Chemistry and Physics of Lipids最新文献_第3页

Lipid membrane composition modulates Hinokitiol's effects on keratinocytes and fibroblasts 脂膜组成调节扁柏醇对角质形成细胞和成纤维细胞的影响

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemistry and Physics of Lipids

Pub Date : 2025-06-11 DOI: 10.1016/j.chemphyslip.2025.105511

Beata Wyżga , Kamil Kamiński , Kinga Głowacka , Katarzyna Hąc-Wydro

Hinokitiol (β-thujaplicin) is a natural antimicrobial agent used in cosmetics. The aim of presented studies was to gain insight into the interactions of hinokitiol with lipids in model membranes and to correlate this with the selective effect of hinokitiol on cells. To reach this goal, the toxicity of hinokitiol was evaluated using keratinocyte and fibroblast cell lines, and studies were performed on lipid monolayers (both one component and mixed systems). During investigations the surface pressure - area measurements, penetration studies and Brewster angle microscopy experiments were done. The analysis of the parameters calculated from the experimental data and the comparison of BAM images evidenced that, at membrane – related surface pressure, hinokitiol does not insert into model keratinocyte and fibroblast membranes and its impact on these systems is very weak. This important conclusion correlates with the in vitro experiments. The results for one component systems evidenced that the effect of hinokitiol on mammalian lipid films depends on the monolayer organisation and the lipid structure (especially the lipid polar head). In consequence, the type and proportion of lipids determines the effect of hinokitiol on the mixed films. The latter corroborates with the differences in the influence of hinokitiol on bacteria compared to mammalian lipids. It was concluded that hinokitiol exhibits selective activity toward bacterial cells compared to mammalian cells and their corresponding model membranes. Thus, the predominance of hinokitiol's antibacterial properties over its toxicity to skin cells may therefore be related to interactions of this compound with membrane lipids.

扁柏醇是一种用于化妆品的天然抗菌剂。提出的研究的目的是深入了解在模型膜中的脂质的相互作用，并将其与杉木醇对细胞的选择性作用联系起来。为了达到这一目标，我们使用角质形成细胞和成纤维细胞系评估了扁柏醇的毒性，并对脂质单层（单组分和混合系统）进行了研究。在研究过程中，进行了表面压力面积测量、渗透研究和布鲁斯特角显微镜实验。通过对实验数据计算参数的分析和BAM图像的对比，证明在与膜相关的表面压力下，扁柏醇不会插入到模型角质形成细胞和成纤维细胞的膜中，对这些系统的影响非常微弱。这一重要结论与体外实验有关。单组分体系的结果证明，扁柏醇对哺乳动物脂膜的影响取决于单层组织和脂质结构（特别是脂质极性头）。因此，脂类的种类和比例决定了桧木醇对混合膜的影响。后者证实了与哺乳动物脂类相比，扁柏酚对细菌的影响存在差异。结果表明，与哺乳动物细胞及其相应的模型膜相比，桧木醇对细菌细胞具有选择性。因此，与对皮肤细胞的毒性相比，扁柏醇的抗菌特性的优势可能与这种化合物与膜脂的相互作用有关。

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引用次数: 0

Solid lipid nanoparticles in the diagnosis and treatment of prostate cancer: A comprehensive review of two decades of advancements 固体脂质纳米颗粒在前列腺癌诊断和治疗中的应用：二十年来进展的全面回顾。

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemistry and Physics of Lipids

Pub Date : 2025-06-06 DOI: 10.1016/j.chemphyslip.2025.105510

Pooja Tiwary , Krishil Oswal , Ryan Varghese , Harsh Anchan , Pardeep Gupta

Background

Prostate cancer (PC) is one of the most prevalent malignancies among men, with a staggering 1.5 million new cases and 350,000 deaths reported globally in 2022. Conventional treatment methods, including chemotherapy, radiation therapy, surgery, and hormonal therapy, often encounter significant challenges such as systemic toxicity and diminished efficacy, particularly in the advanced stages of the disease. Treatment of prostate cancer remains a formidable challenge because of the poor water solubility of many chemotherapeutic agents, which severely limits their bioavailability. However, the rise of targeted therapies has catalyzed the development of innovative drug delivery systems designed to enhance the bioavailability and precision of therapeutic agents. Solid lipid nanoparticles (SLNs) are a promising solution that can effectively encapsulate chemotherapeutic agents and genetic materials. Their unique attributes, such as biocompatibility, controlled release profile, and customizable surface properties, make them advantageous alternatives to conventional treatment strategies, effectively addressing the inherent limitations of prostate cancer therapy.

