Biochimica et biophysica acta. Molecular cell research最新文献_第6页

Hippocampal reelin and GAD67 gene expression and methylation in the GFAP.HMOX1 mouse model of schizophrenia 海马reelin和GAD67基因在GFAP中的表达和甲基化。精神分裂症HMOX1小鼠模型。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-09 DOI: 10.1016/j.bbamcr.2025.119899

Ayda Tavitian , Elad Lax , Wei Song , Moshe Szyf , Hyman M. Schipper

Schizophrenia is a complex neuropsychiatric disorder featuring enhanced brain oxidative stress and deficient reelin protein. GFAP.HMOX1^0-12m mice that overexpress heme oxygenase-1 (HO-1) in astrocytes manifest a schizophrenia-like neurochemical, neuropathological and behavioral phenotype including brain oxidative stress and reelin downregulation. We used RT-PCR, targeted bisulfite next-generation sequencing, immunohistochemistry and in situ hybridization on hippocampal tissue of GFAP.HMOX1^0-12m mice to delineate a possible molecular mechanism for the downregulation of reelin and to identify the neuronal and non-neuronal (glial) cell types expressing reelin in our model. We found reduced reelin and increased DNMT1 and TET1 mRNA expression in the hippocampus of male GFAP.HMOX1^0-12m mice and reduced GAD67 mRNA expression in females. These mRNA changes were accompanied by sexually dimorphic alterations in DNA methylation levels of Reln and Gad1 genes. Reelin protein was expressed by oligodendrocytes and GABAergic interneurons, but not by astrocytes or microglia in GFAP.HMOX1^0-12m and wild-type brains of both sexes. Reelin mRNA was also observed in oligodendrocytes. Moreover, a significant downregulation of reelin-expressing oligodendrocytes was detected in the hippocampal dentate gyrus of male GFAP.HMOX1^0-12m mice. These results suggest a novel mechanism for brain reelin depletion in schizophrenia. Containment of the astrocytic HO-1 cascade by pharmacological or other means may protect against stress-induced brain reelin depletion in schizophrenia and other neurodevelopmental disorders.

精神分裂症是一种复杂的神经精神疾病，其特点是大脑氧化应激增强和缺乏卷曲蛋白。GFAP。在星形胶质细胞中过表达血红素氧化酶-1 （HO-1）的HMOX10-12m小鼠表现出类似精神分裂症的神经化学、神经病理和行为表型，包括脑氧化应激和rein下调。我们对GFAP海马组织进行了RT-PCR、靶向亚硫酸氢盐下一代测序、免疫组织化学和原位杂交。HMOX10-12m小鼠来描述reelin下调的可能分子机制，并鉴定在我们的模型中表达reelin的神经元和非神经元（胶质）细胞类型。我们发现雄性GFAP海马中reelin减少，DNMT1和TET1 mRNA表达增加。HMOX10-12m小鼠并降低GAD67 mRNA在雌性中的表达。这些mRNA的变化伴随着Reln和Gad1基因DNA甲基化水平的性别二态改变。在GFAP中，少突胶质细胞和gaba能中间神经元表达Reelin蛋白，星形胶质细胞和小胶质细胞不表达Reelin蛋白。HMOX10-12m和野生型大脑。在少突胶质细胞中也观察到Reelin mRNA的表达。此外，在雄性GFAP海马齿状回中检测到表达reelin的少突胶质细胞的显著下调。HMOX10-12m老鼠。这些结果提示了精神分裂症患者脑reelin耗竭的一种新机制。在精神分裂症和其他神经发育障碍患者中，通过药物或其他手段控制星形细胞HO-1级联可防止应激诱导的脑reelin耗竭。

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引用次数: 0

The multiple facets of Rab proteins modulating the cellular distribution of cholesterol from the late endosomal compartment Rab蛋白从晚内体室调节胆固醇的细胞分布的多个方面。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-07 DOI: 10.1016/j.bbamcr.2025.119896

Mai Khanh Linh Nguyen , Céline Pinkenburg , Jonathan James Du , Marc Bernaus-Esqué , Carlos Enrich , Carles Rentero , Thomas Grewal

