Archives of biochemistry and biophysics最新文献_第10页

Hirudin promotes peripheral nerve repair and alleviates pain by regulating the EGFR-PI3K/AKT/mTOR pathway 水蛭素通过调节EGFR-PI3K/AKT/mTOR通路促进周围神经修复，减轻疼痛。

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2026-01-01 Epub Date: 2025-11-10 DOI: 10.1016/j.abb.2025.110671

Long Wu , Zhe Zhang , Dongbo Tian , Kaiye Chen , Jing-hao Liang , Heng Yu , Ke Wang , Kongbin Chen , Yifan Wu , Hede Yan

Purpose

Peripheral nerve injury (PNI) often results in severe neuropathic pain and impaired nerve regeneration. Hirudin, derived from the traditional Chinese medicinal leech, has not yet been investigated for its therapeutic potential in the treatment of PNI.

Methods

A total of 144 male Sprague-Dawley rats were subjected to a sciatic nerve crush injury model. Rats were grouped into 5 cohorts: sham, control, PNI + Hirudin (10 mg/kg), PNI + Hirudin (15 mg/kg), and PNI + Hirudin (15 mg/kg) + NSC228155. There were various assessments conducted, including histological staining, immunofluorescence, transmission electron microscopy (TEM), behavioral tests, and Western blot analyses.

Results

Our experiments demonstrated that Hirudin significantly improved the structural integrity of regenerating nerves, enhanced orderly axonal regeneration and remyelination. It also alleviated neuropathic pain, as evidenced by reduced autotomy scores and decreased expression of pain-related markers (Iba-1, C-Fos, and substance P). Mechanistic studies revealed that Hirudin downregulated the activation of the EGFR-dependent PI3K/AKT/mTOR signaling pathway, which contributed to its therapeutic effects.

Conclusion

Hirudin can effectively enhance peripheral nerve regeneration and alleviate neuropathic pain following PNI. These findings suggest that Hirudin holds promise as a therapeutic agent for the treatment of PNI-induced neuropathic pain and impaired nerve regeneration.

目的：周围神经损伤（PNI）常导致严重的神经性疼痛和神经再生受损。水蛭素来源于中药水蛭，目前尚未对其治疗PNI的潜力进行研究。方法：采用144只雄性sd大鼠建立坐骨神经挤压损伤模型。将大鼠分为5组：假手术组、对照组、PNI +水蛭素（10 mg/kg）、PNI +水蛭素（15 mg/kg）、PNI +水蛭素(15 mg/kg) + NSC228155。进行了各种评估，包括组织学染色，免疫荧光，透射电子显微镜（TEM），行为测试和western blot分析。结果：水蛭素能明显改善再生神经的结构完整性，促进轴突有序再生和髓鞘再生。自体切开术评分降低，疼痛相关标记物（Iba-1、C-Fos和P物质）表达降低，也可以缓解神经性疼痛。机制研究显示水蛭素下调egfr依赖性PI3K/AKT/mTOR信号通路的激活，这有助于其治疗效果。结论：水蛭素能有效促进周围神经再生，减轻PNI术后神经性疼痛。这些发现表明水蛭素有望作为治疗pni诱导的神经性疼痛和神经再生受损的治疗剂。

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引用次数: 0

Emergence and characterization of lipidated β-lactamases 脂化β-内酰胺酶的出现和特性。

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2026-01-01 Epub Date: 2025-11-03 DOI: 10.1016/j.abb.2025.110644

Thomas Smisek , Walter Fast , Christian P. Whitman

Since the discovery of penicillin, β-lactam antibiotics have been a mainstay for the treatment of bacterial infections. Resistance to β-lactam antibiotics via β-lactamase enzymes was identified before β-lactams even reached a clinical setting, and decades of use has only increased the risk posed by β-lactam resistance, largely driven by β-lactamase enzymes. While most β-lactamases are soluble periplasmic enzymes, a minority are membrane anchored lipoproteins. With the emergence and proliferation of the highly potent New Delhi metallo-β-lactamase (NDM) in the late 2000's, lipidated β-lactamases have catapulted from little more than biochemical curiosities, to key features of one of the most potent and prevalent antibiotic resistance enzymes. NDM is the most well-known lipidated β-lactamase. However, recent work highlights both emerging lipidated β-lactamases as well as the fact that lipidation may be more common in previously characterized β-lactamases than thought.

