Biochimie最新文献_第10页

Functional and immunological variability of Viperid venoms across continents and cross-neutralization by Peruvian antivenoms 各大洲毒蛇毒液的功能和免疫变异以及秘鲁抗蛇毒血清的交叉中和作用

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimie

Pub Date : 2025-10-25 DOI: 10.1016/j.biochi.2025.10.013

Daniel Torrejón , Alexander Llontop , Alex Proléon , Fanny Lazo , Felix Urra , Armando Yarlequé , Dan E. Vivas-Ruiz

Snake envenomation remains a significant neglected tropical disease primarily treated with antivenoms, which, despite inherent limitations, continue to be the gold standard therapy. Snake venoms exhibit extensive compositional and functional diversity, posing challenges for universal antivenom efficacy. This study comprehensively evaluated venom composition, enzymatic activities, and immunological cross-reactivity across 24 Viperidae species from diverse geographic regions. Using protein profiling, enzymatic assays (proteolytic, amidolytic, clotting, and PLA₂ activities), and phylogenetic analyses, we revealed marked interspecific variation. Bothrops species exhibited elevated SVMP-driven proteolytic activity, while Crotalus venoms demonstrated more balanced enzymatic profiles. Phylogenetic clustering highlighted evolutionary divergence and functional convergence among taxa. Immunoreactivity assays with Peruvian antibothropic, anticrotalic, and antilachesic antivenoms showed broad cross-recognition within Bothrops and Crotalus venoms, but limited efficacy against more distantly related Viperinae species. Western blot analyses confirmed these specificity patterns. Neutralization assays revealed differential inhibition: antibothropic antivenom effectively neutralized proteolytic activity, whereas anticrotalic antivenom preferentially inhibited PLA₂-mediated effects. This functional variability highlights the biochemical complexity of viperid venoms and the constraints of current antivenoms. Our findings emphasize the urgent need to develop improved, broadly effective antivenom formulations capable of targeting the diverse toxin profiles of geographically and phylogenetically distinct viperid species, ultimately enhancing clinical management of snakebite envenomation worldwide.

蛇中毒仍然是一种主要用抗蛇毒血清治疗的严重被忽视的热带病，尽管存在固有的局限性，但抗蛇毒血清仍然是金标准疗法。蛇毒具有广泛的成分和功能多样性，这对普遍的抗蛇毒血清功效提出了挑战。本研究综合评估了来自不同地理区域的24种蝰蛇科物种的毒液成分、酶活性和免疫交叉反应性。通过蛋白质分析、酶分析（蛋白水解、酰胺水解、凝血和PLA2活性）和系统发育分析，我们发现了明显的种间差异。Bothrops物种表现出更高的svmp驱动的蛋白水解活性，而Crotalus毒液表现出更平衡的酶谱。系统发育聚类突出了分类群之间的进化分化和功能趋同。秘鲁抗蛇毒、抗蛇毒和抗lachesic抗蛇毒血清的免疫反应性分析显示，在Bothrops和Crotalus毒液中有广泛的交叉识别，但对更近缘的Viperinae物种的效力有限。Western blot分析证实了这些特异性模式。中和试验显示了不同的抑制作用：抗抗蛇毒血清有效地中和了蛋白水解活性，而抗抗蛇毒血清优先抑制pla2介导的作用。这种功能变异性突出了蛇毒的生化复杂性和当前抗蛇毒血清的局限性。我们的研究结果强调，迫切需要开发改进的、广泛有效的抗蛇毒血清制剂，能够针对地理上和系统发育上不同的毒蛇物种的不同毒素谱，最终加强全球蛇咬中毒的临床管理。

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引用次数: 0

The functional significance of intrinsic disorder in enzymes 酶内在紊乱的功能意义。

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimie

Pub Date : 2025-10-23 DOI: 10.1016/j.biochi.2025.10.016

Munishwar Nath Gupta , Vladimir N. Uversky

The role of intrinsic disorder in enzymes has not attracted the attention which it deserves. This perspective discusses how tails and loops in structured proteins, as well as molten globular protein forms, in spite of being disordered, are associated with biocatalysis. Protein kinases illustrate the importance of structural disorder for the function of some enzymes in their native state. Intrinsic disorder actually facilitates moonlighting. Furthermore, disorder-based engineered biomolecular condensates are emerging as enzymatic microreactors.