Methods

To provide the context, relevant publications were searched on Google Scholar, PubMed, Science Direct, Dimension AI, and EBSCO Host using specific keywords such as controlled drug release, cationic surfactants, drug delivery, drug loading, drug encapsulation lipid, prostate cancer, surface modification, solid lipid nanoparticles (SLNs), tumor microenvironment, to list a few. We did not add any limits to the publication date during the inclusion of papers. However, it is noteworthy that the initial reports including the aforementioned keywords have been published starting from 2010.

Conclusion

SLNs demonstrate substantial potential as effective nanocarriers for precise delivery of chemotherapeutic agents and genetic materials to prostate cancer cells. Their targeted delivery to these cells by surface modification with suitable ligands, antigens, peptides, and other recognition molecules has enhanced therapeutic efficacy. Further research on the interaction of SLN with the tumor environment is imperative to fully comprehend the uptake pathways. Extensive translation and preclinical studies are required to determine the safety and efficacy of SLNs before their use in clinical settings.

背景：前列腺癌（PC）是男性中最常见的恶性肿瘤之一，2022年全球报告的新病例高达150万例，死亡人数达到35万例。传统的治疗方法，包括化疗、放射治疗、手术和激素治疗，经常遇到重大的挑战，如全身毒性和疗效下降，特别是在疾病的晚期。前列腺癌的治疗仍然是一个巨大的挑战，因为许多化疗药物的水溶性差，这严重限制了它们的生物利用度。然而，靶向治疗的兴起促进了创新药物输送系统的发展，旨在提高治疗药物的生物利用度和精度。固体脂质纳米颗粒（SLNs）是一种很有前途的解决方案，可以有效地封装化疗药物和遗传物质。它们独特的特性，如生物相容性、控释特性和可定制的表面特性，使它们成为传统治疗策略的有利替代品，有效地解决了前列腺癌治疗的固有局限性。方法：以谷歌Scholar、PubMed、Science Direct、Dimension AI、EBSCO Host等网站为背景，检索药物控释、阳离子表面活性剂、给药、载药、包封脂质、前列腺癌、表面修饰、固体脂质纳米颗粒（SLNs）、肿瘤微环境等相关文献。在收录论文的过程中，我们没有对发表日期进行任何限制。但值得注意的是，包含上述关键词的初始报告是从2010年开始发布的。结论：sln作为一种有效的纳米载体，具有向前列腺癌细胞精确递送化疗药物和遗传物质的巨大潜力。它们通过与合适的配体、抗原、肽和其他识别分子进行表面修饰，靶向递送到这些细胞中，提高了治疗效果。进一步研究SLN与肿瘤环境的相互作用是充分了解其摄取途径的必要条件。在临床使用sln之前，需要进行广泛的翻译和临床前研究来确定其安全性和有效性。

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引用次数: 0

Detergent-resistant membranes in HeLa cells. A comparative study with an electrochemical and lipidomic perspective HeLa细胞中的抗洗涤剂膜。电化学与脂质组学的比较研究。

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemistry and Physics of Lipids

Pub Date : 2025-05-30 DOI: 10.1016/j.chemphyslip.2025.105509

Anastasie Mateckaja , Martina Zatloukalová , Gabriel Gonzalez , Richard Masař , Lukáš Najdekr , Zdeněk Dostál , Vlastimil Dorčák , Jan Vacek

