Biochimica et biophysica acta. Molecular and cell biology of lipids最新文献_第9页

Effect of α-ketoglutarate on maternal lipid homeostasis and mitochondrial status perturbed by gestational arsenic exposure α-酮戊二酸对妊娠期砷暴露扰乱的母体脂质稳态和线粒体状态的影响

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2025-07-16 DOI: 10.1016/j.bbalip.2025.159665

Tong Zhan , Shuang-Rui Bao , Ying Sun , Hong-Yan Wu , Wen-Kang Tao , Xin-Ru Liang , Zhi-Yan Wan , Qian Yang , Hua Wang , Yi-Chao Huang , Jian-Qing Wang , De-Xiang Xu , Cheng Zhang

Arsenic is a common environmental toxicant with known hepatotoxic effects, yet its impact on maternal lipid metabolism during pregnancy remains poorly understood. In this study, we established a pregnant mouse model to investigate the effects of gestational arsenic exposure and the potential protective role of α-ketoglutarate (α-KG), a key tricarboxylic acid (TCA) cycle intermediate. In the first experiment, arsenic exposure led to significant disruptions in maternal serum and hepatic lipid profiles. Mechanistically, arsenic reduced hepatic α-KG concentrations, impaired mitochondrial ultrastructure, altered mitochondria-related gene expression, induced oxidative stress, and decreased multiple TCA cycle intermediates, collectively indicating compromised mitochondrial function. In the second experiment, α-KG supplementation during gestation effectively restored hepatic α-KG levels and reversed arsenic-induced lipid metabolic imbalances. Moreover, α-KG preserved mitochondrial morphology, normalized the expression of mitochondrial genes, alleviated oxidative stress, and partially rescued the levels of disrupted TCA intermediates. These results suggest that arsenic disrupts maternal lipid homeostasis primarily through mitochondrial dysfunction and oxidative stress, and that α-KG supplementation can alleviate these disturbances by supporting mitochondrial function. Although the exact molecular mechanisms require further clarification, our findings highlight the potential therapeutic role of α-KG in maintaining maternal lipid metabolic health during arsenic exposure during pregnancy.

砷是一种常见的环境毒物，已知具有肝毒性作用，但其对怀孕期间母体脂质代谢的影响仍知之甚少。在这项研究中，我们建立了妊娠小鼠模型，研究妊娠期砷暴露的影响和α-酮戊二酸（α-KG）的潜在保护作用，α-酮戊二酸是三羧酸（TCA）循环的关键中间体。在第一个实验中，砷暴露导致母体血清和肝脏脂质谱的显著破坏。从机制上说，砷降低了肝脏α-KG浓度，破坏了线粒体超微结构，改变了线粒体相关基因表达，诱导氧化应激，减少了多个TCA循环中间体，共同表明线粒体功能受损。在第二个试验中，妊娠期补充α-KG可有效恢复肝脏α-KG水平，逆转砷诱导的脂质代谢失衡。此外，α-KG还能保持线粒体形态，使线粒体基因表达正常化，减轻氧化应激，部分恢复被破坏的TCA中间体水平。这些结果表明，砷主要通过线粒体功能障碍和氧化应激破坏母体脂质稳态，而α-KG的补充可以通过支持线粒体功能来缓解这些干扰。虽然确切的分子机制需要进一步澄清，但我们的研究结果强调了α-KG在维持妊娠期砷暴露期间母体脂质代谢健康方面的潜在治疗作用。

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引用次数: 0

Metformin promotes lipid droplet-mitochondria coupling and improves insulin secretion in pancreatic β-cells exposed to lipotoxicity 二甲双胍促进脂滴-线粒体偶联并改善脂肪毒性胰腺β细胞的胰岛素分泌。

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2025-07-12 DOI: 10.1016/j.bbalip.2025.159664

Aneta M. Dobosz , Ewelina Krogulec , Nataniel Stefanowski , Maria Kendziorek , Magdalena Lebiedzinska-Arciszewska , Mariusz R. Wieckowski , Justyna Janikiewicz , Agnieszka Dobrzyn

