International Journal of Biochemistry & Cell Biology最新文献_第2页

A modified model of PANoptosisto identify prognosis and immunotherapy response in bladder cancer 一种用于鉴别膀胱癌预后和免疫疗法反应的改良泛凋亡模型

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2024-10-04 DOI: 10.1016/j.biocel.2024.106672

Weichao Lv , Xiaohang Lei , Hongyuan Wang , Tongtong Wang , Jianguo Zhang

Background

Cell death, including apoptosis and necrosis, collectively known as widespread apoptosis. The present study aims to investigate the mechanism of action in widespread apoptosis-related modification patterns in bladder cancer.

Methods

Using a clinical genomics database, we obtained transcriptomic data and related clinical information of bladder cancer patients. By employing the least absolute shrinkage analysis, we were able to construct a risk model and single-cell sequencing analysis of differential genes in bladder cancer.

Results

Five differentially expressed genes (TMPRSS4, TPST1, FOXD1, ELOVL4, EMP1) associated with widespread apoptosis were identified as features for predicting the prognosis of bladder cancer patients. Survival curve analysis revealed significant differences in prognosis (P<0.05). Additionally, multivariate Cox regression analysis determined the independent risk factor for bladder cancer prognosis as the risk score (P<0.001), with high confidence in the scoring model validated internally (P<0.001). Single-cell sequencing reveals high expression of CDKN2A, ERBB2, and TMPRSS4 in B cells, while HRAS is significantly expressed in fibroblasts.

Conclusion

PANscore, as a potential prognostic and immunotherapeutic biomarker, will provide more precise and rational basis for personalized treatment strategies

背景：细胞死亡包括凋亡和坏死，统称为广泛凋亡。本研究旨在探讨膀胱癌广泛凋亡相关修饰模式的作用机制：方法：利用临床基因组学数据库，我们获得了膀胱癌患者的转录组数据和相关临床信息。方法：利用临床基因组学数据库，我们获得了膀胱癌患者的转录组数据和相关临床信息，通过最小绝对缩减分析，我们构建了一个风险模型，并对膀胱癌中的差异基因进行了单细胞测序分析：结果：五个与广泛凋亡相关的差异表达基因（TMPRSS4、TPST1、FOXD1、ELOVL4、EMP1）被确定为预测膀胱癌患者预后的特征。生存曲线分析显示了预后的显著差异（PConclusion：PANscore作为一种潜在的预后和免疫治疗生物标志物，将为个性化治疗策略提供更精确、更合理的依据。

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引用次数: 0

Visualizing, quantifying and mapping chromatin remodelers at work with single-molecule and single-cell imaging 利用单分子和单细胞成像技术可视化、量化和绘制染色质重塑者的工作图。

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2024-10-01 DOI: 10.1016/j.biocel.2024.106667

Hendrik Sielaff , Ziqing Winston Zhao

Chromatin remodeling, carried out by four major subfamilies of ATP-dependent remodeler complexes across eukaryotes, alleviates the topological challenge posed by nucleosomes to regulate genome access. Recently, single-molecule and single-cell imaging techniques have been widely employed to probe this crucial process, both in vitro and in cellulo. Herein, we provide an integrated account of key recent efforts that leverage these approaches to visualize, quantify and map chromatin remodelers at work, elucidating diverse aspects of the remodeling process in both space and time, including molecular mechanisms of DNA wrapping/unwrapping, nucleosome translocation and histone exchange, dynamics of chromatin binding/target search and their intranuclear organization into hotspots or phase condensates, as well as functional coupling with transcription. The mechanistic insights and quantitative parameters revealed shed light on a multi-modal yet shared landscape for regulating remodeling across molecular and cellular scales, and pave the way for further interrogating the implications of its misregulation in disease contexts.