酶的内在紊乱的作用还没有引起应有的重视。这一观点讨论了结构蛋白的尾部和环，以及熔融球状蛋白形式，尽管是无序的，是如何与生物催化相关联的。蛋白质激酶说明了结构紊乱对某些酶在天然状态下的功能的重要性。内在紊乱实际上有利于兼职。此外，基于无序的工程生物分子凝聚物正在作为酶微反应器出现。

引用次数: 0

The HEK293T cells manage overload by the overexpressed full-length Htt variants via proteasome activation HEK293T细胞通过蛋白酶体激活过表达全长Htt变异体来管理过载。

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimie

Pub Date : 2025-10-21 DOI: 10.1016/j.biochi.2025.10.014

Nataliia N. Gotmanova , Tatiana V. Bobik , Viacheslav A. Kriachkov , Alexander A. Ezhov , Anna V. Bacheva

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a pathological mutation that results in the abnormal expansion of more than 37 consecutive trinucleotide repeats (CAG) in the HTT gene. These repeats encode the polyglutamine tract (polyQ tract) in the huntingtin protein (Htt). Progressive lethal Huntington's chorea is characterized by impaired motor activity and marked cerebral atrophy. The disease affects neurons in specific areas of the central nervous system, mainly GABAergic neurons in the striatum and cortex. It is believed that the neuron-specific proteotoxicity of mutant Htt (mHtt) results from its conformational instability and tendency to aggregate due to elongation of the polyQ-tract. However, recent structural findings challenge these assumptions. To elucidate some key aspects of the molecular mechanisms of HD, we describe the transient expression of full-length normal or mutant huntingtin in HEK293T eukaryotic cells, and options of isolation and purification of huntingtin variants according to the optimized procedure. The short-termed overexpression of Htt/mHtt has been demonstrated to be associated with elevated proteasome and non-proteasome caspase activity, and change in subunit expression. The cellular response to mHtt production manifested primarily as an increase in β1, β5i and in less extent β1i subunits as well as 11Sαβ expression, as observed through both Western blot and RT-qPCR. The microscopy study also revealed an enhancement in the β1i subunit content in HEK293T cells overexpressed Htt and especially mHtt suggesting an immunoproteasome activation.

亨廷顿氏病（HD）是一种常染色体显性神经退行性疾病，由病理突变引起HTT基因中超过37个连续三核苷酸重复（CAG）的异常扩增。这些重复序列编码亨廷顿蛋白（Htt）中的聚谷氨酰胺通道（polyQ通道）。进行性致死性亨廷顿舞蹈病的特征是运动活动受损和显著的脑萎缩。这种疾病影响中枢神经系统特定区域的神经元，主要是纹状体和皮层的gaba能神经元。据认为，突变体Htt （mHtt）的神经元特异性蛋白质毒性是由于其构象不稳定和多q通道伸长导致的聚集倾向。然而，最近的结构性发现挑战了这些假设。为了阐明HD的一些关键分子机制，我们描述了正常或突变的亨廷顿蛋白全长在HEK293T真核细胞中的瞬时表达，以及根据优化的程序分离和纯化亨廷顿蛋白变体的选择。Htt/mHtt的过表达已被证明与蛋白酶体和非蛋白酶体半胱天冬酶活性升高以及亚基表达的变化有关。通过Western blot和RT-qPCR观察到，细胞对mHtt产生的反应主要表现为β1、β5i和少量β1i亚基以及11Sαβ表达的增加。显微镜研究还发现，HEK293T细胞中β1i亚基含量增加，过量表达Htt，特别是mHtt，提示免疫蛋白酶体活化。

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引用次数: 0

Isoform switching in the CD44/ESRP1 axis as a driver of EMT and cancer stemness across tumor types 从同种异构体到侵袭——cd44 / esrp1同种异构体转换如何驱动转移和癌症的发生。