Lipotoxicity that is caused by excess lipid accumulation is a major factor that contributes to gradual impairments of β-cell function and the development of type 2 diabetes. Metformin has shown protective effects against lipid-induced damage in β-cells, but its specific mechanisms of action within pancreatic islets remain unclear. The present study comprehensively examined direct effects of metformin on lipid metabolism pathways in INS-1E β-cells that were exposed to lipotoxic stress. Our results showed that metformin reduced both the number and size of lipid droplets in palmitate-treated INS-1E cells. This was followed by an increase in fatty acid utilization and the enhanced association between mitochondria and lipid droplets. Under conditions of palmitate overexposure, metformin limited the activity of adipose triglyceride lipase and lipogenic regulators, such as stearoyl-CoA desaturase, and suppressed fatty acid uptake into cells. Additionally, metformin alleviated triglyceride and free fatty acid accumulation and partially reversed palmitate-induced impairments in insulin secretion in INS-1E cells that were subjected to lipotoxicity. Notably, this beneficial effect of metformin on insulin secretion in INS-1E cells exposed to lipotoxic stress was less pronounced when the balance between mitochondrial fusion and fission was disturbed. These findings provide additional mechanistic insights into pleiotropic effects of metformin and its role in regulating β-cell function.

过量脂质积累引起的脂肪毒性是导致β细胞功能逐渐受损和2型糖尿病发展的主要因素。二甲双胍已显示出对β细胞脂质损伤的保护作用，但其在胰岛内的具体作用机制尚不清楚。本研究全面考察了二甲双胍对暴露于脂毒性应激的INS-1E β-细胞脂质代谢途径的直接影响。我们的研究结果表明，二甲双胍减少了棕榈酸处理的INS-1E细胞中脂滴的数量和大小。随后，脂肪酸利用率增加，线粒体和脂滴之间的关联增强。在棕榈酸过度暴露的条件下，二甲双胍限制了脂肪甘油三酯脂肪酶和脂肪生成调节因子（如硬脂酰辅酶a去饱和酶）的活性，并抑制了脂肪酸进入细胞的摄取。此外，二甲双胍减轻了甘油三酯和游离脂肪酸的积累，并部分逆转了棕榈酸引起的脂毒性INS-1E细胞胰岛素分泌的损伤。值得注意的是，当线粒体融合和裂变之间的平衡受到干扰时，二甲双胍对暴露于脂毒性应激的INS-1E细胞胰岛素分泌的有益作用就不那么明显了。这些发现为二甲双胍的多效作用及其在调节β细胞功能中的作用提供了额外的机制见解。

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引用次数: 0

Molecular mechanisms of cytochrome P450-derived epoxy-fatty acids neuroprotection 细胞色素p450衍生的环氧脂肪酸神经保护的分子机制。

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2025-07-10 DOI: 10.1016/j.bbalip.2025.159663

Cynthia Navarro-Mabarak, Julio Morán

The epoxyeicosatrienoic acids (EETs) are metabolites that result from the oxidation of the arachidonic acid by cytochrome P450 (CYP) epoxygenases. EETs are known to exert anti-inflammatory, antioxidant, vasodilatory, pro-angiogenic and anti-apoptotic actions. In the nervous system, EETs have been found to be neuroprotective in different models of neuronal damage. However, the molecular mechanisms responsible for these effects are not yet fully understood. This article seeks to review what is known about the signaling pathways involved in the EETs mediated neuroprotection. The mechanisms responsible for these effects are complex and involve several biological pathways that often crosstalk, including an inhibition of NFκB pathway, the activation of PPARα/γ nuclear receptors, and the activation of the PI3K/Akt pathway, among others. We also review what is known about the production and the biological significance of the epoxyeicosatrienoic acid ethanolamides (EET-EAs) and the epoxyeicosatrienoic acid glycerols (EET-EGs), metabolites that result from the epoxidation of the anandamide (AEA) and 2-arachidonylglycerol (2-AG) by CYP epoxygenases, which show endocannabinoid features.

环氧二碳三烯酸（EETs）是花生四烯酸被细胞色素P450 （CYP）环氧合酶氧化的代谢物。已知eet具有抗炎、抗氧化、血管扩张、促血管生成和抗凋亡作用。在神经系统中，已发现eet在不同的神经元损伤模型中具有神经保护作用。然而，导致这些效应的分子机制尚未完全了解。本文旨在回顾脑电图介导的神经保护所涉及的信号通路。这些作用的机制是复杂的，涉及几种经常相互作用的生物学途径，包括NFκB途径的抑制、PPARα/γ核受体的激活和PI3K/Akt途径的激活等。我们还回顾了环氧二碳三烯酸乙醇酰胺（EET-EAs）和环氧二碳三烯酸甘油（EET-EGs）的生产和生物学意义，这些代谢产物是由CYP环氧化酶环氧化anandamide （AEA）和2-花生四烯酰基甘油（2-AG）产生的，具有内源性大麻素特征。

