Polyunsaturated Fatty Acids Research Articles

Lipoprotein Lipidomics as a Frontier in Non-Alcoholic Fatty Liver Disease Biomarker Discovery.

Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease characterized by the build-up of fat in the liver of individuals in the absence of alcohol consumption. This condition has become a burden in modern societies aggravated by the lack of appropriate predictive biomarkers (other than liver biopsy). To better understand this disease and to find appropriate biomarkers, a new technology has emerged in the last two decades with the ability to explore the unmapped role of lipids in this disease: lipidomics. This technology, based on the combination of chromatography and mass spectrometry, has been extensively used to explore the lipid metabolism of NAFLD. In this review, we aim to summarize the knowledge gained through lipidomics assays exploring tissues, plasma, and lipoproteins from individuals with NAFLD. Our goal is to identify common features and active pathways that could facilitate the finding of a reliable biomarker from this field. The most frequent observation was a variable decrease (1-9%) in polyunsaturated fatty acids in phospholipids and non-esterified fatty acids in NAFLD patients, both in plasma and liver. Additionally, a reduction in phosphatidylcholines is a common feature in the liver. Due to the scarcity of studies, further research is needed to properly detect lipoprotein, plasma, and tissue lipid signatures of NAFLD etiologies, and NAFLD subtypes, and to define the relevance of this technology in disease management strategies in the push toward personalized medicine.

Effect of genotype and outdoor enrichment on productive performance and meat quality of slow growing chickens

The optimization of animal welfare, meat quality, environmental impact, and economic sustainability in alternative poultry farming can be achieved by modulating several productive factors and improving the synergy between the chicken genotype and the outdoor environment. The objective of the study was to characterize 4 slow-growing chicken genotypes reared in free range conditions. Eight hundred chickens (SGs; 25 chickens/replicates/genotype/enrichment) belonging to the following genotypes, Red JA57 (RJ), Naked Neck (NN), Lohmann Dual meat-type (LD), and an Italian crossbreed (Robusta Maculata x Sasso, CB). were utilised and slaughtered at 81 d: The grazing areas were alternatively provided with enrichment constituted by strips of sorghum plants (ENR) or only grass (NO ENR). Productive performance (daily weight gain, daily feed intake, feed conversion ratio, live weight) were recorded weekly. Behaviour observations (walking and grass pecking), carcass and meat quality of breast and drumstick were also assessed in 15 chickens/replicate/genotypes/enrichment. Results demonstrated that both LD and CB showed the highest walking activity, but the different strains were differently capable of using the foraging resources (eating grass). The better productive performance was recorded in RJ followed by NN, CB and LD. In LD and CB, the different walking activities also affected the physico-chemical profiles (lower pHu, WHC, and lipids) of the breast and drumstick. The oxidative status was worse in CB than in the other groups (lower tocols, higher carbonyls), in both meat cuts. Fatty acid profile was also related to the genetic strain: a higher amount of n-3 polyunsaturated fatty acids was recorded both in the breast and drumstick of RJ and NN. The Healthy Fatty Index resulted excellent in all the chicken genotypes. In conclusion, the environment/animal interaction resulted as an important factor affecting the adaptability of genotypes to an extensive rearing system. All four genotypes, to different extents, showed good adaptability and production performance, with the exception of LD and CB, which were too light for the commercial supply chain requirements.

Protein extracts from microalgae and cyanobacteria biomass. Techno-functional properties and bioactivity: A review

Microalgae and cyanobacteria are photosynthetic and unicellular organisms that contain considerable amounts of proteins, lipids, carbohydrates, and polyunsaturated fatty acids, among others, with applications in the cosmetic, pharmaceutical, and food industries. These microorganisms can accumulate protein up to 70 % of total biomass depending on the microalgal strain, hence they have been regarded as an alternative protein source for the future. Microalgal proteins have important applications such as emulsifying, foaming, and gelation properties, which are important for the determination of quality and texture of foods. Some microalgal peptides possess important bioactivity with many health-benefit effects. Therefore, to maximize the production of proteins from microalgae and cyanobacteria, many protein extraction procedures have been studied to increase the economic return. They have been tested towards higher protein yields at low energy cost, the preservation of protein native properties, and lower cell debris. This later is fundamental to facilitate the subsequent purification processes so that the overall cost can be reduced. The aim of this work is to review some cell disruption processes for the extraction of protein from microalgae and cyanobacteria, considering that this step is crucial for the overall process due to the high rigidness of microalgal cell covering, which can hamper the release of proteins. It also aims at reviewing the purification techniques after cellular disruption, from conventional to more recent approaches, and finally addresses the antioxidant, antidiabetic, antihypertensive, antibacterial and other bioactive properties of microalgal protein hydrolysates and peptides.

