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Cyanobacteria have great potential in CO2-based bio-manufacturing and synthetic biological studies. The filamentous cyanobacterium, Leptolyngbya sp. strain BL0902, is comparable to Arthrospira (Spirulina) platensis in commercial-scale cultivation while proving to be more genetically tractable. Here, we report the analyses of the whole genome sequence, gene inactivation/overexpression in the chromosome and deletion of non-essential chromosomal regions in this strain. The genetic manipulations were performed via homologous double recombination using either an antibiotic resistance marker or the CRISPR/Cpf1 editing system for positive selection. A desD-overexpressing strain produced γ-linolenic acid in an open raceway photobioreactor with the productivity of 0.36 g·m-2·d-1. Deletion mutants of predicted patX and hetR, two genes with opposite effects on cell differentiation in heterocyst-forming species, were used to demonstrate an analysis of the relationship between regulatory genes in the non-heterocystous species. Furthermore, a 50.8-kb chromosomal region was successfully deleted in BL0902 with the Cpf1 system. These results supported that BL0902 can be developed into a stable photosynthetic cell factory for synthesizing high value-added products, or used as a model strain for investigating the functions of genes that are unique to filamentous cyanobacteria, and could be systematically modified into a genome-streamlined chassis for synthetic biological purposes.
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Previously, we constructed engineered M. circinelloides strains that can not only utilize cellulose, but also increase the yield of γ-linolenic acid (GLA). In the present study, an in-depth analysis of lipid accumulation by engineered M. circinelloides strains using corn straw was to be explored. When a two-stage temperature control strategy was adopted with adding 1.5% cellulase and 15% inoculum, the engineered strains led to increases in the lipid yield (up to 1.56 g per 100 g dry medium) and GLA yield (up to 274 mg per 100 g dry medium) of 1.8- and 2.3-fold, respectively, compared with the control strain. This study proved the engineered M. circinelloides strains, especially for Mc-C2PD6, possess advantages in using corn straw to produce GLA. This work provided a reference for transformation from agricultural cellulosic waste to functional lipid in one step, which might play a positive role in promoting the sustainable development of biological industry.
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Celulosa 1,4-beta-Celobiosidasa , Fermentación , Mucor , Zea mays , Zea mays/metabolismo , Mucor/genética , Mucor/metabolismo , Mucor/enzimología , Celulosa 1,4-beta-Celobiosidasa/metabolismo , Celulosa 1,4-beta-Celobiosidasa/genética , Ácido gammalinolénico/metabolismo , Lípidos/biosíntesis , Ácido Graso Desaturasas/metabolismo , Ácido Graso Desaturasas/genética , Celulosa/metabolismo , Ingeniería Metabólica/métodos , Metabolismo de los LípidosRESUMEN
Long-chain polyunsaturated fatty acids (LCPUFAs) are essential for both fetal and placental development. We characterized the FA composition and gene expression levels of FA-metabolizing enzymes in rabbit placentas. Total FA compositions from term rabbit placentas (n = 7), livers, and plasma (both n = 4) were examined: among LCPUFAs with more than three double bonds, dihomo-γ-linolenic acid (DGLA) was the most abundant (11.4 ± 0.69 %, mean ± SE), while arachidonic acid was the second-most rich component (6.90 ± 0.56 %). DGLA was barely detectable (<1 %) in livers and plasma from term rabbits, which was significantly lower than in placentas (both p < 0.0001). Compared with the liver, transcript levels of the LCPUFA-metabolizing enzymes FADS2 and ELOVL5 were 7- and 4.5-fold higher in placentas (both p < 0.05), but levels of FADS1 and ELOVL2 were significantly lower (both p < 0.01). Our results suggest a placenta-specific enzyme expression pattern and LCPUFA profile in term rabbits, which may support a healthy pregnancy.
