Prostaglandins, leukotrienes, and essential fatty acids最新文献

{"title":"Linoleic acid promotes mammary tumor growth and metastasis to brain and lung in female Balb/cJ mice","authors":"Maria Sanchez-Juarez ,&nbsp;Monica Vizcarra-Soto ,&nbsp;Rocio Castillo-Sanchez ,&nbsp;Pablo Torres-Alamilla ,&nbsp;Pedro Cortes-Reynosa ,&nbsp;Gustavo Acosta-Altamirano ,&nbsp;Monica Sierra-Martinez ,&nbsp;Eduardo Perez Salazar","doi":"10.1016/j.plefa.2025.102687","DOIUrl":"10.1016/j.plefa.2025.102687","url":null,"abstract":"<div><div>Breast cancer is the leading cause of mortality among women worldwide. The largest prevalence of breast cancer is present in high-income nations, but the incidence in low- to middle-income countries has risen in recent years, which is the consequence of various causes, such as dietary habits. Dietary fat intake is a factor associated with the risk of developing breast cancer, and a moderate positive association between n-6 fatty acids and breast cancer risk has been described. Linoleic acid (LA) is an omega-6 polyunsaturated fatty acid (PUFA), which represents an essential PUFA and the major fatty acid consumed in occidental diets. It has been demonstrated that LA promotes cellular processes involved with invasion/metastasis in MDA-MB-231 breast cancer cells. In this study, we demonstrate that LA induces migration via FFAR1 and FFAR4, invasion and secretion of matrix metalloproteinase (MMP)-2 and MMP-9 in 4T1 triple negative breast cancer cells. In addition, 4T1 cells treated with 60 µM LA for 7 days and then inoculated in Balb/cJ mice induces an increase in the weight and volume of mammary tumors, and an increase in the metastasis to brain and liver compared with Balb/cJ mice inoculated with untreated 4T1 cells. In conclusion, LA induces cellular processes involved with invasion/metastasis and an increase in the growth of mammary tumors and metastasis in a murine model of breast cancer using Balb/cJ mice and 4T1 cells.</div></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"206 ","pages":"Article 102687"},"PeriodicalIF":3.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205319","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}

{"title":"Impact of n-3 polyunsaturate fatty acids supplementation on visual health throughout the life cycle: A systematic review","authors":"Claudia Tabilo ,&nbsp;Valentina Squella ,&nbsp;Paola Illesca ,&nbsp;Yasna Muñoz ,&nbsp;Camila Farías ,&nbsp;Rodrigo Valenzuela","doi":"10.1016/j.plefa.2025.102686","DOIUrl":"10.1016/j.plefa.2025.102686","url":null,"abstract":"<div><h3>Introduction</h3><div>N-3 polyunsaturated fatty acids (n-3 PUFA) are important for mammals and have relevant functions in the body. These fatty acids play an important role in brain development, in the protection of the retina, and in the prevention of macular degeneration. Currently, clinical trials do not yet confirm a clear benefit of n-3 PUFA supplementation on vision throughout the life cycle. Therefore, the aim of this study is to systematically evaluate the available scientific evidence to determine the effects of n-3 PUFA supplementation on visual health throughout the life cycle.</div></div><div><h3>Material and Methods</h3><div>A search of scientific literature was performed, based on randomized, controlled clinical studies, published in PubMed, using keywords. We included people of both sexes throughout the life cycle that evaluated the impact of n-3 PUFA supplementation on visual health.</div></div><div><h3>Results</h3><div>Of the 87 articles included in this review, there are important contradictions in the literature regarding the effects of supplementation in pregnant women, infants and older adults. While some studies highlight beneficial effects, an equal number of studies report no impact. In the case of preschoolers and schoolchildren, predominantly positive effects were identified, especially in children with Attention Deficit Hyperactivity Disorder (ADHD). For youth and adults, the impact of supplementation varied according to the health condition assessed, mostly supporting significant benefits in individuals with dry eye symptoms.</div></div><div><h3>Conclusion</h3><div>Evidence supports supplementation with n-3 PUFA, especially docosahexaenoic acid (DHA), to improve visual development in infants, schoolchildren, especially those with ADHD. Despite variability in visual outcomes, these findings suggest a crucial role of n-3 PUFA supplementation in visual health in the first steps of life, but in adults and older adults remain uncertain or null. Therefore, it is critical to investigate optimal dosing, duration of the intervention as the age of the participants in future research.</div></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"206 ","pages":"Article 102686"},"PeriodicalIF":3.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144253997","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}

