Protective effect of long-chain polyunsaturated fatty acids on hepatorenal syndrome in rats

BACKGROUND Hepatorenal syndrome(HRS)is the most prevalent form of acute kidney injury in cirrhotic patients.It is characterized by reduced renal blood flow and represents the most severe complication in cirrhotic patients with advanced disease.Previous research has indicated that antioxidants can delay the onset of a hyperdynamic circulatory state in cirrhosis and improve renal function in HRS patients.Regular omega-3 supplementation has significantly reduced the risk of liver disease.This supplementation could represent an additional therapy for individuals with HRS.AIM To evaluated the antioxidant effect of omega-3 polyunsaturated fatty acid supplementation on the kidneys of cirrhotic rats.METHODS Secondary biliary cirrhosis was induced in rats by biliary duct ligation(BDL)for 28 d.We used 24 male Wistar rats divided into the following groups:I(control);II(treated with omega-3,1 g/kg of body weight);III(BDL treated with omega-3,1 g/kg of body weight);and IV(BDL without treatment).The animals were killed by overdose of anesthetic;the kidneys were dissected,removed,frozen in liquid nitrogen,and stored in a freezer at-80℃for later analysis.We evaluated oxidative stress,nitric oxide(NO)metabolites,DNA damage by the comet assay,cell viability test,and apoptosis in the kidneys.Data were analyzed by one-way analysis of variance,and means were compared using the Tukey test,with P≤0.05.RESULTS Omega-3 significantly decreased the production of reactive oxygen species(P<0.001)and lipoperoxidation in the kidneys of cirrhotic rats treated with omega-3(P<0.001).The activity of the antioxidant enzymes superoxide dismutase and catalase increased in the BDL+omega-3 group compared to the BDL group(P<0.01).NO production,DNA damage,and caspase-9 cleavage decreased significantly in the omega-3-treated BDL group.There was an increase in mitochondrial electrochemical potential(P<0.001)in BDL treated with omega-3 compared to BDL.No changes in the cell survival index in HRS with omega-3 compared to the control group(P>0.05)were observed.CONCLUSION The study demonstrates that omega-3 can protect cellular integrity and function by increasing antioxidant enzymes,inhibiting the formation of free radicals,and reducing apoptosis.

The LXRB-SREBP1 network regulates lipogenic homeostasis by controlling the synthesis of polyunsaturated fatty acids in goat mammary epithelial cells

Background:In rodents,research has revealed a role of liver X receptors(LXR) in controlling lipid homeostasis and regulating the synthesis of polyunsaturated fatty acids(PUFA).Recent data suggest that LXRB is the predominant LXR subtype in ruminant mammary cells,but its role in lipid metabolism is unknown.It was hypothesized that LXRB plays a role in lipid homeostasis via altering the synthesis of PUFA in the ruminant mammary gland.We used overexpression and knockdown of LXRB in goat primary mammary epithelial cells(GMEC) to evaluate abundance of lipogenic enzymes,fatty acid profiles,content of lipid stores and activity of the stearoyl-Co A desaturase(SCD1) promoter.Results:Overexpression of LXRB markedly upregulated the protein abundance of LXRB while incubation with si RNA targeting LXRB markedly decreased abundance of LXRB protein.Overexpression of LXRB plus T0901317(T09,a ligand for LXR) dramatically upregulated SCD1 and elongation of very long chain fatty acid-like fatty acid elongases 5–7(ELOVL 5–7),which are related to PUFA synthesis.Compared with the control,cells overexpressing LXRB and stimulated with T09 had greater concentrations of C16:0,16:1,18:1n7,18:1n9 and C18:2 as well as desaturation and elongation indices of C16:0.Furthermore,LXRB-overexpressing cells incubated with T09 had greater levels of triacylglycerol and cholesterol.Knockdown of LXRB in cells incubated with T09 led to downregulation of genes encoding elongases and desaturases.Knockdown of LXRB attenuated the increase in triacylglycerol and cholesterol that was induced by T09.In cells treated with dimethylsulfoxide,knockdown of LXRB increased the concentration of C16:0 at the expense of C18:0,while a significant decrease in C18:2 was observed in cells incubated with both si LXRB and T09.The abundance of sterol regulatory element binding transcription factor 1 precursor(p SREBP1) and its mature fragment(n SREBP1) was upregulated by T09,but not LXRB overexpression.In the cells cultured with T09,knockdown of LXRB downregulated the abundance for p SREBP1 and n SREBP1.Luciferase reporter assays revealed that the activities of wild type SCD1 promoter or fragment with SREBP1 response element(SRE) mutation were decreased markedly when LXRB was knocked down.Activity of the SCD1 promoter that was induced by T09 was blocked when the SRE mutation was introduced.Conclusion:The current study provides evidence of a physiological link between the LXRB and SREBP1 in the ruminant mammary cell.An important role was revealed for the LXRB-SREBP1 network in the synthesis of PUFA via the regulation of genes encoding elongases and desaturases.Thus,targeting this network might elicit broad effects on lipid homeostasis in ruminant mammary gland.

