Staged suppression of microglial autophagy facilitates regeneration in CNS demyelination by enhancing the production of linoleic acid.

Microglia play a critical role in the clearance of myelin debris, thereby ensuring functional recovery from neural injury. Here, using mouse model of demyelination following two-point LPC injection, we show that the microglial autophagic-lysosomal pathway becomes overactivated in response to severe demyelination, leading to lipid droplet accumulation and a dysfunctional and pro-inflammatory microglial state, and finally failed myelin debris clearance and spatial learning deficits. Data from genetic approaches and pharmacological modulations, via microglial Atg5 deficient mice and intraventricular BAF A1 administration, respectively, demonstrate that staged suppression of excessive autophagic-lysosomal activation in microglia, but not sustained inhibition, results in better myelin debris degradation and exerts protective effects against demyelination. Combined multi-omics results in vitro further showed that enhanced lipid metabolism, especially the activation of the linoleic acid pathway, underlies this protective effect. Supplementation with conjugated linoleic acid (CLA), both in vivo and in vitro, could mimic these effects, including attenuating inflammation and restoring microglial pro-regenerative properties, finally resulting in better recovery from demyelination injuries and improved spatial learning function, by activating the peroxisome proliferator-activated receptor (PPAR-γ) pathway. Therefore, we propose that pharmacological inhibition targeting microglial autophagic-lysosomal overactivation or supplementation with CLA could represent a potential therapeutic strategy in demyelinated disorders.

Linoleic acid-derived diol 12,13-DiHOME enhances NLRP3 inflammasome activation in macrophages.

12,13-dihydroxy-9z-octadecenoic acid (12,13-DiHOME) is a linoleic acid diol derived from cytochrome P-450 (CYP) epoxygenase and epoxide hydrolase (EH) metabolism. 12,13-DiHOME is associated with inflammation and mitochondrial damage in the innate immune response, but how 12,13-DiHOME contributes to these effects is unclear. We hypothesized that 12,13-DiHOME enhances macrophage inflammation through effects on NOD-like receptor protein 3 (NLRP3) inflammasome activation. To test this hypothesis, we utilized human monocytic THP1 cells differentiated into macrophage-like cells with phorbol myristate acetate (PMA). 12,13-DiHOME present during lipopolysaccharide (LPS)-priming of THP1 macrophages exacerbated nigericin-induced NLRP3 inflammasome activation. Using high-resolution respirometry, we observed that priming with LPS+12,13-DiHOME altered mitochondrial respiratory function. Mitophagy, measured using mito-Keima, was also modulated by 12,13-DiHOME present during priming. These mitochondrial effects were associated with increased sensitivity to nigericin-induced mitochondrial depolarization and reactive oxygen species production in LPS+12,13-DiHOME-primed macrophages. Nigericin-induced mitochondrial damage and NLRP3 inflammasome activation in LPS+12,13-DiHOME-primed macrophages were ablated by the mitochondrial calcium uniporter (MCU) inhibitor, Ru265. 12,13-DiHOME present during LPS-priming also enhanced nigericin-induced NLRP3 inflammasome activation in primary murine bone marrow-derived macrophages. In summary, these data demonstrate a pro-inflammatory role for 12,13-DiHOME by enhancing NLRP3 inflammasome activation in macrophages.

Polyunsaturated fatty acids stimulate immunity and eicosanoid production in Drosophila melanogaster.

Eicosanoids are a class of molecules derived from C20 polyunsaturated fatty acids (PUFAs) that play a vital role in mammalian and insect biological systems, including development, reproduction, and immunity. Recent research has shown that insects have significant but lower levels of C20 PUFAs in circulation in comparison to C18 PUFAs. It has been previously hypothesized in insects that eicosanoids are synthesized from C18 precursors, such as linoleic acid (LA), to produce downstream eicosanoids. In this study, we show that introduction of arachidonic acid (AA) stimulates production of cyclooxygenase, lipoxygenase, and cytochrome P450-derived eicosanoids. Downstream immune readouts showed that LA stimulates phagocytosis by hemocytes, while both LA and AA stimulate increased antimicrobial peptide production when D. melanogaster is exposed to a heat-killed bacterial pathogen. In totality, this work identifies PUFAs that are involved in insect immunity and adds evidence to the notion that Drosophila utilizes immunostimulatory lipid signaling to mitigate bacterial infections. Our understanding of immune signaling in the fly and its analogies to mammalian systems will increase the power and value of Drosophila as a model organism in immune studies.