{"title":"Dysfunction of COX-2/mPGES-1/PGE2 pathway and EP4 receptor in bronchi from COPD patients","authors":"Salma Mani ,&nbsp;Zhipeng Li ,&nbsp;Hichem Badji ,&nbsp;Gaelle Merheb ,&nbsp;Sébastien Dupont ,&nbsp;Yves Castier ,&nbsp;Olivier Thibaudeau ,&nbsp;Mathilde Varret ,&nbsp;Alice Guyard ,&nbsp;Dan Longrois ,&nbsp;Xavier Norel","doi":"10.1016/j.plefa.2025.102685","DOIUrl":"10.1016/j.plefa.2025.102685","url":null,"abstract":"<div><div>Progressive airflow obstruction and chronic lung inflammation are hallmarks of chronic obstructive pulmonary disease (COPD). Prostaglandin E2 (PGE₂), synthesized by the cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1), acts as a lipid mediator with bronchodilatory effects mediated by the EP4 receptor. Altered expression and function of COX-2, mPGES-1, PGE₂ and EP receptors may contribute to the pathophysiology of COPD. This study investigates whether COPD is associated with dysregulated expression or function of COX-2, mPGES-1, EP receptors and PGE₂ production in human bronchi. We analyzed the expression of COX-2, mPGES-1, PGE₂ and EP receptors in human bronchi samples using Western blot, real-time qPCR, ELISA and immunohistochemistry (IHC). Our results reveal significantly elevated COX-2 protein, mPGES-1 mRNA, and PGE₂ levels in COPD patients compared to controls. Conversely, in COPD preparations EP4 receptor mRNA and protein levels were markedly reduced, a result confirmed by IHC. In addition, IHC also showed that the EP4 receptor was mainly localized in the epithelium of control bronchi. Notably, there was a significant negative correlation between EP4 and PGE₂ levels. The hypothesis of EP4 internalization due to increased PGE₂ in COPD patients is credible. These data demonstrate a significant alteration of the COX-2/mPGES-1/PGE₂/EP4 pathway in COPD and suggest that pharmacological targeting of this pathway may be of interest to treat COPD.</div></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"206 ","pages":"Article 102685"},"PeriodicalIF":3.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144270423","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}

{"title":"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","authors":"Ren Wang,&nbsp;Dhruvesh Patel,&nbsp;Susan Goruk,&nbsp;Magaly Rivas Serna,&nbsp;Vera Mazurak,&nbsp;Caroline Richard,&nbsp;Catherine Field","doi":"10.1016/j.plefa.2025.102689","DOIUrl":"10.1016/j.plefa.2025.102689","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Objective</h3><div>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.</div></div><div><h3>Method</h3><div>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 <em>ex vivo</em> splenocyte oxylipin production after OVA stimulation.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>Early-life feeding of ARA+DHA beneficially modulated the oxylipin profile in the ileum and OVA-challenged splenocytes to support OT development.</div></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"206 ","pages":"Article 102689"},"PeriodicalIF":3.0,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144146810","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}

{"title":"Fatty acid tissue composition in mice fed diets containing varying levels of Omega-3 fatty acids","authors":"Nahed Hussein ,&nbsp;Irina Dahms ,&nbsp;Norman Salem Jr.","doi":"10.1016/j.plefa.2025.102688","DOIUrl":"10.1016/j.plefa.2025.102688","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"206 ","pages":"Article 102688"},"PeriodicalIF":3.0,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212514","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}

{"title":"Association of birth outcomes with maternal and infant FADS1 rs174547 genotypes in Japanese participants","authors":"Reiko Nita ,&nbsp;Terue Kawabata ,&nbsp;Yasuo Kagawa ,&nbsp;Kumiko Shoji ,&nbsp;Kazuhiro Nakayama ,&nbsp;Sadahiko Iwamoto ,&nbsp;Yoshiko Yanagisawa ,&nbsp;Fumiko Kimura ,&nbsp;Teruo Miyazawa ,&nbsp;Nozomi Tatsuta ,&nbsp;Takahiro Arima ,&nbsp;Nobuo Yaegashi ,&nbsp;Kunihiko Nakai","doi":"10.1016/j.plefa.2025.102683","DOIUrl":"10.1016/j.plefa.2025.102683","url":null,"abstract":"<div><div>N-3 long-chain polyunsaturated fatty acids (n-3LCPUFAs) are crucial for child growth and development particularly for fetal growth <em>in utero</em> and brain development and function. This study examined the relationship between birth outcomes and <em>FADS1</em> 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 <em>FADS1</em> genotypes may influence fetal growth. Furthermore, in <em>FADS1</em> 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 <em>FADS1</em> 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.</div></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"206 ","pages":"Article 102683"},"PeriodicalIF":3.0,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123232","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}

{"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 ,&nbsp;Hildegunn Aarsetoey ,&nbsp;Volker Poenitz ,&nbsp;Trygve Brugger-Andersen ,&nbsp;William S. Harris ,&nbsp;Harry Staines ,&nbsp;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 &lt;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}

{"title":"Fatty acid metabolism in the placentae of gestational diabetes mellitus","authors":"Nikita Joshi,&nbsp;Sadhana Joshi","doi":"10.1016/j.plefa.2025.102682","DOIUrl":"10.1016/j.plefa.2025.102682","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"205 ","pages":"Article 102682"},"PeriodicalIF":3.0,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143808231","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}

{"title":"HYPOTHESIS: Lipid-protecting disulfide bridges are the missing molecular link between ApoE4 and sporadic Alzheimer's disease in humans","authors":"Christopher E. Ramsden ,&nbsp;Roy G. Cutler ,&nbsp;Xiufeng Li ,&nbsp;Gregory S. Keyes","doi":"10.1016/j.plefa.2025.102681","DOIUrl":"10.1016/j.plefa.2025.102681","url":null,"abstract":"<div><div>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. <em>APOE</em> 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 <em>specific</em> 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 <em>APOE</em> 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.</div></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"205 ","pages":"Article 102681"},"PeriodicalIF":3.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143799315","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}

{"title":"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","authors":"Yanling Wu ,&nbsp;Claes Dahlgren ,&nbsp;Huamei Forsman ,&nbsp;Martina Sundqvist","doi":"10.1016/j.plefa.2025.102680","DOIUrl":"10.1016/j.plefa.2025.102680","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":94179,"journal":{"name":"Prostaglandins, leukotrienes, and essential fatty acids","volume":"205 ","pages":"Article 102680"},"PeriodicalIF":3.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143790944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}