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引用次数: 0

Fatty acid binding protein 1 (FABP1) depletion promotes an oxidative metabolic shift in Caco-2 colorectal cancer cells 脂肪酸结合蛋白1 （FABP1）的缺失促进Caco-2结直肠癌细胞的氧化代谢转变。

IF 3.3 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2025-07-08 DOI: 10.1016/j.bbalip.2025.159661

Delfina Lucía Borús , Giorgia Zadra , Daniel Minsky , María Lucía Costa , Betina Córsico , Judith Storch , Natalia Scaglia

Lipid metabolism reprogramming is a well-established hallmark of many cancer types, including colorectal cancer (CRC). Nevertheless, a clear understanding on how fatty acid (FA) metabolism is fine-tuned during CRC development and progression is still missing. Given that CRC is the second leading cause of cancer-related death, addressing these critical aspects may provide the rationale for new therapeutic approaches and early biomarker identification. Fatty acid binding protein 1 (FABP1) is a small protein that binds FA and other lipophilic compounds, acting as a lipid transporter in the intestine. Little is currently known about the function of FABP1 in CRC. Here we show that the knockdown of FABP1 in CRC cells impairs de novo FA and cholesterol synthesis, specifically, via altering the transcriptional regulation of lipid metabolism genes. FABP1 depletion suppresses the expression of FA and cholesterol synthesis-associated genes while promoting that of FA oxidation genes and mitochondrial oxidative pathways. The latter is associated with increased oxygen consumption rate and activation of the energy sensor 5’ AMP-activated kinase (AMPK). Taken together, our results show that FABP1 orchestrates the balance between FA synthesis and oxidation, most likely to prevent the cytotoxic effects of circulating unbound free fatty acids. Thus, targeting FABP1 function may represent a potential therapeutic strategy in advanced CRC.

脂质代谢重编程是许多癌症类型的一个公认的标志，包括结直肠癌（CRC）。然而，在结直肠癌的发生和发展过程中，脂肪酸（FA）代谢是如何微调的，目前还没有明确的认识。鉴于结直肠癌是癌症相关死亡的第二大原因，解决这些关键问题可能为新的治疗方法和早期生物标志物鉴定提供基础。脂肪酸结合蛋白1 （FABP1）是一种结合FA和其他亲脂化合物的小蛋白，在肠道中起脂质转运体的作用。目前对FABP1在CRC中的作用知之甚少。本研究表明，在结直肠癌细胞中，FABP1的敲低会损害FA和胆固醇的新生合成，特别是通过改变脂质代谢基因的转录调节。FABP1缺失抑制FA和胆固醇合成相关基因的表达，同时促进FA氧化基因和线粒体氧化途径的表达。后者与氧气消耗率增加和能量传感器5' amp活化激酶（AMPK）的激活有关。综上所述，我们的研究结果表明，FABP1协调了FA合成和氧化之间的平衡，最有可能阻止循环未结合的游离脂肪酸的细胞毒性作用。因此，靶向FABP1功能可能是晚期结直肠癌的一种潜在治疗策略。

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引用次数: 0

LIMP-2 deficiency-associated glycolipid abnormalities in mice 小鼠中与LIMP-2缺乏相关的糖脂异常。

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2025-07-08 DOI: 10.1016/j.bbalip.2025.159657

Paulo Gaspar , André R.A. Marques , Maria J. Ferraz , Markus Damme , Gertjan Kramer , Mina Mirzaian , Marion Gijbels , Roelof Ottenhoff , Cindy van Roomen , Herman S. Overkleeft , Michael Schwake , Saskia Heybrock , Maria Carmo Macário , Paul Saftig , Johannes M. Aerts

