Prostaglandins, leukotrienes, and essential fatty acids最新文献_第3页

Early-life feeding of arachidonic acid and docosahexaenoic acid beneficially modulated ileum and splenocyte oxylipins to support oral tolerance development in allergy-prone BALB/c mice 早期喂养花生四烯酸和二十二碳六烯酸有利于调节回肠和脾细胞氧脂，以支持易过敏BALB/c小鼠的口服耐受性发展

IF 3

Prostaglandins, leukotrienes, and essential fatty acids

Pub Date : 2025-05-23 DOI: 10.1016/j.plefa.2025.102689

Ren Wang, Dhruvesh Patel, Susan Goruk, Magaly Rivas Serna, Vera Mazurak, Caroline Richard, Catherine Field

Background

Early-life feeding of arachidonic acid (ARA)+docosahexaenoic acid (DHA) has been shown to promote immune changes associated with oral tolerance (OT). Oxylipins have been demonstrated to be modulated by diet and alter immune function.

Objective

To determine whether early-life feeding of ARA+DHA modulated the ileum and ovalbumin (OVA)-challenged splenocyte oxylipin profile in a way that is beneficial for OT development.

Method

Allergy-prone BALB/c dams were fed a control (0 %ARA, 0 %DHA) or ARA+DHA (1 %ARA, 1 %DHA) diet during suckling. At 3wks, half of the pups were killed to analyze ileum morphology and oxylipin profile. The remaining pups continued consuming the maternal diets. From day 21–25, pups received daily oral gavage of sucrose or OVA, followed by intraperitoneal OVA injections on day 35 and 41. At 6wks, pups were killed to analyze plasma OVA-specific-IgE and -IgG, ileum morphology, splenocyte phospholipid fatty acid composition and ex vivo splenocyte oxylipin production after OVA stimulation.

Results

ARA+DHA supplementation resulted in a 5-fold reduction in plasma OVA-IgE concentration, confirming OT development. At 3wks, ARA+DHA-fed mice had higher ileum levels of 8-HETE, 14,15-DiHETrE, 4-HDHA, 17-HDHA and 19,20-EpDPE and lower levels of 13-HODE and 20-HETE, which suggests better ileum maturation, lower inflammation and enhanced tolerogenic immune regulation to support OT. The longer villi, shorter crypts and higher villus/crypt ratio confirmed the superior ileum maturation. At 6wks, ARA+DHA supplementation increased oxylipin substrates (ARA, DHA, linoleic acid and eicosapentaenoic acid) in splenocyte phospholipids. After OVA stimulation, splenocytes from ARA+DHA-fed mice produced more PGD2, 5-HETE, 15-HETE and 20-HDHA and less TXB2 and 12-HETE, which suggests inhibited Th2 and allergic responses and enhanced tolerogenic immune modulation to support OT.

Conclusion

Early-life feeding of ARA+DHA beneficially modulated the oxylipin profile in the ileum and OVA-challenged splenocytes to support OT development.

幼儿喂养花生四烯酸(ARA)+二十二碳六烯酸（DHA）已被证明可促进与口服耐受性（OT）相关的免疫变化。氧脂素已被证明可以通过饮食调节并改变免疫功能。目的探讨早期喂养ARA+DHA是否能调节回肠和卵清蛋白（OVA）挑战的脾细胞氧脂谱，从而有利于OT的发展。方法在哺乳期给易过敏BALB/c母鼠饲喂对照组（0% ARA, 0% DHA）或ARA+DHA （1% ARA, 1% DHA）饲粮。在3周时，杀死一半的幼崽，分析回肠形态和氧脂质谱。剩下的幼崽继续吃母鼠的食物。第21-25天，每天灌胃蔗糖或卵细胞，第35天和第41天分别腹腔注射卵细胞。6周时，处死幼崽，分析卵细胞刺激后血浆卵细胞特异性ige和igg、回肠形态、脾细胞磷脂脂肪酸组成和体外脾细胞氧脂生成。结果补充sara +DHA导致血浆OVA-IgE浓度降低5倍，证实了OT的发生。在3周时，ARA+ dha喂养的小鼠回肠中8-HETE、14,15- dihetre、4-HDHA、17-HDHA和19,20- epdpe水平较高，13-HODE和20-HETE水平较低，这表明回肠成熟程度更高，炎症程度更低，耐受性免疫调节增强，支持OT。较长的绒毛，较短的隐窝和较高的绒毛/隐窝比证实了上回肠的成熟。在6周时，补充ARA+DHA增加了脾细胞磷脂中的氧化脂质底物（ARA、DHA、亚油酸和二十碳五烯酸）。卵子刺激后，ARA+ dha喂养小鼠脾细胞产生更多的PGD2、5-HETE、15-HETE和20-HDHA，减少TXB2和12-HETE，这表明抑制Th2和过敏反应，增强耐受性免疫调节，支持OT。结论早期喂养ARA+DHA有利于调节回肠和ova刺激的脾细胞中的氧脂质分布，支持OT的发展。

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引用次数: 0

Fatty acid tissue composition in mice fed diets containing varying levels of Omega-3 fatty acids 喂食含有不同水平欧米伽-3脂肪酸饮食的小鼠的脂肪酸组织组成

IF 3

Prostaglandins, leukotrienes, and essential fatty acids

Pub Date : 2025-05-23 DOI: 10.1016/j.plefa.2025.102688

Nahed Hussein , Irina Dahms , Norman Salem Jr.