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Ácido 8,11,14-Eicosatrienoico , delta-5 Desaturasa de Ácido Graso , Ácido Graso Desaturasas , Placenta , Animales , Conejos , Femenino , Ácido Graso Desaturasas/metabolismo , Ácido Graso Desaturasas/genética , Embarazo , Placenta/metabolismo , Ácido 8,11,14-Eicosatrienoico/metabolismo , Elongasas de Ácidos Grasos/metabolismo , Elongasas de Ácidos Grasos/genética , Hígado/metabolismo , Ácido Araquidónico/metabolismo , Acetiltransferasas/metabolismo , Acetiltransferasas/genéticaRESUMEN
Ozone (O3) is a major air pollutant that directly threatens the respiratory system, lung fatty acid metabolism disorder is an important molecular event in pulmonary inflammatory diseases. Liver kinase B1 (LKB1) and nucleotide-binding domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome not only regulate inflammation, but also have close relationship with fatty acid metabolism. However, the role and mechanism of LKB1 and NLRP3 inflammasome in lung fatty acid metabolism, which may contribute to ozone-induced lung inflammation, remain unclear, and effective strategy for preventing O3-induced pulmonary inflammatory injury is lacking. To explore these, mice were exposed to 1.00 ppm O3 (3 h/d, 5 days), and pulmonary inflammation was determined by airway hyperresponsiveness, histopathological examination, total cells and cytokines in bronchoalveolar lavage fluid (BALF). Targeted fatty acids metabolomics was used to detect medium and long fatty acid in lung tissue. Then, using LKB1-overexpressing adenovirus and NLRP3 knockout (NLRP3-/-) mice to explore the mechanism of O3-induced lung fatty acid metabolism disorder. Results demonstrated that O3 exposure caused pulmonary inflammatory injury and lung medium and long chain fatty acids metabolism disorder, especially decreased dihomo-γ-linolenic acid (DGLA). Meanwhile, LKB1 expression was decreased, and NLRP3 inflammasome was activated in lung of mice after O3 exposure. Additionally, LKB1 overexpression alleviated O3-induced lung inflammation and inhibited the activation of NLRP3 inflammasome. And we found that pulmonary fatty acid metabolism disorder was ameliorated of NLRP3 -/- mice compared with those in wide type mice after O3 exposure. Furthermore, administrating DGLA intratracheally prior to O3 exposure significantly attenuated O3-induced pulmonary inflammatory injury. Taken together, these findings suggest that fatty acids metabolism disorder is involved in O3-induced pulmonary inflammation, which is regulated by LKB1-mediated NLRP3 pathway, DGLA supplement could be a useful preventive strategy to ameliorate ozone-associated lung inflammatory injury.
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Ácidos Grasos , Proteína con Dominio Pirina 3 de la Familia NLR , Ozono , Animales , Ratones , Ácidos Grasos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Neumonía/metabolismo , Neumonía/prevención & control , Contaminantes Atmosféricos/toxicidad , Pulmón/metabolismo , Pulmón/efectos de los fármacos , Pulmón/patología , Inflamasomas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismoRESUMEN
BACKGROUND & AIMS: Some ω3 polyunsaturated fatty acids (PUFAs) are said to demonstrate a dose-related risk of atrial fibrillation (AF), conversely, some ω6 PUFAs might have AF protective potential. However, few investigated the relation among ischemic strokes. Primarily, we aimed to examine a relation between ω3 and ω6 PUFAs and the presence of AF in ischemic strokes. Further, since, some PUFAs are said to affect the cardiac load, we secondarily aimed to investigate the association between ω3 and ω6 PUFAs and brain natriuretic peptide (BNP) and the occurrence of cerebral large vessel occlusion (LVO) in ischemic strokes with AF. METHODS: Consecutive patients with ischemic stroke admitted between 2012 and 2022 were retrospectively screened. Plasma levels of PUFAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid, dihomo-γ-linolenic acid (DGLA) and arachidonic acid (AA), were assayed. Data were analyzed using a Poisson regression analysis with a robust variance estimator and a multiple linear regression analysis. RESULTS: We screened 2112 consecutive ischemic strokes, including 1574 (1119 [71%] males, median age 69 years). Lower DGLA (prevalence ratio (PR) 0.885, 95% CI 0.811-0.966, p = 0.006), lower AA (PR 0.797, 95% CI 0.649-0.978, p = 0.030), and higher EPA/AA ratio (PR 1.353, 95% CI 1.036-1.767, p = 0.026) were associated with AF. Checking the linearity between AF and PUFAs, negative linear trends were observed between DGLA quartiles (Q1: PR 1.901, Q2: PR 1.550, Q3: PR 1.423, Q4: 1.000, p < 0.001 for trend) and AA quartiles (Q1: PR 1.499, Q2: PR 1.204, Q3: PR 1.125, Q4: 1.000, p = 0.004 for trend), with positive linear trends between EPA/AA ratio quartiles (Q1: 1.000, Q2: PR 1.555, Q3: PR 1.612, Q4: PR 1.797, p = 0.001 for trend). Among patients with AF, a negative association between AA and BNP (unstandardized coefficient -1.316, 95% CI -2.290â¼-0.342, p = 0.008) was observed, and lower AA was associated with LVO (PR 0.707, 95% CI 0.527-0.950, p = 0.021). CONCLUSION: Lower DGLA and AA and a higher EPA/AA ratio might be related to the development of AF in ischemic strokes. Further, AA might have a cardio-cerebrovascular protective role in ischemic strokes with AF.