Arachidonic acid metabolism regulates the development of retinopathy of prematurity among preterm infants.

Extremely preterm infants are at risk of developing retinopathy of prematurity (ROP), characterized by neovascularization and neuroinflammation leading to blindness. Polyunsaturated fatty acid (PUFA) supplementation is recommended in preterm infants to lower the risk of ROP, however, with no significant improvement in visual acuity. Reasonably, this could be as a result of the non-consideration of PUFA metabolizing enzymes. We hypothesize that abnormal metabolism of the arachidonic acid (AA) pathway may contribute to severe stages of ROP. The present study investigated the AA-metabolizing enzymes in ROP pathogenesis by a targeted gene expression analysis of blood (severe ROP = 70, No/Mild = 56), placenta (preterm placenta = 6, full term placenta = 3), and human primary retinal cell cultures and further confirmed at the protein level by performing IHC in sections of ROP retina. The lipid metabolites were identified by LC-MS in the vitreous humor (VH; severe ROP = 15, control = 15). Prostaglandins D2 (p = 0.02), leukotrienes B5 (p = 0.0001), 11,12-epoxyeicosatrienoic acid (p = 0.01), and lipid-metabolizing enzymes of the AA pathway such as CYP1B1, CYP2C8, COX2, and ALOX15 were significantly upregulated while EPHX2 was significantly (0.04) downregulated in ROP cases. Genes involved in hypoxic stress, angiogenesis, and apoptosis showed increased expression in ROP. An increase in the metabolic intermediates generated from the AA metabolism pathway further confirmed the role of these enzymes in ROP, while metabolites for EPHX2 activity were low in abundance. Inflammatory lipid intermediates were higher compared to anti-inflammatory lipids in VH and showed an association with enzyme activity. Both the placenta of preterm infants who developed ROP and hypoxic retinal cultures showed a reduced expression of EPHX2. These findings suggested a strong involvement of EPHX2 in regulating retinal neovascularization and inflammation. The study results underscore the role of arachidonic acid metabolism in the development of ROP and as a potential target for preventing vision loss among preterm-born infants.

Omega-3 fatty acids effectively mitigate high-sensitivity C-reactive protein (hs-CRP) biomarker of inflammation in acute myocardial infarction patients: a randomized, double-blind, placebo-controlled clinical trial.

Myocardial infarction (MI) is considered an inflammatory disease and among the leading causes of death globally. An essential indicator of inflammation, high-sensitivity C-reactive protein (hs-CRP), is linked with the acute MI prognosis. We aimed to examine the impact of omega-3 polyunsaturated fatty acids (PUFAs) as an anti-inflammatory supplement on hs-CRP levels in acute MI patients. Sixty patients with acute MI participated in this randomized, placebo-controlled trial. For 30 days, patients were randomized to receive omega-3 PUFAs (2 g/day, N = 30) or placebo (N = 30) on top of guideline-directed medical therapy. An initial and endpoint measurement of hs-CRP was performed. We found that the hs-CRP levels in both omega-3 PUFAs and placebo groups remarkably decreased following 30 days of treatment (decreasing from 1.84 (2.3) and 1.3 (2.6) to 0.38 (0.54) and 0.63 (1.12) mg/dL, respectively; P < 0.001). Following the 30 days of treatment, the reducing impact of omega-3 PUFAs (↓ 1.54 (1.98) mg/dL) on hs-CRP was more robust than the placebo group (↓ 0.92 (1.57) mg/dL, P = 0.008). Furthermore, the WBC, cholesterol, LDL, and triglyceride levels were markedly decreased in omega-3 and placebo groups after 30 days of therapy (P < 0.001 for all). However, no remarkable differences were reported in the level of these parameters after 30 days of therapy between both studied groups. Our findings showed that omega-3 PUFAs decrease hs-CRP amounts in patients with acute MI. Omega-3 PUFA supplementation may be an appropriate candidate in patients with early-stage acute MI for inhibiting inflammation.