Novel Lipase from Golden Pompano(Trachinotus ovatus)Viscera:Purification,Characterization,and Application in the Concentrating of n-3 Polyunsaturated Fatty Acids

Lipases have been widely applied in a variety of industrial fields,such as food,pharmaceuticals,biofuels,and biotechnology.Recent years have witnessed a great interest in modifying lipids for the production of triacylglycerols enriched with n-3 polyunsaturated fatty acids(PUFAs).Here,a novel salt-tolerant,organic solvent-stable,and bile salt-activated lipase was purified from golden pompano(Trachinotus ovatus)viscera,which was named as golden pompano lipase(GPL).GPL had a specific activity of 57.2U mg^(-1)with an estimated molecular weight of 14 k Da,exhibited optimal activity at 40℃a nd pH 8.0,and showed K_(m)and V_(max)of 40.16μmol L^(-1)and 769.23μmol L^(-1)min^(-1),respectively.GPL activity was enhanced by Mn^(2+)and sodium deoxycholate.It was active in organic solvents,including methanol,ethanol,chloroform,and hexane.GPL also showed a good salinity tolerance of up to 1 mol L^(-1).n-3PUFA enrichment in the glyceride fraction of golden pompano oil was performed by GPL-catalyzed hydrolysis and yielded a total PUFA concentration of 56.99%.EPA,DHA,and DPA were enriched by 10.4-,3.2-,and 1.8-fold of their initial levels,respectively.This study recognized the industrial applicability of GPL to prepare enriched C_(20-22)n-3 PUFA.

Comparison of the effects of 3 kinds of oils rich in omega-3 polyunsaturated fatty acids on glycolipid metabolism and lipoprotein subfractions

Dietary omega-3 polyunsaturated fatty acids(ω-3 PUFAs)can be classifi ed into animal-and plant-derivedω-3 PUFAs.Patients with type 2 diabetes(T2DM)are frequently accompanied by dyslipidemia,which is closely related to the high-density lipoprotein(HDL-C)subfractions change.This study aimed to determine the effects of different sourcesω-3 PUFAs on glucolipid metabolism and lipoprotein subfractions in T2DM with dyslipidemia.Ninety T2DM patients with dyslipidemia were randomly assigned to take 3 g/day fi sh oil(FO,containing eicosapentaenoic acid(EPA)and docosahexaenoic acid(DHA)),3 g/day perilla oil(PO,containingα-linolenic acid(ALA)),or 3 g/day blend oil(BO,containing EPA,DHA and ALA)for 3 months.90 patients completed the intervention.There was a significant reduction of glycated hemoglobin(HbA1c)in all the groups.The triglycerides(TG)in the FO group were signifi cantly different with a group×time interaction(P=0.043),which was higher compared with the other two groups.The serum small HDL-C subfractions in the PO group was higher and the serum large HDL-C subfractions in the PO group was lower than those in the BO and FO groups.Plant-derivedω-3 PUFAs are more effective at controlling blood glucose than animal-derivedω-3 PUFAs.However,animal-derivedω-3 PUFAs have a signifi cant lowering effect on TG compared with plant-derivedω-3 PUFAs.Particularly,large HDL-C subfractions after animal-derivedω-3 PUFAs intake were higher than plant-derivedω-3 PUFAs intake;while small HDL-C subfractions were lower.Both the animal-and plant-derivedω-3 PUFAs have practical value in improving glucose and lipids metabolism in T2DM patients with dyslipidemia.

