Adrenic Acid Research Articles

DNA methylation of tumour necrosis factor (TNF) alpha gene is associated with specific blood fatty acid levels in a gender-specific manner.

BackgroundFatty acids, specifically polyunsaturated fatty acids (PUFAs) play an important role in inflammation and its resolution, however, their interaction with the epigenome is relatively unexplored. Here we investigate the relationship between circulating blood fatty acids and the DNA methylation of the cytokine encoding gene tumour necrosis factor (TNF, OMIM 191160).MethodsUsing a cross‐sectional study approach, we collected blood samples from adults (N=88 (30 males, 58 females); 18–74 years old) for DNA methylation pyrosequencing analysis at four sites in TNF exon 1 and gas‐chromatography mass‐spectrometry analysis of the fatty acid profile of dried blood spots (DBS).ResultsMethylation levels of TNF exon 1 are significantly correlated with specific fatty acids in a gender‐specific manner. In the males the PUFAs Docosahexaenoic Acid (DHA) and Arachidonic Acid (AA) were positively associated with TNF methylation, as was the saturated fatty acid (SFA) Stearic Acid; in contrast, mono‐unsaturated fatty acids (MUFAs) had a negative association. In the females, omega‐6 PUFA γ‐Linolenic acid (GLA) was negatively correlated with TNF methylation; Adrenic acid and Eicosadienoic Acid were positively correlated with TNF methylation.ConclusionThese results suggest that one way that fatty acids interact with the inflammation is through altered methylation profiles of cytokine genes; thus, providing potential therapeutic targets for nutritional and health interventions.

Plasma fatty acids and primary open-angle glaucoma in the elderly: the Montrachet population-based study

BackgroundTo compare plasma fatty acids (FAs) between participants with primary open-angle glaucoma (POAG) and participants without neuropathy in an elderly population and to investigate specific FAs pattern in POAG.MethodsWe conducted a population-based study in participants older than 75 years. Participants underwent a comprehensive eye examination with optic nerve photographs, visual field test and optic nerve OCT with RNFL thickness measurement. Glaucomatous status was defined according to the International Society for Epidemiologic and Geographical Ophthalmology classification. Lipids were extracted from plasma and FAs methylesters prepared and analyzed by gas chromatography-mass spectrometry.ResultsAmong the 1153 participants of the Montrachet study 810 were retained for analysis and 68 had POAG. The mean age was 82.11 ± 3.67. In multivariable analysis FAs levels were not different between POAG participants and controls (P = 0.078). A FAs pattern characterized by high negative weight of gamma-linoleic acid, eicosapentaenoic acid polyunsaturated FAs (PUFAs), Cis-7 hexadecenoic acid monounsaturated FAs (MUFAs) and high positive weight of eicosadienoic acid, docosatetraenoic acid, docosapentaenoic n-6, alpha linoleic acid PUFAs, eicosenoic acid MUFAs, margaric acid and behenic acid saturated FAs was positively associated with POAG. After adjustment for major confounders, individuals in the upper tertile of FAs pattern scores compared with those in the lower tertile were more likely to present POAG (OR = 3.09 [95% CI 1.29–7.40] P = 0.013).ConclusionsWe found no significant difference regarding isolated plasma FAs between participants with POAG and participants without neuropathy in elderly but specific FAs pattern might be associated with POAG.

An imaging mass spectrometry atlas of lipids in the human neurologically normal and Huntington's disease caudate nucleus.

