A Plasma Exosomal Metabolic Profiling of Nonalcoholic Fatty Liver Disease Patients Complicated with Impaired Fasting Glucose.

BACKGROUND/AIMS: Nonalcoholic fatty liver disease is considered as the hepatic manifestation of metabolic syndrome. Detection of circulating exosomes together with metabolomic analysis of their cargo would provide early signals for metabolic derangements and complications associated with nonalcoholic fatty liver disease. Therefore, this study profiled exosomal metabolome of patients with nonalcoholic fatty liver disease and impaired fasting glucose. MATERIALS AND METHODS: Plasma exosomes were extracted from nonalcoholic fatty liver disease patients with or without impaired fasting glucose through differential ultracentrifugation. Their metabolite profiles were examined by ultrahigh-performance liquid chrom atography-quadrupole time-of-flight mass spectrometry. Pathway analysis was carried out on platform MetaboAnalyst 4.0. RESULTS: Thirty-nine patients were enrolled, including nonalcoholic fatty liver disease-alone group (n = 26) and age-and gender-comparable nonalcoholic fatty liver disease plus impaired fasting glucose group (n = 13). Although less than and different from their plasma counterparts, a total of 10 significantly differential exosomal metabolites were identified. Nonalcoholic fatty liver disease plus impaired fasting glucose group had higher concentrations of linoleic acid, palmitamide, stearamide, and oleamide, as well as a lower concentration of phosphatidylethanolamine [20:5(5Z,8Z,11Z,14Z,17Z)/20:5(5Z,8Z,11Z,14Z,17Z)]. Pathway analysis showed an obviously changed metabolism of linoleic acid. CONCLUSION: Metabolomic analysis of plasma exosomes revealed a distinct change in fatty acids and related pathways in nonalcoholic fatty liver disease patients with impaired fasting glucose. These preliminary results provide a metabolomic snapshot and basis for further investigation of exosome biology for these patients.

Biochar and conservation tillage affect the agronomic performance and fatty acid composition of Nigella sativa L. under both irrigated and dryland conditions.

Soils in arid and semi-arid regions like Iran have suffered greatly from low organic matter content and low water availability. Traditional tillage and the overuse of chemical fertilizers are accelerating the problems in the region. So, sensible and sustainable strategies such as conservation tillage and natural organic inputs are becoming increasingly important to enhance organic matter and humidity in the soil and grow high-quality crops in agroecosystems. Thus, in 2019 and 2020, a split-split plot arrangement within a randomized complete block design was conducted in Iran to assess the effects of irrigated conditions, tillage systems, and biochar on the aforementioned traits. There were two irrigation conditions (irrigated and dryland) as the main plots, three tillage methods (conventional, minimum, and no-tillage) as sub-plots, and two application rates for biochar (0 and 15 ton ha-1) as sub-sub plots. The findings indicated that biochar application enhanced grain yield across all tillage methods under both irrigation conditions. Biochar with minimum tillage improved oil yield by 23% and 29% compared to those that did not use biochar under the dryland and irrigated conditions, respectively. Moreover, oil yield was higher in 2020 than in 2019 for all tillage systems and biochar rates. The main components of Nigella sativa L. oil belong to linoleic, oleic, and palmitic acids. Minimum tillage with biochar under irrigated conditions in 2020 and no-tillage without biochar under dryland conditions in 2019 had the most (59%) and the least linoleic acid (53%), respectively. Conventional, minimum, and no-tillage with biochar in dryland conditions significantly increased linoleic acid by 2%, 3%, and 5% compared to those without biochar in 2020, respectively. In general, adopting biochar with minimum tillage produced the best outcomes for Nigella sativa L. yield, and grain oil quality under both irrigation conditions. It is recommended that farmers incorporate these practices to produce high-quality Nigella sativa L. in sustainable agricultural systems.

Oleic and linoleic acids promote chondrocyte apoptosis by inhibiting autophagy via downregulation of SIRT1/FOXO1 signaling.