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Fibrilación Atrial , Ácidos Grasos Omega-3 , Ácidos Grasos Omega-6 , Accidente Cerebrovascular Isquémico , Humanos , Masculino , Femenino , Anciano , Fibrilación Atrial/sangre , Fibrilación Atrial/complicaciones , Ácidos Grasos Omega-3/sangre , Accidente Cerebrovascular Isquémico/sangre , Accidente Cerebrovascular Isquémico/epidemiología , Accidente Cerebrovascular Isquémico/etiología , Estudios Retrospectivos , Ácidos Grasos Omega-6/sangre , Persona de Mediana Edad , Anciano de 80 o más Años , Péptido Natriurético Encefálico/sangre , Isquemia Encefálica/sangre , Isquemia Encefálica/epidemiología , Isquemia Encefálica/etiología , Factores de RiesgoRESUMEN
Fatty acid desaturase 1 (FADS1) is a rate-limiting enzyme in long-chain polyunsaturated fatty acid (LCPUFA) synthesis. Reduced activity of FADS1 was observed in metabolic dysfunction-associated steatotic liver disease (MASLD). The aim of this study was to determine whether adeno-associated virus serotype 8 (AAV8) mediated hepatocyte-specific overexpression of Fads1 (AAV8-Fads1) attenuates western diet-induced metabolic phenotypes in a rat model. Male weanling Sprague-Dawley rats were fed with a chow diet, or low-fat high-fructose (LFHFr) or high-fat high-fructose diet (HFHFr) ad libitum for 8 weeks. Metabolic phenotypes were evaluated at the endpoint. AAV8-Fads1 injection restored hepatic FADS1 protein levels in both LFHFr and HFHFr-fed rats. While AAV8-Fads1 injection led to improved glucose tolerance and insulin signaling in LFHFr-fed rats, it significantly reduced plasma triglyceride (by ~50%) and hepatic cholesterol levels (by ~25%) in HFHFr-fed rats. Hepatic lipidomics analysis showed that FADS1 activity was rescued by AAV8-FADS1 in HFHFr-fed rats, as shown by the restored arachidonic acid (AA)/dihomo-γ-linolenic acid (DGLA) ratio, and that was associated with reduced monounsaturated fatty acid (MUFA). Our data suggest that the beneficial role of AAV8-Fads1 is likely mediated by the inhibition of fatty acid re-esterification. FADS1 is a promising therapeutic target for MASLD in a diet-dependent manner.
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delta-5 Desaturasa de Ácido Graso , Dieta Occidental , Ácido Graso Desaturasas , Hepatocitos , Animales , Masculino , Ratas , delta-5 Desaturasa de Ácido Graso/metabolismo , Dependovirus/genética , Dieta Occidental/efectos adversos , Modelos Animales de Enfermedad , Ácido Graso Desaturasas/metabolismo , Ácido Graso Desaturasas/genética , Fructosa/metabolismo , Hepatocitos/metabolismo , Hígado/metabolismo , Fenotipo , Ratas Sprague-Dawley , Triglicéridos/metabolismoRESUMEN
Patatin-like phospholipase domain-containing 1 (PNPLA1) is crucial in the esterification of linoleic acid (LA; 18:2n-6) to ω-hydroxy fatty acids (FA) of ceramide 1 (Cer1), the major barrier lipid of the differentiated epidermis. We previously reported that γ-linolenic acid (GLA; 18:3n-6) as well as LA is esterified to Cer1 subspecies with sphingosine (d18:1) or eicosasphingosine (d20:1) amide-linked to two different ω-hydroxy FA (30wh:0; 32wh:1). Here, we further investigated whether PNPLA1 is also responsible for esterification of GLA to these Cer1 subspecies in normal human keratinocytes (NHK). As late/terminal differentiation was induced in NHK, PNPLA1 and differentiation markers were expressed, and LA-esterified Cer1 subspecies (18:2n-6/C30wh:0 or C32wh:0/d18:1; 18:2n-6/C32wh:0/d20:1) were detected, which were further increased with LA treatment. GLA-esterified Cer1 subspecies (18:3n-6/C30wh:0 or C32wh:0/d18:1; 18:3n-6/C32wh:0/d20:1) were detected only with GLA treatment. Specific small interfering RNA-mediated knockdown of PNPLA1 (KDP) in differentiated NHK decreased levels of these LA-esterified Cer1 subspecies overall and of involucrin (IVL), a terminal differentiation marker. Moreover, KDP resulted in lesser LA/GLA responses as characterized by more significant decreases in IVL and LA/GLA-esterified Cer1 subspecies overall and an accumulation of non-esterified ω-hydroxy ceramides, their putative precursors; the decrease of 18:3n-6/C32wh:0/d18:1, the predominant GLA-esterified Cer1 subspecies, specifically paralleled the increase of C32wh:0/d18:1, its corresponding precursor. PNPLA1 is responsible for NHK terminal differentiation and also for esterification of GLA to the ω-hydroxy FA of Cer1.
