DNA damage by oxidized fatty acids detected by DNA/SPE biosensor

Electrochemical DNA/screen-printed electrode biosensor (DNA/SPE biosensor) was tested for the detection of alterations in DNA formed as a consequence of the reaction between DNA and oxidative products of fatty acids. Interaction of DNA with a mixture of products generated during the oxidation of linoleic and oleic acids manifested DNA damage depending on a tested fatty acid and the presence of hydroperoxides and thiobarbituric acid reactive substances (TBARS) determined after the oxidation of fatty acids. A bigger extent of the DNA damage was registered in the case of the interaction with oxidized linoleic acid with the high content of TBARS. The results achieved suggest the possible application of DNA/SPE biosensor in the detection of an interaction between DNA and products of fatty acid oxidation.

Eicosanoids in the pancreatic tumor microenvironment: a multicellular, multifaceted progression

Eicosanoids, oxidized fatty acids that serve as cell-signaling molecules, have been broadly implicated in tumorigenesis. To identify eicosanoids relevant to pancreatic tumorigenesis, we profiled normal pancreas and pancreatic ductal adenocarcinoma (PDAC) in mouse models and patient samples using mass spectrometry. We interrogated RNA sequencing datasets for eicosanoid synthase or receptor expression. Findings were confirmed by immunostaining. In murine models, we identified elevated levels of PGD2, prostacyclin, and thromboxanes in PDAC while PGE2, 12-HHTre, HETEs, and HDoHEs are elevated specifically in tumors. Analysis of scRNA-seq datasets suggests that PGE2 and prostacyclins are derived from fibroblasts, PGD2 and thromboxanes from myeloid cells, and PGD2 and 5-HETE from tuft cells. In patient samples, we identified a transition from PGD2 to PGE2-producing enzymes in the epithelium during the transition to PDAC, fibroblast/tumor expression of PTGIS, and myeloid/tumor cell expression of TBXAS1. Altogether, our analyses identify key changes in eicosanoid species during pancreatic tumorigenesis and the cell types responsible for their synthesis.

Multi-Omics Analysis to Generate Hypotheses for Mild Health Problems in Monkeys

Certain symptoms associated with mild sickness and lethargy have not been categorized as definitive diseases. Confirming such symptoms in captive monkeys (Macaca fascicularis, known as cynomolgus monkeys) can be difficult; however, it is possible to observe and analyze their feces. In this study, we investigated the relationship between stool state and various omics data by considering objective and quantitative values of stool water content as a phenotype for analysis. By examining the food intake of the monkeys and assessing their stool, urine, and plasma, we attempted to obtain a comprehensive understanding of the health status of individual monkeys and correlate it with the stool condition. Our metabolomics data strongly suggested that many lipid-related metabolites were correlated with the stool water content. The lipidomic analysis revealed the involvement of saturated and oxidized fatty acids, metallomics revealed the contribution of selenium (a bio-essential trace element), and intestinal microbiota analysis revealed the association of several bacterial species with the stool water content. Based on our results, we hypothesize that the redox imbalance causes minor health problems. However, it is not possible to make a definite conclusion using multi-omics alone, and other hypotheses could be proposed.

iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4

Here, we identify iPLA2β as a critical regulator for p53-driven ferroptosis upon reactive oxygen species (ROS)-induced stress. The calcium-independent phospholipase iPLA2β is known to cleave acyl tails from the glycerol backbone of lipids and release oxidized fatty acids from phospholipids. We found that iPLA2β-mediated detoxification of peroxidized lipids is sufficient to suppress p53-driven ferroptosis upon ROS-induced stress, even in GPX4-null cells. Moreover, iPLA2β is overexpressed in human cancers; inhibition of endogenous iPLA2β sensitizes tumor cells to p53-driven ferroptosis and promotes p53-dependent tumor suppression in xenograft mouse models. These results demonstrate that iPLA2β acts as a major ferroptosis repressor in a GPX4-independent manner. Notably, unlike GPX4, loss of iPLA2β has no obvious effect on normal development or cell viability in normal tissues but iPLA2β plays an essential role in regulating ferroptosis upon ROS-induced stress. Thus, our study suggests that iPLA2β is a promising therapeutic target for activating ferroptosis-mediated tumor suppression without serious toxicity concerns.

Multi-omics Analysis of Redox Imbalance-Related Mild Health Problems in Monkeys

Certain symptoms associated with mild sickness and lethargy have not been categorized as definitive diseases. Confirming such symptoms in captive monkeys (Macaca fascicularis) can be difficult; however, it is possible to observe and analyze their feces. Even among monkeys that are housed under carefully monitored conditions, some monkeys occasionally have poor stool conditions. In this study, we investigated the relationship between stool state and various omics data by considering objective and quantitative values of stool water content as a phenotype for analysis. By examining the food intake of the monkeys, the stool and urine they expel, and the plasma circulating in their bodies, we attempted to obtain a comprehensive understanding of the health status of a single individual and understand its relationship with stool condition. Our metabolomics data strongly suggested an association between lipids and stool water content. Lipidomic analysis revealed the involvement of saturated and oxidized fatty acids, metallomics revealed the contribution of selenium (a bio-essential trace element), and intestinal microbiota analysis revealed the association of several bacterial species with the stool water content. Taken together, these results suggest that selenium-induced disturbance in redox balance may cause minor health problems.