Osteoarthritis (OA) is a complex joint disease that currently has no cure. OA involves metabolic disorders in chondrocytes and an imbalance between autophagy and apoptosis. As a common risk factor for OA, obesity induces changes in the fatty acid composition of synovial fluid, thereby disturbing chondrocyte homeostasis. However, whether unsaturated fatty acids affect the development of OA by regulating chondrocyte autophagy remains unclear. This study aimed to determine the effects of oleic and linoleic acids on chondrocyte autophagy and related mechanisms. Based on the mass spectrometry results, the levels of multiple unsaturated fatty acids, including oleic and linoleic acids, in the synovial fluid of patients with OA and obesity were significantly higher than those in patients with OA only. Moreover, we found that FOXO1 and SIRT1 were downregulated after oleic and linoleic acids treatment of chondrocytes, which inhibited chondrocyte autophagy. Importantly, the upregulation of SIRT1 and FOXO1 expression not only increased the level of autophagy but also improved the expression of chondrocyte extracellular matrix proteins. Furthermore, upregulated SIRT1 and FOXO1 expression alleviated the destruction of the articular cartilage in an OA rat model. Our results suggest that SIRT1/FOXO1 signaling can alleviate oleic acid- and linoleic acid-induced cartilage degradation both in vitro and in vivo and that the SIRT1/FOXO1 pathway may serve as an effective treatment target for inhibiting OA progression.

The effect of Oenothera biennis (Evening primrose) oil on inflammatory diseases: a systematic review of clinical trials.

BACKGROUND: Evening primrose oil (EPO), extracted from the seeds of Oenothera biennis, has gained attention for its therapeutic effects in various inflammatory conditions. METHOD: We performed a systematic search in multiple databases and defined the inclusion criteria based on the following PICOs: P: Patients with a form of inflammatory condition, I: EPO, C: Placebo or other therapeutic interventions, O: changes in inflammatory markers or patients' symptoms; S: randomized controlled trials. The quality of the RCTs was evaluated using Cochrane's RoB tool. RESULTS: Several conditions were investigated in the literature. In rheumatoid arthritis, mixed results were observed, with some studies reporting significant improvements in symptoms while others found no significant impact. EPO showed some results in diabetes mellitus, atopic eczema, menopausal hot flashes, and mastalgia. However, it did not demonstrate effectiveness in chronic hand dermatitis, tardive dyskinesia, psoriatic arthritis, cystic fibrosis, hepatitis B, premenstrual syndrome, contact lens-associated dry eyes, acne vulgaris, breast cyst, pre-eclampsia, psoriasis, or primary Sjogren's syndrome. Some results were reported from multiple sclerosis after EPO consumption. Studies in healthy volunteers indicated no significant effect of EPO on epidermal atrophy, nevertheless, positive effects on the skin regarding hydration and barrier function were achieved. CONCLUSION: Some evidence regarding the potential benefits of EPO in inflammatory disorders were reported however caution is due to the limitations of the current survey. Overall, contemporary literature is highly heterogeneous and fails to provide strong recommendations regarding the efficacy of EPO on inflammatory disorders. Further high-quality studies are necessitated to draw more definite conclusions and establish O. biennis oil effectiveness as an assuring treatment option in alleviating inflammatory conditions.

Can humans smell tastants?

Although studies have shown that olfaction may contribute to the perception of tastant, literature is scarce or circumstantial, especially in humans. This study aims to (i) explore whether humans can perceive solutions of basic prototypical tastants through orthonasal and retronasal olfaction and (ii) to examine what volatile odor compounds (VOCs) underlie this ability. Solutions of 5 basic tastants (sucrose, sodium chloride, citric acid, monosodium glutamate [MSG], quinine) dissolved in water, and 2 fatty acids (oleic and linoleic acid) dissolved in mineral oil were prepared. Triangle discrimination tests were performed (n = 41 in duplicate) to assess whether the tastant solutions can be distinguished from blanks (solvents) through ortho- and retronasal olfaction. Participants were able to distinguish all tastant solutions from blank through orthonasal olfaction. Only sucrose, sodium chloride, oleic acid, and linoleic acid were distinguished from blank by retronasal olfaction. Ethyl dichloroacetate, methylene chloride, and/or acetone were identified in the headspace of sucrose, MSG, and quinine solutions but not in the headspace of water, sodium chloride, and citric acid solutions. Fat oxidation compounds such as alcohols and aldehydes were detected in the headspace of the oleic and linoleic acid solutions but not the mineral oil. We conclude that prototypical tastant solutions can be discriminated from water and fatty acid solutions from mineral oil through orthonasal olfaction. Differences in the volatile headspace composition between blanks and tastant solutions may have facilitated the olfactory discrimination. These findings can have methodological implications for future studies assessing gustatory perception using these prototypical taste compounds.

Impaired Reverse Cholesterol Transport is Associated with Changes in Fatty Acid Profile in Children and Adolescents with Abdominal Obesity.