This study compares varying levels of dietary α-linolenic acid (ALA) as well as eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) on the fatty acid composition of multiple tissues. Two-day pregnant, C57Bl6 mice were fed through gestation and lactation with four custom made diets and the offspring were weaned to the corresponding diet: n-3 deficient (ALA, 0.07wt % of dietary fatty acids), Low ALA (0.4wt %), High ALA (5wt %), and a Low ALA enriched with DHA (2wt %) plus EPA (2wt %). The fatty acid profiles in nine tissues/organs were determined at 12 wk of age by gas chromatography. In the brain, dietary DHA+ EPA supplementation produced a slight increase in DHA but produced no effect on retina in comparison to the High ALA diet. This contrasted with liver, heart, plasma, thigh muscle where the EPA+DHA diet produced higher levels of tissue EPA and DHA compared with the ALA diets. The proportion of arachidonic acid (AA) was depressed at the DHA+ EPA intake in retina, but not brain when compared to the High ALA diet. Tissue incorporation of EPA appeared maximal for the DHA+ EPA supplementation diet, with more than a 3-fold increase in the heart when compared to the High ALA diet. The highest level of DHA was found in heart (32 %), followed by retina (27 %) in the DHA+EPA supplemented diet. These results suggest that even high levels of ALA generally cannot support the higher tissue levels of EPA or DHA found when preformed long chain n-3 PUFA are supplied in the diet.

本研究比较了饲粮中不同水平α-亚麻酸（ALA）和二十碳五烯酸（EPA）加二十二碳六烯酸（DHA）对多种组织脂肪酸组成的影响。怀孕2天的C57Bl6小鼠在妊娠期和哺乳期饲喂4种定制的日粮，断奶后分别饲喂n-3缺乏（ALA， 0.07wt %的日粮脂肪酸）、低ALA （0.4wt %）、高ALA （5wt %）和富含DHA （2wt %）和EPA （2wt %）的低ALA。12周龄时用气相色谱法测定9个组织/器官的脂肪酸谱。在大脑中，与高ALA饮食相比，饮食中DHA+ EPA的补充会产生DHA的轻微增加，但对视网膜没有影响。这与肝脏、心脏、血浆和大腿肌肉形成对比，EPA+DHA饮食比ALA饮食产生了更高水平的组织EPA和DHA。与高ALA饮食相比，DHA+ EPA摄入降低了视网膜中花生四烯酸（AA）的比例，但大脑中没有。在DHA+ EPA补充饮食中，EPA的组织掺入量最大，与高ALA饮食相比，心脏的EPA掺入量增加了3倍以上。在DHA+EPA补充饮食中，DHA含量最高的部位是心脏（32%），其次是视网膜（27%）。这些结果表明，即使是高水平的ALA通常也不能支持在饮食中提供预形成的长链n-3 PUFA时所发现的较高组织水平的EPA或DHA。

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引用次数: 0

Association of birth outcomes with maternal and infant FADS1 rs174547 genotypes in Japanese participants 日本参与者出生结局与母婴FADS1 rs174547基因型的关系

IF 3

Prostaglandins, leukotrienes, and essential fatty acids

Pub Date : 2025-04-14 DOI: 10.1016/j.plefa.2025.102683

Reiko Nita , Terue Kawabata , Yasuo Kagawa , Kumiko Shoji , Kazuhiro Nakayama , Sadahiko Iwamoto , Yoshiko Yanagisawa , Fumiko Kimura , Teruo Miyazawa , Nozomi Tatsuta , Takahiro Arima , Nobuo Yaegashi , Kunihiko Nakai

N-3 long-chain polyunsaturated fatty acids (n-3LCPUFAs) are crucial for child growth and development particularly for fetal growth in utero and brain development and function. This study examined the relationship between birth outcomes and FADS1 rs174547 genotypes in Japanese mothers and infants. The study included 406 mothers and 373 infants, i.e., 373 infant–mother pairs, from a supplementary survey of the Japan Environment and Children's Study. Multiple regression analysis revealed that infants with the CC genotype had significantly smaller head circumference at birth compared to those with the TT genotype. Moreover, an interaction between infant genotype and cord blood docosahexaenoic acid (DHA; 22:6n-3) composition affected head circumference at birth. The findings suggest that maternal and infant FADS1 genotypes may influence fetal growth. Furthermore, in FADS1 genotype-stratified multiple regression analysis, infants with maternal and infant CC genotypes exhibited a significant positive association between head circumference at birth and maternal erythrocyte DHA/α-linolenic acid (ALA; 18:3n-3) ratio or fish intake. We highlighted lower metabolic efficiency for endogenous long-chain polyunsaturated fatty acids synthesis in infant–mother pairs homozygous for the minor C allele of FADS1 rs174547. In conclusion, for mothers and infants with this genetic background, maternal fish intake during pregnancy may be potentially important for fetal growth and development.