Effects of n-3 polyunsaturated fatty acids from seal oils on nonalcoholic fatty liver disease associated with hyperlipidemia

AIM: To investigate the efficacy and safety of n-3 polyunsaturated fatty acids (PUFA) from seal oils for patients with nonalcoholic fatty liver disease (NAFLD) associated with hyperlipidemia. METHODS: One hundred and forty-four patients with NAFLD associated with hyperlipidemia were included in the 24-wk, randomized, controlled trial. The patients were randomized into two groups. Group A (n = 72) received recommended diet and 2 g n-3 PUFA from seal oils, three times a day. Group B (n = 72) received recommended diet and 2 g placebo, three times a day. Primary endpoints were fatty liver assessed by symptom scores, liver alanine aminotransferase (ALT) and serum lipid levels after 8, 12, 16, and 24 wk. Hepatic fat inf iltration was detected by ultrasonography at weeks 12 and 24 after treatment. RESULTS: A total of 134 patients (66 in group A, 68 in group B) were included in the study except for 10 patients who were excluded from the study. After 24 wk of treatment, no change was observed in body weight, fasting blood glucose (FBG), renal function and blood cells of these patients. Total symptom scores, ALT and triglyceride (TG) levels decreased more significantly in group A than in group B (P < 0.05). As expected, there was a tendency toward improvement in aspartate aminotransferase (AST), γ-glutamyltranspeptidase (GGT), and total cholesterol (TCHO) and high- density lipoprotein (HDL) cholesterol levels (P < 0.05) after administration in the two groups. However, no significant differences were found between the two groups. The values of low-density lipoprotein (LDL) were significantly improved in group A (P < 0.05), but no significant change was found in group B at different time points and after a 24-wk treatment. After treatment, complete fatty liver regression was observed in 19.70% (13/66) of the patients, and an overall reduction was found in 53.03% (35/66) of the patients in group A. In contrast, in group B, only f ive patients (7.35%, 5/68) achieved complete fatty liver regression (P = 0.04), whereas 24 patients (35.29%, 24/68) had a certain improvement in fatty liver (P = 0.04). No serious adverse events occurred in all the patients who completed the treatment. CONCLUSION: Our results indicate that n-3 PUFA from seal oils is safe and effi cacious for patients with NAFLD associated with hyperlipidemia and can improve their total symptom scores, ALT, serum lipid levels and normalization of ultrasonographic evidence. Further study is needed to confi rm these results.

Omega-3 polyunsaturated fatty acids promote liver regeneration after 90% hepatectomy in rats

AIM:To evaluate the effectiveness of omega-3 polyunsaturated fatty acid(ω-3 PUFA) administration on liver regeneration after 90% partial hepatectomy(PH) in rats.METHODS:ω-3 PUFAs were intravenously injected in the ω-3 PUFA group before PH surgery.PH,sparing only the caudate lobe,was performed in both the control and the ω-3 PUFA group.Survival rates,liver weight/body weight ratios,liver weights,HE staining,transmission electron microscope imaging,nuclearassociated antigen Ki-67,enzyme-linked immunosorbent assay and signal transduction were evaluated to analyze liver regeneration.RESULTS:All rats in the control group died within 30 h after hepatectomy.Survival rates in the ω-3 PUFA group were 20/20 at 30 h and 4/20 1 wk after PH.Liver weight/body weight ratios and liver weights increased significantly in the ω-3 PUFA group.The structure of sinusoidal endothelial cells and space of Disse was greatly restored in the ω-3 PUFA group compared to the control group after PH.In the ω-3 PUFA group,interleukin(IL)-4 and IL-10 levels were significantly increased whereas IL-6 and tumor necrosis factor-levels were dramatically decreased.In addition,activation of protein kinase B(Akt) and of signal transducer and activator of transcription 3 signaling pathway were identified at an earlier time after PH in the ω-3 PUFA group.CONCLUSION:Omega-3 polyunsaturated fatty acids may prevent acute liver failure and promote liver regeneration after 90% hepatectomy in rats.