Two C18 hydroxy-cyclohexenone fatty acids from mammalian epidermis: Potential relation to 12R-lipoxygenase and covalent binding of ceramides.

A key requirement in forming the water permeability barrier in the mammalian epidermis is the oxidation of linoleate esterified in a skin-specific acylceramide by the sequential actions of 12R-lipoxygenase, epidermal lipoxygenase-3, and the epoxyalcohol dehydrogenase SDR9C7 (short-chain dehydrogenase-reductase family 7 member 9). By mechanisms that remain unclear, this oxidation pathway promotes the covalent binding of ceramides to protein, forming a critical structure of the epidermal barrier, the corneocyte lipid envelope. Here, we detected, in porcine, mouse, and human epidermis, two novel fatty acid derivatives formed by KOH treatment from precursors covalently bound to protein: a "polar" lipid chromatographing on normal-phase HPLC just before omega-hydroxy ceramide and a "less polar" lipid nearer the solvent front. Approximately 100 µg of the novel lipids were isolated from porcine epidermis, and the structures were established by UV-spectroscopy, LC-MS, GC-MS, and NMR. Each is a C18 fatty acid and hydroxy-cyclohexenone with the ring on carbons C9-C14 in the polar lipid and C8-C13 in the less polar lipid. Overnight culture of [14C]linoleic acid with whole mouse skin ex vivo led to recovery of the 14C-labeled hydroxy-cyclohexenones. We deduce they are formed from covalently bound precursors during the KOH treatment used to release esterified lipids. KOH-induced intramolecular aldol reactions from a common precursor can account for their formation. Discovery of these hydroxy-cyclohexenones presents an opportunity for a reverse pathway analysis, namely to work back from these structures to identify their covalently bound precursors and relationship to the linoleate oxidation pathway.

Host cell-specific metabolism of linoleic acid controls Toxoplasma gondii growth in cell culture.

The obligate intracellular parasite Toxoplasma gondii can infect and replicate in any warm-blooded cell tested to date, but much of our knowledge about T. gondii cell biology comes from just one host cell type: human foreskin fibroblasts (HFFs). To expand our knowledge of host-parasite lipid interactions, we studied T. gondii in intestinal epithelial cells, the first site of host-parasite contact following oral infection and the exclusive site of parasite sexual development in feline hosts. We found that highly metabolic Caco-2 cells are permissive to T. gondii growth even when treated with high levels of linoleic acid (LA), a polyunsaturated fatty acid (PUFA) that kills parasites in HFFs. Caco-2 cells appear to sequester LA away from the parasite, preventing membrane disruptions and lipotoxicity that characterize LA-induced parasite death in HFFs. Our work is an important step toward understanding host-parasite interactions in feline intestinal epithelial cells, an understudied but important cell type in the T. gondii life cycle.

Evolution of Linoleic Acid Biosynthesis Paved the Way for Ecological Success of Termites.