BACKGROUND: Abdominal obesity is an important cardiovascular disease risk factor. Plasma fatty acids display a complex network of both pro and antiatherogenic effects. High density lipoproteins (HDL) carry out the antiatherogenic pathway called reverse cholesterol transport (RCT), which involves cellular cholesterol efflux (CCE), and lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) activities. OBJECTIVES: Our aim was to characterize RCT and its relation to fatty acids present in plasma in pediatric abdominal obesity. METHODS: Seventeen children and adolescents with abdominal obesity and 17 healthy controls were studied. Anthropometric parameters were registered. Glucose, insulin, lipid levels, CCE employing THP-1 cells, LCAT and CETP activities, plus fatty acids in apo B-depleted plasma were measured. RESULTS: The obese group showed a more atherogenic lipid profile, plus lower CCE (Mean±Standard Deviation) (6 ± 2 vs. 7 ± 2%; P < 0.05) and LCAT activity (11 ± 3 vs. 15 ±5 umol/dL.h; P < 0.05). With respect to fatty acids, the obese group showed higher myristic (1.1 ± 0.3 vs. 0.7 ± 0.3; P < 0.01) and palmitic acids (21.5 ± 2.8 vs. 19.6 ± 1.9; P < 0.05) in addition to lower linoleic acid (26.4 ± 3.3 vs. 29.9 ± 2.6; P < 0.01). Arachidonic acid correlated with CCE (r = 0.37; P < 0.05), myristic acid with LCAT (r = -0.37; P < 0.05), palmitioleic acid with CCE (r = -0.35; P < 0.05), linoleic acid with CCE (r = 0.37; P < 0.05), lauric acid with LCAT (r = 0.49; P < 0.05), myristic acid with LCAT (r = -0.37; P < 0.05) ecoisatrienoic acid with CCE (r = 0.40; P < 0.05) and lignoseric acid with LCAT (r = -0.5; P < 0.01). CONCLUSIONS: Children and adolescents with abdominal obesity presented impaired RCT, which was associated with modifications in proinflammatory fatty acids, such as palmitoleic and myristic, thus contributing to increased cardiovascular disease risk.

Consuming a Linoleate-Rich Diet Increases Concentrations of Tetralinoleoyl Cardiolipin in Mouse Liver and Alters Hepatic Mitochondrial Respiration.

BACKGROUND: Hepatic mitochondrial dysfunction is a major cause of fat accumulation in the liver. Individuals with fatty liver conditions have hepatic mitochondrial structural abnormalities and a switch in the side chain composition of the mitochondrial phospholipid, cardiolipin, from poly- to monounsaturated fatty acids. Linoleic acid (LA), an essential dietary fatty acid, is required to remodel nascent cardiolipin (CL) to its tetralinoleoyl cardiolipin (L4CL, CL with 4 LA side chains) form, which is integral for mitochondrial membrane structure and function to promote fatty acid oxidation. It is unknown, however, whether increasing LA in the diet can increase hepatic L4CL concentrations and improve mitochondrial respiration in the liver compared with a diet rich in monounsaturated and saturated fatty acids. OBJECTIVES: The main aim of this study was to test the ability of a diet fortified with LA-rich safflower oil (SO), compared with the one fortified with lard (LD), to increase concentrations of L4CL and improve mitochondrial respiration in the livers of mice. METHODS: Twenty-four (9-wk-old) C57 BL/J6 male mice were fed either the SO or LD diets for ∼100 d, whereas food intake and body weight, fasting glucose, and glucose tolerance tests were performed to determine any changes in glycemic control. RESULTS: Livers from mice fed SO diet had higher relative concentrations of hepatic L4CL species compared with LD diet-fed mice (P value = 0.004). Uncoupled mitochondria of mice fed the SO diet, compared with LD diet, had an increased baseline oxygen consumption rate (OCR) and succinate-driven respiration (P values = 0.03 and 0.01). SO diet-fed mice had increased LA content in all phospholipid classes compared with LD-fed mice (P < 0.05). CONCLUSIONS: Our findings reveal that maintaining or increasing hepatic L4CL may result in increased OCR in uncoupled hepatic mitochondria in healthy mice whereas higher oleate content of CL reduced mitochondrial function shown by lower OCR in uncoupled mitochondria.

Mechanisms of the Formation of Nonvolatile and Volatile Oxidation Products from Methyl Linoleic Acid at High Temperatures.