Cholesterol is an essential lipid that ensures the functional integrity of mammalian cells. Most cells acquire cholesterol via endocytosis of low-density lipoproteins (LDL). Upon reaching late endosomes/lysosomes (LE/Lys), incoming ligands, including LDL-derived cholesterol, are distributed to other organelles. Niemann-Pick Type C1/2 (NPC1/2) proteins, members of the steroidogenic acute regulatory-related lipid transfer domain (StARD) and oxysterol-binding protein (OSBP) families facilitate the cellular distribution of cholesterol. NPC disease, a rare neurodegenerative disorder characterized by LE/Lys-cholesterol accumulation due to loss-of-function NPC1/2 mutations, underscores the physiological importance of LE/Lys-cholesterol distribution. Several Rab-GTPase family members, which play fundamental roles in directional membrane and lipid transport, including Rab7, 8 and 9, are critical for the delivery of cholesterol from LE/Lys to other organelles along vesicular and non-vesicular pathways. The insights gained from these regulatory circuits provide a foundation for the development of therapeutic strategies that could effectively address the cellular pathogenesis triggered by NPC1 deficiency and other lysosomal storage disorders.

胆固醇是确保哺乳动物细胞功能完整的必需脂质。大多数细胞通过内吞低密度脂蛋白（LDL）获得胆固醇。到达晚期内体/溶酶体（LE/Lys）后，进入的配体，包括低密度脂蛋白衍生的胆固醇，被分配到其他细胞器。Niemann-Pick Type C1/2 （NPC1/2）蛋白是甾体源性急性调节相关脂质转移域（standard）和氧甾醇结合蛋白（OSBP）家族的成员，促进胆固醇的细胞分布。NPC疾病是一种罕见的神经退行性疾病，其特征是由于NPC1/2突变丧失功能而导致LE/ lys -胆固醇积累，强调了LE/ lys -胆固醇分布的生理重要性。Rab7、rab8和rab9等Rab7 - gtpase家族成员在定向膜和脂质运输中起着重要作用，它们对于胆固醇沿着囊泡和非囊泡途径从LE/Lys传递到其他细胞器至关重要。从这些调控回路中获得的见解为开发治疗策略提供了基础，这些策略可以有效地解决由NPC1缺陷和其他溶酶体储存疾病引发的细胞发病机制。

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引用次数: 0

Steroid sulfatase suppresses keratinization by inducing proteasomal degradation of E-cadherin via Hakai regulation

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-06 DOI: 10.1016/j.bbamcr.2025.119898

Tae-Uk Kwon , Yeo-Jung Kwon , Hyemin Park , Hyein Lee , Ji-Heung Kwak , Keon Wook Kang , Young-Jin Chun

X-linked ichthyosis (XLI) is a genetic disorder characterized by a steroid sulfatase (STS) deficiency inducing excessive cholesterol sulfate accumulation and keratinization. Our study utilizes STS knockout mice to reproduce the hyperkeratinization typical of XLI, providing a valuable model for investigating the underlying mechanisms. From the experiment of STS-deficient keratinocytes using the CRISPR/Cas9 system, we observed upregulation of E-cadherin, which is associated with keratinocyte differentiation and stratification. This was accompanied by elevated levels of keratinization markers, including involucrin and loricrin. We also found an increased expression of SULT2B1, which converts cholesterol to cholesterol sulfate, further accelerating cholesterol sulfate accumulation. As a result, STS deficiency and cholesterol sulfate accumulation lead to decreased expression of Hakai, the ubiquitin E3 ligase for E-cadherin. With reduced Hakai, endocytosis and ubiquitin-mediated degradation of E-cadherin are inhibited, resulting in its stabilization. This stabilization of E-cadherin is accompanied by increased expression of involucrin and loricrin, which is suppressed when the N-terminal extracellular domain of E-cadherin, responsible for cell-cell adhesion, is genetically modified. We propose that inhibition of E-cadherin, genetic modification of the N-terminal extracellular domain, and treatment with miR-6766 targeting E-cadherin significantly reduce the expression of keratinization markers, suggesting a potential therapeutic approach. We further suggest that the increased expression of E-cadherin observed in keratinocytes with STS deficiency is regulated by Hakai, underscoring the central role of E-cadherin in the pathogenesis of XLI.