Glucocerebrosidase (GCase) catalyzes the lysosomal degradation of glucosylceramide (GlcCer). GCase deficiency results in Gaucher disease (GD), a lysosomal storage disorder with characteristic hepatosplenomegaly. Transport of GCase to lysosomes is mediated by the lysosomal integral membrane protein type 2 (LIMP-2). Deficiency of LIMP-2 leads to reduced cellular GCase levels and manifests as Action Myoclonic Renal Failure Syndrome (AMRF). We investigated the cause for the markedly different symptomatology of GD and AMRF. In tissues of Limp2 −/− mice no prominent abnormalities in lysosomal enzymes were noted except for variable deficiency of GCase, as measured with enzymatic activity assay and detection of active GCase molecules with an activity-based probe. Noteworthy, in LIMP-2-deficient mice, residual GCase is remarkably high in leukocytes. GCase deficiency in tissues does not correlate with increases in GlcCer, but rather with increases in glucosylsphingosine (GlcSph) and glucosylated cholesterol (GlcChol), both glucosylated metabolites derived from GlcCer. Isolated lysosomes from hepatocytes of Limp2 −/− mice revealed no prominent abnormalities in lysosomal matrix proteins except GCase. The Limp2 −/− tritosomes showed clear increases in GlcSph and GlcChol but not in GlcCer. In conclusion, our data imply a critical role of LIMP-2 in glycosphingolipid homeostasis. Despite low GCase levels striking GlcCer accumulation is avoided in tissues of LIMP-2 deficient mice.

葡萄糖脑苷酶（GCase）催化溶酶体降解葡萄糖神经酰胺（glcer）。GCase缺乏导致戈谢病（GD），一种伴有特征性肝脾肿大的溶酶体积存疾病。GCase转运到溶酶体是由溶酶体整体膜蛋白2 （LIMP-2）介导的。LIMP-2缺乏导致细胞GCase水平降低，表现为行动性肌阵挛性肾衰竭综合征（AMRF）。我们探讨了GD和AMRF明显不同症状的原因。在Limp2 -/-小鼠的组织中，除了GCase的可变缺陷外，没有发现明显的溶酶体酶异常，这是通过酶活性测定和活性探针检测活性GCase分子来测量的。值得注意的是，在limp -2缺陷小鼠中，白细胞中残留的GCase非常高。组织中GCase的缺乏与glcer的增加无关，而是与葡萄糖基鞘氨酸（GlcSph）和葡萄糖基化胆固醇（GlcChol）的增加有关，这两种糖基化代谢产物均来源于glcer。从Limp2 -/-小鼠肝细胞分离的溶酶体显示除GCase外，溶酶体基质蛋白无明显异常。Limp2 -/-三体GlcSph和GlcChol明显升高，glcer无明显升高。总之，我们的数据表明，在鞘糖脂稳态中，LIMP-2起着至关重要的作用。尽管GCase水平较低，但在LIMP-2缺陷小鼠的组织中避免了显著的glcer积累。

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引用次数: 0

Partial inhibition of adipose CIDEC improves insulin sensitivity and increases energy expenditure in high-fat diet-fed mice via activating ATGL-PPARα pathway 部分抑制脂肪CIDEC通过激活ATGL-PPARα途径改善高脂饮食小鼠的胰岛素敏感性和增加能量消耗

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2025-07-07 DOI: 10.1016/j.bbalip.2025.159659

Qinghua Fu , Peng Wang , Weilin Li , Zhenhua Cai , Shiji Zhao , Weidong Ling , Mingxun Li , Xiaochuan Tang , Ziyi Song

Obesity poses a significant risk for metabolic disorders, such as insulin resistance and metabolic-associated fatty liver disease (MAFLD), yet effective treatments remain limited. Cell Death-Inducing DNA Fragmentation Factor-α-Like Effector C (CIDEC), a lipid droplet membrane protein, facilitates lipid droplet fusion and is crucial for adipose tissue expansion, making it a key target for obesity and related metabolic diseases. However, previous research revealed that complete genetic deletion of Cidec in adipose tissues, while reducing fat accumulation, induced severe insulin resistance in high-fat diet (HFD)-fed mice, potentially due to ectopic fat storage in the liver. Given that complete knockout is an extreme approach, partial inhibition holds greater clinical relevance. Therefore, this study aimed to investigate the effects of partial inhibition of CIDEC in adipose tissues on fat accumulation and insulin sensitivity in mice. Using the Cre-LoxP system, we generated adipose Cidec haploinsufficient mice. Under a standard diet, these mice exhibited normal body weight, fat accumulation, and insulin sensitivity. Notably, under HFD conditions, mice with partial Cidec deficiency showed reduced fat accumulation in adipose tissues while hepatic fat accumulation remained unchanged, accompanied by improved insulin sensitivity and increased energy expenditure. Mechanistically, we found partial Cidec deficiency activated thermogenic program in adipocytes in vivo and in vitro through the ATGL-PPARα pathway. In conclusion, adipose CIDEC partial inhibition attenuates HFD-induced obesity and insulin resistance by enhancing ATGL-PPARα-mediated energy expenditure, establishing this approach as a promising therapeutic strategy for obesity and related metabolic diseases.