The impact of the oxidation of linoleic acid cannot be overlooked in daily food consumption. This study used gas chromatography-mass spectrometry (GC-MS) to identify both nonvolatile oxidation products and volatile oxidation products of methyl linoleic acid at 180 °C and density function theory to investigate oxidation mechanisms. An analysis of nonvolatile oxidation products revealed the presence of three primary oxidation products. The three primary oxidation products were identified as hydroperoxides, peroxide-linked dimers, and heterocyclic compounds in a ratio of 2.70:1:3.69 (mmol/mmol/mmol). The volatile components of secondary oxidation products were found including aldehydes (40.77%), alkanes (19.89%), alcohols (9.02%), furans (6.11%), epoxides (0.46%), and acids (2.50%). DFT calculation proved that the secondary oxidation products mainly came from peroxides (77%). Finally, we look forward to our research contributing positively to lipid autoxidation and human health.

Elucidation for the pharmacological effects and mechanism of Shen Bai formula in treating myocardial injury based on energy metabolism and serum metabolomic approaches.

ETHNOPHARMACOLOGICAL RELEVANCE: Shen Bai formula (SBF) is a proven effective traditional Chinese medicine for treating viral myocarditis (VMC) sequelae in clinic, and myocardial injury is the pathological basis of VMC sequelae. However, the pharmacological action and mechanism of SBF have not been systematically elucidated. AIM OF THE STUDY: In present research, the doxorubicin-induced myocardial injury rat model was used to evaluate the efficacy of SBF, and energy metabolism and metabolomics approaches were applied to elucidate the effects of SBF on myocardial injury. MATERIALS AND METHODS: Through energy metabolism measurement system and UPLC-Q-TOF-MS/MS oriented blood metabolomics, directly reflected the therapeutic effect of SBF at a macro level, and identified biomarkers of myocardial injury in microcosmic, revealing its metabolomic mechanism. RESULTS: Results showed that SBF significantly improved the electrocardiogram (ECG), heart rate (HR), extent of myocardial tissue lesion, and ratio of heart and spleen. In addition, the serum levels of AST, CK, LDH, α-HBDH, cTnI, BNP, and MDA decreased, whereas SOD and ATP activity and content increased. Moreover, SBF increased locomotor activity and basic daily metabolism in rats with myocardial injury, restoring their usual level of energy metabolism. A total of 45 potential metabolomic biomarkers were identified. Among them, 44 biomarkers were significantly recalled by SBF, including representative biomarkers arachidonic acid (AA), 12-HETE, prostaglandin J2 (PGJ2), 15-deoxy-Δ-12,14-PGJ2, 15-keto-PGE2, 15(S)-HPETE, 15(S)-HETE, 8,11,14-eicosatrienoic acid and 9(S)-HODE, which involved AA metabolism, biosynthesis of unsaturated fatty acids and linoleic acid metabolism. CONCLUSION: We successfully replicated a myocardial injury rat model with the intraperitoneal injection of doxorubicin, and elucidated the mechanism of SBF in treating myocardial injury. This key mechanism may be achieved by targeting action on COX, Alox, CYP, and 15-PGDH to increase or decrease the level of myocardial injury biomarker, and then emphatically interven in AA metabolism, biosynthesis of unsaturated fatty acids and linoleic acid metabolism, and participate in regulating purine metabolism, sphingolipid metabolism, primary bile acid biosynthesis, and steroid hormone synthesis.

Cholesterol is more readily oxidized than phospholipid linoleates in cell membranes to produce cholesterol hydroperoxides.

Cholesterol is an essential component of cell membranes and serves as an important precursor of steroidal hormones and bile acids, but elevated levels of cholesterol and its oxidation products have been accepted as a risk factor for maintenance of health. The free and ester forms of cholesterol and fatty acids are the two major biological lipids. The aim of this hypothesis paper is to address the long-standing dogma that cholesterol is less susceptible to free radical peroxidation than polyunsaturated fatty acids (PUFAs). It has been observed that cholesterol is peroxidized much slower than PUFAs in plasma but that, contrary to expectations from chemical reactivity toward peroxyl radicals, cholesterol appears to be more readily autoxidized than linoleates in cell membranes. The levels of oxidation products of cholesterol and linoleates observed in humans support this notion. It is speculated that this discrepancy is ascribed to the fact that cholesterol and phospholipids bearing PUFAs are localized apart in raft and non-raft domains of cell membranes respectively and that the antioxidant vitamin E distributed predominantly in the non-raft domains cannot suppress the oxidation of cholesterol lying in raft domains which are relatively deficient in antioxidant.

Differences in Absorption and Metabolism between Structured 1,3-Oleate-2-palmitate Glycerol and 1-Oleate-2-palmitate-3-linoleate Glycerol on C57BL/6J Mice.