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引用次数: 0

A novel super-resolution STED microscopy analysis approach to observe spatial MCU and MICU1 distribution dynamics in cells 一种新的超分辨率STED显微镜分析方法观察细胞中MCU和MICU1的空间分布动态。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-05 DOI: 10.1016/j.bbamcr.2025.119900

Martin Hirtl , Benjamin Gottschalk , Olaf A. Bachkoenig , Furkan E. Oflaz , Corina Madreiter-Sokolowski , Morten Andre Høydal , Wolfgang F. Graier

The uptake of Ca²⁺ by mitochondria is an important and tightly controlled process in various tissues. Even small changes in the key proteins involved in this process can lead to significant cellular dysfunction and, ultimately, cell death. In this study, we used stimulated emission depletion (STED) microscopy and developed an unbiased approach to monitor the sub-mitochondrial distribution and dynamics of the mitochondrial calcium uniporter (MCU) and mitochondrial calcium uptake 1 (MICU1) under resting and stimulated conditions. To visualize the inner mitochondrial membrane, the STED-optimized dye called pkMitoRed was used. The study presented herein builds on the previously verified exclusive localization of MICU1 in the intermembrane space, and that MCU moves exclusively laterally along the inner mitochondrial membrane (IMM). We applied a multi-angled arrow histogram to analyze the distribution of proteins within mitochondria, providing a one-dimensional view of protein localization along a defined distance. Combining this with optimal transport colocalization enabled us to further predict submitochondrial protein distribution. Results indicate that in HeLa cells Ca²⁺ elevation yielded MCU translocation from the cristae membrane (CM) to the inner boundary membrane (IBM). In AC16 cardiomyocyte cell line, MCU is mainly located at the IBM under resting conditions, and it translocates to the CM upon rising Ca²⁺. Our data describe a novel unbiased super-resolution image analysis approach. Our showcase sheds light on differences in spatial distribution dynamics of MCU in cell lines with different MICU1:MCU abundance.

在各种组织中，线粒体对Ca2+的摄取是一个重要且受到严格控制的过程。参与这一过程的关键蛋白即使发生很小的变化，也会导致显著的细胞功能障碍，并最终导致细胞死亡。在这项研究中，我们使用受激发射损耗（STED）显微镜，并开发了一种无偏的方法来监测静息和受激条件下线粒体钙单输体（MCU）和线粒体钙摄取1 （MICU1）的亚线粒体分布和动态。为了使线粒体内膜可视化，使用了sted优化的pkmitoror染料。本文的研究建立在先前证实的MICU1在膜间空间的排他性定位的基础上，并且MCU只沿着线粒体内膜（IMM）横向移动。我们应用多角度箭头直方图来分析线粒体内蛋白质的分布，提供沿定义距离的蛋白质定位的一维视图。将其与最佳运输共定位相结合，使我们能够进一步预测亚线粒体蛋白的分布。结果表明，在HeLa细胞中，Ca2+升高导致MCU从嵴膜（CM）向内边界膜（IBM）易位。在AC16心肌细胞系中，静息状态下MCU主要位于IBM，当Ca2+升高时，MCU易位至CM。我们的数据描述了一种新的无偏超分辨率图像分析方法。我们的展示揭示了不同MICU1:MCU丰度细胞系中MCU空间分布动态的差异。

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引用次数: 0

Molecular aspects of cytoprotection by Optineurin during stress and disease 应激和疾病中optinurin细胞保护的分子机制。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-01-02 DOI: 10.1016/j.bbamcr.2024.119895

Ghanshyam Swarup , Swetha Medchalmi , Gopalakrishna Ramachandran , Zuberwasim Sayyad