自从发现青霉素以来，β-内酰胺类抗生素一直是治疗细菌感染的主要药物。通过β-内酰胺酶对β-内酰胺类抗生素的耐药性在β-内酰胺类抗生素进入临床之前就已被发现，几十年的使用只会增加β-内酰胺类抗生素耐药的风险，这主要是由β-内酰胺酶驱动的。虽然大多数β-内酰胺酶是可溶性质周酶，但少数是膜锚定脂蛋白。随着高效的新德里金属β-内酰胺酶（NDM）在2000年代后期的出现和扩散，脂化β-内酰胺酶已经从仅仅是生物化学上的好奇心，一跃成为最有效和最普遍的抗生素抗性酶之一的关键特征。NDM是最著名的脂化β-内酰胺酶。然而，最近的工作强调了新兴的脂化β-内酰胺酶，以及脂化在以前表征的β-内酰胺酶中可能比想象的更常见的事实。

引用次数: 0

Docosahexaenoic acid improved vincristine-induced peripheral neuropathy in a rat model 二十二碳六烯酸改善长春新碱诱导的大鼠周围神经病变模型。

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2026-01-01 Epub Date: 2025-10-26 DOI: 10.1016/j.abb.2025.110664

Cheng-Yi Chang , Chih-Cheng Wu , Ping-Ho Pan , Chung-Yuh Tzeng , Tung-Min Yu , Shih-Yi Lin , Ya-Yu Wang , Su-Lan Liao , Chun-Jung Chen

Peripheral neuropathy is a common and debilitating complication of chemotherapy, characterized by nociceptive hypersensitivity with concurrent mitochondrial dysfunction, oxidative stress, and inflammation. Although nutraceutical supplement with Docosahexaenoic Acid (DHA) improves cancer treatment outcome and complications, molecular mechanisms responsible for beneficial effects are not well understood. Using a Sprague-Dawley rat model of vincristine-induced peripheral neuropathy, herein, we provide behavioral, histological, biochemical, and molecular evidence showing that DHA pretreatment alleviates chemotherapy-induced peripheral neuropathy. Nociceptive hypersensitivity and spinal cord dorsal horn neurodegeneration were accompanied by spinal cord dorsal horn nociceptive Interleukin-6 expression, NADPH oxidase 2 elevation, malondialdehyde production, superoxide dismutase activity inhibition, and glutathione reduction as well as circulating immune cell activation. In parallel, reduction of protein expression crucial to mitochondrial biogenesis, fission, and mitophagy as well as antioxidative defense and anti-inflammation was seen. DHA had alleviative effects on vincristine-induced changes. In assessing molecular targets, Peroxisome Proliferator-Activated Receptor γ (PPAR-γ) represented a surrogate candidate to coordinate action cascades in alleviating mitochondrial dysfunction, oxidative stress, and inflammation when activated by DHA. Although there remain limitations and further investigation is warranted, DHA supplementation is proposed as a protective strategy to alleviate chemotherapy-induced peripheral neuropathy. Our findings further imply that the mechanisms by which DHA is able to induce pain relief, directly or indirectly, could involve mitochondrial dysfunction, oxidative stress, and inflammation.

周围神经病变是一种常见的化疗并发症，其特点是伤害性超敏，同时伴有线粒体功能障碍、氧化应激和炎症。虽然二十二碳六烯酸（DHA）的营养补充剂可以改善癌症治疗结果和并发症，但其有益作用的分子机制尚不清楚。通过长春新碱诱导的周围神经病变的Sprague-Dawley大鼠模型，我们提供了行为学、组织学、生化和分子证据，表明DHA预处理减轻了化疗诱导的周围神经病变。损伤性超敏反应和脊髓背角神经退行性变伴随着脊髓背角损伤性白细胞介素-6表达、NADPH氧化酶2升高、丙二醛产生、超氧化物歧化酶活性抑制和谷胱甘肽减少以及循环免疫细胞活化。与此同时，对线粒体生物发生、裂变和线粒体自噬以及抗氧化防御和抗炎症至关重要的蛋白质表达减少。DHA对长春新碱引起的改变有缓解作用。在评估分子靶点时，过氧化物酶体增殖物激活受体γ (PPAR-γ)代表了协调级联反应的替代候选物，当DHA激活时，可以缓解线粒体功能障碍、氧化应激和炎症。尽管仍有局限性，需要进一步的研究，但DHA补充被认为是一种缓解化疗诱导的周围神经病变的保护策略。我们的研究结果进一步表明，DHA能够直接或间接地诱导疼痛缓解的机制可能涉及线粒体功能障碍、氧化应激和炎症。