Two procedures are compared for the isolation of detergent-resistant membranes (DRMs) from the HeLa model cell line. The isolation was based on application of Triton X-100 followed by 4 or 18 h ultracentrifugation in sucrose (5–42.5, % w) or Optiprep™ (10–25, % w) gradients. In the fractions obtained, the total amount of protein, cholesterol, and free thiols was evaluated using spectrophotometry. Increased protein as well as free thiol contents were demonstrated in higher density fractions. In contrast, the highest cholesterol levels were observed in light or medium heavy fractions with a low proportion of sucrose or Optiprep, especially after 18 h of centrifugation. For the sucrose gradient, we used voltammetric determination of the catalytic hydrogen evolution reaction at the Hg-electrode for individual fractions. The catalytic response, expressed as the height of the presodium wave, increased from light to heavy fractions corresponding to the protein content and/or other catalytically active species. The size of the DRMs or their associates ranged from 20 to 1000 nm, independently of the isolation protocol used. Proteins typically associated with DRMs such as caveolin and flotillin and characteristic for light and medium heavy gradient fractions, were determined using immunochemistry. We studied the subcellular localization of caveolin, flotillin, raftlin and transferrin, a control protein found intracellularly in the cytoplasm. Using confocal fluorescence microscopy, we confirmed the presence of caveolin and flotillin in the cytoplasmic membrane of HeLa cells. Raftlin was identified in both the membrane, and as part of the cell nucleus. We also performed untargeted lipidomic LC-MS analysis of the individual fractions of sucrose ultracentrifugation gradient obtained after 18 h. The predominant lipid subclasses were phosphatidylcholines and diacylglycerols. Apart from cholesterol and its ester, the rest of identified lipid classes was similar to that found in full HeLa cell lysates. The presented findings could be important for interpreting interlaboratory results and may be used as a guide for further studies on DRMs.

比较了从HeLa模型细胞系中分离耐洗涤剂膜（DRMs）的两种方法。应用Triton X-100进行分离，然后在蔗糖（5-42.5,% w）或OptiprepTM （10-25, % w）梯度下进行4或18h的超离心。所得馏分中，用分光光度法测定蛋白质、胆固醇和游离硫醇的总量。密度越高，蛋白质和游离硫醇含量越高。相比之下，在低比例蔗糖或Optiprep的轻或中重馏分中观察到最高的胆固醇水平，特别是在离心18h后。对于蔗糖梯度，我们使用伏安法在氢电极上测定催化析氢反应。催化反应，表示为钠前波的高度，从轻馏分增加到重馏分，对应于蛋白质含量和/或其他催化活性物质。与所使用的隔离协议无关，drm或其关联物的尺寸范围为20至1000nm。通常与DRMs相关的蛋白质，如caveolin和flotillin，以及轻和中重梯度分数的特征，使用免疫化学测定。我们研究了小窝蛋白、浮蛋白、浮蛋白和转铁蛋白的亚细胞定位，转铁蛋白是胞内细胞质中的一种控制蛋白。利用共聚焦荧光显微镜，我们证实HeLa细胞的细胞质膜中存在小泡蛋白和浮蛋白。在细胞膜和细胞核中都发现了Raftlin。我们还对18h后获得的蔗糖超离心梯度的单个部分进行了非靶向脂质组学LC-MS分析。主要的脂类是磷脂胆碱和二酰基甘油。除了胆固醇及其酯外，其余鉴定的脂类与完整的HeLa细胞裂解物相似。所提出的研究结果可能对解释实验室间的结果很重要，并可作为进一步研究drm的指南。

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引用次数: 0

The effect of α-tocopherol (vitamin E) on the phase behaviour of fully-hydrated dioleoyl phosphatidylcholine membranes α-生育酚（维生素E）对全水合二酰磷脂酰胆碱膜相行为的影响。

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemistry and Physics of Lipids

Pub Date : 2025-05-30 DOI: 10.1016/j.chemphyslip.2025.105507

Chi Long Chan , Divya Malia , Miguel Paez-Perez , Laurent Sagalowicz , Olivier Schafer , Robert V. Law , Nicholas J. Brooks , John M. Seddon