肥胖会导致代谢紊乱，如胰岛素抵抗和代谢相关脂肪性肝病（MAFLD），但有效的治疗方法仍然有限。细胞死亡诱导DNA碎片因子-α样效应因子C （Cell Death-Inducing DNA Fragmentation Factor-α-Like Effector C， CIDEC）是脂滴膜蛋白，促进脂滴融合，对脂肪组织扩张至关重要，是肥胖及相关代谢疾病的关键靶点。然而，先前的研究表明，脂肪组织中Cidec的完全基因缺失，在减少脂肪积累的同时，在高脂肪饮食（HFD）喂养的小鼠中诱导了严重的胰岛素抵抗，这可能是由于肝脏中的异位脂肪储存。考虑到完全敲除是一种极端的方法，部分抑制具有更大的临床意义。因此，本研究旨在探讨部分抑制脂肪组织中CIDEC对小鼠脂肪积累和胰岛素敏感性的影响。使用Cre-LoxP系统，我们产生了脂肪单倍体不足的小鼠。在标准饮食下，这些小鼠表现出正常的体重、脂肪积累和胰岛素敏感性。值得注意的是，在HFD条件下，部分Cidec缺乏的小鼠脂肪组织中的脂肪积累减少，而肝脏脂肪积累保持不变，并伴有胰岛素敏感性改善和能量消耗增加。在机制上，我们发现部分Cidec缺乏通过ATGL-PPARα途径激活体内和体外脂肪细胞的产热程序。综上所述，脂肪部分抑制CIDEC通过增强atgl - ppar α-介导的能量消耗来减轻hfd诱导的肥胖和胰岛素抵抗，使该方法成为肥胖和相关代谢疾病的一种有前景的治疗策略。

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引用次数: 0

Agonist- and stress-driven compartmentalized phosphoinositide signaling in cells 细胞中激动剂和应激驱动的区隔化磷酸肌苷信号。

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2025-07-05 DOI: 10.1016/j.bbalip.2025.159662

Mo Chen , Jay Xiaojun Tan , Yue Sun , Narendra Thapa , Vincent L. Cryns , Richard A. Anderson

Phosphoinositides (PIPs) are essential lipid messengers that regulate cellular responses to external stimuli and stress through spatially organized signaling pathways. In recent years, compartment-specific mechanisms by which PIP signaling integrates diverse cellular processes have been extensively expanded. This review discusses the distinct roles of PIP signaling across cellular compartments, including the plasma membrane, endosomes, lysosomes, protein scaffolds, and the nucleus. PIPs coordinate key processes such as receptor trafficking, cytoskeletal remodeling, autophagy, and signal transduction. Dynamic lysosomal PIP switches regulate critical functions like nutrient sensing, mTORC1 activity, and membrane repair, emphasizing their adaptability in maintaining cellular homeostasis. Furthermore, emerging evidence highlights nuclear PIP signaling in transcriptional regulation, DNA repair, and oncogenic pathways. Dysregulation of PIP signaling pathways is implicated in diseases such as cancer, neurodegeneration, and lysosomal storage disorders, underscoring their therapeutic potential in various pathological conditions.

磷酸肌苷（PIPs）是一种重要的脂质信使，通过空间组织的信号通路调节细胞对外部刺激和应激的反应。近年来，PIP信号整合多种细胞过程的室特异性机制已被广泛扩展。本文讨论了PIP信号在细胞质膜、核内体、溶酶体、蛋白支架和细胞核中的不同作用。pip协调关键过程，如受体运输、细胞骨架重塑、自噬和信号转导。动态溶酶体PIP开关调节营养感知、mTORC1活性和膜修复等关键功能，强调其在维持细胞稳态中的适应性。此外，新出现的证据强调了核PIP信号在转录调控、DNA修复和致癌途径中的作用。PIP信号通路的失调与癌症、神经退行性变和溶酶体贮积障碍等疾病有关，强调了它们在各种病理条件下的治疗潜力。

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引用次数: 0

The inositol 5-phosphatases OCRL and INPP5B: Cellular functions and roles in disease 肌醇5-磷酸酶ocl和INPP5B：细胞功能及其在疾病中的作用