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引用次数: 0

Ureaplasma parvum SMC-ScpAB complex is capable of loop extrusion and demonstrates properties that distinguish it from Bacillus subtilis homologue 细小脲原体SMC-ScpAB复合物能够挤出环，并显示出与枯草芽孢杆菌同源物不同的特性。

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2025-12-01 Epub Date: 2025-10-13 DOI: 10.1016/j.abb.2025.110641

Natalia A. Rumyantseva , Antonina P. Sapozhnikova , Aizilya A. Khasanova, Ekaterina Yu Zapryagaeva, Maria A. Kudryavtseva, Natalia E. Morozova, Alexey D. Vedyaykin

Structural Maintenance of Chromosomes (SMC) complexes are present in virtually all organisms and perform a variety of functions associated with maintaining the integrity and spatial organization of DNA. The best-studied SMC complexes are eukaryotic condensins, cohesins, and Smc5/Smc6. It is extremely important that eukaryotic SMC have been shown to exhibit the ability for so-called loop extrusion in vitro, which is the active formation of loops from DNA molecules and is a cosequence of the DNA translocase activity of SMC complexes. For majority of bacterial SMC complexes, including the most widespread Smc-ScpAB complex, loop extrusion has not yet been demonstrated in vitro, although it is in good agreement with the results of in vivo experiments. In this work, we compared the properties of two Smc-ScpAB complexes from different organisms, Bacillus subtilis and Ureaplasma parvum. The results of the work indicate significant differences in the properties of these homologous complexes. In particular, the Smc-ScpAB complex of U. parvum was shown to have the ability to extrude loops, which was not observed for B. subtilis SMC.

染色体结构维持复合物（SMC）几乎存在于所有生物体中，并执行与维持DNA完整性和空间组织相关的各种功能。研究得最好的SMC复合物是真核凝缩蛋白、内聚蛋白和Smc5/Smc6。非常重要的是，真核SMC在体外显示出所谓的环挤压能力，这是DNA分子形成环的活性，是SMC复合物的DNA转座酶活性的结果。对于大多数细菌SMC复合物，包括最广泛的SMC - scpab复合物，体外循环挤出尚未得到证实，尽管它与体内实验结果很好地一致。在这项工作中，我们比较了两种Smc-ScpAB复合物的性质，从不同的生物体，枯草芽孢杆菌和细小脲原体。研究结果表明，这些同源配合物的性质存在显著差异。特别是，细小芽孢杆菌的SMC - scpab复合物具有挤出环的能力，这在枯草芽孢杆菌的SMC中没有观察到。

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引用次数: 0

Molecular and functional identification of tyrosine hydroxylase in the yellow fever mosquito, Aedes aegypti 埃及伊蚊酪氨酸羟化酶的分子和功能鉴定。

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2025-12-01 Epub Date: 2025-09-26 DOI: 10.1016/j.abb.2025.110626

Xiaojing Zhu , Linlong Jiang , Xue Gong , Jing Chen , Yanhui Liu , Pablo Sobrado , Yingying Guo , Qian Han

Aedes aegypti, an arthropod vector that transmits arboviral infectious diseases via blood feeding, has garnered significant attention. However, the in vitro biochemical activity of tyrosine hydroxylase (TH) in Ae. aegypti remains to be confirmed, and the functional role of this enzyme in mosquito has yet to be thoroughly elucidated. TH is a rate-limiting enzyme in the tyrosine metabolic pathway. Here, we identified the sequence and biochemical activity of TH in the mosquito, Aedes aegypti. To investigate the biological function of TH in the development of Ae. aegypti, RNA interference was used in the larvae and adults of Ae. Aegypti. The larvae were fed with chitosan-coated double stranded (ds) Ae. aegypti TH (AeTH) and adult mosquitoes were microinjected with dsAeTH. The number of pupae developed was decreased after AeTH knockdown in larvae, and the number of eggs laid, egg hatching rate, and blood intake of adult mosquitoes after AeTH knockdown were also decreased. The unhatched eggs laid had no normal larvae inside. The results here suggest that AeTH is involved in pupation and affects the normal development and fertility of the adults. The expression levels of melanization- and immune-related genes were examined. The results revealed that TH significantly affected bothmelanization and immune pathways. Collectively, these findings deepen our understanding of the functional role of TH in mosquitoes.

