Redox Biology最新文献_第4页

Diallyl disulfide alleviates hepatic steatosis by the conservative mechanism from fish to tetrapod: Augment Mfn2/Atgl-Mediated lipid droplet-mitochondria coupling 从鱼类到四足动物，二烯丙基二硫化物通过保守机制缓解肝脏脂肪变性：增强 Mfn2/Atgl 介导的脂滴-线粒体耦合。

IF 10.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2024-10-15 DOI: 10.1016/j.redox.2024.103395

Ling-Jiao Wang , Xiao-Hong Lai , Zhi Luo , Guang-Li Feng , Yu-Feng Song

Despite increasing evidences has highlighted the importance of mitochondria-lipid droplet (LD) coupling in maintaining lipid homeostasis, little progress in unraveling the role of mitochondria-LD coupling in hepatic lipid metabolism has been made. Additionally, diallyl disulfide (DADS), a garlic organosulfur compound, has been proposed to prevent hepatic steatosis; however, no studies have focused on the molecular mechanism to date. To address these gaps, this study investigated the systemic control mechanisms of mitochondria-LD coupling regulating hepatic lipid metabolism, and also explored their function in the process of DADS alleviating hepatic steatosis. To this end, an animal model of lipid metabolism, yellow catfish Pelteobagrus fulvidraco were fed four different diets (control, high-fat, DADS and high-fat + DADS diet) in vivo for 8 weeks; in vitro experiments were conducted to inhibit Mfn2/Atgl-mediated mitochondria-LD coupling in isolated hepatocytes. The key findings are: (1) the activations of hepatic LDs lipolysis and mitochondrial β-oxidation are likely the major drivers for DADS alleviating hepatic steatosis; (2) the underlying mechanism is that DADS enhances mitochondria-LD coupling by promoting the interaction between mitochondrion-localized Mfn2 with LD-localized Atgl, which facilitates the hepatic LDs lipolysis and the transfer of fatty acids (FAs) from LDs to mitochondria for subsequent β-oxidation; (3) Mfn2-mediated mitochondrial fusion facilitates mitochondria to form more PDM, which possess higher β-oxidation capacity in hepatocytes. Significantly, the present research unveils a previously undisclosed mechanism by which Mfn2/Atgl-mitochondria-LD coupling relieves hepatic LDs accumulation, which is a conserved strategy from fish to tetrapod. This study provides another dimension for mitochondria-LD coupling and opens up new avenues for the therapeutic interventions in hepatic steatosis.

尽管越来越多的证据强调了线粒体-脂滴（LD）耦合在维持脂质平衡中的重要性，但在揭示线粒体-LD耦合在肝脏脂质代谢中的作用方面进展甚微。此外，有人提出大蒜有机硫化合物二烯丙基二硫化物（DADS）可预防肝脏脂肪变性，但迄今为止还没有研究关注其分子机制。针对这些空白，本研究调查了线粒体-二硫化物耦联调节肝脏脂质代谢的系统控制机制，并探讨了它们在 DADS 缓解肝脂肪变性过程中的功能。为此，在体内喂食四种不同的饮食（对照组、高脂组、DADS组和高脂+DADS组）8周，以黄颡鱼为脂代谢动物模型；在体外实验中抑制离体肝细胞中Mfn2/Atgl介导的线粒体-LD偶联。主要发现有(1）肝脏 LDs 脂肪分解和线粒体 β 氧化的激活可能是 DADS 缓解肝脏脂肪变性的主要驱动力；(2）其基本机制是，DADS通过促进线粒体定位的Mfn2与LD定位的Atgl之间的相互作用，增强线粒体-LD耦联，从而促进肝脏LDs脂肪分解和脂肪酸（FA）从LDs转移到线粒体进行后续的β氧化；（3）Mfn2介导的线粒体融合促进线粒体形成更多的PDM，而PDM在肝细胞中具有更高的β氧化能力。重要的是，本研究揭示了一种以前未曾披露的机制，即Mfn2/Atgl-线粒体-LD耦合缓解肝脏LDs积累，这是一种从鱼类到四足动物的保守策略。这项研究为线粒体-LD耦合提供了另一个维度，并为肝脏脂肪变性的治疗干预开辟了新途径。