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Queratinocitos , Ácido gammalinolénico , Humanos , Ácido gammalinolénico/metabolismo , Esterificación , Epidermis/metabolismo , Ceramidas/metabolismo , Ácidos Grasos/metabolismo , Ácido Linoleico/metabolismo , Aciltransferasas/metabolismo , Fosfolipasas/metabolismoRESUMEN
The modulatory role of primrose oil (PO) supplementation enriched with γ-linolenic acid and D/L-alpha tocopherol acetate against a carbon tetrachloride (CCl4)-induced liver damage model was assessed in this study. Twenty male Albino rats were divided into four groups. The control group received corn oil orally. The PO group received 10 mg/kg P O orally. The CCl4 group received 2 mL/kg CCl4 orally and PO/CCl4 group; received PO and 2 mL/kg CCl4 orally. The relative liver weight was recorded. Serum liver enzymes, hepatic malondialdehyde (MDA), hepatic reduced glutathione (GSH) and the expression of hepatic tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6) were assessed. The binding affinities of γ-linolenic acid and D/L-alpha tocopherol constituents with IL-1ß, IL-6 and TNF-α were investigated using molecular docking simulations. Histopathological and electron microscopic examinations of the liver were performed. The results indicated that CCl4 elevated serum liver enzyme and hepatic MDA levels, whereas GSH levels were diminished. The upregulation of IL-1ß, IL-6, and TNF-α gene expressions were induced by CCl4 treatment. The PO/CCl4-treated group showed amelioration of hepatic injury biomarkers and oxidative stress. Restoration of histopathological and ultrastructural alterations while downregulations the gene expressions of TNF-α, IL1-ß and IL-6 were observed. In conclusion, evening primrose oil enriched with γ-linolenic acid and D/L-alpha tocopherol acetate elicited a potential amelioration of CCl4-induced hepatic toxicity.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Hígado , Oenothera biennis , Aceites de Plantas , Ácido gammalinolénico , Animales , Masculino , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Aceites de Plantas/farmacología , Aceites de Plantas/química , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Hígado/ultraestructura , Ácido gammalinolénico/farmacología , Oenothera biennis/química , Interleucina-1beta/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Estrés Oxidativo/efectos de los fármacos , Simulación del Acoplamiento Molecular , Tetracloruro de Carbono/toxicidad , Interleucina-6/metabolismo , Ratas , Ácidos Linoleicos/farmacología , Antioxidantes/farmacología , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
In the last few years, there has been a growing interest in the more efficient utilization of agricultural and food by-products. Apples are among the most processed fruits in the world that generate huge quantities of processing waste biomasses. Therefore, the objective of this study was to improve the nutritional value of apple pomaces with γ-linolenic acid (GLA) and carotenoid pigments by solid-state fermentation (SSF) using two Zygomycetes fungi (Actinomucor elegans and Umbelopsis isabellina). The impact of fermentation periods on the polyphenol content and antioxidant capacity of the bioprocessed apple pomace was also investigated. The accumulated lipids were composed primarily of neutral fractions (mostly triacylglycerols). SSF with U. isabellina yielded a 12.72% higher GLA content than with A. elegans (3.85 g GLA/kg DW of pomace). Contrary to the lipogenic capacity, A. elegans showed higher carotenoids and phenolic antioxidants productivity than U. isabellina. The maximum concentrations for ß-carotene (433.11 µg/g DW of pomace-SSF with A. elegans and 237.68 µg/g DW of pomace-SSF with U. isabellina), lutein (374.48 µg/g DW- A. elegans and 179.04 µg/g DW- U. isabellina) and zeaxanthin (247.35 µg/g DW- A. elegans and 120.41 µg/g DW- U. isabellina) were registered on the 12th day of SSFs. In the case of SSF with A. elegans, the amount of total phenolics increased significantly (27%) by day 4 from the initial value (2670.38 µg of gallic acid equivalents/g DW) before slowly decreasing for the remaining period of the fungal growth. The experimental findings showed that a prolonged fermentation (between 8 and 12 days) should be applied to obtain value-added apple pomaces (rich in GLA and carotenoids) with potential pharmaceutical and functional food applications. Moreover, the SSF processes of simultaneous bioaccumulation of valuable fatty acids, carotenoids and phenolic antioxidants proposed in the present study may open up new challenges for biotechnological production of industrially important biomolecules using abundant and unexploited apple pomaces.