埃及伊蚊（Aedes aegypti）是一种通过血液传播虫媒病毒传染病的节肢动物媒介，已经引起了极大的关注。然而，Ae的酪氨酸羟化酶（TH）的体外生化活性。埃及伊蚊尚未得到证实，该酶在蚊子体内的功能作用尚未完全阐明。TH是酪氨酸代谢途径中的限速酶。本研究鉴定了埃及伊蚊体内TH的序列和生化活性。探讨TH在Ae发育中的生物学功能。对埃及伊蚊幼虫和成虫进行RNA干扰。蚊。用壳聚糖包被双链（ds） Ae饲喂幼虫。对埃及伊蚊（AeTH）和成蚊微量注射dsAeTH。敲除AeTH后，幼虫蛹数减少，成蚊产卵数、卵孵化率和采血量均降低。未孵化的蛋里面没有正常的幼虫。结果表明，AeTH参与化蛹过程，影响成虫的正常发育和繁殖。检测黑色素化和免疫相关基因的表达水平。结果显示，TH显著影响黑素化和免疫途径。总的来说，这些发现加深了我们对TH在蚊子中的功能作用的理解。

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引用次数: 0

Novel epigenetic biomarkers following ferroptosis and pyroptosis in a hypobaric hypoxia-induced renal injury model 在低压缺氧诱导的肾损伤模型中，铁下垂和焦下垂后的新表观遗传生物标志物。

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2025-12-01 Epub Date: 2025-10-09 DOI: 10.1016/j.abb.2025.110637

Hongxuan Liu , Huishu Lin , Yuhong He , Shuhao Shi , Jiayan Ni , Lei Zhao , Yuxuan Ma , Weixia Li , Yuanyuan Yu , Chen Li , Qisijing Liu , Shike Hou , Xiaoxue Li , Liqiong Guo

Background

Rapid hypobaric hypoxia exposure damages oxygen-sensitive organs like the kidneys. Ferroptosis and pyroptosis, oxygen-dependent cell death mechanisms, remain understudied in this context, as does the role of mitochondrial DNA (mtDNA) methylation.

Methods

We established a rat model of hypobaric hypoxia (6000 m/7000 m, 6 h/72 h). Kidney ferroptosis (Prussian blue staining, LPO/MDA/GSH assays, ACSL4/GPX4 expression) and pyroptosis (Caspase1/GSDMD activation) were analyzed. mt-cox1/2/3 methylation was assessed in renal mitochondrial DNA, cytoplasmic DNA, and serum cell-free DNA (cf mtDNA) via pyrosequencing. PCA identified biomarkers.

Results

Hypobaric hypoxia induced renal iron accumulation, lipid peroxidation, and tubular injury. Ferroptosis was mediated by ACSL4 upregulation and GPX4 suppression, while pyroptosis activated Caspase1/GSDMD. Mitochondrial damage and mtDNA leakage were observed via TEM. mt-cox3 pos2 hypermethylation in serum cell-free mtDNA distinctly distinguished hypoxia-exposed rats via PCA.

Conclusion

Ferroptosis and pyroptosis synergize to drive hypobaric hypoxia-induced renal injury. mt-cox3 pos2 methylation in cell-free mtDNA emerges as a novel biomarker for renal pathogenesis.