We report on the lyotropic phase behaviour of fully-hydrated mixtures of α-tocopherol (α-toc) with the unsaturated phospholipid dioleoyl phosphatidylcholine (DOPC), as studied by synchrotron small-angle x-ray diffraction. Increasing amounts of α-toc progressively swell the layer spacing of the fluid lamellar L_α phase of DOPC, and then induce a transition to an inverse hexagonal H_II phase. Low-resolution electron density profiles show that this increase is largely due to an increased thickness of the bilayer, with little change in the water layer thickness. In the range 30 – 50 mol% α-toc, additional weak low-angle peaks were observed, whose characteristic ratios are in agreement with the presence of swollen inverse bicontinuous cubic phases of spacegroups Im3m / Pn3m. This research has applications both in the biological field and for industrial product development. We show that the effect of α-toc addition in DOPC membranes has some similarities to that of cholesterol by stabilizing inverse curvature structures, which play crucial roles in cell division, membrane trafficking and endocytosis. Concerning industrial applications, the stabilization of inverted hexagonal (H_II) and swollen bicontinuous cubic phases offers the opportunity to develop new delivery systems.

用同步小角x射线衍射研究了α-生育酚（α-toc）与不饱和磷脂二油基磷脂酰胆碱（DOPC）的完全水合混合物的溶变相行为。α-toc含量的增加使DOPC流体层状Lα相的层间距逐渐膨胀，并诱导其向逆六方HII相转变。低分辨率电子密度谱显示，这种增加主要是由于双层厚度的增加，而水层厚度变化不大。在30 ~ 50mol% α-toc范围内，观察到额外的弱低角峰，其特征比与空间群Im3m / Pn3m存在膨胀的逆双连续立方相一致。这项研究在生物领域和工业产品开发中都有应用。我们发现α-toc在DOPC膜中的作用与胆固醇的作用有一些相似之处，即稳定了在细胞分裂、膜运输和内吞作用中起关键作用的逆曲率结构。在工业应用方面，倒六边形（HII）和膨胀双连续立方相的稳定为开发新的输送系统提供了机会。

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引用次数: 0

Nanoscale dynamics in model phospholipid biomembranes probed by muon spin resonance spectroscopy: The effects of membrane composition and temperature on acyl chain and cholesterol motion 用μ子自旋共振光谱探测模型磷脂生物膜的纳米尺度动力学：膜组成和温度对酰基链和胆固醇运动的影响。

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemistry and Physics of Lipids

Pub Date : 2025-05-30 DOI: 10.1016/j.chemphyslip.2025.105496

Iain McKenzie , Mitchell DiPasquale , Maksymilian Dziura , Thomas Gutberlet , Nathan A. Hartwig , Victoria L. Karner , Robert Scheuermann , Drew Marquardt

The physical properties of lipid bilayers are known to depend on their composition, but there has recently been controversy about whether cholesterol (chol) does or does not stiffen biomembranes containing unsaturated phospholipids. Herein, avoided level crossing muon spin resonance (ALC-

μ

SR) spectroscopy has been used to probe the local dynamics in model biomembranes composed of the saturated phospholipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), the unsaturated phospholipids 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and the sterol chol. The presence of chol significantly stiffens the acyl chains in lipid mixtures as evident from the reduction of the amplitude of restricted reorientational motion in the acyl chain at the C

_{9}

-C₁₀ position and the increase of the torsional barrier for rotation about the bonds in the acyl chain. Swapping POPC for DOPC slightly increases the amplitude of restricted reorientational motion and decreases the torsional barrier of the acyl chains, but the magnitude of the effect is much smaller than the inclusion of chol.