Optimization of differentiation conditions for porcine adipose-derived mesenchymal stem cells and analysis of fatty acids in cultured fat

Cultured fat is an important part of cultured meat, and the ability of adipose-derived mesenchymal stem cells (ADSCs) to differentiate into mature adipose tissue affects the quality of cultured fat. Thus, the primary aim of this study was to screen for combinations of differentiation-inducing factors (DIF) using single-factor experiment and orthogonal experimental design under two-dimensional culture conditions for ADSCs. The results showed that a combination of DIF consisting of 1 μmol/L dexamethasone, 0.1 mmol/L 3-isobutyl-1-methylxanthine, 10 μg/mL insulin, 0.1 mmol/L indomethacin, and 2 μmol/L rosiglitazone was a good choice for the differentiation of ADSCs. An combination of DIF was applied to the preparation of cultured fat with collagen as scaffolds. Forty-eight fatty acids were detected in cultured fat by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Among them, the content of twenty-one fatty acids in cultured fat was significantly higher than that of conventional porcine subcutaneous adipose tissue (P < 0.05), and the content of 14 fatty acids was not significantly different (P > 0.05). The ratio of ω-6 polyunsaturated fatty acids content to ω-3 polyunsaturated fatty acids content was 1.23:1, which meant cultured fat was beneficial for human health. This study provides a method to improve the differentiation ability of ADSCs while also providing a reference for indicating the nutritional value of cultured fat.

Evaluating the Stability and Digestibility of Long-Chain Omega-3 Algal Oil Nanoemulsions Prepared with Lecithin and Tween 40 Emulsifiers Using an In Vitro Digestion Model.

The health benefits of long-chain omega-3 polyunsaturated fatty acid (LCn-3PUFA) intake have been well documented. However, currently, the consumption of oily fish (the richest dietary source of LCn-3PUFA) in the UK is far below the recommended level, and the low digestibility of LCn-3PUFA bulk oil-based supplements from triglyceride-based sources significantly impacts their bioavailability. LCn-3PUFA-rich microalgal oil offers a potential alternative for populations who do not consume oily fish, and nanoemulsions have the potential to increase LCn-3PUFA digestibility and bioavailability. The aims of this study were to produce stable algal oil-in-water nanoemulsions with ultrasonic technology to increase DHA digestibility, measured using an in vitro digestion model. A nanoemulsion of LCn-3PUFA algal oil was developed with 6% w/w emulsifiers: lecithin (LE) or an equal ratio of Tween 40 (3%) and lecithin (LTN) (3%), 50% w/w, algal oil and 44% w/w water using rotor-stator and ultrasound homogenization. The in vitro digestion experiments were conducted with a gastric and duodenal digestion model. The results showed the creation of nanoemulsions of LCn-3PUFA algal oils offers potentially significant increases in the bioavailability of DHA in the human body. The increase in digestibility can be attributed to the smaller particle size of the nanoemulsions, which allows for higher absorption in the digestive system. This showed that the creation of nanoemulsions of LCn-3PUFA algal oils offers a potentially significant increase in the bioavailability of DHA in the human body. The LE and LTN nanoemulsions had average droplet sizes of 0.340 ± 0.00 µm and 0.267 ± 0.00 µm, respectively, but the algal oil mix (sample created with same the components as the LTN nanoemulsion, hand mixed, not processed by rotor-stator and ultrasound homogenization) had an average droplet size of 73.6 ± 6.98 µm. The LTN algal oil nanoemulsion was stable in the gastric and duodenal phases without detectable destabilization; however, the LE nanoemulsion showed signs of oil phase separation in the gastric phase. Under the same conditions, the amount of DHA digested from the LTN nanoemulsion was 47.34 ± 3.14 mg/g, compared to 16.53 ± 0.45 mg/g from the algal oil mix, showing DHA digestibility from the LTN nanoemulsion was 2.86 times higher. The findings of this study contribute to the insight of in vitro DHA digestion under different conditions. The stability of the LTN nanoemulsion throughout digestion suggests it could be a promising delivery system for LCn-3PUFAs, such as DHA, in various food and pharmaceutical applications.

Association of Omega-3 Polyunsaturated Fatty Acids with Sarcopenia in Liver Cirrhosis Patients with Hepatocellular Carcinoma.