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimie

Pub Date : 2025-10-21 DOI: 10.1016/j.biochi.2025.10.015

K. Jankowska , W. Wójtowicz , M. Wierzbinka , K. Raszczok , K. Bajdak-Rusinek

Alternative splicing of cluster of differentiation 44 (CD44), regulated by epithelial splicing regulatory protein 1 (ESRP1), plays a critical role in cancer progression. The switch between CD44 variant (CD44v) and standard (CD44s) isoforms is tightly linked to epithelial–mesenchymal transition (EMT), metastatic potential and cancer stem cell (CSC) maintenance. This review integrates recent isoform-resolved findings to elucidate the molecular mechanisms underlying CD44/ESRP1-mediated splicing and its involvement in oncogenic signaling pathways promoting invasion, plasticity and therapy resistance. We also examine cancer-specific CD44 isoform expression patterns and assess their prognostic and therapeutic relevance. We propose that isoform-specific profiling of the CD44/ESRP1 axis may serve as a predictive framework for metastasis and therapy response, paving the way for targeted splicing-based therapeutics.

由上皮剪接调节蛋白1 （ESRP1）调控的CD44选择性剪接在癌症进展中起关键作用。CD44变体（CD44v）和标准（CD44s）亚型之间的转换与上皮-间质转化（EMT）、转移潜能和癌症干细胞（CSC）维持密切相关。这篇综述整合了最近的研究结果，阐明了CD44/ esrp1介导的剪接的分子机制及其在促进侵袭、可塑性和治疗抗性的致癌信号通路中的作用。我们还研究了癌症特异性CD44亚型表达模式，并评估其预后和治疗相关性。我们提出CD44/ESRP1轴的亚型特异性分析可以作为转移和治疗反应的预测框架，为靶向剪接治疗铺平道路。

引用次数: 0

Deadly innovations: Molecular phylogenetics and evolution of phospholipase A2 toxins in viperid snake venoms 致命的创新：毒蛇毒液中磷脂酶A2毒素的分子系统发育和进化。

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimie

Pub Date : 2025-10-18 DOI: 10.1016/j.biochi.2025.10.010

Lorenzo Seneci , Vivek Suranse , Marco Mancuso , Tobias Senoner , Bing Xie , Ivan Koludarov , Kartik Sunagar , Bryan G. Fry

Snake venoms have surged as model systems in evolutionary biology thanks to the dynamic diversification and accelerated evolution of many toxin families. Among these, phospholipase A₂ (PLA₂) constitute a prime example as they are ubiquitous across the venomous snake radiation and have evolved a wide variety of pathophysiological activities. This is especially true in vipers (family Viperidae), one of the most successful and medically significant venomous snake lineages worldwide. In this study, we gathered publicly available sequences of viper venom PLA₂s to recreate the molecular phylogeny and toxicological evolution of this toxin family to date. Furthermore, we determined the selection regimes regulating the evolution of these toxins with a comparative approach that combines multiple methodologies of phylogenetic reconstruction and analysis of selection signatures. Our phylogeny confirms the basal position of Asp49 PLA₂s (proteins with Asp at position 49), while derived clades, such as the non-enzymatic Lys49 myotoxins and the poorly characterised Ser49 type, are nested within. Neurotoxicity arose on multiple independent occasions (all within the Asp49 clade), with monomeric and dimeric forms only distantly related to each other. Positive Darwinian selection was widespread across the viper PLA₂ tree, in line with previous research. However, purifying selection was also preponderant (perhaps due to structural constraints imposed by the pathophysiological targets of these toxins) and relatively neutral substitutions were observed in certain clades. Overall, this study provides novel insights into the evolutionary history of viper venom PLA₂s through a comprehensive phylogenetic framework and highlights the need for complementary genomic and functional research into these toxins.

由于许多毒素家族的动态多样化和加速进化，蛇毒已成为进化生物学中的模型系统。其中，磷脂酶A2 （PLA2）是一个典型的例子，因为它们在毒蛇辐射中无处不在，并且已经进化出各种各样的病理生理活动。这在毒蛇（毒蛇科）中尤其如此，毒蛇是世界上最成功和医学上最重要的毒蛇血统之一。在这项研究中，我们收集了公开的毒蛇毒液PLA2s序列，以重建迄今为止该毒素家族的分子系统发育和毒理学进化。此外，我们确定了选择制度调节这些毒素的进化与比较的方法，结合多种方法的系统发育重建和选择特征分析。我们的系统发育证实了Asp49 PLA2s的基础位置（Asp位于49位的蛋白质），而衍生分支，如非酶促Lys49肌毒素和特征不佳的Ser49型，则嵌套在其中。神经毒性出现在多个独立的场合（都在Asp49分支内），单体和二聚体形式彼此之间只有遥远的关系。积极的达尔文选择在毒蛇PLA2树中广泛存在，这与之前的研究一致。然而，净化选择也占优势（可能是由于这些毒素的病理生理目标所施加的结构限制），并且在某些进化枝中观察到相对中性的替代。总的来说，这项研究通过一个全面的系统发育框架为毒蛇毒液PLA2s的进化史提供了新的见解，并强调了对这些毒素进行补充基因组和功能研究的必要性。