Termites are dominant animals of tropical terrestrial ecosystems. Their success is due to their eusocial organization as well as their ability to digest dead plant tissues. While being extremely abundant, the termite diet is poor in crucial nutrients, such as fatty acids. Linoleic acid (LA) is a precursor for many vital biomolecules, and most animals depend on its dietary supply. Termites count among the exceptions known to produce LA de novo, presumably via the action of an unknown Δ12 fatty acyl desaturase (FAD) introducing the second double bond into monounsaturated oleic acid. Here, we search for the evolutionary origin of LA biosynthesis in termites. To this end, we compile the repertoire of FAD homologs from 57 species of termites and their closest relatives, the cockroaches, analyze FAD phylogeny, and identify a potential Δ12 FAD branch, which arose through duplication of a likely Δ9 FAD. We functionally characterize both paralogs and identify the Δ9 activity in the ancestral FAD-A1a and the Δ12 activity responsible for LA biosynthesis in FAD-A1b. Through the combination of homology modeling and site-directed mutagenesis, we pinpoint structural features possibly contributing to the distinct functions, regiospecificities, and substrate preferences of the two enzymes. We confirm the presence of both paralogs in all 36 studied species of the Blattoidea lineage (Blattidae, Lamproblattidae, Cryptocercidae, and termites) and conclude that we identified an evolutionary event important for the ecological success of termites, which took place in their cockroach ancestors roughly 160 My and remained conserved throughout termite diversification into 3,000 extant species.

Identification of High Linoleic Acid Varieties in Tetraploid perilla through Gamma-ray Irradiation and CRISPR/Cas9.

Perilla [Perilla frutescens (L.) var frutescens] is a traditional oil crop in Asia, recognized for its seeds abundant in α-linolenic acid (18:3), a key omega-3 fatty acid known for its health benefits. Despite the known nutritional value, the reason behind the higher 18:3 content in tetraploid perilla seeds remained unexplored. Gamma irradiation yielded mutants with altered seed fatty acid composition. Among the mutants, DY-46-5 showed a 27% increase in 18:2 due to the 4-bp deletion of PfrFAD3b, and NC-65-12 displayed a 16% increase in 18:2 due to the loss of function of PfrFAD3a through a large deletion. Knocking out both copies of FATTY ACID DESATURASE3 (PfrFAD3a and PfrFAD3b) simultaneously using CRISPR/Cas9 resulted in an increase in 18:2 by up to 75% and a decrease in 18:3 to as low as 0.3% in seeds, emphasizing the pivotal roles of both genes in 18:3 synthesis in tetraploid perilla. Furthermore, diploid Perilla citriodora, the progenitor of cultivated tetraploid perilla, harbors only PfrFAD3b, with a fatty acid analysis revealing lower 18:3 levels than tetraploid perilla. In conclusion, the enhanced 18:3 content in cultivated tetraploid perilla seeds can be attributed to the acquisition of two FAD3 copies through hybridization with wild-type diploid perilla.

Metabolic determinants of leukemia onset variability in genetically homogeneous AKR mice.

Leukemia is a complex disease shaped by the intricate interplay of genetic and environmental factors. Given our preliminary data showing different leukemia incidence in genetically homogenous AKR mice harboring the spontaneous leukemia-inducing mutation Rmcfs, we sought to unravel the role of metabolites and gut microbiota in the leukemia penetrance. Our metabolomic analysis revealed distinct serum metabolite profiles between mice that developed leukemia and those that did not. We discovered that linoleic acid (LA), an essential ω-6 polyunsaturated fatty acid, was significantly decreased in the leukemia group, with the lower levels observed starting from 25 weeks before the onset. A predictive model based on LA levels demonstrated high accuracy in predicting leukemia development (area under curve 0.82). In vitro experiment confirmed LA's cytotoxic effects against leukemia cells, and in vivo study showed that a diet enriched with LA prolonged survival in AKR mice. Furthermore, gut microbiome analysis identified specific Lachnospiraceae species, that affect host lipid metabolism, are exclusively present in the leukemia group, suggesting their potential influence on LA metabolism and leukemia development. These findings shed light on the complex relationship between metabolites, gut microbiota, and leukemia development, providing valuable insights into the role of non-genetic factors in leukemia penetrance and potential strategies for leukemia prevention.

Early and long-term responses of intestinal microbiota and metabolites to 131I treatment in differentiated thyroid cancer patients.