N-3长链多不饱和脂肪酸（n-3LCPUFAs）对儿童的生长发育至关重要，特别是对胎儿在子宫内的生长和大脑的发育和功能。本研究探讨了日本母婴FADS1 rs174547基因型与出生结局的关系。该研究包括406名母亲和373名婴儿，即373对婴儿-母亲，来自日本环境与儿童研究的补充调查。多元回归分析显示，CC基因型婴儿出生时头围明显小于TT基因型婴儿。此外，婴儿基因型与脐带血二十二碳六烯酸(DHA；[22:6]成分影响出生时的头围。研究结果表明，母婴FADS1基因型可能影响胎儿生长。此外，在FADS1基因型分层多元回归分析中，母亲和婴儿CC基因型的婴儿出生时头围与母亲红细胞DHA/α-亚麻酸(ALA；18:3n-3)比例或鱼的摄入量。我们强调了FADS1 rs174547小等位基因C纯合的母婴对内源性长链多不饱和脂肪酸合成的代谢效率较低。总之，对于具有这种遗传背景的母亲和婴儿来说，母亲在怀孕期间摄入鱼类可能对胎儿的生长发育有潜在的重要影响。

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引用次数: 0

Dihomo-gamma-linolenic acid (DGLA) is inversely related to risk for cardiac death and cardiovascular events during 2 years follow-up after admission for an acute coronary syndrome 急性冠状动脉综合征入院后2年随访期间，二同γ -亚麻酸（DGLA）与心源性死亡和心血管事件风险呈负相关

IF 3

Prostaglandins, leukotrienes, and essential fatty acids

Pub Date : 2025-04-10 DOI: 10.1016/j.plefa.2025.102684

Dennis W.T. Nilsen , Hildegunn Aarsetoey , Volker Poenitz , Trygve Brugger-Andersen , William S. Harris , Harry Staines , Heidi Grundt

Background/Aim

Dihomo-gamma-linolenic acid (DGLA) is derived from linoleic acid. Its presence in red blood cell (RBC) membranes is mainly due to metabolism and not diet. RBC DGLA was negatively associated with all-cause mortality during 7 years follow-up in patients admitted with an acute coronary syndrome (ACS). We now present its 2-year cardiovascular prognostic utility compared to other n-6 fatty acids (FAs).

Methods

A total of 139 females and 259 males with a mean age of 71.9 ± 13.0 years were admitted consecutively in this study. Stepwise Cox regression models, applying continuous values of DGLA weight percent (wt %) and quartiles, were fitted for the biomarkers with cardiac death and a combined cardiovascular (CV) endpoint consisting of cardiac death or myocardial infarction (MI) or stroke as the dependent variables.

Results

Cardiac death was recorded in 57 patients, and the composite CV endpoint in 144 patients, respectively. DGLA was negatively associated with both endpoints, each with a p-value of <0.001 in univariate analysis. The hazard ratio (HR, per 1 wt % increase) remained significant after multivariable adjustment [cardiac death HR 0.51 (95 %CI 0.27–0.98), p = 0.042, and composite CV endpoint HR 0.61 (95 %CI 0.41–0.92), p = 0.017]. A similar pattern was obtained in ACS patients presenting with an acute MI at admission.

No association with any outcome was found with the other n-6 FAs [linoleic acid, arachidonic acid and adrenic acid].

Conclusion

Higher RBC DGLA predicts lower risk for cardiac death and cardiovascular outcomes at 2 years follow-up in ACS patients, whereas other n-6 FAs do not.

Clinical trial registration: ClinicalTrials.gov Identifier: NCT00521976

二同γ -亚麻酸（DGLA）来源于亚油酸。它在红细胞（RBC）膜中的存在主要是由于代谢而不是饮食。在急性冠脉综合征（ACS）患者7年随访期间，RBC DGLA与全因死亡率呈负相关。我们现在将其与其他n-6脂肪酸（FAs）相比，在2年心血管预后方面的效用进行了介绍。方法本研究共收治女性139例，男性259例，平均年龄71.9±13.0岁。采用DGLA权重百分比（wt %）和四分位数连续值的逐步Cox回归模型，拟合心脏死亡和由心脏死亡或心肌梗死（MI）或中风组成的心血管（CV）联合终点作为因变量的生物标志物。结果心脏死亡57例，复合CV终点144例。DGLA与两个终点均呈负相关，在单变量分析中，每个终点的p值均为<；0.001。多变量校正后，风险比（HR，每增加1 wt %）仍然显著[心脏死亡HR 0.51 (95% CI 0.27-0.98), p = 0.042，复合CV终点HR 0.61 (95% CI 0.41-0.92), p = 0.017]。在入院时出现急性心肌梗死的ACS患者中也出现了类似的模式。其他n-6脂肪酸[亚油酸、花生四烯酸和肾上腺酸]与任何结果均无关联。结论：在ACS患者2年随访中，较高的RBC DGLA预示着较低的心源性死亡风险和心血管结局，而其他n-6 FAs则不然。临床试验注册：ClinicalTrials.gov标识符：NCT00521976