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引用次数: 0

MicroRNA expression profiling of white adipose tissue in the torpor response of the house mouse (Mus musculus) 家鼠（小家鼠）冬眠反应中白色脂肪组织的MicroRNA表达谱。

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimie

Pub Date : 2025-10-16 DOI: 10.1016/j.biochi.2025.10.012

Yuhong Hu , Stuart R. Green , Ningmei Wang , Jing Zhang , Han Wang , Ziheng Zhao , Yue Gao , Kenneth B. Storey , Jingze Liu , Hui Wang

MicroRNAs (miRNAs), a critical class of short non-coding RNAs, regulate metabolic processes associated with mammalian torpor (e.g., Mus musculus), though their precise functional mechanisms remain incompletely characterized. Here, we employ RNA-seq to profile miRNA expression in white adipose tissue (WAT) of active versus torpid C57BL/6 mice. Among 863 detected miRNAs, 12 showed significant differential expression during torpor. In silico prediction of miRNA targets revealed these miRNAs preferentially target cancer-related pathways, indicating their potential role in suppressing cell proliferation during metabolic depression. Intriguingly, steroid biosynthesis genes escaped miRNA-mediated inhibition, suggesting active endocrine modulation by WAT during torpor. Machine learning helped to identify biomarkers for torpor in the mice, specifically a minimum of three miRNAs were sufficient to distinguish adipose samples from control versus torpid conditions. Taken together, this study demonstrates the role of miRNAs as transcriptional regulators of cell signalling pathways within WAT during mouse torpor.

MicroRNAs （miRNAs）是一类重要的短非编码rna，调节与哺乳动物（如小家鼠）冬眠相关的代谢过程，尽管其精确的功能机制尚未完全确定。在这里，我们使用RNA-seq分析了活跃和迟钝C57BL/6小鼠白色脂肪组织（WAT）中miRNA的表达。在863个检测到的mirna中，有12个在冬眠期间表现出显著的差异表达。miRNA靶点的计算机预测显示，这些miRNA优先靶向癌症相关通路，表明它们在代谢抑制期间抑制细胞增殖的潜在作用。有趣的是，类固醇生物合成基因逃脱了mirna介导的抑制，表明WAT在睡眠期间积极调节内分泌。机器学习有助于识别小鼠冬眠的生物标志物，特别是至少三个mirna足以区分对照组和冬眠条件下的脂肪样本。综上所述，本研究证明了mirna在小鼠冬眠期间作为WAT细胞信号通路的转录调节因子的作用。

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引用次数: 0

Premature aging in chronic kidney disease: Decoding senescence biomarkers and therapeutic opportunities 慢性肾脏疾病的过早衰老：解码衰老生物标志物和治疗机会。

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimie

Pub Date : 2025-10-15 DOI: 10.1016/j.biochi.2025.10.008

Carlos Eduardo H.V. P.F. Braga , Jessyca S. de Brito , Marcia Ribeiro , Karen Salve Coutinho-Wolino , Bruna Regis , Bruna Calixto , Renata Cristina Bezerra Rodrigues , Angela Yee-Moon Wang , Peter Stenvinkel , Denise Mafra