染色质重塑由真核生物中依赖 ATP 的重塑复合体的四个主要亚家族完成，它缓解了核小体带来的拓扑挑战，从而调节基因组的访问。最近，单分子和单细胞成像技术被广泛用于体外和细胞内探究这一关键过程。在此，我们综合介绍了近期利用这些方法对染色质重塑者的工作进行可视化、量化和绘图的主要工作，阐明了重塑过程在空间和时间上的不同方面，包括DNA包裹/解包裹、核小体易位和组蛋白交换的分子机制，染色质结合/目标搜索的动态及其在核内组织成热点或相凝聚体的过程，以及与转录的功能耦合。所揭示的机理见解和定量参数揭示了跨分子和细胞尺度调控重塑的多模式但共享的格局，并为进一步探究其在疾病中的失调影响铺平了道路。

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引用次数: 0

MIEN1 on the 17q12 amplicon facilitates the malignant behaviors of gastric cancer via activating IL-6/JAK2/STAT3 pathway 17q12扩增片段上的MIEN1通过激活IL-6/JAK2/STAT3通路促进胃癌的恶性行为。

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2024-09-27 DOI: 10.1016/j.biocel.2024.106666

Jing Lin , Dong Wang , Jiahui Zhou , Jing Bai , Shouzhen Sun , Xueyuan Jia , Xiao Liang , Songbin Fu , Jingcui Yu

Oncogene amplification is a significant factor contributing to poor prognosis and limited treatment in patients with advanced gastric cancer. Therefore, identifying amplified oncogenes and elucidating their oncogenic mechanisms will provide reliable therapeutic targets for the clinical treatment of gastric cancer. In this study, we identify a high amplification of 17q12, which includes five oncogenes that are co-amplified and co-overexpressed with ERBB2 using array comparative genomic hybridization, with migration and invasion enhancer 1 (MIEN1) being particularly highlighted for its clinical significance, function, and role in gastric cancer progression. By detecting MIEN1 copy number and expression level across eight gastric cancer cell lines and in tissue microarrays from 543 primary gastric cancer tissues, we found that MIEN1 amplification and overexpression correlated with sex and Lauren’s intestinal type classification of gastric cancer. Besides that, elevated MIEN1 expression was associated with poorer patient survival. In vitro experiments have shown that MIEN1 overexpression enhanced cell proliferation, invasion, and migration, whereas MIEN1 knockdown reversed these malignant phenotypes in vitro. Furthermore, MIEN1 knockdown inhibited tumorigenesis and metastasis of gastric cancer cells in nude mice. Mechanistically, MIEN1 activates the IL-6/JAK2/STAT3 signaling pathway, which drives the proliferation, invasion, and migration of gastric cancer cells. This study demonstrates that MIEN1 contributes to the malignant behavior of gastric cancer through the IL-6/JAK2/STAT3 pathway, suggesting that MIEN1 could serve as a valuable therapeutic target for gastric cancer.

癌基因扩增是导致晚期胃癌患者预后不良和治疗受限的一个重要因素。因此，识别扩增的癌基因并阐明其致癌机制将为胃癌的临床治疗提供可靠的治疗靶点。在本研究中，我们利用阵列比较基因组杂交技术发现了17q12的高扩增，其中包括5个与ERBB2共扩增和共表达的癌基因，其中迁移和侵袭增强子1（MIEN1）因其临床意义、功能和在胃癌进展中的作用而尤为突出。通过检测八种胃癌细胞系和 543 例原发性胃癌组织芯片中 MIEN1 的拷贝数和表达水平，我们发现 MIEN1 的扩增和过表达与胃癌的性别和劳伦肠型分类有关。此外，MIEN1 表达的升高与患者生存率的降低有关。体外实验表明，MIEN1的过表达会增强细胞的增殖、侵袭和迁移，而MIEN1的敲除会逆转体外实验中的这些恶性表型。此外，MIEN1敲除抑制了裸鼠胃癌细胞的肿瘤发生和转移。从机理上讲，MIEN1激活了IL-6/JAK2/STAT3信号通路，而IL-6/JAK2/STAT3信号通路驱动了胃癌细胞的增殖、侵袭和迁移。这项研究表明，MIEN1通过IL-6/JAK2/STAT3通路促进了胃癌的恶性行为，提示MIEN1可作为胃癌的一个有价值的治疗靶点。

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引用次数: 0

Classical psychedelics’ action on brain monoaminergic systems 经典迷幻药对大脑单胺能系统的作用。

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2024-09-25 DOI: 10.1016/j.biocel.2024.106669

Jasmine Jade Butler , Daria Ricci , Chloé Aman , Anna Beyeler , Philippe De Deurwaerdère