Role of omega-3 polyunsaturated fatty acids,citrus pectin,and milk-derived exosomes on intestinal barrier integrity and immunity in animals

The gastrointestinal tract of livestock and poultry is prone to challenge by feedborne antigens,pathogens,and other stress factors in the farm environment.Excessive physiological inflammation and oxidative stress that arises firstly disrupts the intestinal epithelial barrier followed by other components of the gastrointestinal tract.In the present review,the interrelationship between intestinal barrier inflammation and oxidative stress that contributes to the pathogenesis of inflammatory bowel disease was described.Further,the role of naturally existing immunomodulatory nutrients such as the omega-3 polyunsaturated fatty acids,citrus pectin,and milk-derived exosomes in preventing intestinal barrier inflammation was discussed.Based on the existing evidence,the possible molecular mechanism of these bioactive nutrients in the intestinal barrier was outlined for application in animal diets.

Effects of dietary ratio of n-6 to n-3 polyunsaturated fatty acids on immunoglobulins, cytokines, fatty acid composition, and performance of lactating sows and suckling piglets

This experiment was conducted to investigate the effects of dietary ratios of n-6：n-3 polyunsaturated fatty acids （PUFA） on the performance of lactating sows and their piglets. Thirty pregnant Landrace sows were assigned to one of three treatments from d 108 of gestation until weaning （26-29 d） and were fed diets containing different ratios of n-6：n-3 PUFA including 3：1,9：1 and 13：1. The effects on sow and litter production traits were examined together with an assessment of sow body condition. No differences were detected among the treatments for the daily feed intake of sows or changes in sow weight and back-fat levels during lactation （P 〉 0.05）. Litter size at d 14 and d 21 were tended to increase in 3：1 treatment compared with 9：1 and 13：1 treatments （P 〈 0.10）. Litter weight gain （1.77 kg/d） from d 0 to d 14 was tended to increase in 9：1 groups compared with the other two treatments （P 〈 0.10）. A significant difference was observed for the content of a -linolenic acid, total n-3 PUFA, and the ratio of n-6：n-3 PUFA in the colostrum, milk, and piglets plasma （P 〈 0.01）. The effects of different ratios of n-6：n-3 PUFA in sow diets on colostrum, milk and piglet plasma immunoglobulin concentrations are studied. No difference was observed among treatments in the concentrations of IgM, and IgA in colostrum （P 〉 0.05）. A great significant difference for IgG concentration was observed among 3 group in colostrum. A great significant difference for IgA, and IgM （P〈 0.01） concentrations in piglet plasma at d14 and a significant difference for IgG（P 〈 0.05） was observed at d14. Furthermore, at d 21 of lactation, piglet plasma IgG and IgA concentration were greater in 3：1 compared with 13：1 group （P 〈 0.01）. In summary, the current study demonstrated that altering the ratio of n-6：n-3 PUFA in lactating sow diet had an effect on the immune component including immunoglobulin and cytokines, and it tended to increase the litter average daily gain and improve the immune status of piglets when dietary ratio of n-6：n-3 PUFA was 9：1.