Chronic kidney disease (CKD) is characterized by a premature aging phenotype. CKD-related stressors, such as inflammation, oxidative stress, the buildup of uremic toxins, hyperphosphatemia, mitochondrial dysfunction, sirtuin inhibition, and klotho deficiency, trigger cell cycle arrest, inducing senescence in tubular epithelial cells, endothelial cells, and podocytes, accelerating CKD progression and leading to the expression of senescence-related genes and the senescence-associated secretory phenotype (SASP). This condition promotes local (e.g., interstitial fibrosis, glomerulosclerosis, endothelial dysfunction) and systemic damage, including micro- and macrovascular dysfunction, early vascular aging, and an increased risk of cardiovascular mortality. Markers such as SA-β-gal, p16^INK4a, p21^CIP1, p53, and SASP components (e.g., IL-6, MCP-1, MMP-3), as well as telomere shortening and mitochondrial DNA accumulation, are frequently used to identify senescence. Despite their predictive potential, the application of these biomarkers for disease progression and cardiovascular complications remains underexplored in patients with CKD. This narrative review explores the complex relationship between senescence and CKD, reviews key senescence biomarkers, emphasizes their importance for diagnosis, and evaluates the potential of senotherapies to reduce complications of premature aging in this population.

慢性肾脏疾病（CKD）的特点是早衰表型。CKD相关的应激源，如炎症、氧化应激、尿毒症毒素的积累、高磷血症、线粒体功能障碍、sirtuin抑制和klotho缺乏，触发细胞周期阻滞，诱导小管上皮细胞、内皮细胞和足细胞衰老，加速CKD进展，导致衰老相关基因的表达和衰老相关分泌表型（SASP）。这种情况促进局部（如间质纤维化、肾小球硬化、内皮功能障碍）和全身损伤，包括微血管和大血管功能障碍、血管早期衰老和心血管死亡风险增加。诸如SA-β-gal、p16INK4a、p21CIP1、p53和SASP成分（如IL-6、MCP-1、MMP-3）以及端粒缩短和线粒体DNA积累等标记常被用于识别衰老。尽管具有预测潜力，但这些生物标志物在慢性肾病患者疾病进展和心血管并发症中的应用仍未得到充分探索。本文探讨了衰老与慢性肾病之间的复杂关系，综述了关键的衰老生物标志物，强调了它们在诊断中的重要性，并评估了衰老疗法在减少这一人群早衰并发症方面的潜力。

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引用次数: 0

Targeting autophagy via mitochondrial uncoupling: Discovery of novel serratin derivative as a potential therapeutic for Parkinson's disease 通过线粒体解偶联靶向自噬：发现新的serratn衍生物作为帕金森病的潜在治疗药物。

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimie

Pub Date : 2025-10-15 DOI: 10.1016/j.biochi.2025.10.011

Alexander Yu Rudenko , Ekaterina А. Guseva , Ratislav M. Ozhiganov , Boris P. Myasnikov , Maria V. Belopolskaya , Olga V. Fadeeva , Elena О. Morgun , Olga A. Averina , Elena A. Tukhovskaya , Gulsara A. Slashcheva , Igor A. Dyachenko , Elena I. Marusich , Mariia Mokhina , Rose-Lys Zaranaina , Yuriy A. Ikhalaynen , Igor A. Rodin , Ljudmila S. Khailova , Yuri N. Antonenko , Vladimir I. Polshakov , Maxim L. Lovat , Petr V. Sergiev

Autophagy, a highly conserved cellular degradation pathway, plays a critical role in maintaining cellular homeostasis across eukaryotes. Dysregulation of autophagy has been implicated in numerous diseases, including neurodegenerative disorders such as Parkinson's disease. Although natural compounds like urolithin A and its synthetic analogue serratin (AN2) have been shown to induce autophagy, their limited potency and safety profiles necessitate the development of improved alternatives. In this study, a library of 27 novel AN2 analogues was synthesized and screened for autophagy-inducing activity. Among them, ORA471 emerged as a lead compound, exhibiting superior autophagy and mitophagy activation compared to AN2, along with reduced cytotoxicity in human fibroblast (VA-13) and neuroblastoma (SH-SY5Y) cell lines. Mechanistic investigations revealed that ORA471 induces autophagy primarily via the AMPK/ULK1 signaling pathway and acts as a mitochondrial uncoupler, dissipating membrane potential and enhancing respiration in isolated rat liver mitochondria. In vivo, ORA471 demonstrated low toxicity in Caenorhabditis elegans, zebrafish (Danio rerio), and mice (maximum tolerated dose: 300 mg/kg). Notably, it significantly improved motor function in a zebrafish model of MPTP-induced Parkinson's disease without eliciting adverse effects. These findings highlight ORA471 as a promising therapeutic candidate for the treatment of autophagy-related disorders, particularly Parkinson's disease.