脂质双分子层的物理性质取决于它们的组成，但最近关于胆固醇是否会使含有不饱和磷脂的生物膜变硬一直存在争议。本文采用避免水平交叉μ子自旋共振（ALC-μSR）光谱，研究了由饱和磷脂1,2-二棕榈酰-2-油基-甘油-3-磷脂胆碱（DPPC）、不饱和磷脂1-棕榈酰-2-油基-甘油-3-磷脂胆碱（POPC）和1,2-二油基- asn -甘油-3-磷脂胆碱（DOPC）和甾醇组成的模型生物膜的局部动力学。从C9-C10位置的酰基链受限重定向运动幅度的减小和酰基链上键旋转的扭转势垒的增加可以看出，胆固醇的存在显著地使脂质混合物中的酰基链变硬。将POPC替换为DOPC略微增加了限制重定向运动的幅度，并降低了酰基链的扭转势垒，但其影响幅度远小于包含chol。

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引用次数: 0

Different propensity to oxidation and responses to compression of unsaturated mono- and di-galactosyldiacylglycerol Langmuir monolayers: Possible role of polymorphic transitions in lipid phase in the context of energy-converting membranes 不同的氧化倾向和对不饱和单和双半乳糖二酰基甘油朗缪尔单分子层的压缩反应：在能量转换膜的背景下，脂相中多态转变的可能作用。

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemistry and Physics of Lipids

Pub Date : 2025-05-30 DOI: 10.1016/j.chemphyslip.2025.105506

S. Benamara , I. Sbartai , H. Sbartai , F. Moroté , T. Cohen-Bouhacina , C. Grauby-Heywang

Monogalactosyldiacylglycerol (MGDG) and digalactosyldiacylglycerol (DGDG) are the main lipids present in thylakoids, site of photosynthesis in chloroplasts. In this work we are interested in the behavior of highly unsaturated MGDG and DGDG, studied by surface pressure measurements. Compression isotherms of these lipids show that they are able to form Langmuir monolayers, remaining in liquid expanded phase during all the compression. However, measurements at constant surface pressure and compression modulus suggest that these monolayers are not stable, even if increasing the number of spread molecules seems to increase the stability, with a particularly noticeable effect in the case of MGDG as compared to DGDG. Monolayers are then transferred on mica supports and resulting Langmuir-Blodgett films are imaged by Atomic Force Microscopy. Images and height profiles reveal the presence of thicker areas showing that some molecules are ejected outside the monolayer’s plane, with a higher propensity in the case of MGDG monolayers. We discuss these results taking into account two mechanisms, which may occur jointly: the oxidation of lipid hydrophobic chains and the desorption of lipids from the interface. The desorption amplitude would be higher in the case of MGDG, due to its propensity to organize in non-bilayer nature.

单半乳糖基二酰基甘油（MGDG）和双半乳糖基二酰基甘油（DGDG）是叶绿体中主要存在于类囊体中的脂类。在这项工作中，我们对高度不饱和的MGDG和DGDG的行为感兴趣，通过表面压力测量研究。这些脂质的压缩等温线表明它们能够形成朗缪尔单分子层，并在所有压缩过程中保持液体膨胀相。然而，在恒定的表面压力和压缩模量下的测量表明，即使增加扩散分子的数量似乎可以增加稳定性，这些单层也不稳定，与DGDG相比，MGDG的效果尤其明显。然后将单层膜转移到云母支架上，得到的Langmuir-Blodgett薄膜通过原子力显微镜成像。图像和高度分布图显示了较厚区域的存在，表明一些分子被喷射到单层的平面外，在MGDG单层的情况下有更高的倾向。我们在讨论这些结果时考虑了两种可能共同发生的机制：脂质疏水链的氧化和脂质从界面上的解吸。在MGDG的情况下，由于其倾向于以非双层性质组织，解吸幅度会更高。

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引用次数: 0

Phenotypic and lipidomic alterations in lung cells induced by organophosphate flame retardants 有机磷阻燃剂诱导肺细胞表型和脂质组学改变。

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemistry and Physics of Lipids

Pub Date : 2025-05-29 DOI: 10.1016/j.chemphyslip.2025.105508

Maryam Pyambri , Athina Pavlidou , Sílvia Lacorte , Joaquim Jaumot , Carmen Bedia