Genetic Variants in the ELOVL5 but not ELOVL2 Gene Associated with Polyunsaturated Fatty Acids in Han Chinese Breast Milk

The present study was designed to examine the contributions of the fatty acid elongase （ELOVL） gene polymorphisms to the levels of polyunsaturated fatty acids （PUFAs） in breast milk. Two hundred and nine healthy Han Chinese mothers were included in the study. Carriers of minor alleles of SNPs （rs2397142 and rs9357760） in ELOVL5 were associated with higher levels of linoleic acid （LA）, dihomo-γ-linolenic acid （DGLA）, arachidonic acid （AA）, docosatetraenoic acid （DTA）, docosahexenoic acid （DHA）, while in rs209512 of ELOVL5 the carriers of minor alleles had lower levels of DTA compared to major homozygote alleles （P ranged from 0.004-0.046）, and genetically explained variability ranged from 3.2% for eicosapentaenoic acid （EPA） to 6.0% for LA. Our findings demonstrated that common variation in ELOVL5 gene encoding rate-limiting enzymes in the metabolism of PUFAs contribute to the PUFAs in breast milk.

Mathematical Modeling of the Oxidation of Polyunsaturated Fatty Acids in Emulsions with Stirring and Limited Oxygen Compensation

The oxidation of polyunsaturated fatty acids （PUFA） in emulsion with stirring and limited oxygen compensation was studied. A mathematical model of diffusion-oxidation was developed considering the mass transfer resistance of a gas-liquid boundary, the resistance of the boundary layer from the emulsifier membrane, and the autocatalytic-type autoxidation reaction of PUFA. The dynamic mass transfer coefficient of the emulsifier membrane, k0, was introduced. The model was verified by comparing the predictions of the model with the experi- mental data. The results indicated that the model was in good agreement with the oxygen diffusion and linoleic acid oxidation in the emulsion, and showed good applicability in the prediction of the effect of the emulsifier type on the oxidation of PUFA in the emulsion. It indicated that the oxidation of PUFA in emulsions, with stirring and limited oxygen compensation from the atmosphere, was controlled mostly by mass transfer resistance from the emulsifier membrane.

Effects of the Ratio of n-6∶n-3 Polyunsaturated Fatty Acids in the Maternal Diet on Immunoglobulins,Fatty Acid Composition,and Performance of Lactating Sows and Suckling Piglets under Conditions of Low Maternal Energy Intake

This experiment was conducted to investigate the effects of different ratios of n-6 ∶ n-3 polyunsaturated fatty acids （PUFA） in sow diets on the performance of lactating sows and their piglets at low digestible energy intakes. Twenty-one pregnant Landrace sows were assigned to one of three diets from day 108 of gestation until weaning （26 to 29 d） ,containing n-6∶n-3 PUFA ratios of 3 ∶1,8 ∶1 and 11 ∶1. The effects on sow and litter production traits and on sow body condition were examined. There were no differences among treatments in daily feed intakes or in changes in sow weight and back-fat levels during lactation. Litter size,litter weight at birth and weaning and litter average daily weight gain were also unaffected by treatment. As expected, large differences were observed in n-6 and n-3 fatty acids in the colostrum and plasma of sows and piglets （P 〈 0. 01） . The ratio of n6 ∶ n-3 PUFA the diet was positively correlated with those in colostrum,sow plasma and piglet plasma （R 2= 0. 55,0. 80 and 0. 80,respectively） . Sow plasma insulin and IGF-I levels at weaning were unaffected by the treatments. Plasma leptin （P 〈 0. 05） concentrations were increased in sows fed the diet with a n-6∶n-3 ratio of 8 ∶ 1. Immunoglobulin concentrations in colostrum were not altered by dietary treatment. Plasma IgG concentrations at d 14 were highest in piglets from sows fed the 8 ∶ 1 ratio of n-6∶n-3. Furthermore,this group had the highest IgA concentrations at day 21 of lactation compared with the other two groups （P 〈 0. 05） . In summary,our study demonstrated that at low digestible energy levels,altering the ratio of n-6 ∶ n-3 PUFA in the diets for lactating sows affected immune components and the fatty acid composition of lactating sows and their piglets. Further studies are needed to examine whether higher levels of fat supplementation than those used in the present study （1. 5%） can successfully enhance performance.