背景：快速低压缺氧暴露会损害氧敏感器官，如肾脏。在这种情况下，依赖氧的细胞死亡机制铁亡和焦亡，以及线粒体DNA （mtDNA）甲基化的作用仍未得到充分研究。方法：建立大鼠低氧缺氧（6000m/7000m, 6h/72h）模型。分析肾铁下垂（普鲁士蓝染色，LPO/MDA/GSH检测，ACSL4/GPX4表达）和焦下垂（Caspase1/GSDMD激活）。通过焦磷酸测序评估肾线粒体DNA、细胞质DNA和血清无细胞DNA （cf mtDNA）的mt-cox1/2/3甲基化。PCA鉴定生物标志物。结果：低压缺氧引起肾铁积累、脂质过氧化和肾小管损伤。铁下垂通过ACSL4上调和GPX4抑制介导，而焦下垂激活Caspase1/GSDMD。透射电镜观察线粒体损伤和mtDNA渗漏。血清无细胞mtDNA mt-cox3 pos2高甲基化通过PCA明显区分缺氧暴露大鼠。结论：铁下垂和焦下垂共同驱动低压缺氧所致肾损伤。无细胞mtDNA中mt-cox3 pos2甲基化成为肾脏发病的一种新的生物标志物。

{"title":"Novel epigenetic biomarkers following ferroptosis and pyroptosis in a hypobaric hypoxia-induced renal injury model","authors":"Hongxuan Liu , Huishu Lin , Yuhong He , Shuhao Shi , Jiayan Ni , Lei Zhao , Yuxuan Ma , Weixia Li , Yuanyuan Yu , Chen Li , Qisijing Liu , Shike Hou , Xiaoxue Li , Liqiong Guo","doi":"10.1016/j.abb.2025.110637","DOIUrl":"10.1016/j.abb.2025.110637","url":null,"abstract":"<div><h3>Background</h3><div>Rapid hypobaric hypoxia exposure damages oxygen-sensitive organs like the kidneys. Ferroptosis and pyroptosis, oxygen-dependent cell death mechanisms, remain understudied in this context, as does the role of mitochondrial DNA (mtDNA) methylation.</div></div><div><h3>Methods</h3><div>We established a rat model of hypobaric hypoxia (6000 m/7000 m, 6 h/72 h). Kidney ferroptosis (Prussian blue staining, LPO/MDA/GSH assays, ACSL4/GPX4 expression) and pyroptosis (Caspase1/GSDMD activation) were analyzed. mt-cox1/2/3 methylation was assessed in renal mitochondrial DNA, cytoplasmic DNA, and serum cell-free DNA (cf mtDNA) via pyrosequencing. PCA identified biomarkers.</div></div><div><h3>Results</h3><div>Hypobaric hypoxia induced renal iron accumulation, lipid peroxidation, and tubular injury. Ferroptosis was mediated by ACSL4 upregulation and GPX4 suppression, while pyroptosis activated Caspase1/GSDMD. Mitochondrial damage and mtDNA leakage were observed via TEM. mt-cox3 pos2 hypermethylation in serum cell-free mtDNA distinctly distinguished hypoxia-exposed rats via PCA.</div></div><div><h3>Conclusion</h3><div>Ferroptosis and pyroptosis synergize to drive hypobaric hypoxia-induced renal injury. mt-cox3 pos2 methylation in cell-free mtDNA emerges as a novel biomarker for renal pathogenesis.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"774 ","pages":"Article 110637"},"PeriodicalIF":3.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Temperature and cosolute regulate the liquid-liquid phase separation in BSA solutions 温度和溶质调节BSA溶液的液-液分离。

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2025-12-01 Epub Date: 2025-09-17 DOI: 10.1016/j.abb.2025.110620

Brigitte Merino Naranjo , Erica Fuoco , Rosa Bartucci , Rita Guzzi

Biomolecular condensates form in vivo in the crowded cellular environment and are favoured in macromolecules containing low structural complexity or large portions of disordered regions. The liquid-liquid phase separation (LLPS) of protein solutions, in which macromolecule-rich regions are separated from the aqueous solution, can also be observed in vitro under specific experimental conditions of temperature, pH, pressure and components concentration. In this study, we investigate the formation of LLPS of bovine serum albumin (BSA) induced by polyethylene glycol (PEG-5000) and temperature. The LLPS of BSA solutions and droplets formation were assessed and characterized by temperature dependent turbidity, optical microscopy and infrared spectroscopy experiments. The results show that the lower the PEG concentration, the lower the LLPS transition temperature of BSA solution. At PEG concentration of 10 % (w/v) the average diameter of BSA droplets is about 9 μm at 10 °C, decreases to about 3 μm at 20 °C and at higher temperature the droplets dissolve and a homogeneous phase is observed. The real time formation of the BSA droplets is also followed by ATR-FTIR kinetic experiments that allow an estimate of protein concentration in the droplets giving a value 50 times higher than the initial solution (100 μM). No variation of the protein secondary structure within the condensates compared to the homogeneous phase is evidenced.