{"title":"Dihomo-gamma-linolenic acid (DGLA) is inversely related to risk for cardiac death and cardiovascular events during 2 years follow-up after admission for an acute coronary syndrome","authors":"Dennis W.T. Nilsen , Hildegunn Aarsetoey , Volker Poenitz , Trygve Brugger-Andersen , William S. Harris , Harry Staines , Heidi Grundt","doi":"10.1016/j.plefa.2025.102684","DOIUrl":"10.1016/j.plefa.2025.102684","url":null,"abstract":"<div><h3>Background/Aim</h3><div>Dihomo-gamma-linolenic acid (DGLA) is derived from linoleic acid. Its presence in red blood cell (RBC) membranes is mainly due to metabolism and not diet. RBC DGLA was negatively associated with all-cause mortality during 7 years follow-up in patients admitted with an acute coronary syndrome (ACS). We now present its 2-year cardiovascular prognostic utility compared to other n-6 fatty acids (FAs).</div></div><div><h3>Methods</h3><div>A total of 139 females and 259 males with a mean age of 71.9 ± 13.0 years were admitted consecutively in this study. Stepwise Cox regression models, applying continuous values of DGLA weight percent (wt %) and quartiles, were fitted for the biomarkers with cardiac death and a combined cardiovascular (CV) endpoint consisting of cardiac death or myocardial infarction (MI) or stroke as the dependent variables.</div></div><div><h3>Results</h3><div>Cardiac death was recorded in 57 patients, and the composite CV endpoint in 144 patients, respectively. DGLA was negatively associated with both endpoints, each with a p-value of <0.001 in univariate analysis. The hazard ratio (HR, per 1 wt % increase) remained significant after multivariable adjustment [cardiac death HR 0.51 (95 %CI 0.27–0.98), <em>p</em> = 0.042, and composite CV endpoint HR 0.61 (95 %CI 0.41–0.92), <em>p</em> = 0.017]. A similar pattern was obtained in ACS patients presenting with an acute MI at admission.</div><div>No association with any outcome was found with the other n-6 FAs [linoleic acid, arachidonic acid and adrenic acid].</div></div><div><h3>Conclusion</h3><div>Higher RBC DGLA predicts lower risk for cardiac death and cardiovascular outcomes at 2 years follow-up in ACS patients, whereas other n-6 FAs do not.</div><div>Clinical trial registration: ClinicalTrials.gov Identifier: NCT00521976</div></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"205 ","pages":"Article 102684"},"PeriodicalIF":3.0,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143838384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Fatty acid metabolism in the placentae of gestational diabetes mellitus 妊娠期糖尿病胎盘脂肪酸代谢的研究

IF 3

Prostaglandins, leukotrienes, and essential fatty acids

Pub Date : 2025-04-05 DOI: 10.1016/j.plefa.2025.102682

Nikita Joshi, Sadhana Joshi

The prevalence of gestational diabetes mellitus (GDM), a metabolic complication during pregnancy is increasing rapidly. It exerts various short and long term effects on the mother and the child. Nonetheless, the mechanisms underlying the pathophysiology of GDM are still not clear. Placenta is a key ‘programming’ agent and any impairment in placental structure and function may hamper the fetal growth and development. Omega-3 and omega-6 fatty acids are key nutrients involved in placental and fetal development. The fatty acids transport from maternal circulation towards the fetus depends on the fatty acid status of the mother, fatty acid metabolism of the placenta and placental transport of fatty acids. Alteration in any of these could influence the fatty acids transport towards the fetus thereby affecting the fetal brain development and leading to impairment in cognitive function in the off-spring. We propose a role for placental fatty acid metabolism in influencing fetal growth and development which in turn can have an impact on cognitive development of the offspring born to GDM women.

妊娠糖尿病（GDM）是一种孕期代谢并发症，其发病率正在迅速上升。它对母婴产生各种短期和长期影响。然而，GDM 的病理生理学机制仍不清楚。胎盘是 "编程 "的关键因素，胎盘结构和功能的任何损伤都可能阻碍胎儿的生长发育。奥米加 3 和奥米加 6 脂肪酸是胎盘和胎儿发育的关键营养素。脂肪酸从母体循环向胎儿的运输取决于母体的脂肪酸状况、胎盘的脂肪酸代谢和胎盘的脂肪酸运输。其中任何一个环节的改变都可能影响脂肪酸向胎儿的运输，从而影响胎儿的大脑发育，导致后代认知功能受损。我们提出了胎盘脂肪酸代谢在影响胎儿生长发育中的作用，而胎儿的生长发育反过来又会影响 GDM 妇女所生后代的认知发展。

引用次数: 0

HYPOTHESIS: Lipid-protecting disulfide bridges are the missing molecular link between ApoE4 and sporadic Alzheimer's disease in humans 假设：保护脂质的二硫桥是ApoE4与人类散发性阿尔茨海默病之间缺失的分子联系