Polyunsaturated fatty acids and DNA methylation in colorectal cancer

Colorectal cancer(CRC) has been designated a major global problem, especially due to its high prevalence in developed countries. CRC mostly occurs sporadically(75%-80%), and only 20%-25% of patients have a family history.Several processes are involved in the development of CRC such as a combination of genetic and epigenetic alterations. Epigenetic changes, including DNA methylation play a vital role in the progression of CRC. Complex interactions between susceptibility genes and environmental factors, such as a diet and sedentary lifestyle, lead to the development of CRC. Clinical and experimental studies have confirmed the beneficial effects of dietary polyunsaturated fatty acids(PUFAs) in preventing CRC. From a mechanistic viewpoint, it has been suggested that PUFAs are pleiotropic agents that alter chromatin remodeling,membrane structure and downstream cell signaling. Moreover, PUFAs can alter the epigenome via modulation of DNA methylation. In this review, we summarize recent investigations linking PUFAs and DNA methylationassociated CRC risk.

Challenges in enriching milk fat with polyunsaturated fatty acids

Milk fatty acid composition is determined by several factors including diet. The milk fatty acid profile of dairy cows is low in polyunsaturated fatty acids, especially those of the n-3 series. Efforts to change and influence fatty acid profile with longer chain polyunsaturated fatty acids have proven challenging. Several barriers prevent easy transfer of dietary polyunsaturated fatty acids to milk fat including rumen biohydrogenation and fatty acid esterification. The potential for cellular uptake and differences in fatty acid incorporation into milk fat might also have an effect, though this has received less research effort. Given physiological impediments to enriching milk fat with polyunsaturated fatty acids, manipulating the genome of the cow might provide a greater increase than diet alone, but this too may be challenged by the physiology of the cow.

The Global Research Progress of Enzymatic Processing of Oils with Omega 3 Polyunsaturated Fatty Acids

This paper has reviewed that Omega 3 polyunsaturated fatty acids (PUFAs), as an essential fatty acids (EFAs), mainly come from fish oil of marine products, has positive effects on treatment and/or prevention of several diseases. In this review, the recent developments by 2019 in the field of enzymatic modification of oils rich in omega 3 PUFAs have summarized. Several different products, such as structured lipids with a variety of FA compositions, nutritional aspects, omega 3 PUFA concentrates and phospholipids,have discussed from the point of process technology as well as possible applications. Enhancing omega 3 PUFA content in diet involves a number of strategies aiming to modify the content of such FAs in fats and oils. Due to the mild reaction conditions used, especially the lipase specificity, the position as well as content of omega 3 PUFAs in lipid molecules being of importance from the point of bioavailability, enzymatic processing of omega 3 PUFA oil is safe, efficient and preferred over chemical treatments.

Combined Effects of Plant Sterols with Low Ratio of n-6/n-3 Polyunsaturated Fatty Acids against Atherosclerosis in ApoE–/–Mice

The effects of low ratio of n-6/n-3 polyunsaturated fatty acids(PUFA)have been clarified against atherosclerosis.Increasing evidence indicated that plant sterols(PS)have a significant cholesterol-lowering effect.This study explored the effects of PS combined with n-6/n-3(2:1)PUFA on atherosclerosis and investigated the possible mechanism.In ApoE−/−mice,the milk fat in high fat diets was replaced with n-6/n-3(2:1)PUFA alone or supplemented with 6%PS for 16 weeks.Results demonstrated that PS combined with PUFA exerted commentary and synergistic effects on ameliorating atherosclerosis,improving lipid metabolism and lipid deposition in liver,and alleviating inflammatory response.These changes were accompanied with decreased serum TC,TG,LDL-C and increased fecal cholesterol efflux,as well as the lower inflammatory cytokine CRP,IL-6,TNF-α.It is suggested that the underlying mechanism of PS combined with n-6/n-3(2:1)PUFA promoting the fecal cholesterol efflux may be mediated by liver X receptorα/ATP-binding cassette transporter A1 pathway.