生物分子凝聚物是在拥挤的细胞环境中形成的，在结构复杂性低或无序区域大的大分子中更受青睐。在温度、pH、压力和组分浓度等特定实验条件下，也可以在体外观察到富含大分子区域的蛋白质溶液的液-液相分离（LLPS）。在本研究中，我们研究了聚乙二醇（PEG-5000）和温度诱导牛血清白蛋白（BSA） LLPS的形成。通过温度依赖浊度、光学显微镜和红外光谱实验对BSA溶液的LLPS和液滴形成进行了评估和表征。结果表明，PEG浓度越低，BSA溶液的LLPS转变温度越低。当PEG浓度为10% （w/v）时，10℃时BSA液滴的平均直径约为9 μm， 20℃时降至3 μm左右，温度升高时液滴溶解，形成均匀相。在实时形成BSA液滴之后，还进行了ATR-FTIR动力学实验，可以估计液滴中的蛋白质浓度，其值比初始溶液（100 μM）高50倍。与均相相比，凝析物中的蛋白质二级结构没有变化。

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引用次数: 0

Exercise alleviates programmed necrosis in myocardial ischemia-reperfusion injury through adipose tissue-derived exosomal miR-17-3p targeting CAMKII 运动通过脂肪组织源性外泌体靶向CAMKII的miR-17-3p减轻心肌缺血再灌注损伤中的程序性坏死

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2025-12-01 Epub Date: 2025-10-10 DOI: 10.1016/j.abb.2025.110640

Zhuyuan Liu, Wenbin Lu, Yanru He, Fuchao Yu

Exercise exerts cardioprotective effects, with prior research implicating exosomal miR-17-3p as a critical mediator in attenuating myocardial ischemia-reperfusion injury (MIRI). The present study aimed to elucidate the influence of exercise on exosomal miR-17-3p and to delineate the underly mechanisms by which it mitigates MIRI. A MIRI model was established using C57BL/6 mice. Exosomes were isolated and their impact on programmed necrosis, cardiac function, infarct size, inflammatory factors (LDH, TNF-α), as well as proteins associated with ventricular remodeling, was evaluated. Complementary in vitro experiments employed primary cardiomyocytes to further investigate these effects. The regulatory relationship between miR-17-3p and calcium/calmodulin-dependent protein kinase II (CAMK II) was examined. Additionally, the contribution of brown adipose tissue (BAT) as the source of exosomal miR-17-3p was assessed. Findings demonstrated that exercise enhanced cardiac function and reduced infarct size in MIRI mice through exosome-mediated mechanisms. Mechanistically, exosomal miR-17-3p directly targeted CAMKII, leading to inhibition of the RIPK3/MLKL pathway, thereby attenuating cardiomyocyte necrosis and inflammation and reversing pathological ventricular remodeling. BAT was identified as the principal origin of exosomal miR-17-3p, and ablation of BAT abrogated the cardioprotective effects conferred by exercise. Collectively, these results suggest that exercise confers protection against MIRI by promoting the uptake of BAT-derived exosomal miR-17-3p uptake by cardiomyocytes, which in turn supresses CAMKII activity and programmed necrosis. This study reveals a novel exercise-induced cardioprotective pathway and identifies potential therapeutic targets for MIRI.