Huntington's disease (HD) is a fatal disorder associated with germline trinucleotide repeat expansions in the HTT gene and characterised by striatal neurodegeneration. No efficacious interventions are available for HD, highlighting a major unmet medical need. The molecular mechanisms underlying HD are incompletely understood despite its monogenic aetiology. However, direct interactions between HTT and membrane lipids suggest that lipidomic perturbations may be implicated in the neuropathology of HD. In this study, we employed matrix-assisted laser desorption/ionisation imaging mass spectrometry (MALDI-IMS) to generate a comprehensive, unbiased and spatially resolved lipidomic atlas of the caudate nucleus (CN) in human post-mortem tissue from neurologically normal (n=10) and HD (n=13) subjects. Fourier transform-ion cyclotron resonance mass spectrometry and liquid chromatography-tandem mass spectrometry were used for lipid assignment. Lipidomic specialisation was observed in the grey and white matter constituents of the CN and these features were highly conserved between subjects. While the majority of lipid species were highly conserved in HD, compared to age-matched controls, CN specimens from HD cases in our cohort spanning a range of neuropathological grades showed a lower focal abundance of the neuroprotective docosahexaenoic and adrenic acids, several cardiolipins, the ganglioside GM1 and glycerophospholipids with long polyunsaturated fatty acyls. HD cases showed a higher focal abundance of several sphingomyelins and glycerophospholipids with shorter monosaturated fatty acyls. Moreover, we demonstrate that MALDI-IMS is tractable as a primary discovery modality comparing heterogeneous human brain tissue, provided that appropriate statistical approaches are adopted. Our findings support further investigation into the potential role of lipidomic aberrations in HD.

Adrenic Acid-Derived Epoxy Fatty Acids Are Naturally Occurring Lipids and Their Methyl Ester Prodrug Reduces Endoplasmic Reticulum Stress and Inflammatory Pain.

Adrenic acid (AdA, 22:4) is an ω-6 polyunsaturated fatty acid (PUFA), derived from arachidonic acid. Like other PUFAs, it is metabolized by cytochrome P450s to a group of epoxy fatty acids (EpFAs), epoxydocosatrienoic acids (EDTs). EpFAs are lipid mediators with various beneficial bioactivities, including exertion of analgesia and reduction of endoplasmic reticulum (ER) stress, that are degraded to dihydroxy fatty acids by the soluble epoxide hydrolase (sEH). However, the biological characteristics and activities of EDTs are relatively unexplored, and, alongside dihydroxydocosatrienoic acids (DHDTs), they had not been detected in vivo. Herein, EDT and DHDT regioisomers were synthesized, purified, and used as standards for analysis with a selective and quantitative high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. Biological verification in AdA-rich tissues suggests that basal metabolite levels are highest in the liver, with 16,17-EDT concentrations consistently being the greatest across the analyzed tissues. Enzyme hydrolysis assessment revealed that EDTs are sEH substrates, with greatest relative rate preference for the 13,14-EDT regioisomer. Pretreatment with an EDT methyl ester regioisomer mixture significantly reduced the onset of tunicamycin-stimulated ER stress in human embryonic kidney cells. Finally, administration of the regioisomeric mixture effectively alleviated carrageenan-induced inflammatory pain in rats. This study indicates that EDTs and DHDTs are naturally occurring lipids, and EDTs could be another therapeutically relevant group of EpFAs.

Serum non-esterified fatty acid levels and hip fracture risk: The Cardiovascular Health Study

Serum non-esterified fatty acids (NEFAs) are bioactive metabolic intermediates that can be taken up by bone tissue. Their associations with hip fracture risk have not been previously examined. Thirty-five individual NEFAs in five classes (saturated [SFA], mono-un-saturated [MUFA], poly-unsaturated n-6 and n-3 [PUFA], and trans-FA) were measured in Cardiovascular Health Study participants (n = 2139, mean age 77.8 years) without known diabetes. The multivariable associations of NEFA levels with hip fracture risk were evaluated in Cox hazards models. We documented 303 incident hip fractures during 11.1 years of follow-up. Among the five NEFA classes, total trans FA levels were positively associated with higher hip fracture risk (HR 1.17 [95% CI, 1.04, 1.31; p = 0.01] per one standard deviation higher level). The SFA lignoceric acid (24:0) was positively associated with higher risk (HR 1.09 [1.04, 1.1]; p < 0.001), while behenic (22:0) and docosatetraenoic (22:4 n6) acids were associated with lower risk (HR 0.76 [0.61, 0.94]; p = 0.01; 0.84 [0.70, 1.00]; p = 0.05, respectively). Total plasma trans NEFA levels are related to hip fracture risk, suggesting an unrecognized benefit of their systematic removal from food. Novel associations of individual NEFAs with hip fracture risk require confirmation in other cohort studies.