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Antioxidantes , Malus , Antioxidantes/metabolismo , Malus/metabolismo , Ácido gammalinolénico , Fermentación , Biofortificación , Carotenoides , FenolesRESUMEN
γ-Linolenic acid-enriched galactosyldiacylglycerols (GDGs-GLA), as the natural form of γ-linolenic acid in microalgae, have a range of functional activities, including anti-inflammatory, antioxidant, and anti-allergic properties. The low abundance of microalgae and the structural stereoselectivity complexity impede microalgae extraction or chemical synthesis, resulting in a lack of supply of GDGs-GLA with a growing demand. At present, there is a growing interest in engineering oleaginous yeasts for mass production of GDGs-GLA based on their ability to utilize a variety of hydrophobic substrates and a high metabolic flux toward fatty acid and lipid (triacylglycerol, TAG) production. Here, we first introduce the GDGs-GLA biosynthetic pathway in microalgae and challenges in the engineering of the native host. Subsequently, we describe in detail the applications of oleaginous yeasts with Yarrowia lipolytica as the representative for GDGs-GLA biosynthesis, including the development of synthetic biology parts, gene editing tools, and metabolic engineering of lipid biosynthesis. Finally, we discuss the development trend of GDGs-GLA biosynthesis in Y. lipolytica.
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Dihomo-γ-linolenic acid (DGLA) is an n-6 polyunsaturated fatty acid that has been shown to have anti-inflammatory and anti-allergic effects in mice and cell study. To date, however, no human intervention study has examined the effects of DGLA. Therefore, we investigated the effects of DGLA on pollen-induced allergic symptoms in healthy adults. We performed a randomized, double-blind, placebo-controlled, parallel-group study comprising healthy Japanese men and women. Each subject received four 250 mg capsules providing 314 mg DGLA/day (DGLA group, n = 18) or olive oil (placebo group, n = 15) for 15 weeks. The primary outcomes, classification of the severity of allergic rhinitis symptoms (CSARS), and the Japanese Rhino-conjunctivitis Quality of Life Questionnaire (JRQLQ) served as symptom scores during the pollen season. In the DGLA group, the cedar pollen associated symptoms of sneezing and a blocked nose in the CSARS were significantly lower than those in the placebo group (p < 0.05, p < 0.01, respectively). Significant trends were observed the symptoms of runny nose in the CSARS and total symptom score (TSS) in the JRQLQ for cedar pollen (p < 0.1). To our knowledge, this is the first study to report the effects of DGLA in humans, and the results suggest that DGLA is effective in reducing allergic symptoms caused by pollen.
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Atherosclerosis is associated with various cardiovascular diseases (CVDs). Measurement of arterial stiffness using pulse wave velocity (PWV) enables assessment of atherosclerosis progression in individuals. The authors screened patients with asymptomatic atherosclerosis, based on the PWV findings, to evaluate appropriate early interventions and assess the efficacy of γ-linolenic acid, Vitis vinifera extract, and acetyl-L-carnitine triple combination therapy in atherosclerosis prevention. This retrospective study analyzed the medical records of adult patients between March 2007 and April 2019, with presenting complaints of fatigue and lethargy. Among patients with vascular stiffness beyond their biological age on brachial-ankle PWV (baPWV) testing, those with ≥80% compliance for three drugs were allocated to the experimental group. Those with compliance of <80% for any one drug were allocated to the control group to assess changes in arterial stiffness, fasting plasma glucose (FPG), lipid level, and blood pressure (BP). After 1 year of triple-combination therapy, there were significant decreases in right and left baPWV (1537.16 ± 274.84 and 1519.00 ± 289.32 cm/s, respectively) as compared to baseline (1633.15 ± 271. 20 and 1598.64 ± 267.95 cm/s, respectively; p < .001). There was no difference in baPWV between sexes. Moreover, neither group showed significant changes in FPG and lipid levels. When triple-combination therapy combining γ-linolenic acid, V. vinifera extract, and acetyl-L-carnitine was administered to patients with high arterial stiffness relative to their age, as assessed by baPWV, the experimental group showed a decrease in arterial stiffness in both sexes.