运动具有心脏保护作用，先前的研究表明外泌体miR-17-3p是减轻心肌缺血再灌注损伤（MIRI）的关键介质。本研究旨在阐明运动对外泌体miR-17-3p的影响，并描述其减轻MIRI的潜在机制。用C57BL/6小鼠建立MIRI模型。分离外泌体，评估其对程序性坏死、心功能、梗死面积、炎症因子（LDH、TNF-α）以及与心室重构相关的蛋白质的影响。补充体外实验采用原代心肌细胞进一步研究这些影响。研究了miR-17-3p与钙/钙调素依赖性蛋白激酶II （CAMK II）之间的调节关系。此外，我们还评估了棕色脂肪组织（BAT）作为外泌体miR-17-3p来源的贡献。研究结果表明，运动通过外泌体介导的机制增强了MIRI小鼠的心功能并减少了梗死面积。在机制上，外泌体miR-17-3p直接靶向CAMKII，导致RIPK3/MLKL通路的抑制，从而减轻心肌细胞坏死和炎症，逆转病理性心室重构。BAT被确定为外泌体miR-17-3p的主要来源，BAT的消融取消了运动所赋予的心脏保护作用。总的来说，这些结果表明，运动通过促进心肌细胞对bat来源的外泌体miR-17-3p的摄取，进而抑制CAMKII活性和程序性坏死，从而提供对MIRI的保护。这项研究揭示了一种新的运动诱导的心脏保护途径，并确定了MIRI的潜在治疗靶点。

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引用次数: 0

Thermodynamics of the transition from the ferryl (F) state to the oxidized form of the solubilized cytochrome c oxidase: implication for the proton pumping 可溶性细胞色素c氧化酶从铁基(F)态到氧化态转变的热力学：对质子泵送的启示。

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2025-12-01 Epub Date: 2025-10-08 DOI: 10.1016/j.abb.2025.110638

Adriana Tomkova , Tereza Sztachova , Jonatan Johannesson , Daniel Jancura , Marian Fabian

Two ferryl intermediates have been identified in the membrane-bound respiratory heme-copper oxygen reductases (HCOs) during reduction of O₂ to water. Apparently, energy released by reduction of these two ferryl forms is utilized to build the transmembrane electrochemical proton gradient by two mechanisms. One of them, the proton pumping, is the key unresolved problem of the contemporary molecular bioenergetics. Even though the position of these ferryl forms in energy transformation is central, the direct and complete thermodynamic characterization of these intermediates is lacking. Here, thermodynamics of redox transition of one of these ferryl intermediates, the F state, was established by isothermal titration calorimetry (ITC) and density functional theory utilizing one representative of HCOs, bovine cytochrome c oxidase (CcO). In CcOs, the reduction of catalytic cytochrome a₃-Cu_B center is accomplished by electron transfer (ET) from ferrocytochrome c via copper Cu_A and cytochrome a center. The energy for the pumping is suggested to be released mainly during the transition of the catalytic center of F initiated by ET from cytochrome a. This transfer results in the conversion of Fe(IV)O to Fe(III) state of heme a₃, yielding the oxidized CcO (O). Based on the enthalpy changes determined by ITC and available entropy values for this process, the estimated ΔG⁰ was found to be −24 kcal/mol, corresponding to the electrode potential of +1.3 V for the F/O couple (pH 8.0, 25 °C). Remarkably, the results indicate that major fraction of energy for the proton pumping is provided by the redox-dependent structural changes of cytochrome a.

在O2还原为水的过程中，在膜结合的呼吸血红素-铜氧还原酶（HCOs）中发现了两个铁基中间体。显然，这两种铁基形式的还原释放的能量通过两种机制用于建立跨膜电化学质子梯度。其中质子抽运是当代分子生物能学尚未解决的关键问题。尽管这些铁基形式在能量转化中的地位是中心的，但这些中间体的直接和完整的热力学表征是缺乏的。本文采用等温滴定量热法（ITC）和密度泛函理论，利用牛细胞色素c氧化酶（CcO），建立了其中一种铁基中间体F态的氧化还原跃迁热力学。在CcOs中，催化细胞色素a3-CuB中心的还原是由铁细胞色素c通过铜CuA和细胞色素a中心的电子转移（ET）完成的。泵送的能量主要是在ET引发的F的催化中心从细胞色素a转移的过程中释放的。这种转移导致血红素a3的Fe(IV)=O向Fe（III）态转化，生成氧化的CcO (O)。根据ITC测定的焓变和该过程的可用熵值，估计ΔG0为-24 kcal/mol，对应于F/O偶对（pH 8.0, 25°C）的+1.3 V电极电位。值得注意的是，结果表明质子泵送的大部分能量是由细胞色素a的氧化还原依赖性结构变化提供的。