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引用次数: 0

Monoamine oxidases: A missing link between mitochondria and inflammation in chronic diseases ? 单胺氧化酶：慢性疾病中线粒体与炎症之间缺失的联系？

IF 10.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2024-10-11 DOI: 10.1016/j.redox.2024.103393

Lise Beucher, Claudie Gabillard-Lefort, Olivier R. Baris, Jeanne Mialet-Perez

The role of mitochondria spans from the regulation of the oxidative phosphorylation, cell metabolism and survival/death pathways to a more recently identified function in chronic inflammation. In stress situations, mitochondria release some pro-inflammatory mediators such as ATP, cardiolipin, reactive oxygen species (ROS) or mitochondrial DNA, that are believed to participate in chronic diseases and aging. These mitochondrial Damage-Associated Molecular Patterns (mito-DAMPs) can modulate specific receptors among which TLR9, NLRP3 and cGAS-STING, triggering immune cells activation and sterile inflammation. In order to counter the development of chronic diseases, a better understanding of the underlying mechanisms of low grade inflammation induced by mito-DAMPs is needed. In this context, monoamine oxidases (MAO), the mitochondrial enzymes that degrade catecholamines and serotonin, have recently emerged as potent regulators of chronic inflammation in obesity-related disorders, cardiac diseases, cancer, rheumatoid arthritis and pulmonary diseases. The role of these enzymes in inflammation embraces their action in both immune and non-immune cells, where they regulate monoamines levels and generate toxic ROS and aldehydes, as by-products of enzymatic reaction. Here, we discuss the more recent advances on the role and mechanisms of action of MAOs in chronic inflammatory diseases.

线粒体的作用包括调节氧化磷酸化、细胞新陈代谢和存活/死亡途径，以及最近发现的慢性炎症功能。在应激情况下，线粒体会释放一些促炎症介质，如 ATP、心磷脂、活性氧（ROS）或线粒体 DNA，这些介质被认为参与了慢性疾病和衰老。这些线粒体损伤相关分子模式（mitochondrial Damage-Associated Molecular Patterns, mito-DAMPs）可以调节特定的受体，其中包括 TLR9、NLRP3 和 cGAS-STING，从而引发免疫细胞活化和无菌性炎症。为了应对慢性疾病的发展，需要更好地了解有丝分裂-DAMPs 诱导低度炎症的基本机制。在这方面，单胺氧化酶（MAO）是线粒体中降解儿茶酚胺和血清素的酶，最近已成为肥胖相关疾病、心脏病、癌症、类风湿性关节炎和肺部疾病中慢性炎症的有效调节剂。这些酶在炎症中的作用包括它们在免疫细胞和非免疫细胞中的作用，它们调节单胺类物质的水平，并产生有毒的 ROS 和醛，作为酶反应的副产品。在此，我们将讨论 MAOs 在慢性炎症性疾病中的作用和作用机制的最新进展。

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引用次数: 0

Role of MTH1 in oxidative stress and therapeutic targeting of cancer MTH1 在氧化应激和癌症靶向治疗中的作用

IF 10.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2024-10-11 DOI: 10.1016/j.redox.2024.103394

Aaliya Taiyab , Anam Ashraf , Md Nayab Sulaimani , Aanchal Rathi , Anas Shamsi , Md Imtaiyaz Hassan

Cancer cells maintain high levels of reactive oxygen species (ROS) to drive their growth, but ROS can trigger cell death through oxidative stress and DNA damage. To survive enhanced ROS levels, cancer cells activate their antioxidant defenses. One such defense is MTH1, an enzyme that prevents the incorporation of oxidized nucleotides into DNA, thus preventing DNA damage and allowing cancer to proliferate. MTH1 levels are often elevated in many cancers, and thus, inhibiting MTH1 is an attractive strategy for suppressing tumor growth and metastasis. Targeted MTH1 inhibition can induce DNA damage in cancer cells, exploiting their vulnerability to oxidative stress and selectively targeting them for destruction. Targeting MTH1 is promising for cancer treatment because normal cells have lower ROS levels and are less dependent on these pathways, making the approach both effective and specific to cancer. This review aims to investigate the potential of MTH1 as a therapeutic target, especially in cancer treatment, offering detailed insights into its structure, function, and role in disease progression. We also discussed various MTH1 inhibitors that have been developed to selectively induce oxidative damage in cancer cells, though their effectiveness varies. In addition, this review provide deeper mechanistic insights into the role of MTH1 in cancer prevention and oxidative stress management in various diseases.