BACKGROUND: Multiple high doses of 131I therapy in patients with differentiated thyroid cancer (DTC) might disrupt the balance of gut microbiota and metabolites. This study aimed to investigate the alterations of intestinal bacteria and metabolism over two courses of 131I therapy, explore the interactions, and construct diagnostic models reflecting enteric microecology based on 131I therapy. METHODS: A total of 81 patients were recruited for the first 131I therapy (131I-1st), among whom 16 received a second course (131I-2nd) after half a year. Fecal samples were collected 1 day before (Pre-131I-1st/2nd) and 3 days after (Post-131I-1st/2nd) 131I therapy for microbiome (16S rRNA gene sequencing) and metabolomic (LC-MS/MS) analyses. RESULTS: A total of six microbial genera and 11 fecal metabolites enriched in three pathways were identified to show significant differences between Pre-131I-1st and other groups throughout the two courses of 131I treatment. In the Post-131I-1st group, the beneficial bacteria Bifidobacterium, Lachnoclostridium, uncultured_bacterium_f_Lachnospiraceae, and Lachnospiraceae_UCG004 were abundant and the radiation-sensitive pathways of linoleic acid (LA), arachidonic acid, and tryptophan metabolism were inhibited compared with the Pre-131I-1st group. Compared with the Pre-131I-1st group, the Pre-131I-2nd group exhibited a reduced diversity of flora and differentially expressed metabolites, with a low abundance of beneficial bacteria and dysregulated radiation-sensitive pathways. However, less significant differences in microbiota and metabolites were found between the Pre/Post-131I-2nd groups compared with those between the Pre/Post-131I-1st groups. A complex co-occurrence was observed between 6 genera and 11 metabolites, with Lachnoclostridium, Lachnospiraceae_UCG004, Escherichia-Shigella, and LA-related metabolites contributing the most. Furthermore, combined diagnostic models of charactered bacteria and metabolites answered well in the early, long-term, and dose-dependent responses for 131I therapy. CONCLUSIONS: Different stages of 131I therapy exert various effects on gut microecology, which play an essential role in regulating radiotoxicity and predicting the therapeutic response.

Linoleic acid: a natural feed compound against porcine epidemic diarrhea disease.

IMPORTANCE: Porcine epidemic diarrhea virus (PEDV) is a pig coronavirus that causes severe diarrhea and high mortality in piglets, but as no effective drugs are available, this virus threatens the pig industry. Here, we found that the intestinal contents of specific pathogen-free pigs effectively blocked PEDV invasion. Through proteomic and metabolic analyses of the intestinal contents, we screened 10 metabolites to investigate their function and found that linoleic acid (LA) significantly inhibited PEDV replication. Further investigations revealed that LA inhibited viral replication and release mainly by binding with PEDV NSP5 to regulate the PI3K pathway and, in particular, inhibiting AKT phosphorylation. In vivo experiments illustrated that orally administered LA protected pigs from PEDV challenge and severe diarrhea. These findings provide strong support for exploring antiviral drugs for coronavirus treatment.

Plasma Levels of Polyunsaturated Fatty Acids and Adverse Kidney Outcomes.