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2025-07-04 DOI: 10.1016/j.bbalip.2025.159660

Aloka de Sa , Gaoyu Li , Connor Byrne , Martin Lowe

OCRL and INPP5B are evolutionary conserved inositol 5-phosphatases that preferentially hydrolyse PI(4,5)P₂, a key regulator of numerous cellular processes. Mutation of OCRL causes Lowe syndrome and Dent-2 disease that manifest in the eye, brain and kidney, whereas mutations in INPP5B have not been reported to cause disease. Here, we provide a current view of the biology of both proteins, describing their subcellular locations, interaction partners and cellular processes they mediate or that are sensitive to their loss of function. There are many similarities in these properties between OCRL and INPP5B, albeit with some important differences. We also discuss the mechanisms underlying Lowe syndrome and Dent-2 disease, and the possible influence of INPP5B in dictating final phenotypic outcome. The knowledge gained studying OCRL and INPP5B has improved understanding of how cells function and will inform the design of new treatments for Lowe syndrome and Dent-2 disease and possibly other conditions.

ocl和INPP5B是进化保守的肌醇5-磷酸酶，它们优先水解PI(4,5)P2， PI(4,5)P2是许多细胞过程的关键调节因子。ocl突变导致Lowe综合征和Dent-2疾病，表现在眼睛、大脑和肾脏，而INPP5B突变尚未报道导致疾病。在这里，我们提供了这两种蛋白质的生物学现状，描述了它们的亚细胞位置、相互作用伙伴和它们介导的细胞过程或对它们的功能丧失敏感的细胞过程。ocl和INPP5B在这些特性上有许多相似之处，尽管有一些重要的区别。我们还讨论了Lowe综合征和Dent-2疾病的潜在机制，以及INPP5B在决定最终表型结果中的可能影响。研究ocl和INPP5B所获得的知识提高了对细胞功能的理解，并将为Lowe综合征和Dent-2疾病以及可能的其他疾病的新治疗方法的设计提供信息。

引用次数: 0

Impact of minor cannabinoids on key pharmacological targets of estrogen receptor-positive breast cancer 少量大麻素对雌激素受体阳性乳腺癌关键药理靶点的影响。

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2025-07-02 DOI: 10.1016/j.bbalip.2025.159658

Cristina Ferreira Almeida, Georgina Correia-da-Silva, Ana Paula Ribeiro, Natércia Teixeira, Cristina Amaral

Endocrine therapy for estrogen receptor-positive (ER⁺) breast cancer has significantly improved over the last decades. However, it presents some limitations that make the search for novel therapeutic options mandatory. Several studies have been conducted to understand the anti-tumor potential of cannabinoids in breast cancer. Yet, most of them are focused on the major phytocannabinoids Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). However, Cannabis has other minor phytocannabinoids whose anti-cancer properties are still to be elucidated. Here, we investigated the mechanisms of action of four minor cannabinoids, cannabigerol (CBG), cannabidivarin (CBDV), cannabinol (CBN), and cannabichromene (CBC), in 2D and 3D ER⁺ breast cancer models. These cannabinoids dysregulate MCF-7aro cell cycle progression, induce apoptosis by different mechanisms, and inhibit the growth of MCF-7aro spheroids. CBG exerts its effects through a down-regulation of both ER and AR protein levels, while CBDV reduces aromatase protein levels. CBN and CBC simultaneously affect the three targets, ER, aromatase, and AR. In fact, CBN and CBC present an AR-dependent cell death, down-regulate aromatase levels, and act as ER negative regulators impairing cancer cell growth. CBN caused the most pronounced effects. Overall, this study highlights the anti-cancer properties and the therapeutic potential of these minor cannabinoids in ER⁺ breast cancer.

雌激素受体阳性（ER+）乳腺癌的内分泌治疗在过去几十年中有了显着改善。然而，它提出了一些限制，使得寻找新的治疗方案势在必行。已经进行了几项研究来了解大麻素在乳腺癌中的抗肿瘤潜力。然而，大多数研究都集中在主要的植物大麻素Δ9-tetrahydrocannabinol （THC）和大麻二酚（CBD）上。然而，大麻还有其他少量的植物大麻素，其抗癌特性仍有待阐明。在这里，我们研究了四种次要大麻素，大麻酚（CBG），大麻二酚（CBDV），大麻酚（CBN）和大麻色素（CBC）在2D和3D ER+乳腺癌模型中的作用机制。这些大麻素通过不同机制调节MCF-7aro细胞周期进程，诱导细胞凋亡，抑制MCF-7aro球体的生长。CBG通过下调ER和AR蛋白水平发挥作用，而CBDV通过降低芳香化酶蛋白水平发挥作用。CBN和CBC同时影响ER、芳香化酶和AR这三个靶标。事实上，CBN和CBC表现出AR依赖性的细胞死亡，下调芳香化酶水平，并作为ER负调节因子损害癌细胞生长。CBN造成了最明显的影响。总的来说，这项研究强调了这些小大麻素在ER+乳腺癌中的抗癌特性和治疗潜力。

