT showed synergistic effect in platelet inhibition with ameliorated MI expansion partially through upregulation of AA/EET and AA/PGI2 synthesis while suppression of AA/TXA2 metabolism. PQS attenuated DAPT-induced gastric injury, which was mechanistically linked to increased mucosal PG production.

Association between CYP4A11 and EPHX2 genetic polymorphisms and chronic kidney disease progression in hypertensive patients

BackgroundThere is evidence indicating that some metabolites of arachidonic acid produced by cytochromes P450 (CYP) and epoxide hydroxylase (EPHX2), such as hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatrienoic acids (EETs) or dihydroxyeicosatrienoic acids (DHETEs), play an important role in blood pressure regulation and they could contribute to the development of hypertension (HT) and kidney damage. Therefore, the main aim of the study was to evaluate whether the genetic polymorphisms of CYP2C8, CYP2C9, CYP2J2, CYP4F2, CYP4F11 and EPHX2, responsible for the formation of HETEs, EETs and DHETEs, are related to the progression of impaired renal function in a group of patients with hypertension. Methods151 HT patients from a hospital nephrology service were included in the study. Additionally, a group of 87 normotensive subjects were involved in the study as control group. For HT patients, a general biochemistry analysis, estimated glomerular filtration rate and genotyping for different CYPs and EPHX2 variant alleles were performed. ResultsCYP4A11 rs3890011, rs9332982 and EPHX2 rs41507953 polymorphisms, according to the dominant model, presented a high risk of impaired kidney function, with odds ratios (OR) of 2.07 (1.00–4.32; P=0.049), 3.02 (1.11–8.23; P=0.030) and 3.59 (1.37–9.41; P=0.009), respectively, and the EPHX2 rs1042032 polymorphism a greater risk according to the recessive model (OR=6.23; 95% CI=1.50–25.95; P=0.007). However, no significant differences in allele frequencies between HT patients and in normotensive subjects for any of the SNP analyzed. In addition, the patients with diagnosis of dyslipidemia (n=90) presented higher frequencies of EPHX2 K55R (rs41507953) and *35A>G (rs1042032) variants than patients without dyslipidemia, 4% vs. 14% (P=0.005) and 16 vs. 27% (P=0.02), respectively. ConclusionsIn this study has been found higher odds of impaired renal function progression associated with rs3890011 and rs9332982 (CYP4A11) and rs41507953 and rs1042032 (EPHX2) polymorphisms, which may serve as biomarkers for improve clinical interventions aimed at avoiding or delaying, in chronic kidney disease patients, progress to end-stage kidney disease needing dialysis or kidney transplant.

Therapy of autoimmune inflammation in sporadic amyotrophic lateral sclerosis: Dimethyl fumarate and H-151 downregulate inflammatory cytokines in the cGAS-STING pathway.

In sporadic amyotrophic lateral sclerosis (sALS), IL-17A- and granzyme-positive cytotoxic T lymphocytes (CTL), IL-17A-positive mast cells, and inflammatory macrophages invade the brain and spinal cord. In some patients, the disease starts following a trauma or a severe infection. We examined cytokines and cytokine regulators over the disease course and found that, since the early stages, peripheral blood mononuclear cells (PBMC) exhibit increased expression of inflammatory cytokines IL-12A, IFN-γ, and TNF-α, as well as granzymes and the transcription factors STAT3 and STAT4. In later stages, PBMCs upregulated the autoimmunity-associated cytokines IL-23A and IL-17B, and the chemokines CXCL9 and CXCL10, which attract CTL and monocytes into the central nervous system. The inflammation is fueled by the downregulation of IL-10, TGFβ, and the inhibitory T-cell co-receptors CTLA4, LAG3, and PD-1, and, in vitro, by stimulation with the ligand PD-L1. We investigated in two sALS patients the regulation of the macrophage transcriptome by dimethyl fumarate (DMF), a drug approved against multiple sclerosis and psoriasis, and the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway inhibitor H-151. Both DMF and H-151 downregulated the expression of granzymes and the pro-inflammatory cytokines IL-1β, IL-6, IL-15, IL-23A, and IFN-γ, and induced a pro-resolution macrophage phenotype. The eicosanoid epoxyeicosatrienoic acids (EET) from arachidonic acid was anti-inflammatory in synergy with DMF. H-151 and DMF are thus candidate drugs targeting the inflammation and autoimmunity in sALS via modulation of the NFκB and cGAS/STING pathways.