癌细胞维持高水平的活性氧（ROS）以驱动其生长，但 ROS 可通过氧化应激和 DNA 损伤引发细胞死亡。为了生存，癌细胞会激活其抗氧化防御系统。MTH1 就是这样一种防御机制，它是一种防止氧化核苷酸掺入 DNA 的酶，从而防止 DNA 损伤，使癌细胞得以增殖。在许多癌症中，MTH1 的水平经常升高，因此，抑制 MTH1 是抑制肿瘤生长和转移的一种有吸引力的策略。靶向抑制 MTH1 可诱导癌细胞 DNA 损伤，利用癌细胞对氧化应激的脆弱性，有选择性地对其进行靶向破坏。靶向 MTH1 在癌症治疗中大有可为，因为正常细胞的 ROS 水平较低，对这些途径的依赖性较低，因此这种方法对癌症既有效又有特异性。本综述旨在研究 MTH1 作为治疗靶点的潜力，尤其是在癌症治疗中的作用，详细介绍其结构、功能和在疾病进展中的作用。我们还讨论了已开发出的各种 MTH1 抑制剂，这些抑制剂可选择性地诱导癌细胞发生氧化损伤，但效果各异。此外，本综述还从机理角度深入探讨了 MTH1 在癌症预防和各种疾病的氧化应激管理中的作用。

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引用次数: 0

HJURP inhibits sensitivity to ferroptosis inducers in prostate cancer cells by enhancing the peroxidase activity of PRDX1 HJURP 通过增强 PRDX1 的过氧化物酶活性来抑制前列腺癌细胞对铁变态诱导剂的敏感性

IF 10.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2024-10-10 DOI: 10.1016/j.redox.2024.103392

Wenjie Lai , Weian Zhu , Jianjie Wu , Jiongduan Huang , Xiaojuan Li , Yun Luo , Yu Wang , Hengda Zeng , Mingqiang Li , Xiaofu Qiu , Xingqiao Wen

Ferroptosis induction has emerged as a promising therapeutic approach for prostate cancer (PCa), either as a monotherapy or in combination with hormone therapy. Therefore, identifying the mechanisms regulating ferroptosis in PCa cells is essential. Our previous study demonstrated that HJURP, an oncogene upregulated in PCa cells, plays a role in tumor proliferation. Here, we expand these findings by elucidating a novel mechanism by which HJURP inhibits sensitivity to ferroptosis inducers in PCa cells via the PRDX1/reactive oxygen species (ROS) pathway in vitro and in vivo. Mechanistically, HJURP forms disulfide-linked intermediates with PRDX1 through Cys³²⁷ and Cys⁴⁵⁷ residues. This disulfide binding promotes PRDX1 redox cycling and inhibits its hyperoxidation. As a result, HJURP enhances the peroxidase activity of PRDX1, leading to a decrease in ROS levels and subsequently suppressing lipid peroxidation induced by ferroptosis inducers. These findings reveal the potential of HJURP/PRDX1 as novel therapeutic targets and biomarkers of ferroptosis in PCa patients.