自噬是一种高度保守的细胞降解途径，在维持真核生物细胞稳态中起着至关重要的作用。自噬失调与许多疾病有关，包括神经退行性疾病，如帕金森病。虽然天然化合物如尿素A及其合成类似物serratin （AN2）已被证明可以诱导自噬，但其有限的效力和安全性要求开发改进的替代品。本研究合成了27个新型AN2类似物，并对其自噬诱导活性进行了筛选。其中，ORA471作为先导化合物出现，与AN2相比，ORA471在人成纤维细胞（VA-13）和神经母细胞瘤（SH-SY5Y）细胞系中表现出更强的自噬和有丝自噬激活能力，并降低细胞毒性。机制研究表明，ORA471主要通过AMPK/ULK1信号通路诱导自噬，并作为线粒体解偶联剂，在离体大鼠肝脏线粒体中消散膜电位并增强呼吸。在体内，ORA471对秀丽隐杆线虫、斑马鱼和小鼠表现出低毒性（最大耐受剂量为300 mg/kg）。值得注意的是，它显著改善了mptp诱导的帕金森病斑马鱼模型的运动功能，而没有引起不良反应。这些发现突出了ORA471作为治疗自噬相关疾病，特别是帕金森病的有希望的治疗候选者。

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引用次数: 0

Differential impact of copper stress in two Ectocarpales: metabolic disruption and defensive signaling in the free-living Ectocarpus sp7 and the endophytic Laminarionema elsbetiae 铜胁迫对两种外腕类的不同影响：自由生活外腕类sp7和内生海带线虫的代谢破坏和防御信号。

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimie

Pub Date : 2025-10-10 DOI: 10.1016/j.biochi.2025.10.006

Maëlle Zonnequin , Marine Vallet , Ludovic Delage , Georg Pohnert , Catherine Leblanc , Gabriel V. Markov

Algae are photosynthetic organisms, responsible for the primary production in oceans and lakes. Brown algae have evolved independently from other major eukaryotic lineages, such as the Opistokonts (animals, fungi) or Archaeplastida (land plants, green and red algae). Within this lineage, there is considerable variation between species, which differ in ecology, diversity, and evolutionary features, suggesting specific adaptations in their changing marine environment. In this context, several questions remain regarding the evolution of brown algal metabolism, particularly in response to oxidative stress. This study explored the consequences of copper stress on two brown algae from the Ectocarpales order: the free-living Ectocarpus sp7 and the endophytic Laminarionema elsbetiae. Using PAM-based fluorescence measurements, we revealed that high copper exposure reduces the photosynthetic capacity and activity of the endophyte. Through a cutting-edge untargeted metabolomic approach using UHPLC-HRMS profiling, we detected metabolic alterations induced by short-term exposure to moderate copper concentration in both free-living and endophytic Ectocarpales. The metabolite-regulated response appears to be substantial in Ectocarpus sp7 compared to L. elsbetiae, as a greater number of up- and down-regulated features were detected. Among the discriminant ions identified by tandem mass spectrometry, our results confirmed that copper exposure triggers the metabolism of algal defense signaling, primarily through the upregulation of oxylipins, but mainly in Ectocarpus sp 7. Altogether, our findings suggest that in Ectocarpales, fine metabolic adaptation may have altered the metabolism linked to defense signaling, such as the oxylipin pathway, particularly in ecological niches like endophytic life.

藻类是光合生物，负责海洋和湖泊的初级生产。褐藻是独立于其他主要真核生物谱系，如Opistokonts（动物、真菌）或Archaeplastida（陆地植物、绿藻和红藻）进化而来的。在这个谱系中，物种之间存在相当大的差异，它们在生态、多样性和进化特征上存在差异，这表明它们对不断变化的海洋环境有特定的适应。在这种情况下，关于褐藻代谢的进化，特别是在氧化应激反应中，仍然存在几个问题。本研究探讨了铜胁迫对两种褐藻（外生褐藻sp7和内生褐藻Laminarionema elsbetiae）的影响。利用pam为基础的荧光测量，我们发现高铜暴露降低了内生菌的光合能力和活性。通过一种先进的非靶向代谢组学方法，使用UHPLC-HRMS分析，我们检测了短期暴露于中等浓度铜所引起的自由生活和内生外皮的代谢变化。与L. elshetiae相比，Ectocarpus sp7的代谢物调控反应似乎更为明显，因为检测到更多的上调和下调特征。在串联质谱鉴定的鉴别离子中，我们的研究结果证实，铜暴露触发了藻类防御信号的代谢，主要是通过上调氧脂素，但主要是在Ectocarpus sp 7中。总之，我们的研究结果表明，在Ectocarpales中，精细的代谢适应可能改变了与防御信号相关的代谢，如氧化脂素途径，特别是在内生生物等生态位中。