This study investigated differences in absorption and metabolism between 1,3-oleate-2-palmitate glycerol (OPO) and 1-oleate-2-palmitate-3-linoleate glycerol (OPL) using C57BL/6J mice. OPL was associated with higher postprandial plasma total triacylglycerol (TG), low-density lipoprotein cholesterol (LDL-C) concentrations, and the ratio of LDL-C to high-density lipoprotein cholesterol (HDL-C) compared to those of OPO (p > 0.05). OPO significantly increased postprandial oleic acid (OA) concentrations compared to OPL over the entire monitoring period (p < 0.05), while OPL significantly elevated linoleic acid (LA) levels compared to OPO (p < 0.05). After 1 month of feeding, the mice in both OPO and OPL groups showed lower final weight, weight gain, and liver TG, LDL-C, and LDL/HDL concentrations compared to the control (soybean oil) group. Lipidomics results showed that OPO increased the biosynthesis of very long-chain fatty acids and decreased the abundance of AcCa (16:1), AcCa (18:2), AcCa (18:1), AcCa (16:0), CarE (16:0), and CarE (16:1) relative to OPL. These lipid metabolites were positively correlated with liver TG, LDL-C, and LDL/HDL levels and negatively related to peroxisome proliferator-activated receptors α (PPARα) and acyl-CoA oxidase (ACOX1) expression. This study showed differences in physiologic functions between OPO and OPL and provided support for the future application of OPL in infant formula.

Senescence-associated 13-HODE production promotes age-related liver steatosis by directly inhibiting catalase activity.

Aging is a major risk factor for metabolic disorders. Polyunsaturated fatty acid-derived bioactive lipids play critical roles as signaling molecules in metabolic processes. Nonetheless, their effects on age-related liver steatosis remain unknown. Here we show that senescent liver cells induce liver steatosis in a paracrine manner. Linoleic acid-derived 9-hydroxy-octadecadienoic acid (9-HODE) and 13-HODE increase in middle-aged (12-month-old) and aged (20-month-old) male mouse livers and conditioned medium from senescent hepatocytes and macrophages. Arachidonate 15-lipoxygenase, an enzyme for 13-HODE and 9-HODE production, is upregulated in senescent cells. A 9-HODE and 13-HODE mixture induces liver steatosis and activates SREBP1. Furthermore, catalase (CAT) is a direct target of 13-HODE, and its activity is decreased by 13-HODE. CAT overexpression reduces 13-HODE-induced liver steatosis and protects male mice against age-related liver steatosis. Therefore, 13-HODE produced by senescent hepatocytes and macrophages activates SREBP1 by directly inhibiting CAT activity and promotes liver steatosis.

[Comparison of fat determination methods and analysis of fatty acids in tea].

OBJECTIVE: Comparative analysis of two method for determining fat and analysis of fatty acid content in tea samples. METHODS: The content of freefatand total fat in tea was determined by Soxhlet extraction method and acid hydrolysis method, and the content of fatty acids were determined by gas chromatography. The composition and content of fatty acids in 21 tea samples from 5 regions were analyzed. RESULTS: The freefat content of tea determined by Soxhlet extraction method was significantly lower than that determined by acid hydrolysis method. The totalfat content in tea determined by acid hydrolysis method was consistent with the total amount of fatty acids determined by gas chromatography, and their content conformed to the logical relationshipsimultaneously. The totalfat content in tea ranged from 0.6 to 4.1 g/100 g, which in green tea, white tea, yellow tea, and black tea were 2.2, 1.8, 1.6 and 0.6 g/100 g, respectively. The content of free fat in tea was less than 58%, with 42%-80% of the fat existing in a bound form. The fatty acids in tea were mainly unsaturated fatty acids, accounting for 67.52%-99.03% of the total fatty acids. There were differences in the composition of fatty acids in different types of tea, with the proportion of unsaturated fatty acids in yellow tea accounting for 98.84% of the total fatty acids, which was significantly higher than that of green tea, white tea, and black tea. The fatty acids with high content in green tea(except Tang chi xiaolan tea, Bawangjian green tea and Liuxi yuye tea)were α-linoleic acid, linoleic acid, and palmitic acid. CONCLUSION: Theacid hydrolysis method is more suitable for the determination of fat in tea samples. The composition and content of fat and fatty acids in tea vary depending onfactors such as the type of tea and the degree of fermentation.

[Fatty acid composition analysis and nutrition evaluation of milk and dairy products sold in Yinchuan City].