Sarcopenia is associated with the prognosis of patients with liver cirrhosis and hepatocellular carcinoma (HCC). Given their diverse physiological activities, we hypothesized that plasma fatty acids might influence the progression of sarcopenia. This study aimed to clarify the association between fatty acids and sarcopenia in cirrhotic patients with HCC. In this single-center retrospective study, we registered 516 cases and analyzed 414 cases of liver cirrhosis and HCC. The skeletal muscle mass index was measured using a transverse computed tomography scan image at the third lumbar vertebra. The cutoff value for sarcopenia followed the criteria set by the Japan Society of Hepatology. Fatty acid concentrations were measured by gas chromatography. Fatty acid levels, particularly omega-3 (n-3) polyunsaturated fatty acid (PUFA), were lower in patients with poor liver function (Child-Pugh grade B/C) and were negatively correlated with the albumin-bilirubin score (p<0.0001). The prognosis of HCC patients with low PUFA levels was significantly worse. Among the different fatty acid fractions, only n-3 PUFAs significantly correlated with skeletal muscle mass index (p=0.0026). In the multivariate analysis, the n-3 PUFA level was an independent variable associated with sarcopenia (p=0.0006). A low level of n-3 PUFAs was associated with sarcopenia in patients with liver cirrhosis and HCC.

Lipidomics by Nuclear Magnetic Resonance Spectroscopy and Liquid Chromatography-High-Resolution Mass Spectrometry in Osteosarcoma: A Pilot Study.

Cancer is a complex disease that can also affect the younger population; however, it is responsible for a relatively high mortality rate of children and youth, especially in low- and middle-income countries (LMICs). Besides that, lipidomic studies in this age range are scarce. Therefore, we analyzed blood serum samples from young patients (12 to 35 years) with bone sarcoma (osteosarcoma) and compared their lipidomics to the ones from the control group of samples, named healthy control (HC group), using NMR and LC-MS techniques. Furthermore, differences in the lipidomic profiles between OS patients with and without metastasis indicate higher glycerophosphocholine (GPC) and glycerophospholipid (GPL) levels in osteosarcoma and increased cholesterol, choline, polyunsaturated fatty acids (PUFAs), and glycerols during the metastasis. These differences, detected in the peripheral blood, could be used as biomarkers for liquid biopsy.

Functional Lipids and Cardiovascular Disease Reduction: A Concise Review.

Functional lipids are dietary substances that may have an impact on human health by lowering the risk of chronic illnesses and enhancing the quality of life. Numerous functional lipids have been reported to have potential health benefits in the prevention, management, and treatment of cardiovascular disease, the leading cause of death in the United States. However, there is still insufficient and contradictory information in the literature about their effectiveness and associated mechanisms of action. The objective of this review, therefore, is to evaluate available literature regarding these functional lipids and their health benefits. Various studies have been conducted to understand the links between functional lipids and the prevention and treatment of chronic diseases. Recent studies on phytosterols have reported that CLA, medium-chain triglycerides, and omega-3 and 6 fatty acids have positive effects on human health. Also, eicosanoids, which are the metabolites of these fatty acids, are produced in relation to the ratio of omega-3 to omega-6 polyunsaturated fatty acids and may modulate disease conditions. These functional lipids are available either in dietary or supplement forms and have been proven to be efficient, accessible, and inexpensive to be included in the diet. However, further research is required to properly elucidate the dosages, dietary intake, effectiveness, and their mechanisms of action in addition to the development of valid disease biomarkers and long-term effects in humans.

Nutrition to support a healthy skeleton

Background. Bone tissue is actively exposed to environmental factors and lifestyle. Since the bone mass accumulated in childhood will determine the state of the skeleton during a person’s subsequent life, it is necessary to promote its maximum increase. Sufficient nutrition is one of the main factors in maintaining bone health. The purpose of our study was to determine the level of daily basic nutrient intake among schoolchildren and to reveal its relationship with clinical disorders of the musculoske­letal system. Materials and methods. Using a computer program, we assessed the actual diet of 65 schoolchildren aged from 8 to 17 years. Results. It was found that 90 % of children were deficient in iodine and calcium, and more than 70 % were deficient in zinc and selenium. The deficiency of potassium, magnesium, iron, copper, fluorine, manganese, and phosphorus was less pronounced. A significant deficiency of vitamin D, β-carotene, vitamin A, biotin, and vitamin E was noted. In almost half of the examined children, the share of saturated fatty acids in the diet exceeds the recommended norm, while the level of polyunsaturated fatty acids is significantly reduced. In 93.8 % of schoolchildren, the nutritional ratio between calcium and phosphorus is disturbed. Conclusions. The obtained results testify to the unbalanced diet of schoolchildren and inconsistency with physiological needs. Deficiency of a number of nutrients can contribute to musculoskeletal pain, convulsive syndrome, fractures, caries and recurrent respiratory di­sease.