Optineurin/OPTN is an adapter protein that plays a crucial role in mediating many cellular functions, including autophagy, vesicle trafficking, and various signalling pathways. Mutations of OPTN are linked with neurodegenerative disorders, glaucoma, and amyotrophic lateral sclerosis (ALS). Recent work has shown that OPTN provides cytoprotection from many types of stress, including oxidative stress, endoplasmic reticulum stress, protein homeostasis stress, tumour necrosis factor α, and microbial infection. Here, we discuss the mechanisms involved in cytoprotective functions of OPTN, which possibly depend on its ability to modulate various stress-induced signalling pathways. ALS- and glaucoma-causing mutants of OPTN are altered in this regulation, which may affect cell survival, particularly under various stress conditions. We suggest that OPTN deficiency created by mutations may cooperate with stress-induced signalling to enhance or cause neurodegeneration. Other functions of OPTN, such as neurotrophin secretion and vesicle trafficking, may also contribute to cytoprotection.

optinurin /OPTN是一种适配器蛋白，在介导许多细胞功能，包括自噬、囊泡运输和各种信号通路中起着至关重要的作用。OPTN突变与神经退行性疾病、青光眼和肌萎缩性侧索硬化症（ALS）有关。最近的研究表明，OPTN可以保护细胞免受多种应激，包括氧化应激、内质网应激、蛋白质稳态应激、肿瘤坏死因子α和微生物感染。在这里，我们讨论了参与OPTN细胞保护功能的机制，这可能取决于其调节各种应激诱导信号通路的能力。引起ALS和青光眼的OPTN突变体在这种调节中发生改变，这可能影响细胞存活，特别是在各种应激条件下。我们认为突变造成的OPTN缺乏可能与应激诱导的信号传导合作，从而增强或导致神经退行性变。OPTN的其他功能，如神经营养因子分泌和囊泡运输，也可能有助于细胞保护。

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引用次数: 0

The loss of keratin 77 in murine skin is functionally compensated by keratin 1 小鼠皮肤角蛋白 77 的缺失可由角蛋白 1 进行功能补偿

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2024-11-26 DOI: 10.1016/j.bbamcr.2024.119881

S. Ghorbanalipoor , T. Hommel , T. Kolbe , T. Fröhlich , B. Wagner , C. Posch , M. Dahlhoff

Keratins, the intermediate filament-forming proteins of the epithelial cells, are mainly expressed in keratinocytes, preserving the structural integrity and cohesion of the epidermis. There are multiple inherited skin conditions arising from mutations in the encoding genes of specific keratins, highlighting their significance in skin health. Furthermore, the aberrant expression of keratins is evidenced in certain skin diseases, such as psoriasis, atopic dermatitis, and skin cancer. Keratin 77 (KRT77) is a type II keratin with demonstrated expression in human and mouse sweat glands' ducts. Using the CRISPR/Cas9 technique, we generated a Krt77-deficient (Krt77-KO) mouse line to reveal its obscure function in skin biology and homeostasis. KRT77 loss did not result in any fetal lethality or detrimental impact on the development of the skin and its appendages. However, we identified a substantially increased expression of KRT1 in the skin of the Krt77-KO mouse line in comparison with control littermates at both mRNA and protein levels using RT-qPCR and western blot analyses, respectively. Based on these findings, we concluded that the absence of KRT77 in the murine skin leads to upregulation of KRT1, an alternative epidermal type II keratin within the same subfamily as KRT77, which rescues the lack of KRT77.

角蛋白是上皮细胞的中间丝形成蛋白，主要在角质形成细胞中表达，可保持表皮结构的完整性和凝聚力。特定角蛋白的编码基因突变会导致多种遗传性皮肤病，这凸显了角蛋白在皮肤健康中的重要作用。此外，某些皮肤病，如牛皮癣、特应性皮炎和皮肤癌，也证明了角蛋白的异常表达。角蛋白 77（KRT77）是一种 II 型角蛋白，在人类和小鼠汗腺导管中均有表达。我们利用 CRISPR/Cas9 技术生成了 Krt77 缺失（Krt77-KO）小鼠品系，以揭示其在皮肤生物学和稳态中的模糊功能。KRT77 缺失不会导致胎儿夭折，也不会对皮肤及其附属器官的发育产生有害影响。然而，通过 RT-qPCR 和 Western 印迹分析，我们发现 Krt77-KO 小鼠品系的皮肤中 KRT1 的表达在 mRNA 和蛋白质水平上都比对照品系高得多。基于这些发现，我们得出结论：小鼠皮肤中 KRT77 的缺失会导致 KRT1 的上调，KRT1 是与 KRT77 属于同一亚家族的另一种表皮 II 型角蛋白，它能挽救 KRT77 的缺失。