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Aterosclerosis , Hipertensión , Rigidez Vascular , Vitis , Femenino , Masculino , Humanos , Adulto , Acetilcarnitina , Ácido gammalinolénico/uso terapéutico , Análisis de la Onda del Pulso , Estudios Retrospectivos , Extractos Vegetales/uso terapéutico , República de Corea/epidemiologíaRESUMEN
As the Greek-style yogurt market continues to experience prosperous growth, finding the most appropriate destination for yogurt acid whey (YAW) is still a challenge for Greek yogurt manufacturers. This study provides a direct alternative treatment of YAW by leveraging the abilities of Mucor circinelloides and Mucor genevensis to raise the pH of YAW and to produce fungal biomass with a high lipid content. Aerobic cultivations of these species were conducted in YAW, both with and without the addition of lactase, at 30 °C, and 200 rpm agitation. The density, pH, biochemical oxygen demand (BOD), biomass production, lipid content, fatty acid profile, and sugar and lactic acid concentrations were regularly measured throughout the 14-day cultivations. The data showed that M. genevensis was superior at deacidifying YAW to a pH above 6.0-the legal limit for disposing of cultured dairy waste. On the other hand, M. circinelloides generated more fungal biomass, containing up to 30% w/w of lipid with high proportions of oleic acid and γ-linolenic acid. Additionally, the treatments with lactase addition showed a significant decrease in the BOD. In conclusion, our results present a viable treatment to increase the pH of YAW and decrease its BOD, meanwhile generating fungal oils that can be further transformed into biodiesel or processed into functional foods or dietary supplements.
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The physiological activity of γ-linolenic acid (GLA)-rich evening primrose oil and eicosapentaenoic and doxosahexaenoic acids-rich fish oil, which affect hepatic fatty acid oxidation and synthesis, and adipose tissue mRNA expression were compared in diabetic obese KK-A y mice. The mice were fed diets containing 100 g/kg of either palm oil (saturated fat), GLA oil, or fish oil for 21 days. These oils, compared with palm oil, greatly increased the activity and mRNA levels of hepatic fatty acid oxidation enzymes. These oils also increased the carnitine concentrations and mRNA levels of carnitine transporter (solute carrier family 22, member 5) in the liver. In general, these effects were comparable between GLA and fish oils. In contrast, GLA and fish oils, compared with palm oil, reduced the activity and mRNA levels of the proteins related to hepatic lipogenesis, except for those of malic enzyme. The reducing effect was stronger for fish oil than for GLA oil. These changes were accompanied by reductions in the triacylglycerol levels in the serum and liver. The reduction in the liver was stronger for fish oil than for GLA oil. These oils also reduced epididymal adipose tissue weight accompanied by a reduction in the mRNA levels of several proteins that regulate adipocyte functions; these effects were stronger for fish oil than for GLA oil. These oils were also effective in reducing serum glucose levels. Therefore, both fish oil and GLA-rich oil were effective at ameliorating metabolic disorders related to obesity and diabetes mellitus.
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Aceites de Pescado , Lipogénesis , Animales , Ratones , Tejido Adiposo , Carnitina , Aceites de Pescado/farmacología , Ácido gammalinolénico/farmacología , Lipogénesis/genética , Hígado , Aceite de Palma , ARN Mensajero/genéticaRESUMEN
Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome. Non-resolving inflammation, triggered by sustained accumulation of lipids, is an important driving force of NASH. Thus, unveiling metabolic immune regulation could help better understand the pathology and intervention of NASH. In this study, we found the recruitment of neutrophils is an early inflammatory event in NASH mice, following the formation of neutrophil extracellular traps (NETs). NET is an initiating factor which exacerbates inflammatory responses in macrophages. Inhibition of NETs using DNase I significantly alleviated inflammation in NASH mice. We further carried out a metabolomic study to identify possible metabolic triggers of NETs, and linoleic acid (LA) metabolic pathway was the most altered pathway. We re-analyzed published clinical data and validated that LA metabolism was highly correlated with NASH. Consistently, both LA and γ-linolenic acid (GLA) were active in triggering NETs formation by oxidative burst. Furthermore, we identified silybin, a hepatoprotective agent, as a potent NETosis inhibitor, which effectively blocked NETs formation both in vitro and in vivo. Together, this study not only provide new insights into metabolism-immune causal link in NASH progression, but also demonstrate silybin as an important inhibitor of NETs and its therapeutical potential in treating NETosis-related diseases.