Organophosphate flame retardants (OPFRs) are widely used as additives in plastics, electronics, and construction materials due to their flame-retardant properties. However, previous evidence suggests that OPFRs may pose potential respiratory health risks, including airway hyperresponsiveness, impaired lung function, and potential carcinogenic effects. This study evaluated the effects of seven OPFRs—TBOEP, TPhP, EHDPhP, TDCPP, TEHP, TCP, and TCEP—on the phenotype and lipidomic profile of A549 lung cancer cells, using both 2D and 3D culture models. TDCPP and TPhP significantly reduced cell viability, while TBOEP caused the highest increase in reactive oxygen species (ROS), followed by TPhP, TDCPP, and TCP. Moreover, TPhP, TDCPP, EHDPhP, and TBOEP also elevated the levels of pro-inflammatory cytokine interleukin-8 (IL-8). The lipidomic analysis of 3D cell spheroids exposed to OPFRs for 72 h revealed distinct lipid profiles for each compound at low (25 μM) and high (100 μM) doses. Common features were observed, particularly at high doses, including significant increases in triacylglycerol, diacylglycerol, ceramide, ether-linked phosphatidylethanolamine, and phosphatidylinositol species. These effects were generally more pronounced for TPhP, TDCPP, EHDPhP, TCP, and TBOEP. The accumulation of triglycerides, indicative of augmented energy storage, was confirmed by the visualization of lipid droplets formation. Results suggest disruptions in key toxicological pathways, including oxidative stress, inflammatory signaling (IL-8 upregulation), and apoptosis (ceramide accumulation), all implicated in lung diseases, such as COPD and fibrosis. These results provide a basis for assessing the health risks associated with OPFRs, highlighting the need for further research on chronic low-dose exposure levels.

有机磷酸酯阻燃剂（OPFRs）由于其阻燃性能被广泛应用于塑料、电子和建筑材料的添加剂。然而，先前的证据表明，OPFRs可能造成潜在的呼吸健康风险，包括气道高反应性、肺功能受损和潜在的致癌作用。本研究利用2D和3D培养模型，评估了7种OPFRs-TBOEP、TPhP、EHDPhP、TDCPP、TEHP、TCP和tcepp对A549肺癌细胞表型和脂质组学特征的影响。TDCPP和TPhP显著降低了细胞活力，而TBOEP引起的活性氧（ROS）增加最多，其次是TPhP、TDCPP和TCP。此外，TPhP、TDCPP、EHDPhP和TBOEP也升高了促炎细胞因子白介素-8 （IL-8）的水平。3D细胞球体暴露于OPFRs 72小时的脂质组学分析显示，低（25 μM）和高（100 μM）剂量下，每种化合物的脂质谱都不同。观察到共同的特征，特别是在高剂量下，包括三酰基甘油、二酰基甘油、神经酰胺、醚连接的磷脂酰乙醇胺和磷脂酰肌醇种类显著增加。这些影响在TPhP、TDCPP、EHDPhP、TCP和TBOEP中更为明显。脂滴形成的可视化证实了甘油三酯的积累，表明能量储存增强。结果表明，关键毒理学途径的破坏，包括氧化应激、炎症信号（IL-8上调）和细胞凋亡（神经酰胺积累），都与肺部疾病有关，如COPD和纤维化。这些结果为评估与OPFRs有关的健康风险提供了基础，突出了进一步研究慢性低剂量暴露水平的必要性。

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引用次数: 0

Corrigendum to “Structural characterization of cholesterol-rich nanoemulsion (LDE) and associates” [Chem. Phys. Lipids 263 (2024) 105418] “富含胆固醇的纳米乳（LDE）及其衍生物的结构表征”的勘误表[化学]。理论物理。Lipids 263 (2024) 105418]

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemistry and Physics of Lipids

Pub Date : 2025-05-28 DOI: 10.1016/j.chemphyslip.2025.105498

Aline S. Perez , Aleksandra T. Morikawa , Raul C. Maranhao , Antonio M. Figueiredo Neto

引用次数: 0

Lipid membrane behavior of nitro-fatty acids and their loading into liposomes to activate Nrf2 pathway in RAW264.7 cells with impact on intracellular NO production RAW264.7细胞中硝基脂肪酸的脂膜行为及其装载到脂质体中激活Nrf2通路对细胞内NO生成的影响