铁氧化诱导已成为治疗前列腺癌（PCa）的一种很有前景的方法，既可作为一种单一疗法，也可与激素疗法结合使用。因此，确定 PCa 细胞中的铁突变调控机制至关重要。我们之前的研究表明，PCa 细胞中上调的癌基因 HJURP 在肿瘤增殖中起作用。在这里，我们通过阐明 HJURP 在体外和体内通过 PRDX1/活性氧（ROS）途径抑制 PCa 细胞对铁突变诱导剂的敏感性的新机制，扩展了这些发现。从机理上讲，HJURP 通过 Cys327 和 Cys457 残基与 PRDX1 形成二硫键中间体。这种二硫键结合促进了 PRDX1 的氧化还原循环，抑制了它的高氧化作用。因此，HJURP 能增强 PRDX1 的过氧化物酶活性，导致 ROS 水平下降，进而抑制铁变态诱导剂诱导的脂质过氧化反应。这些发现揭示了 HJURP/PRDX1 作为新的治疗靶点和 PCa 患者铁变态反应生物标志物的潜力。

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引用次数: 0

Methionine oxidation of actin cytoskeleton attenuates traumatic memory retention via reactivating dendritic spine morphogenesis 肌动蛋白细胞骨架的蛋氨酸氧化可通过重新激活树突棘形态发生减轻创伤记忆的保持

IF 10.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2024-10-09 DOI: 10.1016/j.redox.2024.103391

Cun-Dong Huang , Yu Shi , Fang Wang , Peng-Fei Wu , Jian-Guo Chen

Post-traumatic stress disorder (PTSD) is characterized by hypermnesia of the trauma and a persistent fear response. The molecular mechanisms underlying the retention of traumatic memories remain largely unknown, which hinders the development of more effective treatments. Utilizing auditory fear conditioning, we demonstrate that a redox-dependent dynamic pathway for dendritic spine morphogenesis in the basolateral amygdala (BLA) is crucial for traumatic memory retention. Exposure to a fear-induced event markedly increased the reduction of oxidized filamentous actin (F-actin) and decreased the expression of the molecule interacting with CasL 1 (MICAL1), a methionine-oxidizing enzyme that directly oxidizes and depolymerizes F-actin, leading to cytoskeletal dynamic abnormalities in the BLA, which impairs dendritic spine morphogenesis and contributes to the persistence of fearful memories. Following fear conditioning, overexpression of MICAL1 in the BLA inhibited freezing behavior during fear memory retrieval via reactivating cytokinesis, whereas overexpression of methionine sulfoxide reductase B 1, a key enzyme that reduces oxidized F-actin monomer, increased freezing behavior during retrieval. Notably, intra-BLA injection of semaphorin 3A, an endogenous activator of MICAL1, rapidly disrupted fear memory within a short time window after conditioning. Collectively, our results indicate that redox modulation of actin cytoskeleton in the BLA is functionally linked to fear memory retention and PTSD-like memory.

创伤后应激障碍（PTSD）的特点是对创伤记忆过度和持续的恐惧反应。创伤记忆保留的分子机制在很大程度上仍然未知，这阻碍了更有效治疗方法的开发。我们利用听觉恐惧条件反射证明，杏仁基底外侧（BLA）树突棘形态发生的氧化还原依赖性动态途径对创伤记忆的保留至关重要。暴露于恐惧诱导的事件明显增加了氧化丝状肌动蛋白（F-actin）的减少，并降低了与CasL 1相互作用的分子（MICAL1）的表达，MICAL1是一种蛋氨酸氧化酶，可直接氧化和解聚F-actin，从而导致杏仁基底节细胞骨架动态异常，这损害了树突棘形态发生，并导致恐惧记忆的持续。恐惧条件反射后，在BLA中过表达MICAL1可通过重新激活细胞分裂抑制恐惧记忆检索过程中的冻结行为，而过表达蛋氨酸亚砜还原酶B 1（一种减少氧化F-肌动蛋白单体的关键酶）则会增加检索过程中的冻结行为。值得注意的是，在BLA内注射内源性激活剂MICAL1的semaphorin 3A会在条件反射后的短时间内迅速破坏恐惧记忆。总之，我们的研究结果表明，BLA中肌动蛋白细胞骨架的氧化还原调节与恐惧记忆保持和创伤后应激障碍样记忆有功能上的联系。

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引用次数: 0

Methionine restriction alleviates diabetes-associated cognitive impairment via activation of FGF21 通过激活 FGF21 限制蛋氨酸摄入可减轻糖尿病相关的认知障碍。