The study of the mechanism of action of classical psychedelics has gained significant interest due to their clinical potential in the treatment of several psychiatric conditions, including major depressive and anxiety disorders. These drugs bind 5-hydroxytryptamine receptors (5-HTR) including 5-HT_1AR, 5-HT_2AR, 5-HT_2BR, and/or 5-HT₂_CR, as well as other targets. 5-HTRs regulate the activity of ascending monoaminergic neurons, a mechanism primarily involved in the action of classical antidepressant drugs, antipsychotics, and drugs of abuse. Sparse neurochemical data have been produced on the control of monoaminergic neuron activity in response to classical psychedelics. Here we review the available data in order to determine whether classical psychedelics have specific neurochemical effects on serotonergic, dopaminergic, and noradrenergic neurons. The data show that these drugs have disparate effects on each monoaminergic system, demonstrating a complex response with state-dependent and region-specific effects. For instance, several psychedelics inhibit the firing of serotonergic neurons, although this is not necessarily associated with a decrease in serotonin release in all regions. Noradrenergic neuron spontaneous activity also appears to be inhibited by psychedelics, also not necessarily associated with a decrease in noradrenaline release in all regions. Psychedelics influence on dopaminergic systems is also complex as the above-mentioned 5-HTRs may have opposing effects on dopaminergic neuron activity, in a state-dependent manner. There is an apparent lack of clear neuronal signature induced by psychedelics on monoaminergic neuron activity despite specific recurrent mechanisms. This review provides a current summary of the action of psychedelics on monoamine neuromodulators serotonin, dopamine and noradrenaline, compiling reoccurring and contradictory findings demonstrating that a monoamine signature of psychedelics, if applicable, would be state- and region-dependant.

由于经典迷幻药在治疗包括重度抑郁和焦虑症在内的多种精神疾病方面具有临床潜力，对其作用机制的研究已引起了人们的极大兴趣。这些药物与 5-羟色胺受体（5-HTR）结合，包括 5-HT1AR、5-HT2AR、5-HT2BR 和/或 5-HT2CR，以及其他靶点。5-HTR 可调节上升单胺能神经元的活动，这一机制主要涉及经典抗抑郁药物、抗精神病药物和滥用药物的作用。关于单胺能神经元活动受经典迷幻药控制的神经化学数据很少。在此，我们回顾了现有的数据，以确定经典迷幻药是否会对血清素能、多巴胺能和去甲肾上腺素能神经元产生特定的神经化学效应。数据显示，这些药物对每种单胺能系统都有不同的影响，表现出一种复杂的反应，具有状态依赖性和区域特异性效应。例如，几种迷幻药会抑制血清素能神经元的发射，但这并不一定与所有区域的血清素释放减少有关。去甲肾上腺素能神经元的自发活动似乎也会受到迷幻药的抑制，但这并不一定与所有区域的去甲肾上腺素释放量减少有关。迷幻药对多巴胺能系统的影响也很复杂，因为上述 5-HTRs 可能会对多巴胺能神经元的活动产生相反的影响，而这种影响的程度则取决于状态。迷幻药对单胺能神经元活动的影响尽管有特定的循环机制，但显然缺乏明确的神经元特征。这篇综述总结了迷幻药对单胺类神经调节剂血清素、多巴胺和去甲肾上腺素的作用，汇集了反复出现且相互矛盾的研究结果，表明迷幻药的单胺类特征（如果适用）将取决于状态和区域。

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引用次数: 0

SUMOylation of cardiac myosin binding protein-C reduces its phosphorylation and results in impaired relaxation following treatment with isoprenaline 心肌肌球蛋白结合蛋白-C 的 SUMOylation 可降低其磷酸化程度，并导致异丙肾上腺素治疗后的松弛功能受损

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2024-09-24 DOI: 10.1016/j.biocel.2024.106668

Alice Main, Sheon Mary, Yuan Yan Sin, Tom A. Wright, Jiayue Ling, Connor M. Blair, Godfrey L. Smith, Will Fuller, George S. Baillie

Systolic and diastolic functions are coordinated in the heart by myofilament proteins that influence force of contraction and calcium sensitivity. Fine control of these processes is afforded by a variety of post-translation modifications that occur on specific proteins at different times during each heartbeat. Cardiac myosin binding protein-C is a sarcomeric accessory protein whose function is to interact transiently with actin, tropomyosin and myosin. Previously many different types of post-translational modification have been shown to influence the action of myosin binding protein-C and we present the first report that the protein can be modified covalently by the small ubiquitin like modifier protein tag. Analysis by mass spectrometry suggests that there are multiple modification sites on myosin binding protein-C for this tag and single point mutations did not serve to abolish the covalent addition of the small ubiquitin like modifier protein. Functionally, our data from both model human embryonic kidney cells and transfected neonatal cardiac myocytes suggests that the modification reduces phosphorylation of the filament protein on serine 282. In cardiac myocytes, the hypo-phosphorylation coincided with a significantly slower relaxation response following isoprenaline induced contraction. We hypothesise that this novel modification of myosin binding protein-C represents a new level of control that acts to alter the relaxation kinetics of cardiac myocytes.