The hotspot of consumers complaints on infant formula: Exploring the relationship among volatile components, sensory evaluation, and aroma recombination and omission experiment

Two-stage infant formula (IF) is rich in polyunsaturated fatty acids (PUFAs), However, PUFAs are susceptible to oxidation, thus affecting the flavor profile of the product. This study aimed to evaluate 4 samples with the participation of 60 consumers. Among these, three samples with the lowest consumer preference and one with the highest preference were selected as controls to explain the causes of off-flavors in two-stage infant formulas. Through qualitative and quantitative analysis of 28 flavor-active compounds in two-stage infant formulas using GC-MS, E-nose, GC-O, odor activity values (OAVs), and variable importance in projection (VIP) values, hexanal, heptanal, pentanal, octanal, and 1-penten-3-one were identified as the important compounds affecting the flavor of two-stage infant formulas. Further, recombination/deficiency experiments confirmed hexanal and heptanal as the key undesirable flavor components in two-stage infant formulas.

Polyunsaturated fatty acids stimulate immunity and eicosanoid production in Drosophila melanogaster

AbstractEicosanoids 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.

Beef production, physicochemical quality, oxidative shelf-life, fatty acid profile and sensory effects of replacing sorghum for maize in finisher diets

Climate change and high demand for maize have prompted the search for climate-smart, energy feedstuffs such as sorghum for use in beef finisher diets. Relative to maize, sorghum has comparable metabolizable energy content and contains more polyunsaturated fatty acids and bioactive phenolic compounds that may enhance beef health value, oxidative shelf-life, and sensory quality. The study investigated the impact of graded sorghum levels replacing maize in beef finisher diets on nutrient utilization, production, physicochemical quality, fatty acid composition, oxidative shelf-life, and sensory quality attributes of beef. Thirty-five, seven-months-old (230 ± 28 kg average initial weight) Angus steers were individually housed in pens and randomly allocated to five pellet diets formulated by replacing white maize in the basal diet (control) with 100, 200, 300, and 400 g/kg DM of sorghum. Diet did not affect (P > 0.05) nutrient intake, digestibility and utilization, growth performance, carcass characteristics, longissimus thoracis (LT) meat physicochemical quality, fatty acid contents and colour coordinates. Metmyoglobin and colour coordinates increased (P ≤ 0.05) with retail display except redness which declined (P ≤ 0.05). Lipid oxidation of LT meat aged for day 1 tended to increase (P ≤ 0.10) with increased dietary substitution of sorghum for maize in beef finishing diets. In addition, antioxidant activity, metallic aroma and liver-like flavour linearly increased (P ≤ 0.05) with sorghum inclusion in the diet. In conclusion, sorghum can fully replace maize in beef finisher diets with neutral effects on beef production, physicochemical quality, health value and colour stability, and somewhat desirable impact on antioxidant activity and myoglobin stability and undesirable effects on aroma and flavour of LT meat.

Serum Phosphatidylcholine Species 32:0 as a Biomarker for Liver Cirrhosis Pre- and Post-Hepatitis C Virus Clearance.

Phosphatidylcholine (PC) is an essential lipid for liver health and lipoprotein metabolism, but its circulating levels have rarely been studied in patients with cirrhosis. Chronic hepatitis C virus (HCV) infection causes lipid abnormalities and is a major cause of cirrhosis. Effective HCV elimination with direct-acting antivirals (DAAs) is associated with the normalization of serum low-density lipoprotein cholesterol levels. Since PC is abundant in all lipoprotein particles, this study analyzed the association between serum PC species levels and liver cirrhosis before and after HCV eradication. Therefore, 27 PC species were measured by Fourier Transform Mass Spectrometry in the serum of 178 patients with chronic HCV infection at baseline and in 176 of these patients at the end of therapy. The PC species did not correlate with viral load, and the levels of 13 PC species were reduced in patients infected with genotype 3a compared to those affected with genotype 1. Four PC species were slightly elevated 12 weeks after DAA initiation, and genotype-related changes were largely normalized. Patients with HCV and cirrhosis had higher serum levels of PC 30:0 and 32:0 before and at the end of therapy. PC species containing polyunsaturated fatty acids were mostly decreased in cirrhosis. The levels of polyunsaturated, but not saturated, PC species were inversely correlated with the model of the end-stage liver disease score. A receiver operating characteristic curve analysis showed area under the curve values of 0.814 and 0.826 for PC 32:0 and 0.917 and 0.914 for % PC 32:0 (relative to the total PC levels) for the classification of cirrhosis at baseline and at the end of therapy, respectively. In conclusion, the specific upregulation of PC 32:0 in cirrhosis before and after therapy may be of diagnostic value in HCV-related cirrhosis.