Association of n3 and n6 polyunsaturated fatty acids in red blood cell membrane and plasma with severity of normal tension glaucoma

AIM: To determine whether red blood cell(RBC)membrane and plasma lipids, particularly long-chain polyunsaturated fatty acids such as eicosapentaenoic acid(EPA), docosahexaenoic acid(DHA), arachidonic acid(AA) are significantly correlated with severity of normal tension glaucoma(NTG).METHODS: This study included 35 patients with NTG and 12 healthy normal control subjects, matched for age and sex with the study group. The stage of glaucoma was determined according to the Hodapp-Parrish-Anderson classification. Lipids were extracted from RBC membranes and plasma, and fatty acid methyl esters prepared and analyzed by gas chromatography-mass spectrometry(GC-MS).RESULTS: When RBC lipids were analyzed, the levels of EPA, the levels of DHA and the ratio of n3 to n6 were positively associated with the Humphrey Perimetry mean Deviation(MD) score(r =0.617, P 【0.001; r =0.727, P 【0.001 and r =0.720, P 【0.001, respectively), while the level of AA was negatively associated with the MD score(r =-0.427, P =0.001). When plasma lipids were analyzed,there was a significant positive relationship between the levels of EPA and the MD score(r =0.648, P 【0.001), and the levels of AA were inversely correlated with the MD score(r =-0.638, P 【0.001). CONCLUSION: The levels of n3 and n6 polyunsaturated fatty acids in RBC membrane and plasma lipids were associated with severity of NTG.

GhATL68b regulates cotton fiber cell development by ubiquitinating the enzyme required for β-oxidation of polyunsaturated fatty acids

E3 ligases are key enzymes required for protein degradation.Here,we identified a C3H2C3 RING domaincontaining E3 ubiquitin ligase gene named GhATL68b.It is preferentially and highly expressed in developing cotton fiber cells and shows greater conservation in plants than in animals or archaea.The four orthologous copies of this gene in various diploid cottons and eight in the allotetraploid G.hirsutum were found to have originated from a single common ancestor that can be traced back to Chlamydomonas reinhardtii at about 992 million years ago.Structural variations in the GhATL68b promoter regions of G.hirsutum,G.herbaceum,G.arboreum,and G.raimondii are correlated with significantly different methylation patterns.Homozygous CRISPR-Cas9 knockout cotton lines exhibit significant reductions in fiber quality traits,including upper-half mean length,elongation at break,uniformity,and mature fiber weight.In vitro ubiquitination and cell-free protein degradation assays revealed that GhATL68b modulates the homeostasis of 2,4-dienoyl-CoA reductase,a rate-limiting enzyme for theβ-oxidation of polyunsaturated fatty acids(PUFAs),via the ubiquitin proteasome pathway.Fiber cells harvested from these knockout mutants contain significantly lower levels of PUFAs important for production of glycerophospholipids and regulation of plasma membrane fluidity.The fiber growth defects of the mutant can be fully rescued by the addition of linolenic acid(C18:3),the most abundant type of PUFA,to the ovule culture medium.This experimentally characterized C3H2C3 type E3 ubiquitin ligase involved in regulating fiber cell elongation may provide us with a new genetic target for improved cotton lint production.

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

Background and Aims: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.Methods:In this singlecenter 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.Results: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).Conclusions:A low level of n-3 PUFAs was associated with sarcopenia in patients with liver cirrhosis and HCC.