心脏的收缩和舒张功能是由影响收缩力和钙敏感性的肌丝蛋白协调的。在每次心跳的不同时间，特定蛋白质会发生各种翻译后修饰，从而对这些过程进行精细控制。心肌肌球蛋白结合蛋白-C 是一种肌纤维附属蛋白，其功能是与肌动蛋白、肌钙蛋白和肌球蛋白发生瞬时相互作用。以前曾有多种不同类型的翻译后修饰被证明会影响肌球蛋白结合蛋白-C 的作用，我们首次报道了该蛋白可通过类似泛素修饰蛋白的小标签进行共价修饰。质谱分析表明，肌球蛋白结合蛋白-C上有多个修饰位点，单点突变并不能取消小泛素修饰蛋白的共价添加。从功能上看，我们从人类胚胎肾脏模型细胞和转染的新生心肌细胞中获得的数据表明，这种修饰减少了丝蛋白在丝氨酸 282 上的磷酸化。在心肌细胞中，低磷酸化与异丙肾上腺素诱导收缩后明显减慢的松弛反应相吻合。我们推测，肌球蛋白结合蛋白-C 的这种新型修饰代表了一种新的控制水平，其作用是改变心肌细胞的松弛动力学。

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引用次数: 0

Metabolic perturbations associated with hIAPP-induced insulin resistance in skeletal muscles: Implications to the development of type 2 diabetes 代谢紊乱与 hIAPP 诱导的骨骼肌胰岛素抵抗有关：对 2 型糖尿病发展的影响。

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2024-09-24 DOI: 10.1016/j.biocel.2024.106665

Arya R. Naik , Shreyada N. Save , Soumya S. Sahoo , Saurabh S. Yadav , Ashutosh Kumar , Jeetender Chugh , Shilpy Sharma

The human islet amyloid polypeptide (hIAPP) tends to misfold and self-assemble to form amyloid fibrils, which has been associated with the loss of function and viability of pancreatic β-cells in type 2 diabetes mellitus (T2DM). The role of hIAPP in the development of insulin resistance (a hallmark of T2DM) in skeletal muscles – the major sites for glucose utilization – needs further investigation. Even though, insulin-resistant conditions have been known to stimulate hIAPP aggregation, the events that lead to the development of insulin resistance due to hIAPP aggregation in skeletal muscles remain unidentified. Here, we have attempted to identify metabolic perturbations in L6 myotubes that were exposed to increasing concentrations of recombinant hIAPP for different time durations. It was observed that hIAPP exposure was associated with increased mitochondrial and cellular ROS levels, loss in mitochondrial membrane potential and viability of the myotubes. Metabolomic investigations of hIAPP-treated myotubes revealed significant perturbations in o-phosphocholine, sn-glycero-3-phosphocholine and dimethylamine levels (p < 0.05). Therefore, we anticipate that defects in glycerophospholipid metabolism and the associated oxidative stress and membrane damage may play key roles in the development of insulin resistance due to protein misfolding in skeletal muscles. In summary, the perturbed metabolites and their pathways have not only the potential to be used as early biomarkers to predict the onset of insulin resistance and T2DM but also as therapeutic targets for the effective management of the same.

人胰岛淀粉样多肽（hIAPP）倾向于错误折叠和自我组装形成淀粉样纤维，这与 2 型糖尿病（T2DM）患者胰岛β细胞功能和存活能力的丧失有关。hIAPP 在骨骼肌--葡萄糖利用的主要场所--胰岛素抵抗（T2DM 的标志）的发展过程中所起的作用需要进一步研究。尽管已知胰岛素抵抗条件会刺激 hIAPP 的聚集，但由于骨骼肌中 hIAPP 的聚集而导致胰岛素抵抗发展的事件仍未确定。在此，我们试图确定在不同时间段内暴露于浓度不断增加的重组 hIAPP 的 L6 肌管中的代谢扰动。据观察，暴露于 hIAPP 与线粒体和细胞 ROS 水平升高、线粒体膜电位下降和肌细胞活力丧失有关。对经 hIAPP 处理的肌管进行的代谢组学研究发现，邻磷酸胆碱、sn-甘油-3-磷酸胆碱和二甲胺水平发生了显著变化（p < 0.05）。因此，我们预计甘油磷脂代谢缺陷以及与之相关的氧化应激和膜损伤可能在骨骼肌蛋白质错误折叠导致的胰岛素抵抗发展过程中发挥关键作用。总之，受干扰的代谢物及其通路不仅有可能被用作预测胰岛素抵抗和 T2DM 发病的早期生物标志物，也有可能被用作有效控制 T2DM 的治疗目标。