Glabridin plays dual action to intensify anti-metastatic potential of paclitaxel via impeding CYP2C8 in liver and CYP2J2/EETs in tumor of an orthotopic mouse model of breast cancer

In spite of unprecedented advances in modern cancer therapy, there is still a dearth of targeted therapy to circumvent triple-negative breast cancer (TNBC). Paclitaxel is the front-line therapy against TNBC, but the main constraints of its treatment are dose-related adverse effects and emerging chemoresistance. In this context, glabridin (phytoconstituent from Glycyrrhiza glabra) is reported to hit multiple signalling pathways at the in-vitro level, but hardly any information is known at the in-vivo level. We aimed here to elucidate glabridin potential with an underlying mechanism in combination with a low dose of paclitaxel using a highly aggressive mouse mammary carcinoma model. Glabridin potentiated the anti-metastatic efficacy of paclitaxel by substantially curtailing tumor burden and diminishing lung nodule formation. Moreover, glabridin remarkably attenuated epithelial-mesenchymal transition (EMT) traits of hostile cancer cells via up-regulating (E-cadherin & occludin) and down-regulating (Vimentin & Zeb1) vital EMT markers. Besides, glabridin amplified apoptotic induction effect of paclitaxel in tumor tissue by declining or elevating pro-apoptotic (Procaspase-9 or Cleaved Caspase-9 & Bax) and reducing anti-apoptotic (Bcl-2) markers. Additionally, concomitant treatment of glabridin and paclitaxel predominantly lessened CYP2J2 expression with marked lowering of epoxyeicosatrienoic acid (EET)'s levels in tumor tissue to reinforce the anti-tumor impact. Simultaneous administration of glabridin with paclitaxel notably enhanced plasma exposure and delayed clearance of paclitaxel, which was mainly arbitrated by CYP2C8-mediated slowdown of paclitaxel metabolism in the liver. The fact of intense CYP2C8 inhibitory action of glabridin was also ascertained using human liver microsomes. Concisely, glabridin plays a dual role in boosting anti-metastatic activity by augmenting paclitaxel exposure via CYP2C8 inhibition-mediated delaying paclitaxel metabolism and limiting tumorigenesis via CYP2J2 inhibition-mediated restricting EETs level. Considering the safety, reported protective efficacy, and the current study results of boosted anti-metastatic effects, further investigations are warranted as a promising neoadjuvant therapy for crux paclitaxel chemoresistance and cancer recurrence.

Genetic variants in epoxyeicosatrienoic acid processing and degradation pathways are associated with gestational diabetes mellitus

AimTo explore the genetic effects of CYP2C8, CYP2C9, CYP2J2, and EPHX2, the key genes involved in epoxyeicosatrienoic acid processing and degradation pathways in gestational diabetes mellitus (GDM) and metabolic traits in Chinese pregnant women.MethodsA total of 2548 unrelated pregnant women were included, of which 938 had GDM and 1610 were considered as controls. Common variants were genotyped using the Infinium Asian Screening Array. Association studies of single nucleotide polymorphisms (SNPs) with GDM and related traits were performed using logistic regression and multivariable linear regression analyses. A genetic risk score (GRS) model based on 12 independent target SNPs associated with GDM was constructed. Logistic regression was used to estimate odds ratios and 95% confidence intervals, adjusting for potential confounders including age, pre-pregnancy body mass index, history of polycystic ovarian syndrome, history of GDM, and family history of diabetes, with GRS entered both as a continuous variable and categorized groups. The relationship between GRS and quantitative traits was also evaluated.ResultsThe 12 SNPs in CYP2C8, CYP2C9, CYP2J2, and EPHX2 were significantly associated with GDM after adjusting for covariates (all P < 0.05). The GRS generated from these SNPs significantly correlated with GDM. Furthermore, a significant interaction between CYP2J2 and CYP2C8 in GDM (PInteraction = 0.014, ORInteraction= 0.61, 95%CI 0.41–0.90) was observed.ConclusionWe found significant associations between GDM susceptibility and 12 SNPs of the four genes involved in epoxyeicosatrienoic acid processing and degradation pathways in a Chinese population. Subjects with a higher GRS showed higher GDM susceptibility with higher fasting plasma glucose and area under the curve of glucose and poorer β-cell function.

CYP2J deficiency leads to cardiac injury and presents dual regulatory effects on cardiac function in rats

Cytochrome P450 2J2 (CYP2J2) enzyme is widely expressed in aortic endothelial cells and cardiac myocytes and affects cardiac function, but the underlying mechanism is still unclear. Based on CYP2J knockout (KO) rats, we have directly studied the metabolic regulation of CYP2J on cardiac function during aging. The results showed that CYP2J deficiency significantly reduced the content of epoxyeicosatrienoic acids (EETs) in plasma, aggravated myocarditis, myocardial hypertrophy, as well as fibrosis, and inhibited the mitochondrial energy metabolism signal network Pgc-1α/Ampk/Sirt1. With the increase of age, the levels of 11,12-EET and 14,15-EET in plasma of KO rats decreased significantly, and the heart injury was more serious. Interestingly, we found that after CYP2J deletion, the heart initiated a self-protection mechanism by upregulating cardiac mechanism factors Myh7, Dsp, Tnni3, Tnni2, and Scn5a, as well as mitochondrial fusion factors Mfn2 and Opa1. However, this protective effect disappeared with aging. In conclusion, CYP2J deficiency not only reduces the amount of EETs, but also plays a dual regulatory role in cardiac function.