IF 10.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2024-10-08 DOI: 10.1016/j.redox.2024.103390

Yuyu Zhang , Yajie Wang , Yiju Li , Jingxi Pang , Annika Höhn , Weixuan Dong , Rui Gao , Yan Liu , Da Wang , Yongbo She , Rui Guo , Zhigang Liu

Glucose metabolism disturbances may result in diabetes-associated cognitive decline (DACI). Methionine restriction (MR) diet has emerged as a potential dietary strategy for managing glucose homeostasis. However, the effects and underlying mechanisms of MR on DACI have not been fully elucidated. Here, we found that a 13-week MR (0.17 % methionine, w/w) intervention starting at 8 weeks of age improved peripheral insulin sensitivity in male db/db mice, a model for type 2 diabetes. Notably, MR significantly improved working as well as long-term memory in db/db mice, accompanied by increased PSD-95 level and reduced neuroinflammatory factors, malondialdehyde (MDA), and 8-hydroxy-2′-deoxyguanosine (8-OHdG). We speculate that this effect may be mediated by MR activating hepatic fibroblast growth factor 21 (FGF21) and the brain FGFR1/AMPK/GLUT4 signaling pathway to enhance brain glucose metabolism. To further delineate the mechanism, we used intracerebroventricular injection of adeno-associated virus to specifically knock down FGFR1 in the brain to verify the role of FGFR1 in MR-mediated DACI. It was found that the positive effects of MR on DACI were offset, reflected in decreased cognitive function, impaired synaptic plasticity, upregulated neuroinflammation, and balanced enzymes regulating reactive oxygen species (Sod1, Sod2, Nox4). Of note, the FGFR1/AMPK/GLUT4 signaling pathway and brain glucose metabolism were inhibited. In summary, our study demonstrated that MR increased peripheral insulin sensitivity, activated brain FGFR1/AMPK/GLUT4 signaling through FGF21, maintained normal glucose metabolism and redox balance in the brain, and thereby alleviated DACI. These results provide new insights into the effects of MR diet on cognitive dysfunction caused by impaired brain energy metabolism.

葡萄糖代谢紊乱可能导致糖尿病相关认知能力下降（DACI）。蛋氨酸限制（MR）饮食已成为管理葡萄糖稳态的一种潜在饮食策略。然而，MR 对 DACI 的影响及其内在机制尚未完全阐明。在这里，我们发现从 8 周龄开始进行为期 13 周的 MR（0.17% 蛋氨酸，w/w）干预可改善雄性 db/db 小鼠（2 型糖尿病模型）的外周胰岛素敏感性。值得注意的是，MR能明显改善db/db小鼠的工作记忆和长期记忆，同时还能提高PSD-95水平，减少神经炎症因子、丙二醛（MDA）和8-羟基-2'-脱氧鸟苷（8-OHdG）。我们推测这种效应可能是通过 MR 激活肝脏成纤维细胞生长因子 21（FGF21）和大脑 FGFR1/AMPK/GLUT4 信号通路来加强大脑葡萄糖代谢。为进一步阐明其机制，我们采用脑室内注射腺相关病毒的方法特异性敲除脑内的FGFR1，以验证FGFR1在MR介导的DACI中的作用。研究发现，MR 对 DACI 的积极作用被抵消，表现为认知功能下降、突触可塑性受损、神经炎症上调以及活性氧调节酶（Sod1、Sod2、Nox4）平衡。值得注意的是，FGFR1/AMPK/GLUT4 信号通路和脑葡萄糖代谢受到抑制。总之，我们的研究表明，MR 提高了外周胰岛素敏感性，通过 FGF21 激活了大脑 FGFR1/AMPK/GLUT4 信号传导，维持了大脑正常的葡萄糖代谢和氧化还原平衡，从而缓解了 DACI。这些结果为研究 MR 饮食对大脑能量代谢受损导致的认知功能障碍的影响提供了新的视角。