Walnut meal improves meat quality by modulating intestinal microbes in white feather broilers

Improving the number of amino acids and unsaturated fatty acids in the diet is a good way to raise the quality of the meat. Currently, most research on the quality of broiler meat focuses on genetic traits; nevertheless, it is unclear how meat quality is regulated. This experiment was conducted to investigate the effects of different supplemental levels of walnut meal (WM) on growth performance, amino acid and fatty acid composition, microbial composition, and meat quality of white feather broilers. 1 week old white feather broilers (n = 120; Body weight 83.76 ± 2.32 g), were randomly divided into 3 treatments and 4 replicates. Walnut meal of basic diet (CK), 5 %(WM-L) and 10 %(WM-H) were added to the diets of white feather broilers, respectively. The results showed that walnut meal could increase L* 24 h (24 h brightness) of breast muscle of white feathered broilers (p < 0.05). The amount of essential amino acids (e.g., isoleucine, methionine, leucine, tryptophan, and phenylalanine), umami amino taste acids (glutamic acid), and PUFA/SFA (polyunsaturated fatty acid) (n-3PUFA and n-6 PUFA) in breast muscle increased as the dose was increased. Furthermore, walnut meal regulated amino acid flavour metabolism by increasing the relative abundance of Bacteroides, bifidobacterium, and enterococcus faecalis, according to 16S rRNA sequencing and functional prediction analysis. The correlation showed that amino acid and fatty acid composition was one of the key factors affecting pH value, meat color and tenderness of chicken. In conclusion, dietary addition of walnut meal can increase the content of essential amino acids and unsaturated fatty acids and the relative abundance of beneficial bacteria of broilers, which is of great significance for improving meat quality of white feather broilers.

Ferroptosis is a targetable detrimental factor in metabolic dysfunction-associated steatotic liver disease

There is an unmet clinical need for pharmacologic treatment for metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatocyte cell death is a hallmark of this highly prevalent chronic liver disease, but the dominant type of cell death remains uncertain. Here we report that ferroptosis, an iron-catalyzed mode of regulated cell death, contributes to MASLD. Unsupervised clustering in a cohort of biopsy-proven MASLD patients revealed a subgroup with hepatic ferroptosis signature and lower glutathione peroxidase 4 (GPX4) levels. Likewise, a subgroup with reduced ferroptosis defenses was discerned in public transcriptomics datasets. Four weeks of choline-deficient L-amino acid-defined high-fat diet (CDAHFD) induced MASLD with ferroptosis in mice. Gpx4 overexpression did not affect steatohepatitis, instead CDAHFD protected from morbidity due to hepatocyte-specific Gpx4 knockout. The ferroptosis inhibitor UAMC-3203 attenuated steatosis and alanine aminotransferase in CDAHFD and a second model, i.e., the high-fat high-fructose diet (HFHFD). The effect of monounsaturated and saturated fatty acids supplementation on ferroptosis susceptibility was assessed in human HepG2 cells. Fat-laden HepG2 showed a drop in ferroptosis defenses, increased phosphatidylglycerol with two polyunsaturated fatty acid (PUFA) lipid tails, and sustained ferroptosis sensitivity. In conclusion, this study identified hepatic ferroptosis as a detrimental factor in MASLD patients. Unexpectedly, non-PUFA supplementation to hepatocytes altered lipid bilayer composition to maintain ferroptosis sensitivity. Based on findings in in vivo models, ferroptosis inhibition represents a promising therapeutic target in MASLD.