Incorporation of Dietary Arachidonic and Docosatetraenoic Acid into Mouse Brain.

It is essential to analyze the metabolism of dietary polyunsaturated fatty acids in the brain for the research and development of functional foods. In this study, a single dose of 2,2-dideuterium-labeled docosatetraenoic acid ((+2)DTA) or 2,2-dideuterium-labeled arachidonic acid ((+2)AA) was orally administered to Institute of Cancer Research (ICR) mice and its metabolism in the brain was investigated. In the (+2)DTA group, the (+2)DTA content in the brain was significantly increased at 4, 8, 24, and 96 h compared to 0 h after administration, while in the (+2)AA group, the (+2)AA content was significantly increased at 4, 8, 24, and 96 h compared to 0 h. However, there was no significant difference in the content of (+2)DTA, a metabolite of (+2)AA, among all the groups. These results suggest that dietary (+2)DTA and (+2)AA pass through the blood-brain barrier and dietary (+2)AA is rather stored in the brain than converted to (+2)DTA.

Metabolomic profiling identifies a novel mechanism for heat stroke‑related acute kidney injury.

Heat stroke can induce a systemic inflammatory response, which may lead to multi-organ dysfunction including acute kidney injury (AKI) and electrolyte disturbances. To investigate the pathogenesis of heat stroke (HS)-related AKI, a mouse model of HS was induced by increasing the animal's core temperature to 41°C. Blood samples obtained from the tail vein were used to measure plasma glucose and creatinine levels. Micro-positron emission tomography-computed tomography (micro-PET/CT), H&E staining and transmission electron microscopy were conducted to examine metabolic and morphological changes in the mouse kidneys. Immunohistochemistry (IHC) and western blot analyses were performed to investigate the expression of apoptosis-inducing factor mitochondria-associated 2 (Aifm2), high-mobility group box 1 (HMGB1) and receptor for advanced glycosylation end products (RAGE). Liquid chromatography-mass spectrometry analysis was conducted to find differential metabolites and signaling pathways. The HS mouse model was built successfully, with significantly increased creatinine levels detected in the serum of HS mice compared with controls, whereas micro-PET/CT revealed active metabolism in the whole body of HS mice. H&E and TUNEL staining revealed that the kidneys of HS mice exhibited signs of hemorrhage and apoptosis. IHC and western blotting demonstrated significant upregulation of Aifm2, HMGB1 and RAGE in response to HS. Finally, 136 differential metabolites were screened out, and enrichment of the ‘biosynthesis of unsaturated fatty acids’ pathway was detected. HS-associated AKI is the renal manifestation of systemic inflammatory response syndrome, and may be triggered by the HMGB1/RAGE pathway. Metabolomics indicated increased adrenic acid, docosahexaenoic acid and eicosapentaenoic acid may serve as metabolic biomarkers for AKI in HS. The findings suggested that a correlation between the HMGB1/RAGE pathway and biosynthesis of unsaturated fatty acids may contribute to the progression of HS-related AKI.

Analysis of Lipid Peroxidation by UPLC-MS/MS and Retinoprotective Effects of the Natural Polyphenol Pterostilbene.

The loss of redox homeostasis induced by hyperglycemia is an early sign and key factor in the development of diabetic retinopathy. Due to the high level of long-chain polyunsaturated fatty acids, diabetic retina is highly susceptible to lipid peroxidation, source of pathophysiological alterations in diabetic retinopathy. Previous studies have shown that pterostilbene, a natural antioxidant polyphenol, is an effective therapy against diabetic retinopathy development, although its protective effects on lipid peroxidation are not well known. Plasma, urine and retinas from diabetic rabbits, control and diabetic rabbits treated daily with pterostilbene were analyzed. Lipid peroxidation was evaluated through the determination of derivatives from arachidonic, adrenic and docosahexaenoic acids by ultra-performance liquid chromatography coupled with tandem mass spectrometry. Diabetes increased lipid peroxidation in retina, plasma and urine samples and pterostilbene treatment restored control values, showing its ability to prevent early and main alterations in the development of diabetic retinopathy. Through our study, we are able to propose the use of a derivative of adrenic acid, 17(RS)-10-epi-SC-Δ15-11-dihomo-IsoF, for the first time, as a suitable biomarker of diabetic retinopathy in plasmas or urine.