Meldonium-induced steatosis is associated with increased delta 6 desaturation and reduced elongation of n-6 polyunsaturated fatty acids

Background and objective Metabolic associated fatty liver disease(MAFLD)is associated with abnormal lipid metabolism.Mitochondrial dysfunction is considered an important factor in the onset of MAFLD,whereas altered fatty acid composition has been linked to the severity of the disease.Tetradecylthioacetic acid(TTA),shown to induce mitochondrial proliferation and alter the fatty acid composition,was used to delay the accumulation of hepatic triacylglycerol.This study aimed to evaluate how impaired mitochondrial fatty acid beta-oxidation affects fatty acid composition by incorporating meldonium into a high-carbohydrate diet.Methods C57BL/6 mice(n=40)were fed high-carbohydrate diets supplemented with meldonium,TTA,or a combination of meldonium and TTA for 21 days.Lipid levels were determined in liver samples,and fatty acid composition was measured in both liver and plasma samples.Additionally,desaturase and elongase activities were estimated.The hepatic activities and gene expression levels of enzymes involved in fatty acid metabolism were measured in liver samples,whereas carnitines,their precursors,and acylcarnitines were measured in plasma samples.Results The meldonium-induced depletion of L-carnitine and mitochondrial fatty acid oxidation was confirmed by reduced plasma levels of L-carnitine and acylcarnitines.Principal component analyses of the hepatic fatty acid composition revealed clustering dependent on meldonium and TTA.The meldonium-induced increase in hepatic triacylglycerol levels correlated negatively with estimated activities of elongases and was associated with higher estimated activities of delta-6 desaturase(D6D;C18:4n-3/C18:3n-3 and C18:3n-6/C18:2n-6),and increased circulating levels of C18:4n-3 and C18:3n-6(gamma-linolenic acid).TTA mitigated meldonium-induced triacylglycerol levels by 80%and attenuated the estimated D6D activities,and elongation of n-6 polyunsaturated fatty acids(PUFAs).TTA also attenuated the meldonium-mediated reduction of C24:1n-9(nervonic acid),possibly by stimulating Elovl5 and increased elongation of erucic acid(C22:1n-9)to nervonic acid.The hepatic levels of nervonic acid and the estimated activity of n-6 PUFA elongation correlated negatively with the hepatic triacylglycerol levels,while the estimated activities of D6D correlated positively.Conclusion Circulating levels of gamma-linolenic acid,along with reduced estimated elongation of n-6 PUFAs and D6D desaturation activities,were associated with hepatic triacylglycerol levels.

Azacarbazole n-3 and n-6 polyunsaturated fatty acids ethyl esters nanoemulsion with enhanced efficacy against Plasmodium falciparum

Alternative therapies are necessary for the treatment of malaria due to emerging drug resistance.However,many promising antimalarial compounds have poor water solubility and suffer from the lack of suitable delivery systems,which seriously limits their activity.To address this problem,we synthesized a series of azacarbazoles that were evaluated for antimalarial activity against D10(chloroquine-sensitive)and W2(chloroquine-resistant)strains of P.falciparum.The most active compound,9H-3-azacarbazole(3),was encapsulated in a novel o/w nanoemulsion consisting of ethyl esters of polyunsaturated fatty acids n-3 and n-6 obtained from flax oil as the oil phase,Smix(Tween 80 and Transcutol HP)and water.This formulation was further analyzed using transmission electron microscopy,dynamic light scattering and in vitro and in vivo studies.It was shown that droplets of the 3-loaded nanosystem were spherical,with satisfactory stability,without cytotoxicity towards fibroblasts and intestinal cell lines at concentrations corresponding to twice the IC50 for P.falciparum.Moreover,the nanoemulsion with this type of oil phase was internalized by Caco-2 cells.Additionally,pharmacokinetics demonstrated rapid absorption of compound 3(tmax=5.0 min)after intragastric administration of 3-encapsulated nanoemulsion at a dose of 0.02 mg/kg in mice,with penetration of compound 3 to deep compartments.The 3-encapsulated nanoemulsion was found to be 2.8 and 4.2 times more effective in inhibiting the D10 and W2 strains of the parasite,respectively,compared to non-encapsulated 3.Our findings support a role for novel o/w nanoemulsions as delivery vehicles for antimalarial drugs.