IF 3

Prostaglandins, leukotrienes, and essential fatty acids

Pub Date : 2025-04-03 DOI: 10.1016/j.plefa.2025.102681

Christopher E. Ramsden , Roy G. Cutler , Xiufeng Li , Gregory S. Keyes

As the principal lipid transporter in the human brain, apolipoprotein E (ApoE) is tasked with transport and protection of highly vulnerable lipids that are required to support and remodel neuronal membranes, in a process that is dependent on ApoE receptors. APOE allele variants that encode proteins differing only in the number of cysteine (Cys)-to-arginine (Arg) exchanges (ApoE2 [2 Cys], ApoE3 [1 Cys], ApoE4 [0 Cys]) comprise the strongest genetic risk factor for sporadic Alzheimer's disease (AD); however, the specific molecular feature(s) and resultant mechanisms that underlie these isoform-dependent effects are unknown. One signature feature of Cys is the capacity to form disulfide (Cys-Cys) bridges, which are required to form disulfide-linked dimers and multimers. Here we propose the overarching hypothesis that super-ability (for ApoE2), intermediate ability (for ApoE3) or inability (for ApoE4) to form lipid-protecting intermolecular disulfide bridges, is the central molecular determinant accounting for the disparate effects of APOE alleles on AD risk and amyloid-β and Tau pathologies in humans. We posit that presence and abundance of Cys in human ApoE3 and ApoE2 respectively, conceal and protect vulnerable lipids transported by ApoE from peroxidation by enabling formation of disulfide-linked homo- and heteromeric ApoE complexes. We thus propose that inability to form intermolecular disulfide bridges makes ApoE4-containing lipoproteins uniquely vulnerable to peroxidation and its downstream consequences. Consistent with our model, we found that brain-enriched polyunsaturated fatty acid-containing phospholipids induce disulfide-dependent dimerization and multimerization of ApoE3 and ApoE2 (but not ApoE4). By contrast, incubation with the peroxidation-resistant lipid DMPC or cholesterol alone had minimal effects on dimerization. These novel concepts and findings are integrated into our unifying model implicating peroxidation of ApoE-containing lipoproteins, with consequent ApoE receptor-ligand disruption, as initiating molecular events that ultimately lead to AD in humans.

作为人脑中主要的脂质转运体，载脂蛋白E （ApoE）的任务是运输和保护高度脆弱的脂质，这些脂质是支持和重塑神经元膜所必需的，这一过程依赖于载脂蛋白E受体。APOE等位基因变异编码的蛋白质仅在半胱氨酸（Cys）与精氨酸（Arg）交换的数量上不同（ApoE2 [2 Cys], ApoE3 [1 Cys], ApoE4 [0 Cys]），是散发性阿尔茨海默病（AD）的最强遗传危险因素；然而，这些异构体依赖效应的具体分子特征和产生机制尚不清楚。Cys的一个显著特征是能够形成二硫化物（Cys-Cys）桥，这是形成二硫化物连接的二聚体和多聚体所必需的。在这里，我们提出了一个总体假设，即APOE等位基因对人类AD风险和淀粉样蛋白β和Tau病理的不同影响，其形成脂质保护分子间二硫桥的超能力（ApoE2）、中等能力（ApoE3）或无能力（ApoE4）是主要的分子决定因素。我们假设，在人类ApoE3和ApoE2中分别存在和丰富的Cys，通过形成二硫化物连接的同源和异聚ApoE复合物，隐藏和保护ApoE运输的易感脂质免于过氧化。因此，我们提出无法形成分子间二硫桥使得含apoe4的脂蛋白特别容易受到过氧化及其下游后果的影响。与我们的模型一致，我们发现富含大脑的含多不饱和脂肪酸的磷脂诱导ApoE3和ApoE2的二聚和多聚（但不包括ApoE4）。相比之下，与抗过氧化脂质DMPC或胆固醇单独孵育对二聚化的影响最小。这些新颖的概念和发现被整合到我们的统一模型中，该模型暗示含ApoE的脂蛋白过氧化，随之而来的ApoE受体配体破坏，是最终导致人类AD的初始分子事件。

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引用次数: 0

LTB4 is converted into a potent human neutrophil NADPH oxidase activator via a receptor transactivation mechanism in which the BLT1 receptor activates the free fatty acid receptor 2 LTB4通过受体转激活机制转化为有效的人中性粒细胞NADPH氧化酶激活剂，其中BLT1受体激活游离脂肪酸受体2