RATIONALE & OBJECTIVE: Many studies have reported polyunsaturated fatty acids (PUFA) as significant predictors of cardiovascular disease, but little is known about the relationship between PUFA levels and chronic kidney disease (CKD). This study explored this relationship among individuals with and without CKD. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 73,419 participants without CKD (cohort 1) and 6,735 participants with CKD (cohort 2) in the UK Biobank Study, with PUFA levels measured between 2007 and 2010. EXPOSURE: Percentage of plasma PUFA, omega-3 fatty acid (FA), omega-6 FA, docosahexaenoic acid (DHA), and linoleic acid relative to total FA. OUTCOME: Incident CKD for cohort 1 and incident kidney failure requiring replacement therapy (KFRT) for cohort 2. ANALYTICAL APPROACH: Cox proportional hazards regression analyses, including a cause-specific competing risk model. RESULTS: In cohort 1, individuals with higher quartiles of plasma PUFA levels had healthier lifestyles and fewer comorbidities. During 841,007 person-years of follow-up (median 11.9 years), incident CKD occurred in 4.5% of participants (incidence rate, 39.1 per 10,000 person-years). For incident CKD in cohort 1, the adjusted cause-specific hazard ratios for quartiles 2, 3, and 4 were 0.83 (95% CI, 0.75-0.92), 0.85 (95% CI, 0.76-0.96), 0.71 (95% CI, 0.62-0.82), respectively, compared with quartile 1. This inverse relationship was consistently observed for all PUFA types. In cohort 2, although total PUFA levels were not associated with KFRT, higher PUFA subtype levels of DHA were associated with a lower risk of KFRT. LIMITATIONS: Observational design and limited generalizability to individuals with higher disease severity; no data on eicosapentaenoic acid. CONCLUSIONS: Among individuals without CKD, higher plasma PUFA levels and all 4 PUFA components were associated with a lower risk of incident CKD. In individuals with CKD, only the omega-3 component of PUFA, DHA, was associated with a lower risk of KFRT. PLAIN-LANGUAGE SUMMARY: Low amounts of polyunsaturated fatty acids (PUFA) in the blood are suspected of increasing the chances of heart disease, but it is not known whether the PUFA relates to kidney disease occurrence. In a large group without kidney disease in the United Kingdom, people with higher levels of PUFA in their blood tended to have a lower risk of developing kidney disease compared to those with lower PUFA levels. This relationship was consistently observed for all PUFA types. However, in the group with kidney disease, only higher levels of docosahexaenoic acid, a subtype of PUFAs, were associated with a lower risk of developing severe kidney problems that required kidney replacement therapy. These findings suggest that higher levels of PUFA, found in certain healthy fats, might protect against the development of kidney disease in the general population. As kidney function declines, only the docosahexaenoic acid, a subtype of PUFA, appears to be associated with preserved kidney function.

Improvements in markers of inflammation and coagulation potential following a 5-day high-fat diet rich in cottonseed oil vs. Olive oil in healthy males.

Low-grade inflammation is believed to be a risk factor for chronic diseases and is nutritionally responsive. Cottonseed oil (CSO), which is rich in n-6 polyunsaturated fats, has been shown to lower cholesterol and other chronic disease risk factors. The purpose of this secondary analysis was to determine the comparative responses of markers of inflammation and coagulation potential of healthy adult males consuming diets rich in CSO vs. olive oil (OO). METHODS: Fifteen normal-weight males, ages 21.7 ± 2.58y, completed a randomized crossover trial. Each intervention consisted of a 3-day lead-in diet and a 5-day outpatient, controlled feeding intervention (CSO or OO). There was a 2 to 4-week washout period between interventions. The 5-day intervention diets were 35 % carbohydrate, 15 % protein, and 50 % fat, enriched with either CSO or OO (44 % of total energy from oil). At pre- and post- diet intervention visits, a fasting blood draw was collected for analysis of markers of inflammation (Tumor Necrosis Factor Alpha (TNF-α), Interleukin-6 (IL-6), C-Reactive Protein (CRP)) and coagulation potential (Tissue Factor (TF), Plasminogen Activator Inhibitor-1 (PAI-1)). RESULTS: The CSO-enriched diets reduced TNF-α (CSO: -0.12 ± 0.02 pg/ml, OO: -0.01 ± 0.05 pg/ml; p < 0.01) and TF (CSO: -0.59 ± 0.68 pg/ml, OO: 1.13 ± 0.83 pg/ml; p = 0.02) compared to OO diets. There were no differences in IL-6, CRP, or PAI-1 between diets. CONCLUSION: A 5-day, CSO-enriched diet may be sufficient to reduce inflammation and coagulation potential compared to OO-enriched diets in a healthy male population which could have implications in chronic disease prevention.

Monomeric Fe(III)-Hydroxo and Fe(III)-Aqua Complexes Display Oxidative Asynchronous Hydrogen Atom Abstraction Reactivity.