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引用次数: 0

TNF promotes osteoclastogenesis by secreting miR-31-5p into small extracellular vesicles via the autotaxin–LPA–LPAR1 axis in arthritic fibroblast-like synoviocytes TNF通过关节炎成纤维细胞样滑膜细胞的autotaxin-LPA-LPAR1轴将miR-31-5p分泌到细胞外小泡中，从而促进破骨细胞的发生

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2025-12-01 Epub Date: 2025-10-01 DOI: 10.1016/j.abb.2025.110631

Thanh Nam Phan , Minju Gal , Okhwa Kim , Hoang Long Le , Cheol Hwangbo , Jeong-Hyung Lee

Fibroblast-like synoviocytes (FLSs) play a crucial role in the pathogenesis of arthritis. However, the impact of small extracellular vesicles (sEVs) secreted by FLSs on osteoclastogenesis remains incompletely understood. In this study, we aimed to investigate the role of tumor necrosis factor (TNF)- and lysophosphatidic acid (LPA)-activated FLSs in sEV-mediated release of osteoclastogenic miRNAs and elucidate their functional contribution to osteoclastogenesis. Stimulation of SW982 cells with LPA or TNF significantly increased sEV secretion. TNF upregulated autotaxin expression and promoted sEV release; however, small interfering RNA (siRNA)-mediated knockdown (KD) of LPAR1 attenuated the increase in sEV release induced by the TNF–autotaxin–LPA axis. Notably, stimulation with TNF or LPA elevated syntenin-1 expression without altering its mRNA level. Furthermore, KD of the syntenin-1 gene (SDCBP) suppressed the LPA-induced increase in sEV release, indicating that syntenin-1 may mediate sEV secretion induced by the TNF–autotaxin–LPA–LPAR1 axis. sEVs derived from TNF- or LPA-treated SW982 cells stimulated osteoclastogenesis. We identified miR-31-5p as an osteoclastogenic miRNA enriched in sEVs. Expression levels of miR-31-5p in sEVs from TNF- and LPA-stimulated rheumatoid arthritis (RA) FLSs were significantly higher than in those from unstimulated RA FLSs. Treatment with a miR-31-5p mimic enhanced osteoclastogenesis by targeting large tumor suppressor kinase 2 (LATS2), whereas treatment with its inhibitor suppressed the sEV-mediated promotion of osteoclastogenesis. These findings reveal a mechanism by which TNF- and LPA-activated FLSs may facilitate sEV-mediated delivery of osteoclastogenic miRNAs, such as miR-31-5p, to osteoclast precursors, thereby contributing to osteoclast formation and bone destruction.

成纤维细胞样滑膜细胞（FLSs）在关节炎的发病机制中起着至关重要的作用。然而，FLSs分泌的小细胞外囊泡（sev）对破骨细胞发生的影响仍不完全清楚。在这项研究中，我们旨在研究肿瘤坏死因子(TNF)-和溶血磷脂酸(LPA)-激活的FLSs在sev介导的破骨microrna释放中的作用，并阐明它们在破骨细胞发生中的功能贡献。LPA或TNF刺激SW982细胞可显著增加sEV分泌。TNF上调autotaxin表达，促进sEV释放；然而，小干扰RNA （siRNA）介导的LPAR1敲低（KD）减弱了TNF-autotaxin-LPA轴诱导的sEV释放的增加。值得注意的是，TNF或LPA刺激可提高syntenin-1的表达，但不改变其mRNA水平。此外，syntenin-1基因（SDCBP）的KD抑制了lpa诱导的sEV释放增加，表明syntenin-1可能介导了TNF-autotaxin-LPA-LPAR1轴诱导的sEV分泌。来自TNF-或lpa处理的SW982细胞的sev刺激了破骨细胞的发生。我们发现miR-31-5p是在sev中富集的破骨细胞microrna。TNF-和lpa刺激的类风湿关节炎（RA） FLSs的sev中miR-31-5p的表达水平显著高于未刺激的类风湿关节炎FLSs。miR-31-5p模拟物通过靶向大肿瘤抑制激酶2 （LATS2）增强破骨细胞的生成，而其抑制剂抑制sev介导的破骨细胞生成。这些发现揭示了TNF-和lpa激活的FLSs可能促进sev介导的破骨细胞microrna（如miR-31-5p）递送到破骨细胞前体的机制，从而促进破骨细胞的形成和骨破坏。

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