High- density lipoprotein function is abnormal in idiopathic inflammatory myopathies

Objective Damage to the vascular endothelium is strongly implicated in the pathogenesis of idiopathic inflammatory myopathies (IIM). Normally, high-density lipoprotein (HDL) protects the vascular endothelium from damage from oxidized phospholipids, which accumulate under conditions of oxidative stress. The current work evaluated the antioxidant function of HDL in IIM patients. Methods HDL’s antioxidant function was measured in IIM patients using a cell-free assay, which assesses the ability of isolated patient HDL to inhibit oxidation of low-density lipoproteins and is reported as the HDL inflammatory index (HII). Cholesterol profiles were measured for all patients, and subgroup analysis included assessment of oxidized fatty acids in HDL and plasma MPO activity. A subgroup of IIM patients was compared with healthy controls. Results The antioxidant function of HDL was significantly worse in patients with IIM (n = 95) compared with healthy controls (n = 41) [mean (S.d.) HII 1.12 (0.61) vs 0.82 (0.13), P < 0.0001]. Higher HII associated with higher plasma MPO activity [mean (S.d.) 13.2 (9.1) vs 9.1 (4.6), P = 0.0006] and higher oxidized fatty acids in HDL. Higher 5-hydroxyeicosatetraenoic acid in HDL correlated with worse diffusion capacity in patients with interstitial lung disease (r = −0.58, P = 0.02), and HDL’s antioxidant function was most impaired in patients with autoantibodies against melanoma differentiation-associated protein 5 (MDA5) or anti-synthetase antibodies. In multivariate analysis including 182 IIM patients, higher HII was associated with higher disease activity and DM diagnosis. Conclusion The antioxidant function of HDL is abnormal in IIM patients and may warrant further investigation for its role in propagating microvascular inflammation and damage in this patient population.

MODELING RECIPES OF DRY BREAKFAST WITH PRESCRIBED INDICATORS OF FOOD VALUE

Разработаны три рецептуры сухих завтраков на основе зернового и орехового сырья с заданными показателями пищевой ценности. В качестве исходного сырья использовали выращенные в Краснодарском крае грецкий орех (сорт Урожайный), миндаль (Форус), фисташки (Лакомка) и фундук (Трапезунд), содержащие 15–22% белка. Инновационным является предложенный авторами способ удаления из орехов и семян бобовых культур части легкоокисляемых жирных кислот с применением жидкого диоксида углерода под давлением 7 МПа при температуре 25–27°С. Предложенный авторами способ холодной экструзии позволяет получать экструдат с максимально сохраненным химическим составом исходного сырья. Сконструированный состав рецептур сухих завтраков соответствует рекомендациям Федерального исследовательского центра питания, биотехнологии и безопасности пищи (Москва) по соотношению частей белки : жиры : углеводы как 1,0 : 0,7 : 1,6. Three recipes of dry breakfast recipes based on grain and nut raw materials with prescribed indicators of food value have been developed. Walnuts (Urozhaynyi grade), almonds (Forus), pistachios (Lakomka) and hazelnuts (Trapezund) grown in the Krasnodar region containing 15–22% protein were used as initial raw materials. The authors' proposal is innovative to remove part of easily oxidized fatty acids from nuts and seeds of legumes using liquid carbon dioxide under a pressure of 7 MPa and a temperature of 25–27°С. The cold extrusion method proposed by the authors makes it possible to obtain an extrudate with the maximum preserved chemical composition of the raw material. The designed composition of breakfast cereal recipes corresponds to the recommendations of the Federal research center for nutrition, biotechnology and food safety (Moscow) for the ratio of protein : fat : carbohydrates as 1,0 : 0,7 : 1,6.

The Type 2 Diabetes Susceptibility PROX1 Gene Variants Are Associated with Postprandial Plasma Metabolites Profile in Non-Diabetic Men

The prospero homeobox 1 (PROX1) gene may show pleiotropic effects on metabolism. We evaluated postprandial metabolic alterations dependently on the rs340874 genotypes, and 28 non-diabetic men were divided into two groups: high-risk (HR)-genotype (CC-genotype carriers, n = 12, 35.3 ± 9.5 years old) and low-risk (LR)-genotype (allele T carriers, n = 16, 36.3 ± 7.0 years old). Subjects participated in two meal-challenge-tests with high-carbohydrate (HC, carbohydrates 89%) and normo-carbohydrate (NC, carbohydrates 45%) meal intake. Fasting and 30, 60, 120, and 180 min after meal intake plasma samples were fingerprinted by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). In HR-genotype men, the area under the curve (AUC) of acetylcarnitine levels was higher after the HC-meal [+92%, variable importance in the projection (VIP) = 2.88] and the NC-meal (+55%, VIP = 2.00) intake. After the NC-meal, the HR-risk genotype carriers presented lower AUCs of oxidized fatty acids (−81–66%, VIP = 1.43–3.16) and higher linoleic acid (+80%, VIP = 2.29), while after the HC-meal, they presented lower AUCs of ornithine (−45%, VIP = 1.83), sphingosine (−48%, VIP = 2.78), linoleamide (−45%, VIP = 1.51), and several lysophospholipids (−40–56%, VIP = 1.72–2.16). Moreover, lower AUC (−59%, VIP = 2.43) of taurocholate after the HC-meal and higher (+70%, VIP = 1.42) glycodeoxycholate levels after the NC-meal were observed. Our results revealed differences in postprandial metabolites from inflammatory and oxidative stress pathways, bile acids signaling, and lipid metabolism in PROX1 HR-genotype men. Further investigations of diet–genes interactions by which PROX1 may promote T2DM development are needed.