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引用次数: 0

Ubiquitin-specific peptidase 11 selectively interacts with and deubiquitination-dependently stabilizes diacylglycerol kinase δ to maintain cellular glucose uptake 泛素特异性肽酶11选择性地与二酰基甘油激酶δ相互作用，并依赖去泛素化作用稳定二酰基甘油激酶δ，以维持细胞的葡萄糖摄取。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2024-11-26 DOI: 10.1016/j.bbamcr.2024.119883

Masayuki Ebina , Yuri Miura , Fumio Sakane

Diacylglycerol kinase δ (DGKδ) phosphorylates diacylglycerol and converts it into phosphatidic acid. DGKδ contributes to glucose uptake as one of its cellular functions. However, detail mechanisms underlying the regulation of DGKδ protein stability remain unelucidated. Herein, we identified ubiquitin-specific peptidase 11 (USP11) in the DGKδ protein complex by DGKδ-interactome analysis. By mapping analysis, we clarified that a wider region of USP11, including the catalytic domain 1 region, and both the C1 domains and catalytic subdomain-a of DGKδ mainly contributed to their association. Cellular dysfunction of USP11 by mitoxiantrone (a USP11-specific inhibitor) or siRNA knockdown markedly decreased DGKδ protein levels. Additionally, we found that DGKδ ubiquitination was increased by USP11 dysfunction, and cumulative ubiquitination was reduced by rescue manipulation. Functionally, USP11 dysfunction reduced cellular glucose uptake. Altogether, our findings provide the first evidence that USP11 deubiquitination-dependently stabilizes DGKδ to maintain cellular glucose uptake.

二酰甘油激酶δ（DGKδ）将二酰甘油磷酸化并转化为磷脂酸。DGKδ 的细胞功能之一是促进葡萄糖吸收。然而，DGKδ蛋白稳定性调控的详细机制仍未得到阐明。在此，我们通过DGKδ-相互作用组分析发现了DGKδ蛋白复合物中的泛素特异性肽酶11（USP11）。通过映射分析，我们明确了包括催化域 1 区在内的 USP11 的较宽区域与 DGKδ 的 C1 域和催化亚域-a 之间的关联。通过米托蒽醌（一种 USP11 特异性抑制剂）或 siRNA 敲除使 USP11 细胞功能失调，可显著降低 DGKδ 蛋白水平。此外，我们还发现，USP11 功能障碍会增加 DGKδ 泛素化，而拯救操作会减少累积泛素化。在功能上，USP11 功能障碍会降低细胞的葡萄糖摄取。总之，我们的研究结果首次证明了 USP11 去泛素化能依赖性地稳定 DGKδ，从而维持细胞的葡萄糖摄取。

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引用次数: 0

ELAVL1 governs breast cancer malignancy by regulating cell stemness ELAVL1 通过调节细胞干性控制乳腺癌恶性程度

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2024-11-25 DOI: 10.1016/j.bbamcr.2024.119880

Long Chen , Menglu Zhao , Linjing Liu , Tan Wang , Xue Gong , Jun Zhang

Despite advances in understanding breast cancer (BC) molecular subtypes, the mechanisms underlying its grade of malignancy remain unclear. Our study reveals that low expression of the RNA-binding protein ELAVL1 is linked to higher-grade malignancy and poorer prognosis in malignant BC subtypes. Notably, knockdown of ELAVL1 increased the expression of key stem cell markers (CD44, SOX2, OCT4, KLF4, and NANOG) and enhanced tumorsphere formation. These findings offer new insights into BC malignancy and suggest potential improvements in prognostic assessment and treatment strategies for better patient outcomes.