Enhancing Nutrient Recovery and Bioactive Compound Extraction from Spirulina through Supercritical Fluid Extraction: Implications for SH-SY5Y Cell Viability.

This work explores the efficiency of supercritical fluid extraction (SFE) to recover minerals, pigments, and antioxidant compounds from the spirulina microalgae. Moreover, the fatty acids and phenolic profiles of the extracts obtained were also investigated, and the effect of the extracts on SH-SY5Y cell viability was tested. The extraction of phycocyanin was improved by SFE compared to conventional extraction, from 2.838 ± 0.081 mg/g dry matter (DM) (control) to 6.438 ± 0.411 mg/g DM (SFE). SFE treatment also improved chlorophyll a and carotenoid recoveries increasing from 5.612 ± 0.547 to 8.645 ± 0.857 mg/g DM and from 0.447 ± 0.096 to 0.651 ± 0.120 mg/g DM, respectively. Regarding minerals, the SFE improved Mg recovery with 77% more than the control extraction. Moreover, palmitoleic, stearic, γ-linolenic, eicosadienoic and eicosatrienoic acids recovery was improved by SFE. Phenolic profiles were identified via triple-TOF-LC-MS-MS. Considering heavy metals, a higher rate of Pb extraction was observed for the SFE extract, while no significant differences were observed for Hg between both extractions. Finally, SFE extract improved cell viability compared to the control extract. Thus, SFE constitutes an interesting tool to sustainably extract high-added-value compounds; however, potential contaminants such as Pb need to be controlled in the resulting extracts.

Enhancement of the liver’s neuroprotective role ameliorates traumatic brain injury pathology

Traumatic brain injury (TBI) is a pervasive problem worldwide for which no effective treatment is currently available. Although most studies have focused on the pathology of the injured brain, we have noted that the liver plays an important role in TBI. Using two mouse models of TBI, we found that the enzymatic activity of hepatic soluble epoxide hydrolase (sEH) was rapidly decreased and then returned to normal levels following TBI, whereas such changes were not observed in the kidney, heart, spleen, or lung. Interestingly, genetic downregulation of hepatic Ephx2 (which encodes sEH) ameliorates TBI-induced neurological deficits and promotes neurological function recovery, whereas overexpression of hepatic sEH exacerbates TBI-associated neurological impairments. Furthermore, hepatic sEH ablation was found to promote the generation of A2 phenotype astrocytes and facilitate the production of various neuroprotective factors associated with astrocytes following TBI. We also observed an inverted V-shaped alteration in the plasma levels of four EET (epoxyeicosatrienoic acid) isoforms (5,6-, 8,9-,11,12-, and 14,15-EET) following TBI which were negatively correlated with hepatic sEH activity. However, hepatic sEH manipulation bidirectionally regulates the plasma levels of 14,15-EET, which rapidly crosses the blood-brain barrier. Additionally, we found that the application of 14,15-EET mimicked the neuroprotective effect of hepatic sEH ablation, while 14,15-epoxyeicosa-5(Z)-enoic acid blocked this effect, indicating that the increased plasma levels of 14,15-EET mediated the neuroprotective effect observed after hepatic sEH ablation. These results highlight the neuroprotective role of the liver in TBI and suggest that targeting hepatic EET signaling could represent a promising therapeutic strategy for treating TBI.

Genetic deletion or pharmacological inhibition of soluble epoxide hydrolase attenuated particulate matter 2.5 exposure mediated lung injury

Air pollution represented by particulate matter 2.5 (PM2.5) is closely related to diseases of the respiratory system. Although the understanding of its mechanism is limited, pulmonary inflammation is closely correlated with PM2.5-mediated lung injury. Soluble epoxide hydrolase (sEH) and epoxy fatty acids play a vital role in the inflammation. Herein, we attempted to use the metabolomics of oxidized lipids for analyzing the relationship of oxylipins with lung injury in a PM2.5-mediated mouse model, and found that the cytochrome P450 oxidases/sEH mediated metabolic pathway was involved in lung injury. Furthermore, the sEH overexpression was revealed in lung injury mice. Interestingly, sEH genetic deletion or the selective sEH inhibitor TPPU increased levels of epoxyeicosatrienoic acids (EETs) in lung injury mice, and inactivated pulmonary macrophages based on the MAPK/NF-κB pathway, resulting in protection against PM2.5-mediated lung injury. Additionally, a natural sEH inhibitor luteolin from Inula japonica displayed a pulmonary protective effect towards lung injury mediated by PM2.5 as well. Our results are consistent with the sEH message and protein being both a marker and mechanism for PM2.5-induced inflammation, which suggest its potential as a pharmaceutical target for treating diseases of the respiratory system.