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引用次数: 0

Specificity mechanism of Group VIA calcium-independent phospholipase A2 toward truncated-oxidized phospholipids and its application for specific inhibitor design VIA组钙非依赖性磷脂酶A2对截断氧化磷脂的特异性机制及其在特异性抑制剂设计中的应用。

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2025-06-29 DOI: 10.1016/j.bbalip.2025.159655

Daiki Hayashi , Charikleia S. Batsika , Asimina Bourboula , Masakazu Shinohara , Kengo Kanamaru , George Kokotos , Edward A. Dennis

Phospholipase A₂ (PLA₂) constitutes a superfamily of enzymes that hydrolyze the sn-2 fatty acyl chain of glycerophospholipids. Polyunsaturated fatty acids (PUFAs) are preferentially attached at the sn-2 position of glycerophospholipids and are easily truncated by oxidation. The truncated-oxidized phospholipids (tr-oxPLs) trigger various cellular responses, and PLA₂s may play a critical role in the metabolism of the tr-oxPLs by removing the oxidized sn-2 chain. In the present study, we demonstrated using an in vitro lipidomics assay that Group VIA calcium-independent PLA₂ (GVIA iPLA₂) showed high activity toward phosphatidylcholine with a 9-oxononanoyl chain, but not with an azelaoyl chain on the sn-2 position. We conducted molecular dynamics simulations which revealed that the hydrophilicity of the sn-2 acyl chain critically affects the binding of the substrate in the active site. Based on the unique specificity of GVIA iPLA₂ toward tr-oxPLs, we synthesized an oxidatively modified inhibitor (GK766) for GVIA iPLA₂, aiming for improvement of its selectivity and/or potency. As we expected, the modified inhibitor improved its selectivity of GVIA iPLA₂ compared to the unmodified inhibitor (GK187), although the inhibitory effect became somewhat weaker. More importantly, we demonstrated that GK766 induces cell death by ferroptosis more effectively than GK187 using an erythroleukemia cell line. In the present study, we have further defined the unique substrate specificity of GVIA iPLA₂ toward tr-oxPLs and its molecular mechanism. Furthermore, we have developed a novel specificity-based inhibitor that induces ferroptosis demonstrating that using substrate selectivity helps in developing more effective therapeutics.

磷脂酶A2 （PLA2）是一个水解甘油磷脂sn-2脂肪酸酰基链的超家族酶。多不饱和脂肪酸（PUFAs）优先附着在甘油磷脂的sn-2位置，容易被氧化截断。截断的氧化磷脂（tr-oxPLs）引发各种细胞反应，PLA2s可能通过去除氧化的sn-2链在tr-oxPLs的代谢中发挥关键作用。在本研究中，我们通过体外脂质组学分析证明了VIA组钙非依赖性PLA2 （GVIA iPLA2）对含有9-氧壬烷基链的磷脂酰胆碱具有较高的活性，而对sn-2位置上的氮杂二烷基链则没有活性。我们进行了分子动力学模拟，结果表明sn-2酰基链的亲水性严重影响底物在活性位点的结合。基于GVIA iPLA2对tro - oxpls的独特特异性，我们合成了GVIA iPLA2的氧化修饰抑制剂（GK766），旨在提高其选择性和效价。正如我们所料，与未修饰的抑制剂（GK187）相比，修饰后的抑制剂提高了GVIA iPLA2的选择性，尽管抑制作用有所减弱。更重要的是，我们利用红白血病细胞系证明GK766比GK187更有效地诱导铁凋亡细胞死亡。在本研究中，我们进一步明确了GVIA iPLA2对tro - oxpls独特的底物特异性及其分子机制。此外，我们已经开发出一种新的特异性抑制剂，诱导铁下垂，表明使用底物选择性有助于开发更有效的治疗方法。

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