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引用次数: 0

Revisiting serotonin’s role in spatial memory: A call for sensitive analytical approaches 重新审视血清素在空间记忆中的作用：呼吁采用敏感的分析方法

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2024-09-24 DOI: 10.1016/j.biocel.2024.106663

Paulina Kazmierska-Grebowska , Witold Żakowski , Dorota Myślińska , Ravindra Sahu , Maciej M. Jankowski

The serotonergic system is involved in various psychiatric and neurological conditions, with serotonergic drugs often used in treatment. These conditions frequently affect spatial memory, which can serve as a model of declarative memory due to well-known cellular components and advanced methods that track neural activity and behavior with high temporal resolution. However, most findings on serotonin's effects on spatial learning and memory come from studies lacking refined analytical techniques and modern approaches needed to uncover the underlying neuronal mechanisms. This In Focus review critically investigates available studies to identify areas for further exploration. It finds that well-established behavioral models could yield more insights with modern tracking and data analysis approaches, while the cellular aspects of spatial memory remain underexplored. The review highlights the complex role of serotonin in spatial memory, which holds the potential for better understanding and treating memory-related disorders.

血清素能系统与各种精神和神经疾病有关，血清素能药物经常被用于治疗。这些病症经常会影响空间记忆，而空间记忆可以作为陈述性记忆的模型，因为它具有众所周知的细胞成分和先进的高时间分辨率跟踪神经活动和行为的方法。然而，大多数有关血清素对空间学习和记忆影响的研究结果都来自于缺乏精细分析技术和现代方法的研究，而这些技术和方法正是揭示潜在神经元机制所必需的。这篇 In Focus 综述对现有研究进行了批判性调查，以确定需要进一步探索的领域。它发现，成熟的行为模型可以通过现代追踪和数据分析方法获得更多的见解，而空间记忆的细胞方面仍未得到充分探索。综述强调了血清素在空间记忆中的复杂作用，这为更好地理解和治疗记忆相关疾病提供了可能。

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引用次数: 0

High glucose induces DNA methyltransferase 1 dependent epigenetic reprogramming of the endothelial exosome proteome in type 2 diabetes 高血糖诱导 DNA 甲基转移酶 1 依赖于 2 型糖尿病内皮外泌体蛋白质组的表观遗传学重编程。

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2024-09-19 DOI: 10.1016/j.biocel.2024.106664

Sampara Vasishta , Shruthi Ammankallu , Ganesha Poojary , Sarah Michael Gomes , Kailash Ganesh , Shashikiran Umakanth , Prashanth Adiga , Dinesh Upadhya , Thottethodi Subrahmanya Keshava Prasad , Manjunath B. Joshi

In response to hyperglycemia, endothelial cells (ECs) release exosomes with altered protein content and contribute to paracrine signalling, subsequently leading to vascular dysfunction in type 2 diabetes (T2D). High glucose reprograms DNA methylation patterns in various cell/tissue types, including ECs, resulting in pathologically relevant changes in cellular and extracellular proteome. However, DNA methylation-based proteome reprogramming in endothelial exosomes and associated pathological implications in T2D are not known. Hence, in the present study, we used Human umbilical vein endothelial cells (HUVECs), High Fat Diet (HFD) induced diabetic mice (C57BL/6) and clinical models to understand epigenetic basis of exosome proteome regulation in T2D pathogenesis . Exosomes were isolated by size exclusion chromatography and subjected to tandem mass tag (TMT) labelled quantitative proteomics and bioinformatics analysis. Immunoblotting was performed to validate exosome protein signature in clinically characterized individuals with T2D. We observed ECs cultured in high glucose and aortic ECs from HFD mouse expressed elevated DNA methyltransferase1 (DNMT1) levels. Quantitative proteomics of exosomes isolated from ECs treated with high glucose and overexpressing DNMT1 showed significant alterations in both protein levels and post translational modifications which were aligned to T2D associated vascular functions. Based on ontology and gene-function-disease interaction analysis, differentially expressed exosome proteins such as Thrombospondin1, Pentraxin3 and Cystatin C related to vascular complications were significantly increased in HUVECs treated with high glucose and HFD animals and T2D individuals with higher levels of glycated hemoglobin. These proteins were reduced upon treatment with 5-Aza-2’-deoxycytidine. Our study shows epigenetic regulation of exosome proteome in T2D associated vascular complications.