OBJECTIVE: To analyze fatty acid composition of milk and dairy products sold in Yinchuan City, and to evaluate their nutritional value. METHODS: Twenty-two types of milk and dairy products were collected in 2022-2023, including 14 types produced in Ningxia and 8 types not produced in Ningxia. Fatty acids were determined and analyzed according to the first method of National Standard for Food Safety Determination of fatty acids in Food(GB 5009.168-2016). The fatty acid polyunsaturated index(PI), atherogenic index(AI) and thrombosis index(TI) were used to evaluate the nutritional value of milk and dairy products. RESULTS: There were 25 kinds of fatty acids in milk and dairy products produced in Ningxia, which were more than those not produced in Ningxia. The main saturated fatty acids(SFA)were palmitic acid(30.14%-42.57%), the main monounsaturated fatty acids(MUFA)were oleic acid(15.45%-25.21%), the main polyunsaturated fatty acids(PUFA)were linoleic acid(1.79%-9.37%), the content of α-linolenic acid was 0.04%-0.95%, n-3 PUFA was 0.14%-0.95%. Oleic acid of adult milk powder, sheep milk powder, pure milk and Ningxia wolfberry milk were higher than others, linoleic acid of adult milk powder and walnut milk were higher than others. The value of oleic acid and linoleic acid of Ningxia pure milk was higher than that in imported pure milk, and the value of n-6 PUFA/n-3 PUFA was much lower than that in imported pure milk. The content of oleic acid and linoleic acid in Ningxia wolfberry milk was close to that of pure milk, higher than that of children's milk, and the total fat content was lower than that of children's milk. The n-6 PUFA/n-3 PUFA ratio of concentrated milk, walnut milk, sweet milk, pure milk, Ningxia wolfberry milk, adult milk powder 1, sheep milk powder was close to the ideal intake value of dietary fatty acids recommended by the Chinese Nutrition Society. Except for low-fat pure milk, ice cream yogurt, imported pure milk, children's milk 1, adult milk powder 1 and sheep milk powder, the n-6 PUFA/n-3 PUFA ratio of other milk and dairy products in Ningxia were close to the recommended value of the Food and Agriculture Organization of the United Nations and World Health Organization. SFA∶MUFA∶PUFA was(1.99-4.23) ∶1∶(0.08-0.38), PI range: 1.87-11.27, AI range: 1.67-4.32, TI range: 2.34-5.76. CONCLUSION: The fatty acid composition of 22 types of milk and dairy products in Yinchuan City was different, and the nutrition was slightly different.

Effect of statin treatment on metabolites, lipids and prostanoids in patients with Statin Associated Muscle Symptoms (SAMS).

BACKGROUND: Between 5-10% of patients discontinue statin therapy due to statin-associated adverse reactions, primarily statin associated muscle symptoms (SAMS). The absence of a clear clinical phenotype or of biomarkers poses a challenge for diagnosis and management of SAMS. Similarly, our incomplete understanding of the pathogenesis of SAMS hinders the identification of treatments for SAMS. Metabolomics, the profiling of metabolites in biofluids, cells and tissues is an important tool for biomarker discovery and provides important insight into the origins of symptomatology. In order to better understand the pathophysiology of this common disorder and to identify biomarkers, we undertook comprehensive metabolomic and lipidomic profiling of plasma samples from patients with SAMS who were undergoing statin rechallenge as part of their clinical care. METHODS AND FINDINGS: We report our findings in 67 patients, 28 with SAMS (cases) and 39 statin-tolerant controls. SAMS patients were studied during statin rechallenge and statin tolerant controls were studied while on statin. Plasma samples were analyzed using untargeted LC-MS metabolomics and lipidomics to detect differences between cases and controls. Differences in lipid species in plasma were observed between cases and controls. These included higher levels of linoleic acid containing phospholipids and lower ether lipids and sphingolipids. Reduced levels of acylcarnitines and altered amino acid profile (tryptophan, tyrosine, proline, arginine, and taurine) were observed in cases relative to controls. Pathway analysis identified significant increase of urea cycle metabolites and arginine and proline metabolites among cases along with downregulation of pathways mediating oxidation of branched chain fatty acids, carnitine synthesis, and transfer of acetyl groups into mitochondria. CONCLUSIONS: The plasma metabolome of patients with SAMS exhibited reduced content of long chain fatty acids and increased levels of linoleic acid (18:2) in phospholipids, altered energy production pathways (ß-oxidation, citric acid cycle and urea cycles) as well as reduced levels of carnitine, an essential mediator of mitochondrial energy production. Our findings support the hypothesis that alterations in pro-inflammatory lipids (arachidonic acid pathway) and impaired mitochondrial energy metabolism underlie the muscle symptoms of patients with statin associated muscle symptoms (SAMS).