Class II ferroptosis inducers are a novel therapeutic approach for t(4;14)-positive multiple myeloma

AbstractMultiple myeloma (MM) is a clonal plasma cell malignancy that is characterized by genetic heterogeneity. The cytogenetic abnormality t(4;14) strongly predicts poor outcome in patients with MM, even in the era of novel drugs. Ferroptosis is a new approach to antitumor therapy, but the relationship between ferroptosis and MM cytogenetic abnormalities remains largely unclear. In this study, we show that t(4;14)-positive but not t(4;14)-negative MM cells are susceptible to class II ferroptosis inducers (FINs) in a preclinical setting, which is dependent on the significant upregulation of the MM SET domain-containing protein (MMSET). Mechanistically, MMSET upregulates acyl-coenzyme A synthetase long-chain family member 4 transcription by binding to its promoter region, leading to increased polyunsaturated fatty acid (PUFA) levels and enhanced sensitivity of t(4;14)-positive MM cells to ferroptosis. Supplementation with PUFAs efficiently restores the susceptibility of t(4;14)-negative MM cells to ferroptosis. In addition, combining class II FIN treatment with bortezomib in t(4;14)-positive MM cells attenuates cellular glutathione and induces both apoptosis and ferroptosis levels by inhibiting the increase in solute carrier family 7 member 11, demonstrating synergistic antitumor activity in vitro and in a xenograft model. Taken together, our findings suggest that targeting ferroptosis with class II FINs is a novel and promising therapeutic approach to improve the outcome of t(4;14)-positive patients with MM.

Increased Odds of Metabolic Dysfunction-Associated Steatotic Liver Disease Are Linked to Reduced n-6, but Not n-3 Polyunsaturated Fatty Acids in Plasma.

The increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) underscores the need for better understanding of its complex pathogenesis. Lipid accumulation in hepatocytes is among principal mechanisms contributing to MASLD development. While routine lipid parameters are well studied, the profile of circulating fatty acids in MASLD patients remains less explored. This study aimed to assess relative proportions of individual fatty acids in plasma of MASLD patients and to explore their associations with other biochemical markers of MASLD. Ninety-one patients and 48 healthy individuals were enrolled. The relative proportions of fatty acids in plasma were determined using gas chromatography with FID detection. Proportions of total n-6 polyunsaturated fatty acids (PUFAs) and linoleic acid (LA) in plasma were lower in MASLD patients (p = 0.001 and p = 0.004, respectively), with no differences observed in n-3 PUFAs. Total plasma n-6 PUFAs correlated negatively with body mass index, hepatic steatosis indices, triglyceride concentration and coronary risk index. Decreased prevalence of n-6 PUFAs in plasma was independently associated with higher odds of MASLD (OR = 0.769; CI: 0.611-0.968; p = 0.025). Our findings indicate an altered circulatory fatty acid distribution in MASLD, characterized by a reduced amount of n-6 PUFAs, particularly LA, which may have significant implications for the prevention and treatment of MASLD.

Changes in the Fatty Acid Profile of Lactating Women Living in Poland-A Comparison with the Fatty Acid Profile of Selected Infant Formulas.

The present study examined the fatty acid content of human milk from Polish women living in the Warmia and Mazury region with regard to different lactation periods and compared it with the fatty acid content of selected infant formulas. The analysis included samples of breast milk-colostrum (n = 21), transitional milk (n = 26), and mature milk (n = 22). Fat was extracted using the Rose-Gottlieb method, and the fatty acid profile was determined by gas chromatography with a flame ionization detector (FID). The proportion of SFAs (saturated fatty acids) > MUFAs (monounsaturated fatty acids) > PUFAs (polyunsaturated fatty acids) was determined in each fraction of breast milk and infant formula. Palmitic, oleic, and linoleic acids predominated in breast milk and infant formulas. Colostrum contained lower contents of selected SFAs (caprylic, capric, lauric) and higher contents of selected MUFAs (ercucic) and PUFAs (arachidonic and docosahexaenoic) (p < 0.05) relative to transitional and mature milk. Infant formulas were distinguished from human milk in terms of their SFA (caproic, caprylic, lauric, arachidic), MUFA (oleic), and PUFA (linoleic, α-linoleic) content. It should be noted that infant formulas contained significantly lower trans fatty acid (TFA) content-more than thirty-six and more than nineteen times lower than in human milk. Furthermore, human milk contained branched-chain fatty acids (BCFAs) at 0.23-0.28%, while infant formulas contained only trace amounts of these acids. The average ratio of n-6 to n-3 fatty acids for human milk was 6.59:1 and was close to the worldwide ratio of 6.53 ± 1.72:1. Both principal component analysis (PCA) and cluster analysis (CA) indicated significant differences in the fatty acid profile relative to lactation and a different profile of infant formulas relative to breast milk.