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引用次数: 0

Insulin oxidation and oxidative modifications alter glucose uptake, cell metabolism, and inflammatory secretion profiles 胰岛素氧化和氧化修饰会改变葡萄糖摄取、细胞代谢和炎症分泌情况。

IF 10.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2024-10-05 DOI: 10.1016/j.redox.2024.103372

Ramona Clemen , Wiebke Dethloff , Julia Berner , Paul Schulan , Alice Martinet , Klaus Dieter Weltmann , Thomas von Woedtke , Tilman Grune , Kristian Wende , Sander Bekeschus

Insulin participates in glucose homeostasis in the body and regulates glucose, protein, and lipid metabolism. Chronic hyperglycemia triggers oxidative stress and the generation of reactive oxygen species (ROS), leading to oxidized insulin variants. Oxidative protein modifications can cause functional changes or altered immunogenicity as known from the context of autoimmune disorders. However, studies on the biological function of native and oxidized insulin on glucose homeostasis and cellular function are lacking. Native insulin showed heterogenous effects on metabolic activity, proliferation, glucose carrier transporter (GLUT) 4, and insulin receptor (INSR) expression, as well as glucose uptake in cell lines of five different human tissues. Diverse ROS compositions produced by different gas plasma approaches enabled the investigations of variously modified insulin (oxIns) with individual oxidative post-translational modification (oxPTM) patterns as identified using high-resolution mass spectrometric analysis. Specific oxIns variants promoted cellular metabolism and proliferation in several cell lines investigated, and nitrogen plasma emission lines could be linked to insulin nitration and elevated glucose uptake. In addition, insulin oxidation modified blood glucose levels in the chicken embryos (in ovo), underlining the importance of assessing protein oxidation and function in health and disease.

胰岛素参与体内葡萄糖平衡，并调节葡萄糖、蛋白质和脂质代谢。长期高血糖会引发氧化应激，产生活性氧（ROS），导致胰岛素变体氧化。氧化蛋白修饰可导致功能性改变或免疫原性改变，这在自身免疫性疾病中已为人所知。然而，有关原生胰岛素和氧化胰岛素对葡萄糖稳态和细胞功能的生物功能的研究还很缺乏。原生胰岛素对新陈代谢活性、增殖、葡萄糖载体转运体（GLUT）4 和胰岛素受体（INSR）的表达以及五种不同人体组织细胞系的葡萄糖摄取显示出不同的影响。采用不同的气体等离子体方法产生的 ROS 成分各不相同，因此能够研究出不同的修饰胰岛素（oxIns），并通过高分辨率质谱分析确定了它们各自的氧化翻译后修饰（oxPTM）模式。特定的氧化胰岛素变体促进了所研究的几种细胞系的细胞代谢和增殖，氮气等离子体发射线可能与胰岛素硝化和葡萄糖摄取增加有关。此外，胰岛素氧化改变了鸡胚胎（卵内）的血糖水平，突出了评估健康和疾病中蛋白质氧化和功能的重要性。

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引用次数: 0

Combinatorial lipidomics and proteomics underscore erythrocyte lipid membrane aberrations in the development of adverse cardio-cerebrovascular complications in maintenance hemodialysis patients 脂质组学和蛋白质组学的结合强调了红细胞膜脂质畸变在维持性血液透析患者心脑血管不良并发症发生过程中的作用

IF 10.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2024-10-05 DOI: 10.1016/j.redox.2024.103389

Ke Zheng , Yujun Qian , Haiyun Wang , Dan Song , Hui You , Bo Hou , Fei Han , Yicheng Zhu , Feng Feng , Sin Man Lam , Guanghou Shui , Xuemei Li