Linoleate-Containing Acylglucosylceramide, Acylceramide, and Events Associated with Formation of the Epidermal Permeability Barrier.

BACKGROUND: Linoleate-containing acylglucosylceramide (GLC-CER[EOx], where x = sphingosine [S], dihydrosphingosine [dS], phytosphingosine (P), or 6-hydroxysphingosine [H]) in the viable epidermis serve as the precursors to the linoleate-containing acylceramides (CER[EOx]) in the stratum corneum (SC) and the corneocyte lipid envelope (CLE), both of which are essential for the barrier function of the skin. SUMMARY: CLE formation and envelope maturation take place across the SC. Hypoxic conditions in the epidermis and anaerobic glycolysis with the production of lactic acid are important in proper SC barrier formation. KEY MESSAGE: CLE formation takes place across the SC. Its formation from linoleate-containing GLC-CER[EOx] requires lipoxygenase action, but anaerobic conditions leading to lactate production and hypoxia-inducible factors are essential for proper barrier formation. A number of unanswered questions are raised regarding formation of the CLE and the epidermal permeability barrier.

Effects of fat source in calf starter on growth performance, blood fatty acid profiles, and inflammatory markers during cold season.

This study was conducted to investigate the effects of supplementation of different fat sources in calf starters on growth performance, health, blood fatty acid profiles, and inflammatory markers during the cold season in dairy calves. A total of 48 Holstein calves (24 males and 24 females) were randomly assigned to 1 of 4 starter diets throughout the experiment (d 3 to 65): (1) no supplemented fat (CON), (2) 3% calcium-salts of soybean oil (Ca-SBO), (3) 3% calcium-salts of fish oil (Ca-FO), and (4) 3% mixture of Ca-SBO and Ca-FO (1.5% each, DM basis; MIX). Calves were given free access to starter feed and water and were raised individually in pens from 3 to 65 d of age. Calves fed Ca-SBO consumed a greater proportion of n-6 FA, while calves fed Ca-FO consumed a greater level of n-3 FA compared to the other dietary treatments. Fat supplementation increased the intake of linoleic acid, the major n-6 FA, with the greater intake observed in the Ca-SBO group compared to the other dietary treatments. Calves fed the Ca-FO and MIX diets consumed more long-chain n-3 FA than the other diets. In addition, calves fed Ca-SBO and Ca-FO diets consumed more starter feed and total dry matter than calves fed MIX and CON throughout the experiment (d 3 to 65). Calves fed Ca-FO had higher average daily gain throughout the trial (d 3 to 65) than the other treatment groups. Of all treatment groups, calves fed Ca-FO achieved the highest final body weight and showed the greatest feed efficiency. Random forest analysis revealed that eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid were the serum levels of FA most affected by the diets. The principal component analysis of blood FA profile, blood parameters, and inflammatory markers showed distinct differences between dietary treatments. Calves fed Ca-SBO had higher plasma concentrations of linoleic acid, while calves fed Ca-FO had higher plasma concentrations of long-chain n-3 polyunsaturated fatty acids (PUFA), such as EPA, docosapentaenoic acid (DPA), and DHA than the other treatment groups. Plasma inflammatory markers were lower in calves fed Ca-FO and higher in calves fed CON than in the other treatment groups. The Ca-FO group had lower levels of inflammatory markers, including serum amyloid A, tumor necrosis factor-alpha, Interferon-γ, haptoglobin, and interleukin-6 compared to the other experimental treatments. Also, the blood malondialdehyde levels, an indicator of oxidative stress, were lower in calves fed Ca-FO compared with calves fed the other treatment diets. In conclusion, the performance of preweaned dairy calves can be improved by adding fat to their starter feed under cold conditions. Overall, the type of fat in milk may affect growth and inflammation of dairy calves before weaning under cold conditions, with n-3 FA (Ca-FO) promoting growth and reducing inflammation more effectively than n-6 FA (Ca-SBO).

Camel milk peptides alleviate hyperglycemia by regulating gut microbiota and metabolites in type 2 diabetic mice.