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Trampas Extracelulares , Enfermedad del Hígado Graso no Alcohólico , Animales , Ratones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Trampas Extracelulares/metabolismo , Silibina/farmacología , Modelos Animales de Enfermedad , Neutrófilos , Ácidos Grasos Insaturados/farmacología , Inflamación/metabolismoRESUMEN
Dihomo-γ-linolenic acid (DGLA) has emerged as a significant molecule differentiating healthy and inflamed tissues. Its position at a pivotal point of metabolic pathways leading to anti-inflammatory derivatives or via arachidonic acid (ARA) to pro-inflammatory lipid mediators makes this n-6 polyunsaturated fatty acid (PUFA) an intriguing research subject. The balance of ARA to DGLA is probably a critical factor affecting inflammatory processes in the body. The aim of this narrative review was to examine the potential roles of DGLA and related n-6 PUFAs in inflammatory conditions, such as obesity-associated disorders, rheumatoid arthritis, atopic dermatitis, asthma, cancers, and diseases of the gastrointestinal tract. DGLA can be produced by cultured fungi or be obtained via endogenous conversion from γ-linolenic acid (GLA)-rich vegetable oils. Several disease states are characterized by abnormally low DGLA levels in the body, while others can feature elevated levels. A defect in the activity of ∆6-desaturase and/or ∆5-desaturase may be one factor in the initiation and progression of these conditions. The potential of GLA and DGLA administrations as curative or ameliorating therapies in inflammatory conditions and malignancies appears modest at best. Manipulations with ∆6- and ∆5-desaturase inhibitors or combinations of long-chain PUFA supplements with n-3 PUFAs could provide a way to modify the body's DGLA and ARA production and the concentrations of their pro- and anti-inflammatory mediators. However, clinical data remain scarce and further well-designed studies should be actively promoted.
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Ácido 8,11,14-Eicosatrienoico , Ácidos Grasos Omega-6 , Inflamación , Humanos , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Ácido Araquidónico , Ácido Graso Desaturasas/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Enfermedad CrónicaRESUMEN
Antibiotic-resistant strains are a global health-threatening problem. Drug-resistant microbes have compromised the control of infectious diseases. Therefore, the search for a novel class of antibiotic drugs is necessary. Streptomycetes have been described as the richest source of bioactive compounds, including antibiotics. This study was aimed to characterize the antibacterial compounds of Streptomyces sp. PJ85 isolated from dry dipterocarp forest soil in Northeast Thailand. The 16S rRNA gene sequence and phylogenetic analysis showed that PJ85 possessed a high similarity to Streptomyces actinomycinicus RCU-197T of 98.90%. The PJ85 strain was shown to produce antibacterial compounds that were active against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA). The active compounds of PJ85 were extracted and purified using silica gel column chromatography. Two active antibacterial compounds, compound 1 and compound PJ85_F39, were purified and characterized with spectroscopy, including liquid chromatography and mass spectrometry (LC-MS). Compound 1 was identified as actinomycin D, and compound PJ85_F39 was identified as dihomo-γ-linolenic acid (DGLA). To the best of our knowledge, this is the first report of the purification and characterization of the antibacterial compounds of S. actinomycinicus.
RESUMEN
Second-generation androgen receptor (AR) inhibitors such as enzalutamide are the first-line treatments for castration-resistant prostate cancer (CRPC). Resistance to enzalutamide will greatly increase the difficulty of prostate cancer treatment and reduce the survival time of patients. However, drug-resistant cancer cells seem to be more sensitive to ferroptosis. Therefore, we constructed a biomimetic tumor-targeting magnetic lipid nanoparticle (t-ML) to codeliver dihomo-γ-linolenic acid (DGLA) and 2,4-dienoyl-CoA reductase 1 (DECR1) siRNA (t-ML@DGLA/siDECR1). DGLA is a dietary polyunsaturated fatty acid (PUFA), while DECR1 is overexpressed in prostate cancer and can inhibit the generation of PUFAs. The combination of DGLA and siDECR1 can efficiently induce ferroptosis by peroxidation of PUFAs, which has been verified both in vitro and in vivo. With the assistance of an external magnet, t-ML showed good tumor targeting ability and biocompatibility, and t-ML@DGLA/siDECR1 exhibited significant ferroptosis induction and tumor suppression capabilities. Moreover, in a nude mouse model of prostate cancer fed on a high-fat diet (HFD), there was no distant organ metastasis when the tumor-bearing mice were treated with t-ML@DGLA/siDECR1 and an external magnet, with upregulated PUFAs and downregulated monounsaturated fatty acids (MUFAs). Hence, this study has broadened the way of treating drug-resistant prostate cancer based on ferroptosis induction.