This paper presents the synthesis and characterization of a series of novel monomeric aqua-ligated iron(III) complexes, [FeIII(L5R)(OH2)]2+ (R=OMe, H, Cl, NO2), supported by an amide-containing pentadentate N5 donor ligand, L5R [HL5R=2-(((1-methyl-1H-imidazol-2-yl)methyl)(pyridin-2-yl-methyl)amino)-N-(5-R-quinolin-8-yl)acetamide]. The complexes were characterized by various spectroscopic and analytical techniques, including electrochemistry and magnetic measurements. The Fe(III)-hydroxo complexes, [FeIII(L5R)(OH)]1+, were generated in situ by deprotonating the corresponding aqua complexes in a pH ~7 aqueous medium. In another way, adding one equivalent of a base to a methanolic solution of the Fe(III)-aqua complexes also produced the Fe(III)-hydroxo complexes. The study uses linoleic fatty acid as a substrate to explore the hydrogen atom abstraction (HAA) reactivity of both hydroxo and aqua complexes. The investigation highlights the substitution effect of the L5R ligand on reactivity, revealing a higher rate when an electron-withdrawing group is present. Hammett analyses and(or) determination of the asynchronicity factor (η) suggest an oxidative asynchronous concerted proton-electron transfer (CPET) pathway for the HAA reactions. Aqua complexes exhibited a higher asynchronicity in CPET, resulting in higher reaction rates than their hydroxo analogs. Overall, the work provides insights into the beneficial role of a higher imbalance in electron-transfer-proton-transfer (ET-PT) contributions in HAA reactivity.

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.

Synthesis of PEGylated amphiphilic block copolymers with pendant linoleic moieties by combining ring-opening polymerization and click chemistry.

This study focused on synthesizing and characterizing PEGylated amphiphilic block copolymers with pendant linoleic acid (Lin) moieties as an alternative to enhance their potential in drug delivery applications. The synthesis involved a two-step process, starting with ring-opening polymerization of ε-caprolactone (CL) and propargylated cyclic carbonate (MCP) to obtain PEG-b-P(CL-co-MCP) copolymers, which were subsequently modified via click chemistry. Various reaction conditions were explored to improve the yield and efficiency of the click chemistry step. The use of anisole as a solvent, N-(3-azidopropyl)linoleamide as a substrate, and a reaction temperature of 60°C proved to be highly efficient, achieving nearly 100% conversion at a low catalyst concentration. The resulting copolymers exhibited controlled molecular weights and low polydispersity, confirming the successful synthesis. Furthermore, click chemistry allows for the attachment of Lin moieties to the copolymer, enhancing its hydrophobic character, as deduced from their significantly lower critical micelle concentration than that of traditional PEG-b-PCL systems, which is indicative of enhanced stability against dilution. The modified copolymers exhibited improved thermal stability, making them suitable for applications that require high processing temperatures. Dynamic light scattering and transmission electron microscopy confirmed the formation of micellar structures with sizes below 100 nm and minimal aggregate formation. Additionally, 1H NMR spectroscopy in deuterated water revealed the presence of core-shell micelles, which provided higher kinetic stability against dilution.

CYP eicosanoid pathway mediates colon cancer-promoting effects of dietary linoleic acid.

Human and animal studies support that consuming a high level of linoleic acid (LA, 18:2ω-6), an essential fatty acid and key component of the human diet, increases the risk of colon cancer. However, results from human studies have been inconsistent, making it challenging to establish dietary recommendations for optimal LA intake. Given the importance of LA in the human diet, it is crucial to better understand the molecular mechanisms underlying its potential colon cancer-promoting effects. Using LC-MS/MS-based targeted lipidomics, we find that the cytochrome P450 (CYP) monooxygenase pathway is a major pathway for LA metabolism in vivo. Furthermore, CYP monooxygenase is required for the colon cancer-promoting effects of LA, since the LA-rich diet fails to exacerbate colon cancer in CYP monooxygenase-deficient mice. Finally, CYP monooxygenase mediates the pro-cancer effects of LA by converting LA to epoxy octadecenoic acids (EpOMEs), which have potent effects on promoting colon tumorigenesis via gut microbiota-dependent mechanisms. Overall, these results support that CYP monooxygenase-mediated conversion of LA to EpOMEs plays a crucial role in the health effects of LA, establishing a unique mechanistic link between dietary fatty acid intake and cancer risk. These results could help in developing more effective dietary guidelines for optimal LA intake and identifying subpopulations that may be especially vulnerable to LA's negative effects.