Spatial Analysis of Phosphatidylinositol Molecular Species in Pork Chop Tissues Using Matrix-assisted Laser Desorption/ionization-Mass Spectrometry Imaging.

Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) is a powerful technique for visualizing lipids in biological tissues. Phosphatidylinositol (PI), a phospholipid in pork, is a major source of inositol in animal-derived foods believed to be protective against diseases related to pregnancy and cancer. However, the distribution of PI molecular species in pork is not well understood. Here, we performed MALDI-MSI analysis to investigate the distribution and composition of PI molecular species in pork chop comprising Longissimus thoracis et lumborum muscle (loin), intermuscular fat tissue, transparent tissue, and spinalis muscle. Twelve diacyl-PI molecular species were identified using liquid chromatography-electrospray ionization-tandem mass spectrometry (MS/MS) and MALDI-MS/MS analysis and visualized using MALDI-MSI. Spinalis muscle had the highest amount of identified PI molecular species, followed by loin, transparent tissue, and intermuscular fat tissue. The diacyl-PI molecular species containing hexadecadienoic, oleic, linoleic and eicosadienoic acids at the sn-2 position were mainly abundant in the loin and spinalis muscle, whereas those containing mead, arachidonic, docosatetraenoic, and docosapentaenoic acids at the sn-2 position were mainly abundant in both muscles as well as transparent tissues. Notably, the balance of PI molecular species differed among the tissues depending on fatty acid compositions at the sn-2 position. These results suggested that MALDI-MSI is a promising tool for assessing the association between individual pork tissues and the protective effects of PI molecular species against diseases related to pregnancy and cancer. To the best of our knowledge, this is the first report showing tissue-specific distributions of PI molecular species in pork chop using MALDI-MSI.

Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer

Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy.

Long chain omega-3 fatty acids and their oxidized metabolites are associated with reduced prostate tumor growth

IntroductionCancer has been associated with increased oxidative stress and deregulation of bioactive oxylipins derived from long-chain polyunsaturated fatty acids (LC-PUFA) like arachidonic acid (AA). There is a debate whether ω-3 LC-PUFA could promote or prevent prostate tumor growth through immune modulation and reduction of oxidative stress. Our aim was to study the association between enzymatically or non-enzymatically produced oxidized-LC-PUFA metabolites and tumor growth in an immune-competent eugonadal and castrated C57BL/6 male mice injected with TRAMP-C2 prostate tumor cells, fed with ω-3 or ω-6 LC-PUFA-rich diets. Materials and methodsTumor fatty acids were profiled by gas chromatography and 26 metabolites derived from either AA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were assessed by liquid chromatography-mass spectrometry. ResultsThe enriched ω-3 diet did not reduce oxidative stress overall in tumors but favored the formation of ω-3 rather than ω-6 derived isoprostanoids. We discovered that EPA and its oxidized-derivatives like F3-isoprostanes and prostaglandin (PG)F3α, were inversely correlated with tumor volume (spearman correlations and T-test, p<0.05). In contrast, F2-isoprostanes, adrenic acid, docosapentaenoic acid (DPAω-6) and PGE2 were positively correlated with tumor volume. Interestingly, F4-neuroprostanes, PGD2, PGF2α, and thromboxane were specifically increased in TRAMP-C2 tumors of castrated mice compared to those of eugonadal mice. DiscussionDecreasing tumor growth under ω-3 diet could be attributed in part to increased levels of EPA and its oxidized-derivatives, a reduced level of pro-angiogenic PGE2 and increased levels of F4-neuroprostanes and resolvins content in tumors, suspected of having anti-proliferative and anti-inflammatory effects.