Patients on maintenance hemodialysis exhibit a notably higher risk of cardio-cerebrovascular complications that constitute the major cause of death. Preceding studies have reported conflicting associations between traditional lipid measures and clinical outcome in dialysis patients. In this prospective longitudinal study, we utilized quantitative lipidomics to elucidate, at molecular resolution, changes in lipidome profiles of erythrocyte and plasma samples collected from maintenance hemodialysis patients followed up for 86 months (≈7 years). Primary outcome was defined as cardiovascular-related deaths or new-onset cardio-cerebrovascular events. Cox regression model uncovered plasma/erythrocyte lipids associated with incident cardio-cerebrovascular events in the erythrocyte cohort (n = 117 patients, 37 events) and plasma cohort (n = 45 patients, 11 events), respectively. Both the erythrocyte lipid panel [PA 40:5, PI 34:2, PC 42:6, AUC = 0.83] and plasma lipid panel [PC O-34:1, GM3 18:1; O2/25:0, TG 44:1(16:1_28:0), AUC = 0.94] significantly improved the prediction of cardio-cerebrovascular-related outcome compared to the base model comprising age, sex and dialysis vintage alone. Our findings underscore the pathophysiological significance of anionic phospholipid accretion in erythrocytes in the development of cardio-cerebrovascular complications in dialysis patients. In particular, distorted membrane lipid asymmetry leads to compromised membrane deformability, aberrant cell-cell interactions and altered glutathione metabolism in the erythrocytes of high-risk individuals even at relatively early stage of hemodialysis. Our findings thus underscore the importance of maintaining the RBC pool to lower the risk of cardio-cerebrovascular complications in dialysis patients.

接受维持性血液透析的患者发生心脑血管并发症的风险明显较高，而这些并发症是导致患者死亡的主要原因。之前的研究报告显示，透析患者的传统血脂指标与临床结果之间存在相互矛盾的关系。在这项前瞻性纵向研究中，我们利用定量脂质组学在分子分辨率上阐明了从随访 86 个月（≈7 年）的维持性血液透析患者采集的红细胞和血浆样本中脂质组特征的变化。主要结果定义为心血管相关死亡或新发心脑血管事件。Cox回归模型发现，血浆/红细胞血脂分别与红细胞队列（n = 117 名患者，37 起事件）和血浆队列（n = 45 名患者，11 起事件）中发生的心脑血管事件有关。与仅包括年龄、性别和透析年份的基础模型相比，红细胞脂质面板[PA 40:5、PI 34:2、PC 42:6，AUC = 0.83]和血浆脂质面板[PC O-34:1、GM3 18:1；O2/25:0、TG 44:1(16:1_28:0)，AUC = 0.94]均显著提高了心脑血管相关结局的预测能力。我们的研究结果表明，红细胞中阴离子磷脂的增生对透析患者心脑血管并发症的发生具有重要的病理生理意义。特别是，即使在血液透析的相对早期阶段，膜脂不对称的扭曲也会导致高危人群的红细胞膜变形能力受损、细胞-细胞相互作用失常和谷胱甘肽代谢改变。因此，我们的研究结果强调了维持红细胞池以降低透析患者心脑血管并发症风险的重要性。

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引用次数: 0

Enhancing Gpx1 palmitoylation to inhibit angiogenesis by targeting PPT1 通过靶向 PPT1 增强 Gpx1 棕榈酰化抑制血管生成

IF 10.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2024-10-05 DOI: 10.1016/j.redox.2024.103376

Yidan Ma , Xinxin Yuan , Aodong Wei , Xiaopeng Li , Azim Patar , Shaobo Su , Songtao Wang , Gaoen Ma , Jiangli Zhu , Eryan Kong

The significance of protein S-palmitoylation in angiogenesis has been largely overlooked, leaving various aspects unexplored. Recent identification of Gpx1 as a palmitoylated protein has generated interest in exploring its potential involvement in novel pathological mechanisms related to angiogenesis. In this study, we demonstrate that Gpx1 undergoes palmitoylation at cysteine-76 and -113, with PPT1 playing a crucial role in modulating the depalmitoylation of Gpx1. Furthermore, we find that PPT1-regulated depalmitoylation negatively impacts Gpx1 protein stability. Interestingly, inhibiting Gpx1 palmitoylation, either through expression of a non-palmitoylated Gpx1 mutant or by expressing PPT1, significantly enhances neovascular angiogenesis. Conversely, in PPT1-deficient mice, angiogenesis is notably attenuated compared to wild-type mice in an Oxygen-Induced Retinopathy (OIR) model, which mimics pathological angiogenesis. Physiologically, under hypoxic conditions, Gpx1 palmitoylation levels are drastically reduced, suggesting that increasing Gpx1 palmitoylation may have beneficial effects. Indeed, enhancing Gpx1 palmitoylation by inhibiting PPT1 with DC661 effectively suppresses retinal angiogenesis in the OIR disease model. Overall, our findings highlight the pivotal role of protein palmitoylation in angiogenesis and propose a novel mechanism whereby the PPT1-Gpx1 axis modulates angiogenesis, thereby providing a potential therapeutic strategy for targeting PPT1 to combat angiogenesis.