IF 3

Prostaglandins, leukotrienes, and essential fatty acids

Pub Date : 2025-04-03 DOI: 10.1016/j.plefa.2025.102680

Yanling Wu , Claes Dahlgren , Huamei Forsman , Martina Sundqvist

The endogenous neutrophil chemoattractant leukotriene B₄ (LTB₄) is a biased signalling agonist that potently increases the intracellular concentration of free calcium ions ([Ca²⁺]_i), but alone is a weak activator of the neutrophil superoxide anion (O₂^-)-generating NADPH oxidase. However, in this study we show that an allosteric modulator of the free fatty acid 2 receptor (FFA2R) converts LTB₄ into a potent NADPH oxidase activating agonist. While an allosteric modulation of FFA2R was required for LTB₄ receptor 1 (BLT₁R)-mediated activation of the NADPH oxidase, the LTB₄-induced increase in [Ca²⁺]_i was not affected by the modulator. Thus, the biased BLT₁R signalling pattern was altered in the presence of the allosteric FFA2R modulator, being biased with a preference towards the signals that activate the NADPH oxidase relative to an increase in [Ca²⁺]_i. Both BLT₁R and FFA2R belong to the family of G protein-coupled receptors (GPCRs), and our results show that a communication between the activated BLT₁R and the allosterically modulated FFA2Rs generates signals that induce NADPH oxidase activity. This is consistent with a previously described receptor transactivation (crosstalk) model whereby the function of one neutrophil GPCR can be regulated by receptor downstream signals generated by another GPCR. Furthermore, the finding that an allosteric FFA2R modulator sensitises not only the response induced by orthosteric FFA2R agonists but also the response induced by LTB₄, violates the receptor restriction properties that normally define the selectivity of allosteric GPCR modulators.

内源性中性粒细胞趋化剂白三烯B4 （LTB4）是一种偏置信号激动剂，可有效增加细胞内游离钙离子（[Ca2+]i）的浓度，但单独是中性粒细胞超氧阴离子（O2-）生成NADPH氧化酶的弱激活剂。然而，在这项研究中，我们发现游离脂肪酸2受体（FFA2R）的变抗调节剂将LTB4转化为一种有效的NADPH氧化酶激活激动剂。虽然LTB4受体1 （BLT1R）介导的NADPH氧化酶激活需要对FFA2R进行变构调节，但LTB4诱导的[Ca2+]i的增加不受调节剂的影响。因此，在变弹性FFA2R调节剂的存在下，偏向的BLT1R信号模式发生了改变，相对于[Ca2+]i的增加，偏向于激活NADPH氧化酶的信号。BLT1R和FFA2R都属于G蛋白偶联受体（gpcr）家族，我们的研究结果表明，激活的BLT1R和变弹性调节的FFA2Rs之间的通信产生了诱导NADPH氧化酶活性的信号。这与先前描述的受体反激活（串扰）模型一致，其中一个中性粒细胞GPCR的功能可以由另一个GPCR产生的受体下游信号调节。此外，发现变构性FFA2R调节剂不仅使正构性FFA2R激动剂诱导的反应敏感，而且使LTB4诱导的反应敏感，这违反了通常定义变构性GPCR调节剂选择性的受体限制特性。

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引用次数: 0

Fatty acid synthase global inducible knockout does not alter brain fatty acid concentrations but attenuates cholesterol synthesis in the adult mouse 脂肪酸合酶的诱导敲除不会改变脑脂肪酸浓度，但会减弱成年小鼠的胆固醇合成

IF 3

Prostaglandins, leukotrienes, and essential fatty acids

Pub Date : 2025-03-31 DOI: 10.1016/j.plefa.2025.102679

Drew R. Seeger, Peddanna Kotha, Svetlana A. Golovko, Eric J. Murphy, Mikhail Y. Golovko

Fatty acid (FA) de novo synthesis, also called de novo lipogenesis (DNL), has a central role in peripheral energy storage and provides structural components for lipid membranes. However, less is known regarding its contribution to brain FA homeostasis. DNL is catalyzed by fatty acid synthase (FAS), which is a multifunctional enzyme expressed in all mammalian tissues. In the present study, we addressed, for the first time, the effect of FAS gene global conditional inducible knockout (Fasn KO) on the adult brain FA concentrations and lipid metabolism. We achieved a 67 % reduction in the brain FAS protein levels, with a significant reduction in total FA synthesis measured by ³H₂O incorporation into FA, which was lethal 10 days after gene recombination induction. However, the concentrations of all 44 FA molecular species assayed by LC-MS were unchanged in the brain. We also did not detect changes in the major proteins involved in FA synthesis regulation and remodeling, including peroxisome proliferator-activated receptor α (PPARα), PPARδ, FA desaturase-1, -2, and -3, and Stearoyl-CoA desaturase 1 but did observe a decrease in PPARɣ levels. In addition, brain cholesterol synthesis was significantly reduced in the Fasn KO brains. These data indicate that DNL is not required to maintain measured FA concentrations in the brain and that dietary FA and liver-derived pools might compensate for decreased brain DNL within the duration of the study. However, our data indicate a possible role of FAS in PPARɣ regulation and cholesterol metabolism in the adult brain.