Factors influencing conjugated linoleic acid content of dairy products: challenges and strategies.

Conjugated linoleic acid (CLA), a bioactive fatty acid that provides various physiological benefits, has gained increasing attention in the food industry, and various studies have focused on enhancing its content in dairy products. The factors influencing CLA content in dairy products vary significantly, including lactation stage, breed type, seasonality, feed, management methods of the animals, the manufacturing processes, storage, and ripening periods of the product. Additionally, the incorporation of CLA-producing probiotic bacteria, such as Lactobacillus, Lactococcus, Bifidobacterium, and Propionibacterium, is an emerging study in this field. Studies have revealed that factors affecting the CLA content in milk affect that in dairy products as well. Furthermore, the species and strains of CLA-producing bacteria, fermentation conditions, ripening period, and type of dairy product are also contributing factors. However, production of CLA-enhanced dairy products using CLA-producing bacteria while maintaining their optimal viability and maximizing exposure to free linoleic acid remains limited. The current review emphasized the factors affecting the CLA content and related mechanisms, challenges in the application of CLA-producing probiotic bacteria, and strategies to address these challenges and enhance CLA production in dairy products. Therefore, the development of functional dairy products with enhanced CLA levels is expected to be possible.

The effects of conjugated linoleic acid supplementation on anthropometrics and body composition indices in adults: a systematic review and dose-response meta-analysis.

Prior meta-analytic investigations over a decade ago rather inconclusively indicated that conjugated linoleic acid (CLA) supplementation could improve anthropometric and body composition indices in the general adult population. More recent investigations have emerged, and an up-to-date systematic review and meta-analysis on this topic must be improved. Therefore, this investigation provides a comprehensive systematic review and meta-analysis of randomised controlled trials (RCT) on the impact of CLA supplementation on anthropometric and body composition (body mass (BM), BMI, waist circumference (WC), fat mass (FM), body fat percentage (BFP) and fat-free mass (FFM)) markers in adults. Online databases search, including PubMed, Scopus, the Cochrane Library and Web of Science up to March 2022, were utilised to retrieve RCT examining the effect of CLA supplementation on anthropometric and body composition markers in adults. Meta-analysis was carried out using a random-effects model. The I2 index was used as an index of statistical heterogeneity of RCT. Among the initial 8351 studies identified from electronic databases search, seventy RCT with ninety-six effect sizes involving 4159 participants were included for data analyses. The results of random-effects modelling demonstrated that CLA supplementation significantly reduced BM (weighted mean difference (WMD): -0·35, 95 % CI (-0·54, -0·15), P < 0·001), BMI (WMD: -0·15, 95 % CI (-0·24, -0·06), P = 0·001), WC (WMD: -0·62, 95% CI (-1·04, -0·20), P = 0·004), FM (WMD: -0·44, 95 % CI (-0·66, -0·23), P < 0·001), BFP (WMD: -0·77 %, 95 % CI (-1·09, -0·45), P < 0·001) and increased FFM (WMD: 0·27, 95 % CI (0·09, 0·45), P = 0·003). The high-quality subgroup showed that CLA supplementation fails to change FM and BFP. However, according to high-quality studies, CLA intake resulted in small but significant increases in FFM and decreases in BM and BMI. This meta-analysis study suggests that CLA supplementation may result in a small but significant improvement in anthropometric and body composition markers in an adult population. However, data from high-quality studies failed to show CLA's body fat-lowering properties. Moreover, it should be noted that the weight-loss properties of CLA were small and may not reach clinical importance.