尽管人们对乳腺癌（BC）分子亚型的认识有所进步，但其恶性程度的内在机制仍不清楚。我们的研究发现，在恶性乳腺癌亚型中，RNA结合蛋白ELAVL1的低表达与恶性程度较高和预后较差有关。值得注意的是，ELAVL1的敲除增加了关键干细胞标志物（CD44、SOX2、OCT4、KLF4和NANOG）的表达，并增强了肿瘤球的形成。这些研究结果提供了对BC恶性肿瘤的新见解，并提出了改善预后评估和治疗策略以改善患者预后的可能性。

引用次数: 0

The association of ABC proteins with multidrug resistance in cancer ABC 蛋白与癌症中多药耐药性的关系。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2024-11-20 DOI: 10.1016/j.bbamcr.2024.119878

Andrezza Viviany Lourenço Marques , Bruna Estelita Ruginsk , Larissa de Oliveira Prado, Diogo Eugênio de Lima, Isabelle Watanabe Daniel, Vivian Rotuno Moure, Glaucio Valdameri

Multidrug resistance (MDR) poses one of the primary challenges for cancer treatment, especially in cases of metastatic disease. Various mechanisms contribute to MDR, including the overexpression of ATP-binding cassette (ABC) proteins. In this context, we reviewed the literature to establish a correlation between the overexpression of ABC proteins and MDR in cancer, considering both in vitro and clinical studies. Initially, we presented an overview of the seven subfamilies of ABC proteins, along with the subcellular localization of each protein. Subsequently, we identified a panel of 20 ABC proteins (ABCA1–3, ABCA7, ABCB1–2, ABCB4–6, ABCC1–5, ABCC10–11, ABCE1, ABCF2, ABCG1, and ABCG2) associated with MDR. We also emphasize the significance of drug sequestration by certain ABC proteins into intracellular compartments. Among the anticancer drugs linked to MDR, 29 were definitively identified as substrates for at least one of the three most crucial ABC transporters: ABCB1, ABCC1, and ABCG2. We further discussed that the most commonly used drugs in standard regimens for mainly breast cancer, lung cancer, and acute lymphoblastic leukemia could be subject to MDR mediated by ABC transporters. Collectively, these insights will aid in conducting new studies aimed at a deeper understanding of the clinical MDR mediated by ABC proteins and in designing more effective pharmacological treatments to enhance the objective response rate in cancer patients.

多药耐药性（MDR）是癌症治疗面临的主要挑战之一，尤其是在转移性疾病的情况下。导致 MDR 的机制多种多样，其中包括 ATP 结合盒（ABC）蛋白的过度表达。在此背景下，我们回顾了相关文献，通过体外研究和临床研究，确定了癌症中 ABC 蛋白过度表达与 MDR 之间的相关性。首先，我们概述了 ABC 蛋白的七个亚家族以及每个蛋白的亚细胞定位。随后，我们确定了与 MDR 相关的 20 种 ABC 蛋白（ABCA1-3、ABCA7、ABCB1-2、ABCB4-6、ABCC1-5、ABCC10-11、ABCE1、ABCF2、ABCG1 和 ABCG2）。我们还强调了某些 ABC 蛋白将药物螯合到细胞内的重要性。在与 MDR 相关的抗癌药物中，有 29 种被明确鉴定为至少一种最关键 ABC 转运体的底物：ABCB1、ABCC1 和 ABCG2。我们进一步讨论了乳腺癌、肺癌和急性淋巴细胞白血病标准疗法中最常用的药物可能会受到 ABC 转运体介导的 MDR 的影响。总之，这些见解将有助于开展新的研究，以便更深入地了解 ABC 蛋白介导的临床 MDR，并设计出更有效的药物治疗方法，提高癌症患者的客观反应率。

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引用次数: 0

Targeting SphK1/S1PR3 axis ameliorates sepsis-induced multiple organ injury via orchestration of macrophage polarization and glycolysis 通过协调巨噬细胞极化和糖酵解，靶向 SphK1/S1PR3 轴可改善败血症诱发的多器官损伤。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2024-11-14 DOI: 10.1016/j.bbamcr.2024.119877