脂肪酸（FA）从头合成，也称为从头脂肪生成（DNL），在外周能量储存中起核心作用，并为脂质膜提供结构成分。然而，它对大脑FA稳态的贡献知之甚少。脂肪酸合成酶（fatty acid synthase， FAS）是一种在哺乳动物所有组织中表达的多功能酶。在本研究中，我们首次讨论了FAS基因全局条件诱导敲除（Fasn KO）对成人脑FA浓度和脂质代谢的影响。我们发现大脑FAS蛋白水平降低了67%，通过将3H2O掺入FA测量的总FA合成显著降低，这在基因重组诱导后10天是致命的。然而，LC-MS检测的所有44种FA分子种在脑内的浓度不变。我们也没有检测到参与FA合成调节和重塑的主要蛋白质的变化，包括过氧化物酶体增殖物激活受体α (PPARα), PPARδ， FA去饱和酶-1，-2和-3以及硬脂酰辅酶a去饱和酶1，但确实观察到PPARα水平下降。此外，Fasn KO脑内胆固醇合成显著减少。这些数据表明，DNL不需要维持大脑中测量的FA浓度，并且饮食FA和肝脏来源的池可能在研究期间补偿大脑中DNL的减少。然而，我们的数据表明FAS在成人大脑中PPAR α调节和胆固醇代谢中的可能作用。

{"title":"Fatty acid synthase global inducible knockout does not alter brain fatty acid concentrations but attenuates cholesterol synthesis in the adult mouse","authors":"Drew R. Seeger, Peddanna Kotha, Svetlana A. Golovko, Eric J. Murphy, Mikhail Y. Golovko","doi":"10.1016/j.plefa.2025.102679","DOIUrl":"10.1016/j.plefa.2025.102679","url":null,"abstract":"<div><div>Fatty acid (FA) <em>de novo</em> synthesis, also called <em>de novo</em> lipogenesis (DNL), has a central role in peripheral energy storage and provides structural components for lipid membranes. However, less is known regarding its contribution to brain FA homeostasis. DNL is catalyzed by fatty acid synthase (FAS), which is a multifunctional enzyme expressed in all mammalian tissues. In the present study, we addressed, for the first time, the effect of FAS gene global conditional inducible knockout (<em>Fasn</em> KO) on the adult brain FA concentrations and lipid metabolism. We achieved a 67 % reduction in the brain FAS protein levels, with a significant reduction in total FA synthesis measured by <sup>3</sup>H<sub>2</sub>O incorporation into FA, which was lethal 10 days after gene recombination induction. However, the concentrations of all 44 FA molecular species assayed by LC-MS were unchanged in the brain. We also did not detect changes in the major proteins involved in FA synthesis regulation and remodeling, including peroxisome proliferator-activated receptor α (PPARα), PPARδ, FA desaturase-1, -2, and -3, and Stearoyl-CoA desaturase 1 but did observe a decrease in PPARɣ levels. In addition, brain cholesterol synthesis was significantly reduced in the <em>Fasn</em> KO brains. These data indicate that DNL is not required to maintain measured FA concentrations in the brain and that dietary FA and liver-derived pools might compensate for decreased brain DNL within the duration of the study. However, our data indicate a possible role of FAS in PPARɣ regulation and cholesterol metabolism in the adult brain.</div></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"205 ","pages":"Article 102679"},"PeriodicalIF":3.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143759005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Plasma oxylipins in children with sickle cell disease: Associations with biomarkers of inflammation and endothelial activation 镰状细胞病儿童血浆氧脂素：与炎症和内皮细胞激活的生物标志物的关联

IF 3

Prostaglandins, leukotrienes, and essential fatty acids

Pub Date : 2025-02-24 DOI: 10.1016/j.plefa.2025.102670

BN Yamaja Setty , Krishna Rao Maddipati , Scott W Keith , Ayako Shimada , Pari Sheerer , Robin E Miller

Oxylipins are polyunsaturated fatty acid (PUFA)-derived inflammatory mediators, and include both pro-inflammatory (prostaglandins, thromboxane, leukotrienes), and pro-resolving (lipoxins, E-resolvins, D-resolvins, protectins, maresins) molecules. Sickle cell disease (SCD) is an inflammatory pathology. We profiled plasma oxylipins in SCD (n = 45) and control children (n = 24), and evaluated their associations with inflammatory biomarkers, and SCD clinical history. We demonstrated the presence of PGE2, TxB2, RvE2, RvD1, AT-RvD3, and numerous monohydroxy-PUFAs in both SCD and control plasma. Levels of TxB2, RvD1, 12-HETE, 5-HEPE, and 7-HDoHE were significantly increased in SCD. 12-HETE and 5-HEPE correlated positively with IL-6 and IL-1β, respectively, while 15-HETE negatively associated with soluble-ICAM-1. 7-HDoHE levels were significantly lower in children with a history of VOC and ACS compared to those without any clinical complications. Since RvD1 is a pro-resolving mediator, the observed increase in RvD1 in SCD may reflect a host mechanism attempting to mitigate disease-associated chronic inflammation by promoting resolution of inflammation.