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引用次数: 0

Bispecific targeting system based on DARPins-modified light-chain ferritin for cancer chemotherapy 基于darpins修饰的轻链铁蛋白的肿瘤化疗双特异性靶向系统。

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimie

Pub Date : 2025-10-09 DOI: 10.1016/j.biochi.2025.10.003

A.Yu. Frolova , E.I. Shramova , D.L. Kakuev , V.I. Martynov , A.A. Pakhomov , S.M. Deyev , G.M. Proshkina

Cancer continues to be one of the leading causes of death worldwide. Due to genome instability, solid tumors are characterized by high heterogeneity of tumor-associated antigen expression, which makes a great challenge for targeted tumor therapy. Targeting two molecular receptors overexpressed on tumor cells is a way to overcome this problem and improve therapeutic efficacy.

In this study we used truncated ferritin L-subunit (FTLsh, lacking 34 a.a. at the carboxyl terminus) as a scaffold for creating a hybrid protein for simultaneous targeting on human epidermal growth factor receptor 2 (HER2) and epithelial cell adhesion molecule (EpCAM), both of which are frequently overexpressed in epithelial carcinomas. As HER2/EpCAM-specific binders we use proteins of non-IgG nature based on ankyrin repeats (Designed Ankyrin Repeat Proteins) – DARPin_9–29 and DARPin-EC1. The hybrid protein DARP_9-29-FTLsh-EC1 generated by genetic method was conjugated to monomethyl auristatin E (MMAE). The protein-drug conjugate DARP_9-29-FTLsh-EC1/MMAE was shown to be mainly composed of dimeric form. The receptor-specific binding and internalization properties of DARP_9-29-FTLsh-EC1 fusion protein were confirmed by flow cytometry and confocal microscopy. In vitro cytotoxicity was shown to be HER2/EpCAM specific and strongly correlated to receptor density. In vivo studies have shown that DARP_9-29-FTLsh-EC1/MMAE is selectively accumulated in HER2/EpCAM-positive tumors in a mouse xenograft model causing significant tumor reduction. Our results demonstrate that bispecific targeting opens new prospects for the development of precise anticancer therapy.

癌症仍然是世界范围内死亡的主要原因之一。由于基因组的不稳定性，实体瘤具有肿瘤相关抗原表达高度异质性的特点，这给肿瘤的靶向治疗带来了很大的挑战。靶向肿瘤细胞上过表达的两种分子受体是克服这一问题并提高治疗效果的一种方法。在这项研究中，我们使用截断的铁蛋白l -亚基（FTLsh，在羧基端缺乏34 a.a.）作为支架，创建了一个杂交蛋白，同时靶向人表皮生长因子受体2 （HER2）和上皮细胞粘附分子（EpCAM），这两种蛋白在上皮癌中经常过表达。作为HER2/ epcam特异性结合物，我们使用基于锚蛋白重复序列（设计锚蛋白重复序列）的非igg性质的蛋白- DARPin_9-29和DARPin-EC1。利用遗传方法合成的杂交蛋白DARP_9-29-FTLsh-EC1与单甲基耳抑素E （MMAE）偶联。蛋白-药物偶联物DARP_9-29-FTLsh-EC1/MMAE主要由二聚体形式组成。通过流式细胞术和共聚焦显微镜证实了DARP_9-29-FTLsh-EC1融合蛋白的受体特异性结合和内化特性。体外细胞毒性被证明是HER2/EpCAM特异性的，并且与受体密度密切相关。体内研究表明，在小鼠异种移植模型中，DARP_9-29-FTLsh-EC1/MMAE选择性地积累在HER2/ epcam阳性肿瘤中，导致肿瘤显著缩小。我们的结果表明，双特异性靶向为精确抗癌治疗的发展开辟了新的前景。

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引用次数: 0