This study aimed to investigate the hypoglycemic effect of Camel milk peptides (CMPs) on Type 2 diabetes mellitus (T2DM) mice and reveal its related mechanism from the aspect of gut microbiota and metabolites. The administering CMPs significantly alleviated the weight loss, polydipsia and polyphagia, reduced fasting blood glucose (FBG), improved insulin resistance and sensitivity, and restored the level of serum hormones, lipopolysaccharide (LPS), lipid metabolic and tissue damage. Furthermore, CMPs intervention remarkably reversed gut microbiota dysbiosis in T2DM mice by reducing the relative abundance of Proteobacteria, Allobaculum, Clostridium, Shigella and the Firmicutes/Bacteroidetes ratio, while increasing the relative abundance of Bacteroidetes and Blautia. Metabolomic analysis identified 84 different metabolites between T2DM and CMPs-treated groups, participating in three pathways of Pantothenate and CoA biosynthesis, Phenylalanine metabolism and Linoleic acid metabolism. Ureidopropionic acid, pantothenic acid, hippuric acid, hydrocinnamic acid and linoleic acid were identified as key acidic metabolites closely related to hypoglycemic effect. Correlation analysis indicated that CMPs might have a hypoglycemic effect through their impact on gut microbiota, leading to variations in short-chain fatty acids (SCFAs), acidic metabolites and metabolic pathways. These findings suggest that CMPs could be a beneficial nutritional supplement for intervention T2DM.

The Synergism of Human Lactobacillaceae and Inulin Decrease Hyperglycemia via Regulating the Composition of Gut Microbiota and Metabolic Profiles in db/db Mice.

This study aimed to evaluate the effects of Limosilactobacillus fermentum and Lactiplantibacillus plantarum isolated from human feces coordinating with inulin on the composition of gut microbiota and metabolic profiles in db/db mice. These supplements were administered to db/db mice for 12 weeks. The results showed that the Lactobacillaceae coordinating with inulin group (LI) exhibited lower fasting blood glucose levels than the model control group (MC). Additionally, LI was found to enhance colon tissue and increase the levels of short-chain fatty acids. 16S rRNA sequencing revealed that the abundance of Corynebacterium and Proteus, which were significantly increased in the MC group compared with NC group, were significantly decreased by the treatment of LI that also restored the key genera of the Lachnospiraceae_NK4A136_group, Lachnoclostridium, Ruminococcus_gnavus_group, Desulfovibrio, and Lachnospiraceae_UCG-006. Untargeted metabolomics analysis showed that lotaustralin, 5-hydroxyindoleacetic acid, and 13(S)-HpODE were increased while L-phenylalanine and L-tryptophan were decreased in the MC group compared with the NC group. However, the intervention of LI reversed the levels of these metabolites in the intestine. Correlation analysis revealed that Lachnoclostridium and Ruminococcus_gnavus_group were negatively correlated with 5-hydroxyindoleacetic acid and 13(S)-HpODE, but positively correlated with L-tryptophan. 13(S)-HpODE was involved in the "linoleic acid metabolism". L-tryptophan and 5-hydroxyindoleacetic acid were involved in "tryptophan metabolism" and "serotonergic synapse". These findings suggest that LI may alleviate type 2 diabetes symptoms by modulating the abundance of Ruminococcus_gnavus_group and Lachnoclostridium to regulate the pathways of "linoleic acid metabolism", "serotonergic synapse", and" tryptophan metabolism". Our results provide new insights into prevention and treatment of type 2 diabetes.

The fa(c)ts that matter: Bumble bees differentially allocate and oxidate three common fatty acids in pollen.

Pollen serves as a crucial source of protein and lipids for numerous insects. Despite the importance of pollen lipids for nutrient regulation in bees, the digestibility and absorption of different fatty acids (FAs) by bees remain poorly understood. We used 13C labeled fatty acids (FAs) to investigate the absorption and allocation of three common dietary FAs in pollen by bumble bees. Palmitic acid, the most common saturated FA in pollen, was poorly absorbed, even when supplied as tripalmitate, emulsified, or mixed in vegetable oil. In contrast, the essential linoleic acid was absorbed and allocated at the highest rate among the three FAs tested. Oleic acid, a non-essential monounsaturated FA, was absorbed and oxidized at lower rates than linoleic acid. Notably, a feeding rate experiment revealed that different fatty acids did not affect the consumption rate of pollen. This results suggests that the specific FA's absorption efficiency and allocation differ in bumble bees, impacting their utilization. These findings demonstrate the importance of considering the digestibility and absorption of different FAs. Furthermore, the study highlights the influence of pollen lipid composition on the nutritional content for pollinators and raises questions about the utilization of polyunsaturated FAs in insect metabolism.