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemistry and Physics of Lipids

Pub Date : 2025-05-16 DOI: 10.1016/j.chemphyslip.2025.105497

Martina Zatloukalova , Gabin Fabre , Lukas Jedinak , Jiří Pospíšil , Damian Dziubak , Aleksandra Pavićević , Zdenek Dostal , Jiri Vrba , Slawomir Sek , Miloš Mojović , Patrick Trouillas , Jan Vacek

Nitro-fatty acids (NO₂-FAs) are endogenous electrophilic signalling modulators, and some of them have been proposed as drug candidates. The main ones include nitro-oleic acid (NO₂-OA) and other derivatives of unsaturated fatty acids such as nitro-linoleic acid (NO₂-LA). In this study, we describe the behavior of 9/10-NO₂-OA, 10-NO₂-LA and the conjugated nitro-linoleic acid (9/12-NO₂-cLA) in a model POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) membrane using molecular dynamics and selected experimental approaches. We showed that when loaded in liposomes, NO₂-FAs undergo degradation (a decay reaction) to a very limited extent, in contrast to the free molecular form in an aqueous environment. This was confirmed by the electron paramagnetic resonance spectroscopic analysis of NO radical release. In general, NO₂-FAs suppress membrane hydration, especially in the segment where the ester groups are located. Further, in the presence of NO₂-FAs, there is increased membrane fluidity and a decrease in the degree of lipid order. These effects are greater for NO₂-FAs than for their non-nitrated versions. The presence of a nitro group in close contact with the polar head groups was confirmed. This drives the tilt of the lipid chain which in turn induces membrane disorder. Protonated NO₂-FAs penetrated more easily/deeper into the membrane structure than the dissociated forms and this makes the membrane bilayer surface more negatively charged based on zeta potential measurement. We also found that NO₂-FAs incorporated into POPC liposomes retained their ability to activate the Nrf2 pathway. This was documented by an increased expression of heme oxygenase-1 at the level of mRNA, with a parallel decrease in protein levels of Keap1, in murine macrophage RAW264.7 cells. The NO₂-FAs treatment resulted in an increase in intracellular NO level in vitro as determined by a genetically encoded G-geNOp sensor. This was confirmed at statistically significant level only for NO₂-OA, not for NO₂-LA or NO₂-cLA. The results indicate that biologically relevant NO release may be strictly dependent on which NO₂-FA is investigated. This study supports the hypothesis that NO₂-FAs are distributed (co-localized) in cells and tissues in the lipid or aqueous phase, which affects whether they are mobile, stable, and thus biologically active.

硝基脂肪酸（NO2-FAs）是内源性亲电信号调节剂，其中一些已被提出作为候选药物。主要有硝基油酸（NO2-OA）和硝基亚油酸（NO2-LA）等不饱和脂肪酸衍生物。在这项研究中，我们用分子动力学和选择的实验方法描述了9/10-NO2-OA、10-NO2-LA和共轭硝基亚油酸（9/12-NO2-cLA）在模型POPC（1-棕榈酰-2-油酰- asn -甘油-3-磷胆碱）膜中的行为。我们发现，与水环境中的自由分子形式相比，当装载在脂质体中时，NO2-FAs在非常有限的程度上进行降解（衰变反应）。通过对NO自由基释放的电子顺磁共振光谱分析证实了这一点。一般来说，NO2-FAs抑制膜水合作用，特别是在酯基所在的部分。此外，在NO2-FAs存在下，膜流动性增加，脂质有序度降低。这些影响对NO2-FAs比它们的非硝化版本更大。与极性头基团密切接触的硝基被证实存在。这导致脂质链倾斜，进而引起膜紊乱。质子化的NO2-FAs比解离的NO2-FAs更容易/更深地渗透到膜结构中，这使得膜双层表面更带负电荷。我们还发现，与POPC脂质体结合的NO2-FAs保留了激活Nrf2途径的能力。在小鼠巨噬细胞RAW264.7细胞中，血红素加氧酶-1 mRNA水平的表达增加，Keap1蛋白水平平行下降，证明了这一点。通过基因编码的G-geNOp传感器测定，NO2-FAs处理导致体外细胞内NO水平升高。只有NO2-OA，而NO2-LA或NO2-cLA没有统计学意义。结果表明，生物学上相关的NO释放可能严格依赖于NO2-FA的研究。本研究支持NO2-FAs在细胞和组织中的脂相或水相分布（共定位）的假设，这影响了它们的流动性、稳定性和生物活性。