蛋白质 S-棕榈酰化在血管生成中的重要性在很大程度上被忽视了，导致各方面的问题尚未得到探索。最近发现 Gpx1 是一种棕榈酰化蛋白，这引起了人们探索其可能参与血管生成相关新病理机制的兴趣。在这项研究中，我们证明了 Gpx1 在半胱氨酸-76 和-113 处发生棕榈酰化，而 PPT1 在调节 Gpx1 的去棕榈酰化过程中起着至关重要的作用。此外，我们还发现 PPT1 调控的去棕榈酰化对 Gpx1 蛋白的稳定性有负面影响。有趣的是，通过表达非棕榈酰化的 Gpx1 突变体或表达 PPT1 来抑制 Gpx1 的棕榈酰化，能显著增强新生血管的生成。相反，在模拟病理性血管生成的氧诱导视网膜病变（OIR）模型中，与野生型小鼠相比，PPT1 缺陷小鼠的血管生成明显减弱。生理学上，在缺氧条件下，Gpx1棕榈酰化水平会急剧下降，这表明增加Gpx1棕榈酰化可能会产生有益的影响。事实上，通过使用 DC661 抑制 PPT1 来增强 Gpx1 的棕榈酰化，能有效抑制 OIR 疾病模型中视网膜血管的生成。总之，我们的研究结果强调了蛋白质棕榈酰化在血管生成中的关键作用，并提出了 PPT1-Gpx1 轴调节血管生成的新机制，从而为靶向 PPT1 对抗血管生成提供了潜在的治疗策略。

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引用次数: 0

Regulation of cardiovascular diseases by histone deacetylases and NADPH oxidases 组蛋白去乙酰化酶和 NADPH 氧化酶对心血管疾病的调节。

IF 10.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2024-10-04 DOI: 10.1016/j.redox.2024.103379

Hui Yan , Yidan Yin , Yichen Zhou , Zhanghang Li , Yuxing Li , Lingxuan Ren , Jiazheng Wen , Weirong Wang

Histone deacetylases (HDACs) play critical roles in cardiovascular diseases (CVDs). In addition, reactive oxygen species (ROS) produced by NADPH oxidases (NOXs) exert damaging effects due to oxidative stress on heart and blood vessels. Although NOX-dependent ROS production is implicated in pathogenesis, the relationship between HDACs and NOXs in CVDs remains to be elucidated. Here, we present an overview of the regulatory effects and interconnected signaling pathways of HDACs and NOXs in CVDs. Improved insights into these relationships will facilitate the discovery of novel therapeutic agents that target HDACs, oxidase stress pathways, and the interactions between these systems which may be highly effective in the prevention and treatment of cardiovascular disorders.

组蛋白去乙酰化酶（HDACs）在心血管疾病（CVDs）中起着至关重要的作用。此外，NADPH 氧化酶（NOXs）产生的活性氧（ROS）会因氧化应激对心脏和血管产生破坏作用。虽然依赖于 NOX 的 ROS 生成与发病机制有关，但 HDAC 与 NOX 在心血管疾病中的关系仍有待阐明。在此，我们概述了 HDAC 和 NOX 在心血管疾病中的调控作用和相互关联的信号通路。提高对这些关系的认识将有助于发现针对 HDACs、氧化酶应激途径以及这些系统之间相互作用的新型治疗药物，这些药物可能对心血管疾病的预防和治疗非常有效。

引用次数: 0