RESUMEN
Gut microbiota regulate physiological functions in various hosts, such as energy metabolism and immunity. Lactic acid bacteria, including Lactobacillus plantarum, have a specific polyunsaturated fatty acid saturation metabolism that generates multiple fatty acid species, such as hydroxy fatty acids, oxo fatty acids, conjugated fatty acids, and trans-fatty acids. How these bacterial metabolites impact host physiology is not fully understood. Here, we investigated the ligand activity of lactic acid bacteria-produced fatty acids in relation to nuclear hormone receptors expressed in the small intestine. Our reporter assays revealed two bacterial metabolites of γ-linolenic acid (GLA), 13-hydroxy-cis-6,cis-9-octadecadienoic acid (γHYD), and 13-oxo-cis-6,cis-9-octadecadienoic acid (γKetoD) activated peroxisome proliferator-activated receptor delta (PPARδ) more potently than GLA. We demonstrate that both γHYD and γKetoD bound directly to the ligand-binding domain of human PPARδ. A docking simulation indicated that four polar residues (T289, H323, H449, and Y473) of PPARδ donate hydrogen bonds to these fatty acids. Interestingly, T289 does not donate a hydrogen bond to GLA, suggesting that bacterial modification of GLA introducing hydroxy and oxo group determines ligand selectivity. In human intestinal organoids, we determined γHYD and γKetoD increased the expression of PPARδ target genes, enhanced fatty acid ß-oxidation, and reduced intracellular triglyceride accumulation. These findings suggest that γHYD and γKetoD, which gut lactic acid bacteria could generate, are naturally occurring PPARδ ligands in the intestinal tract and may improve lipid metabolism in the human intestine.
Asunto(s)
Intestino Delgado , Lactobacillales , PPAR delta , Ácido gammalinolénico , Humanos , Ácido gammalinolénico/metabolismo , Lactobacillales/metabolismo , Ligandos , Organoides/metabolismo , PPAR delta/metabolismo , Intestino Delgado/metabolismo , Intestino Delgado/microbiologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Descurainia sophia (L.)(Brassicaceae), popularly known as "Khaksheer", is a native species widely distributed in Iran. The seeds and essential oil has been used in local traditional medicine (Persian folk ethnomedicine) to treat fever, inflammation, back pain, and headache. AIM OF THE STUDY: To investigate in vitro anti-nociceptive and antineuropathic activities of Descurainia sophia seeds essential oil (DSEO) in rats and to determine the possible mechanism(s) involved. MATERIALS AND METHODS: The antinociceptive activity of DSEO or Linolenic acid (LA) was evaluated using the formalin induced paw licking test followed by determination on the role of NO-cGMP-K+ channel pathway as well as a number of non-opioid receptor systems (vanilloid, dopamine, cannabinoid, serotonin, peroxisome proliferator activated, and adrenergic receptors) in the modulation of DSEO-induced antinociceptive activity. Additionally, the cervical spinal cord contusion (CCS) model was used to study antineuropathic potential of DSEO or LA. RESULTS: DSEO exerted significant (p < 0.05) antinociceptive activity in formalin test (both phases) and altered mechanical allodynia and hyperalgesia observed in the CCS model. Pretreatment with glibenclamide, Nω-nitro-L-arginine methyl ester, tranilast, methylene blue, SCH23390, SR141716A and SR144528 restored DSEO-induced antinociceptive activity observed in the formalin test. Furthermore, LA also reduced nociceptive responses induced in the formalin and CCS models. CONCLUSION: DSEO inhibits inflammatory mediated nociceptive response partly via the modulation of NO-cGMP-K+ channels pathway well as the activation of vanilloid, dopamine, and cannabinoid receptors, and exerts antineuropathic activity possibly via the modulation of inflammatory mediated activity. Thus, these findings confirm the Persian ethno-medicine claim on the efficacy of D. Sophia.