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引用次数: 0

Decoding the Lipid-POI connection: The mediating role of inflammatory factors 解码脂质- poi连接：炎症因子的中介作用

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemistry and Physics of Lipids

Pub Date : 2025-05-03 DOI: 10.1016/j.chemphyslip.2025.105495

Tingyu Lang , Shaoqi Hua , Xiaolei Liang , Yongxiu Yang

POI is a highly heterogeneous, multifactorial condition, and dysregulated lipid metabolism has been implicated in its inflammatory pathogenesis This study is the first to systematically investigate causal relationships between 179 lipid species, 91 inflammatory factors, and POI using Two-Sample Mendelian Randomization (TSMR) and Multivariable Mendelian Randomization (MVMR). By integrating lipidomics and inflammatories data with POI from Genome-wide association study (GWAS) and FinnGen, we identified 18 causally significant lipids, including risk-elevating phosphatidylcholines and sphingomyelins, and protective triglycerides. Methodologically, we innovatively applied Bayesian Weighted Mendelian Randomization (BWMR) to confirm the robustness of causal estimates, addressing limitations of conventional MR in pleiotropy-prone metabolic networks. Biologically, we discovered IL-10 mediates 7.02–9.03 % of the effects of sphingomyelin (d40:2) and (d42:2) on POI, reconciling lipid-driven inflammation with ovarian aging—a mechanism previously unreported. Sensitivity analyses confirmed no horizontal pleiotropy (p > 0.05). This work establishes three advances: (1) First MR evidence linking specific lipid subclasses (not just broad categories) to POI; (2) Identification of IL-10 as a novel inflammatory mediator bridging sphingolipids and POI pathogenesis; (3) A validated framework combining MVMR and mediation analysis to disentangle direct/indirect effects in reproductive aging. Our findings provide clinically actionable insights: IL-10 emerge as potential biomarkers, while triglycerides highlight dietary/therapeutic targets. This mechanistic clarity advances POI research beyond prior observational associations into causal biology.

POI是一种高度异质性、多因素的疾病，脂质代谢失调与其炎症发病机制有关。本研究首次采用双样本孟德尔随机化（TSMR）和多变量孟德尔随机化（MVMR）系统地研究了179种脂质、91种炎症因子与POI之间的因果关系。通过整合来自全基因组关联研究（GWAS）和FinnGen的脂质组学和炎症数据，我们确定了18种具有因果意义的脂质，包括风险升高的磷脂酰胆碱和鞘磷脂，以及保护性甘油三酯。在方法上，我们创新地应用贝叶斯加权孟德尔随机化（BWMR）来确认因果估计的稳健性，解决了传统MR在多向性倾向代谢网络中的局限性。生物学上，我们发现IL-10介导鞘磷脂（d40:2）和鞘磷脂（d42:2）对POI的影响的7.02-9.03 %，调和脂质驱动的炎症和卵巢老化-这是一种以前未报道的机制。敏感性分析证实无水平多效性（p >； 0.05）。这项工作建立了三个进展：(1)第一个磁共振证据将特定的脂质亚类（不仅仅是宽泛的类别）与POI联系起来；(2) IL-10作为连接鞘脂和POI发病机制的新型炎症介质的鉴定；(3)结合MVMR和中介分析的验证框架来理清生殖老龄化的直接/间接影响。我们的研究结果提供了临床可操作的见解：IL-10成为潜在的生物标志物，而甘油三酯则突出了饮食/治疗靶点。这种机制的清晰性使POI研究超越了先前的观察关联，进入因果生物学。

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