为应对高血糖，内皮细胞（ECs）会释放蛋白质含量改变的外泌体，并促进旁分泌信号的传递，从而导致 2 型糖尿病（T2D）患者的血管功能障碍。高血糖会对包括血管内皮细胞在内的各种细胞/组织类型的DNA甲基化模式进行重编程，从而导致蛋白质组发生病理相关变化。然而，内皮外泌体中基于 DNA 甲基化的蛋白质组重编以及对 T2D 的相关病理影响尚不清楚。因此，在本研究中，我们使用人脐静脉内皮细胞（HUVECs）、高脂饮食（HFD）诱导的糖尿病小鼠（C57BL/6）和临床模型来了解外泌体蛋白质组对高糖和 DNMT1 过表达的反应。外泌体通过尺寸排阻色谱法分离，并进行串联质量标签（TMT）标记的定量蛋白质组学和生物信息学分析。免疫印迹法验证了具有临床特征的 T2D 患者的外泌体蛋白特征。我们观察到在高糖环境下培养的心血管细胞和来自高密度脂蛋白胆固醇（HFD）小鼠的主动脉心血管细胞表达了升高的DNA甲基转移酶1（DNMT1）水平。从经高糖处理并过表达 DNMT1 的心血管细胞中分离出的外泌体的定量蛋白质组学研究显示，蛋白质水平和翻译后修饰都发生了显著变化，这与 T2D 相关的血管功能一致。根据本体论和基因-功能-疾病相互作用分析，与血管并发症有关的不同表达的外泌体蛋白，如Thrombospondin1、Pentraxin3和胱抑素C，在高糖和高脂蛋白胆固醇动物以及糖化血红蛋白水平较高的T2D患者的HUVECs中显著增加。用 5-Aza-2'-deoxycytidine 处理后，这些蛋白会减少。我们的研究显示了外泌体蛋白质组在 T2D 相关血管并发症中的表观遗传调控。

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引用次数: 0

PIAS1 S510G variant acts as a genetic modifier of spinocerebellar ataxia type 3 by selectively impairing mutant ataxin-3 proteostasis PIAS1 S510G变体通过选择性损害突变型共济失调蛋白-3的蛋白稳态，成为脊髓小脑共济失调3型的遗传修饰因子。

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2024-09-16 DOI: 10.1016/j.biocel.2024.106662

Yi-Ching Chang , Yao-Chou Tsai , En-Cheng Chang , Yu-Chien Hsu , Yi-Ru Huang , Yan-Hua Lee , Yu-Shuen Tsai , Yin-Quan Chen , Yi-Chung Lee , Yi-Chu Liao , Jean-Cheng Kuo , Ming-Tsan Su , Ueng-Cheng Yang , Yijuang Chern , Tzu-Hao Cheng

Dysregulated protein homeostasis, characterized by abnormal protein accumulation and aggregation, is a key contributor to the progression of neurodegenerative disorders such as Huntington's disease and spinocerebellar ataxia type 3 (SCA3). Previous studies have identified PIAS1 gene variants in patients with late-onset SCA3 and Huntington's disease. This study aims to elucidate the role of PIAS1 and its S510G variant in modulating the pathogenic mechanisms of SCA3. Through in vitro biochemical analyses and in vivo assays, we demonstrate that PIAS1 stabilizes both wild-type and mutant ataxin-3 (ATXN3). The PIAS1 S510G variant, however, selectively reduces the stability and SUMOylation of mutant ATXN3, thereby decreasing its aggregation and toxicity while maintaining the stability of wild-type ATXN3. This effect is mediated by a weakened interaction with the SUMO-conjugating enzyme UBC9 in the presence of mutant ATXN3. In Drosophila models, downregulation of dPIAS1 resulted in reduced levels of mutant ATXN3 and alleviated associated phenotypes, including retinal degeneration and motor dysfunction. Our findings suggest that the PIAS1 S510G variant acts as a genetic modifier of SCA3, highlighting the potential of targeting SUMOylation as a therapeutic strategy for this disease.