ANALYSIS OF FATTY ACID PROFILES FOR EASTERN BOX (TERRAPENE CAROLINA CAROLINA) AND COMMON SNAPPING (CHELYDRA SERPENTINE) TURTLES IN WILD AND MANAGED CARE ENVIRONMENTS

The housing of wild animals in managed care facilities requires attention to all aspects of husbandry. Diets of wild animals often differ in composition, consistency, and quantity when compared with those in managed care settings including zoos, rehabilitation facilities, and aquaria. It was hypothesized that dietary differences from wild versus managed care would be reflected in data of circulating fatty acids based on previous studies. The current study examined the effect of species and environment on fatty acid concentrations in two omnivorous species of chelonians: Eastern box turtles, Terrapene carolina carolina, and common snapping turtles, Chelydra serpentina, located in the wild and managed care. Whole blood was collected and placed on spot cards for analysis of 26 fatty acids in a total lipid fatty acid profile. The present research indicated that Eastern box turtles have significantly (P < 0.05) higher percentages of linoleic acid (18:2n6), eicosadienoic acid (20:2n6), and mead acid (20:3n9). Common snapping turtles have significantly (P < 0.05) higher percentages of myristic acid (14:0), dihomo-γ-linolenic acid (20:3n6), erucic acid (22:1n9), and n-6 docosapentaenoic acid (22:5n6). Environmental effects also were noted; wild turtles had higher percentages of α-linolenic acid (18:3n3), arachidic acid (20:0), eicosadienoic acid (20:2n6), and eicosatrienoic acid (20:3n3) (P < 0.05), whereas n-6 docosapentaenoic acid (22:5n6) was higher for the managed care group. Eicosadienoic acid (20:2n6), behenic acid; 22:0), adrenic acid (22:4n6), n-6 docosapentaenoic acid (22:5n6), and nervonic acid (24:1) were significantly different (P < 0.05) in species-environment interactions without any noted species or environment patterns. Fatty acids are useful for many important biological functions including proper immune system regulation, and therefore, the present research provides medically relevant data for reptile diagnostics. This research may help further improve diets of all chelonians kept in managed care, regardless of species.

Anti-Inflammatory and Proresolving Effects of the Omega-6 Polyunsaturated Fatty Acid Adrenic Acid.

Polyunsaturated fatty acids (PUFAs) and their metabolites are potent regulators of inflammation. Generally, omega (n)-3 PUFAs are considered proresolving whereas n-6 PUFAs are classified as proinflammatory. In this study, we characterized the inflammatory response in murine peritonitis and unexpectedly found the accumulation of adrenic acid (AdA), a poorly studied n-6 PUFA. Functional studies revealed that AdA potently inhibited the formation of the chemoattractant leukotriene B4 (LTB4), specifically in human neutrophils, and this correlated with a reduction of its precursor arachidonic acid (AA) in free form. AdA exposure in human monocyte-derived macrophages enhanced efferocytosis of apoptotic human neutrophils. In vivo, AdA treatment significantly alleviated arthritis in an LTB4-dependent murine arthritis model. Our findings are, to our knowledge, the first to indicate that the n-6 fatty acid AdA effectively blocks production of LTB4 by neutrophils and could play a role in resolution of inflammation in vivo.

Abstract PO-022: Plasma fatty acid levels in treatment-naïve metastatic pancreatic cancer patients are associated with clinical indicators of cachexia