Dan Wang , Xinwen Bi , Le Zhao , Shijian Xiang , Wenjie Xi , Shushu Yang , Weijie Wu , Tufeng Chen , Lei Zheng , Xinjin Chi , Yang Kang

Sepsis is a heterogeneous and imprecise disorder characterized by aberrant response to infection which has been accredited for detrimental impact on immune homeostasis. Recently, macrophage metabolism has been recognized as attractive targets to develop novel immunomodulatory therapy for sepsis research. However, the fine-tuning regulators dictating macrophage functions and the specific mechanisms underlying macrophage metabolic reprogramming remain largely obscure. Sphingosine-1-phosphate (S1P), a metabolic mediator of sphingolipid catabolism, predominantly formed through sphingosine kinase 1 (SphK1) catalyzing, mediates inflammation in sepsis by binding to S1P receptor 3 (S1PR3) expressed in macrophages. Here we demonstrate that SphK1/S1PR3 axis was upregulated in lipopolysaccharide (LPS)-induced macrophages and septic mice lungs, cascading the activation of proglycolytic signaling such as HIF-1α, HK2 and PFKFB3. Targeted inhibition of Sphk1 by PF-543 effectively abrogated upregulated SphK1/S1PR3 axis in vitro and in vivo. In addition, PF-543 significantly suppressed sepsis-related inflammation and multi-organ injury in vivo. Furthermore, PF-543 not only blunted key glycolytic enzymes HIF-1α, HK2, and PFKFB3 in LPS-treated macrophages but also inhibited HK2 and PFKFB3 in septic mice. Silencing or inhibiting SphK1 tempered pro-inflammatory M1 macrophages while boosted anti-inflammatory M2 macrophages. Intriguingly, S1PR3 knockdown proficiently dampened glycolysis-associated markers, retrieved LPS-modulated M1/M2 polarization and attenuated NF-κB p65 activation. In conclusion, our study provides the first evidence that PF-543 orchestrates proportional imbalance of macrophage polarization and the Warburg effect in a SphK1/S1PR3 dependent manner during sepsis, mitigating both hyperinflammation and multi-organ failure, adding a novel puzzle piece to pharmacologically exploitable therapy for sepsis.

败血症是一种异质性和不精确的疾病，其特点是对感染的异常反应，已被证实对免疫稳态有不利影响。最近，巨噬细胞代谢被认为是开发新型败血症免疫调节疗法的诱人靶点。然而，决定巨噬细胞功能的微调调节因子以及巨噬细胞代谢重编程的具体机制在很大程度上仍然模糊不清。Sphingosine-1-phosphate（S1P）是一种鞘脂分解代谢介质，主要通过鞘氨醇激酶1（SphK1）催化形成，通过与巨噬细胞中表达的S1P受体3（S1PR3）结合介导脓毒症中的炎症。我们在此证明，SphK1/S1PR3 轴在脂多糖（LPS）诱导的巨噬细胞和脓毒症小鼠肺中上调，并级联激活 HIF-1α、HK2 和 PFKFB3 等预溶解信号。PF-543 对 Sphk1 的靶向抑制能有效抑制体外和体内上调的 SphK1/S1PR3 轴。此外，PF-543 还能显著抑制败血症相关炎症和体内多器官损伤。此外，PF-543 不仅能抑制 LPS 处理巨噬细胞中的关键糖酵解酶 HIF-1α、HK2 和 PFKFB3，还能抑制败血症小鼠体内的 HK2 和 PFKFB3。沉默或抑制 SphK1 可抑制促炎性 M1 巨噬细胞，同时增强抗炎性 M2 巨噬细胞。有趣的是，敲除 S1PR3 能有效抑制糖酵解相关标记物，恢复 LPS 调节的 M1/M2 极化，并减轻 NF-κB p65 的激活。总之，我们的研究首次证明了在脓毒症期间，PF-543 以一种依赖于 SphK1/S1PR3 的方式协调了巨噬细胞极化和沃伯格效应的比例失衡，缓解了高炎症和多器官衰竭，为脓毒症的药物治疗增添了一个新的难题。

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引用次数: 0