氧脂素是多不饱和脂肪酸（PUFA）衍生的炎症介质，包括促炎（前列腺素、血栓素、白三烯）和促溶解（脂毒素、e -溶解蛋白、d -溶解蛋白、保护蛋白、蛋白）分子。镰状细胞病（SCD）是一种炎性病理。我们分析了45名SCD儿童和24名对照儿童的血浆氧脂素，并评估了它们与炎症生物标志物和SCD临床病史的关系。我们证实在SCD和对照血浆中存在PGE2、TxB2、RvE2、RvD1、AT-RvD3和许多单羟基pufas。SCD患者TxB2、RvD1、12-HETE、5-HEPE、7-HDoHE水平显著升高。12-HETE和5-HEPE分别与IL-6和IL-1β呈正相关，而15-HETE与可溶性icam -1呈负相关。与没有任何临床并发症的儿童相比，有VOC和ACS病史的儿童的7-HDoHE水平明显较低。由于RvD1是一种促溶解介质，因此在SCD中观察到的RvD1的增加可能反映了一种宿主机制，它试图通过促进炎症的溶解来减轻疾病相关的慢性炎症。

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引用次数: 0

The single-dose kinetics of [1–14C]-labelled EPA and DHA, administered to male rats as TAG, phosphatidylcholine (PC), and lyso-phosphatidylcholine (LPC), is structurally similar across lipid forms and can be described using the same compartmental models [1-14C]标记的EPA和DHA以TAG、磷脂酰胆碱（PC）和溶磷脂酰胆碱（LPC）的形式单剂量给予雄性大鼠，其结构在脂质形式上是相似的，可以用相同的室室模型来描述

IF 3

Prostaglandins, leukotrienes, and essential fatty acids

Pub Date : 2025-02-24 DOI: 10.1016/j.plefa.2025.102671

Nils Hoem , Stephen Harris , Grace Scott , Petter-Arnt Hals

To investigate the systemic kinetics of EPA and DHA across different lipid classes, male rats were administered [1–¹⁴C]-radiolabelled EPA and DHA as triglycerides (TAG), phosphatidylcholine (PC), or lyso-phosphatidylcholine (LPC) by gavage. LPC was also administered intravenously. Plasma and whole blood concentration-time profiles were recorded from 0 to 168 hours, while cumulative radioactivity in expired air, faeces, and urine was recorded for up to 336 hours.

Non-compartmental analysis and compartmental modelling demonstrated overall first-order radiotracer kinetics for both fatty acids, with comparable terminal half-lives. The primary difference was in maximum concentration (Cmax ((µg-eq/g)/(mg/kg)): DHA = 0.18± 0.089, EPA = 0.24± 0.103; P < 0.0001). Between TAG and PC, only time to maximum concentration (Tmax (h)) differed (PC = 3.23 ± 0.94, TAG = 2.55 ± 0.77; P = 0.0004). LPC showed significant differences from TAG and PC in area under the curve (AUC0-inf), Cmax, Tmax, and total clearance (CL/F (mL/(kg h))). Cumulative radioactivity levels in expired air and faeces were consistent with blood and plasma kinetics.

As suggested by early-phase (0 to 48 hours) radioactivity accumulation, which deviated from first-order behaviour, TAG and PC, but not LPC, exhibited some faecal loss without systemic absorption.

The compartmental models developed performed equally well for radiolabelled EPA and DHA, regardless of whether administered as TAG, PC, or LPC. The model can be adapted to handle non-zero endogenous baselines and was successfully applied to non-radiolabelled EPA, docosapentaenoic acid (DPA), and DHA, quantified via LC-MS/MS. These models can be applied to both radioactive and stable isotopes and adapted to include organ-specific kinetics, as well as those of EPA, DPA, and DHA in other species, including humans.

为了研究EPA和DHA在不同脂类中的全身动力学，雄性大鼠通过灌胃给予[1-14C]放射性标记的EPA和DHA作为甘油三酯（TAG）、磷脂酰胆碱（PC）或溶磷脂酰胆碱（LPC）。LPC也通过静脉注射。从0到168小时记录血浆和全血浓度-时间曲线，而在过期空气、粪便和尿液中记录累积放射性长达336小时。非区室分析和区室建模证明了这两种脂肪酸的总体一级放射性示踪动力学，具有相似的末端半衰期。最大浓度差异(Cmax（（µg-eq/g）/(mg/kg)）： DHA = 0.18±0.089,EPA = 0.24±0.103；P & lt;0.0001)。两组间仅达到最大浓度所需时间（Tmax (h)）有差异(PC = 3.23±0.94,TAG = 2.55±0.77；P = 0.0004)。在曲线下面积（AUC0-inf）、Cmax、Tmax和总清除率(CL/F （mL/(kg h)）方面，LPC与TAG和PC有显著差异。过期空气和粪便中的累积放射性水平与血液和血浆动力学一致。早期（0 ~ 48小时）放射性积累偏离一阶行为，TAG和PC，但LPC没有，表现出一些粪便损失，没有全身吸收。无论以TAG、PC还是LPC方式给药，所建立的室室模型对放射性标记的EPA和DHA表现同样良好。该模型可用于处理非零内源基线，并成功应用于非放射性标记的EPA、二十二碳五烯酸（DPA）和DHA，通过LC-MS/MS进行定量。这些模型可以应用于放射性和稳定同位素，并适应于包括器官特异性动力学，以及EPA， DPA和DHA在其他物种，包括人类中的动力学。

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引用次数: 0