Abstract Cachexia is a multifactorial syndrome characterized by weight loss and tissue wasting, which is associated with reduced quality of life, responsiveness to chemotherapy, and decreased survival. We aim to determine whether changes in plasma fatty acid content in pancreatic ductal adenocarcinoma (PDAC): 1) are predictive of developing cachexia, and 2) whether these changes are influenced by other clinical parameters, like diabetes, that could contribute to malnutrition. Treatment-naïve metastatic PDAC subjects (n=51) were enrolled in NCT01280058 in which plasma samples and clinical data were collected prior to treatment. Subjects were assigned to either weight stable (&amp;lt;5% relative body weight loss, n=26) or “cachectic” (≥5% weight loss, n=25). Plasma fatty acid composition was analyzed via gas chromatography and reported as a percentage of the total identified fatty acids. Oleic (p=0.004) and adrenic acids (p=0.018) were significantly increased in cachectic subjects, regardless of age, sex, or BMI. Docosapentaenoic n-6 acid was more commonly elevated in older cachectic subjects compared to younger subjects (p=0.048). Adrenic acid levels were higher in subjects with cachexia and diabetes compared to subjects without diabetes with cachexia (p=0.0019) or stable weight (p=0.029). Additionally, linoleic acid was lower in subjects with cachexia and diabetes compared to subjects with cachexia and no diabetes (p=0.015) and subjects with stable weight (p=0.017). Area under the receiver operator curves (AUC) showed that oleic acid (AUC=0.726) and adrenic acid (AUC=0.706) are mildly effective at predicting cachexia, and the combination slightly improved the predictive ability (AUC=0.757). Our pilot study identified several plasma fatty acids that are associated with PDAC-associated cachexia, and are influenced by age and diabetes status. Further studies examining how fatty acids contribute to or arise from the development of cachexia may create opportunities for developing effective therapies for cachexia. Citation Format: Kristyn Gumpper, Phil A. Hart, Martha Belury, Olivia Crowe, Rachel M. Cole, Niharika Badi, Alice Hinton, Mitchell L. Ramsey, Anne Noonan, Darwin L. Conwell, Zobeida Cruz-Monserrate. Plasma fatty acid levels in treatment-naïve metastatic pancreatic cancer patients are associated with clinical indicators of cachexia [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-022.

One-Year Effects of Omega-3 Treatment on Fatty Acids, Oxylipins, and Related Bioactive Lipids and Their Associations with Clinical Lipid and Inflammatory Biomarkers: Findings from a Substudy of the Vitamin D and Omega-3 Trial (VITAL).

Omega-3 (n-3) treatment may lower cardiovascular risk, yet its effects on the circulating lipidome and relation to cardiovascular risk biomarkers are unclear. We hypothesized that n-3 treatment is associated with favorable changes in downstream fatty acids (FAs), oxylipins, bioactive lipids, clinical lipid and inflammatory biomarkers. We examined these VITAL200, a nested substudy of 200 subjects balanced on demographics and treatment and randomly selected from the Vitamin D and Omega-3 Trial (VITAL). VITAL is a randomized double-blind trial of 840 mg/d eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) vs. placebo among 25,871 individuals. Small polar bioactive lipid features, oxylipins and FAs from plasma and red blood cells were measured using three independent assaying techniques at baseline and one year. The Women’s Health Study (WHS) was used for replication with dietary n-3 intake. Randomized n-3 treatment led to changes in 143 FAs, oxylipins and bioactive lipids (False Discovery Rate (FDR) < 0.05 in VITAL200, validated (p-values < 0.05)) in WHS with increases in 95 including EPA, DHA, n-3 docosapentaenoic acid (DPA-n3), and decreases in 48 including DPA-n6, dihomo gamma linolenic (DGLA), adrenic and arachidonic acids. N-3 related changes in the bioactive lipidome were heterogeneously associated with changes in clinical lipid and inflammatory biomarkers. N-3 treatment significantly modulates the bioactive lipidome, which may contribute to its clinical benefits.

Altered metabolic profiles and biomarkers associated with astragaloside IV-mediated protection against cisplatin-induced acute kidney injury in rats: An HPLC-TOF/MS-based untargeted metabolomics study

Cisplatin (CDDP)-induced acute kidney injury (AKI) limits the therapeutic use of CDDP, which urgently needs to be addressed. Our previous study demonstrated that astragaloside IV (AS IV), an active compound of the traditional Chinese herb Astragalus membranaceus, alleviated CDDP-induced AKI. To explore the mechanism, we performed a metabolomics study to explore the altered metabolic pathways and screen for sensitive biomarkers. Twenty-four rats were randomly divided into three groups, which were treated with vehicle solutions (Control), intraperitoneally injected CDDP, and intraperitoneally injected CDDP plus oral AS IV, respectively. Metabolic profiles of serum, urine, and kidney samples were analyzed by high-performance liquid chromatography-time of flight mass spectrometry. There were 38 key metabolites in the urine samples, 20 in the serum samples, and 16 in the kidney samples that were significantly altered due to AS IV-mediated protection against CDDP-induced AKI relative to CDDP-only treatment. CDDP + AS IV co-treatment significantly altered two pathways in the blood (biosynthesis of unsaturated fatty acids and alanine, aspartate, and glutamate metabolism), five pathways in the urine (phenylalanine metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis; arginine biosynthesis; arginine and proline metabolism; and histidine metabolism), and five pathways in the kidneys (glutathione metabolism; alanine, aspartate, and glutamate metabolism; glyoxylate and dicarboxylate metabolism; arginine and proline metabolism; and D-glutamine and D-glutamate metabolism). The metabolic pathways were mainly associated with improvements in inflammatory responses, oxidative stress, and energy metabolism. Adrenic acid in serum and L-histidine and L-methionine in urine were identified as sensitive biomarkers. This study provides new insights to understand the mechanism of AS IV-mediated protection against CDDP-induced AKI and has identified three candidate biomarkers to evaluate preventative treatment and assess therapeutic effectiveness.