以蛋白质异常积累和聚集为特征的蛋白质平衡失调是亨廷顿氏病和脊髓小脑共济失调 3 型（SCA3）等神经退行性疾病恶化的关键因素。先前的研究已在晚发性 SCA3 和亨廷顿病患者中发现了 PIAS1 基因变异。本研究旨在阐明PIAS1及其S510G变体在调节SCA3致病机制中的作用。通过体外生化分析和体内试验，我们证明了 PIAS1 可稳定野生型和突变型共济失调蛋白-3（ATXN3）。然而，PIAS1 S510G 变体会选择性地降低突变体 ATXN3 的稳定性和 SUMOylation，从而降低其聚集性和毒性，同时保持野生型 ATXN3 的稳定性。在突变型 ATXN3 存在的情况下，与 SUMO 结合酶 UBC9 的相互作用减弱，从而产生了这种效应。在果蝇模型中，下调 dPIAS1 可降低突变型 ATXN3 的水平，并减轻相关表型，包括视网膜退化和运动功能障碍。我们的研究结果表明，PIAS1 S510G变体是SCA3的遗传修饰因子，突出了靶向SUMO酰化作为该疾病治疗策略的潜力。

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引用次数: 0

Unveiling the role of taurine and SLC6A6 in tumor immune evasion: Implications for gastric cancer therapy 揭示牛磺酸和 SLC6A6 在肿瘤免疫逃避中的作用：对胃癌治疗的启示

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2024-09-12 DOI: 10.1016/j.biocel.2024.106661

Jianqiao Shentu, Xinming Su, Yueqi Yu, Shiwei Duan

Metabolic changes are key drivers of tumor progression. Understanding how metabolic reprogramming promotes tumor development and identifying key metabolic activities are essential for improving tumor diagnosis and treatment. Among the numerous transporters in the body, solute carriers (SLCs) are particularly significant, often overexpressed in cancer cells to meet the tumor's demand for nutrients and energy. While the role of SLCs in nutrient absorption within the gastrointestinal tract is well-established, their specific role in gastric cancer (GC) remains unclear. Recently, Xiaodi Zhao's team investigated the critical role of taurine and its transporter, SLC6A6, in anti-tumor immunity and clinical outcomes. Notably, this research marks the first instance of taurine exhibiting a dual role. It promotes tumor growth in immunodeficient mice while inhibiting it in immunocompetent mice. The study found that taurine exerts its anti-cancer effects by modulating CD8⁺ T cells rather than directly inhibiting tumor cells, revealing the SP1-SLC6A6 axis as a key mechanism behind chemotherapy-induced immune evasion. Our work further explored the potential, advantages, and challenges of using taurine and SLC6A6 as biomarkers and therapeutic targets in gastric cancer. We aim to underscore their importance in both basic research and clinical applications, providing valuable insights and guidance for future investigations.

代谢变化是肿瘤进展的关键驱动因素。了解代谢重编程如何促进肿瘤发生以及确定关键代谢活动对于改善肿瘤诊断和治疗至关重要。在人体的众多转运体中，溶质运载体（SLCs）的作用尤为重要，它通常在癌细胞中过度表达，以满足肿瘤对营养和能量的需求。虽然SLCs在胃肠道营养吸收中的作用已得到证实，但它们在胃癌（GC）中的具体作用仍不清楚。最近，赵小迪团队研究了牛磺酸及其转运体SLC6A6在抗肿瘤免疫和临床结果中的关键作用。值得注意的是，这项研究标志着牛磺酸首次表现出双重作用。它既能促进免疫缺陷小鼠的肿瘤生长，又能抑制免疫功能健全小鼠的肿瘤生长。研究发现，牛磺酸通过调节 CD8+ T 细胞而不是直接抑制肿瘤细胞来发挥抗癌作用，揭示了 SP1-SLC6A6 轴是化疗诱导免疫逃避背后的关键机制。我们的研究进一步探讨了将牛磺酸和 SLC6A6 作为胃癌生物标记物和治疗靶点的潜力、优势和挑战。我们旨在强调它们在基础研究和临床应用中的重要性，为未来的研究提供有价值的见解和指导。

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引用次数: 0