The effects of conjugated linoleic acid supplementation on cardiovascular risk factors in patients at risk of cardiovascular disease: A GRADE-assessed systematic review and dose-response meta-analysis.

The present systematic review and meta-analysis sought to evaluate the effects of conjugated linoleic acid (CLA) supplementation on cardiovascular risk factors in patients at risk of CVD. Relevant studies were obtained by searching the PubMed, SCOPUS and Web of Science databases (from inception to January 2023). Weighted mean differences (WMD) and 95% CI were pooled using a random-effects model. Heterogeneity, sensitivity analysis and publication bias were reported using standard methods. A pooled analysis of 14 randomised controlled trials (RCT) with 17 effect sizes revealed that CLA supplementation led to significant reductions in body weight (WMD: -0·72 kg, 95% CI: -1·11, -0·33, P < 0·001), BMI (WMD: -0·22 kg/m2, 95% CI: -0·44, -0·00, P = 0·037) and body fat percentage (BFP) (WMD: -1·32 %, 95% CI: -2·24, -0·40, P = 0·005). However, there was no effect on lipid profile and blood pressure in comparison with the control group. In conclusion, CLA supplementation may yield a small but significant beneficial effect on anthropometric indices in patients at risk of CVD. Moreover, CLA seems not to have adverse effects on lipid profiles and blood pressure in patients at risk of CVD. It should be noted that the favourable effects of CLA supplementation on anthropometric variables were small and may not reach clinical importance.

Gut microbiota-induced CXCL1 elevation triggers early neuroinflammation in the substantia nigra of Parkinsonian mice.

Gut microbiota disturbance and systemic inflammation have been implicated in the degeneration of dopaminergic neurons in Parkinson's disease (PD). How the alteration of gut microbiota results in neuropathological events in PD remains elusive. In this study, we explored whether and how environmental insults caused early neuropathological events in the substantia nigra (SN) of a PD mouse model. Aged (12-month-old) mice were orally administered rotenone (6.25 mg·kg-1·d-1) 5 days per week for 2 months. We demonstrated that oral administration of rotenone to ageing mice was sufficient to establish a PD mouse model and that microglial activation and iron deposition selectively appeared in the SN of the mice prior to loss of motor coordination and dopaminergic neurons, and these events could be fully blocked by microglial elimination with a PLX5622-formulated diet. 16 S rDNA sequencing analysis showed that the gut microbiota in rotenone-treated mice was altered, and mice receiving faecal microbial transplantation (FMT) from ageing mice treated with rotenone for 2 months exhibited the same pathology in the SN. We demonstrated that C-X-C motif chemokine ligand-1 (CXCL1) was an essential molecule, as intravenous injection of CXCL1 mimicked almost all the pathology in serum and SN induced by oral rotenone and FMT. Using metabolomics and transcriptomics analyses, we identified the PPAR pathway as a key pathway involved in rotenone-induced neuronal damage. Inhibition of the PPARγ pathway was consistent in the above models, whereas its activation by linoleic acid (60 mg·kg-1·d-1, i.g. for 1 week) could block these pathological events in mice intravenously injected with CXCL1. Altogether, these results reveal that the altered gut microbiota resulted in neuroinflammation and iron deposition occurring early in the SN of ageing mice with oral administration of rotenone, much earlier than motor symptoms and dopaminergic neuron loss. We found that CXCL1 plays a crucial role in this process, possibly via PPARγ signalling inhibition. This study may pave the way for understanding the "brain-gut-microbiota" molecular regulatory networks in PD pathogenesis. The aged C57BL/6 male mice with rotenone intragastric administration showed altered gut microbiota, which caused systemic inflammation, PPARγ signalling inhibition and neuroinflammation, brain iron deposition and ferroptosis, and eventually dopaminergic neurodegeneration in PD.