Integrative Analysis of Energy Partition Patterns and Plasma Metabolomics Profiles of Modern Growing Pigs Raised at Different Ambient Temperatures.

Simple SummaryMost of the studies focusing on energy partition patterns of growing pigs and the related mechanisms raised at different ambient temperatures were carried out during the 1970s to the early 2000s. With the rapid developments in pig breeding, research updates on such topics concerning modern growing pigs have been absent in the last decade. Therefore, this study focused on the energy partition patterns of modern growing pigs with different bodyweights at gradient-ambient temperatures and investigated the underlying changes in plasma metabolites under such conditions. Modern growing pigs at heavier bodyweight were more sensitive to high temperatures on energy intake and partition. At high ambient temperatures, most of the identified metabolites altered are associated with decreased fatty acid oxidation, increased lipid formation, and increased protein degradation. The findings of this study will provide possible solutions to precisely formulate diets for modern growing pigs raised at different ambient temperatures, and can help to improve our knowledge on potential mechanisms of thermoregulation in modern pig breeds.This study explores the energy partition patterns of modern growing pigs at 25 kg and 65 kg raised at gradient-ambient temperatures. It also investigates the underlying changes in plasma under such conditions, based on the integrative analysis of indirect calorimetry and non-target metabolomics profiling. Thirty-six barrows with initial BW of 26.4 ± 1.9 kg and 24 barrows with initial BW of 64.2 ± 3.1 kg were successively allotted to six respiration chambers with ambient temperatures set as 18 °C, 21 °C, 23 °C, 27 °C, 30 °C, and 32 °C, and four respiration chambers with ambient temperatures set as 18 °C, 23 °C, 27 °C, and 32 °C, respectively. Each pig was kept in an individual metabolic crate and consumed feed ad libitum, then transferred into the respiration chamber after a 7-day adaptation period for 5-day indirect calorimetry assay and 1-day fasting. As the ambient temperature increased from 18 °C to 32 °C, the voluntary feed intake, metabolizable energy intake, nitrogen intake, and retention, total heat production, and energy retention as a protein of growing pigs at 25 kg and 65 kg all linearly decreased (p < 0.05), with greater coefficients of variation for pigs at 65 kg when temperatures changed from 18 °C to 32 °C. The cortisol and thyroid hormone levels in the plasma of 25 kg pigs linearly decreased as the ambient temperature increased from 18 °C to 32 °C (p < 0.05), and 13 compounds were identified through metabolomics analysis, including up-regulated metabolites involved in fatty acid metabolism, such as adrenic acid and down-regulated metabolites involved in amino acid metabolism, such as spermidine at 32 °C. These results suggested that modern growing pigs at heavier bodyweight were more sensitive to high temperatures on energy intake and partition. Most of the identified metabolites altered at high ambient temperatures are associated with suppressed fatty acid oxidation and elevated lipogenesis and protein degradation.

Omega-3 and Omega-6 fatty acids and risk of psychotic outcomes in the ALSPAC birth cohort

BackgroundLong chain polyunsaturated fatty acid (PUFA) levels have been implicated in the pathology of psychotic disorders. We investigated the relationship between childhood PUFA levels and later psychotic experiences (PE's) in a large birth cohort. MethodsPlasma levels of Ω-3 and Ω-6 fatty acids (FA's) were assayed at ages 7 and 16 years. PE's were assessed at ages 12 and 18 years using a semi-structured interview. Primary outcome was any PE's at 18 years; sensitivity analyses examined incident PE's between ages 12 and 18 years, persistent PE's (at 12 and 18) and psychotic disorder at 18 years. Genetic instruments for Ω-3 and Ω-6 were derived and used in a multivariable Mendelian Randomization analysis. ResultsHigher levels of Ω-6 FA's AA, OA and AdA at age 7 years were weakly associated with a reduced risk for PE's at 18 years, however, effect sizes were small and attenuated after adjusting for confounders (strongest evidence for OA; adjusted OR, 0.842; 95% CI, 0.711, 0.998; p, 0.048). Total Ω-6 levels at age 16 years were associated with an increased odds of psychotic disorder at age 18 years. However, there was no association between Ω-6/Ω-3 ratio and psychosis outcomes, nor with genetic instruments of total Ω-3 or Ω-6 levels. ConclusionsThere is no strong evidence that total plasma Ω-3 FA levels or Ω-6/Ω-3 ratios in childhood and mid-adolescence are associated with increased risk for PE's or psychotic disorder, but very marginal evidence that alterations in the Ω-6 pathway at developmental time points might influence risk22AA, arachidonic acid (20:4n-6); AdA, docosatetraenoic acid (trivial name adrenic acid; 22:4n-6); OA, omega-6 docosapentaenoic acid (trivial name osbond acid; 22:5n-6)..

Changes in the cellular fatty acid profile drive the proteasomal degradation of α-synuclein and enhance neuronal survival.

Parkinson's disease is biochemically characterized by the deposition of aberrant aggregated α-synuclein in the affected neurons. The aggregation properties of α-synuclein greatly depend on its affinity to bind cellular membranes via a dynamic interaction with specific lipid moieties. In particular, α-synuclein can interact with arachidonic acid (AA), a polyunsaturated fatty acid, in a manner that promotes the formation of α-helix enriched assemblies. In a cellular context, AA is released from membrane phospholipids by phospholipase A2 (PLA2 ). To investigate the impact of PLA2 activity on α-synuclein aggregation, we have applied selective PLA2 inhibitors to a SH-SY5Y cellular model where the expression of human wild-type α-synuclein is correlated with a gradual accumulation of soluble oligomers and subsequent cell death. We have found that pharmacological and genetic inhibition of GIVA cPLA2 resulted in a dramatic decrease of intracellular oligomeric and monomeric α-synuclein significantly promoting cell survival. Our data suggest that alterations in the levels of free fatty acids, and especially AA and adrenic acid, promote the formation of α-synuclein conformers which are more susceptible to proteasomal degradation. This mechanism is active only in living cells and is generic since it does not depend on the absolute quantity of α-synuclein, the presence of disease-linked point mutations, the expression system or the type of cells. Our findings indicate that the α-synuclein-fatty acid interaction can be a critical determinant of the conformation and fate of α-synuclein in the cell interior and, as such, cPLA2 inhibitors could serve to alleviate the intracellular, potentially pathological, α-synuclein burden.

Adrenic acid induces oxidative stress in hepatocytes

Adrenic acid (ADA), which is an endogenously synthesized polyunsaturated free fatty acid, was significantly increased in nonalcoholic fatty liver disease (NAFLD) patients and NAFLD-model mice compared with the corresponding controls in our previous study. To elucidate the involvement of ADA in NAFLD and nonalcoholic steatohepatitis (NASH), we examined ADA-induced lipotoxicity in human hepatocarcinoma HepG2 cells. The ROS production in HepG2 cells was increased by exposure to ADA. It was also shown that the treatment with ADA decreased cell viability in a dose-dependent manner. The N-Acetyl-L-Cysteine pretreatment counteracted this ADA-induced ROS production and cell death. Furthermore, ADA modulated the expressions of SOD2, HO-1 and Gpx1 as antioxidant enzymes. These findings suggest that ADA could induce oxidative stress accompanied by cell death, providing new insights into lipotoxicity that is involved in the pathogenesis of NAFLD and NASH.