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Protective effect of resveratrol against colistin-induced nephrotoxicity through regulating Nrf2 pathway and inhibiting ferroptosis. 白藜芦醇通过调控Nrf2通路和抑制铁下垂对粘菌素所致肾毒性的保护作用。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-05 DOI: 10.1016/j.freeradbiomed.2026.02.009
Zhisheng Hu, Weihua Hao, Na Cui, Xin Gao, Wenqing Dai, Minge Wang, Liangxing Fang, Jian Sun, Hongyan Zhang, Xiaoping Liao

Resveratrol (Res), a natural polyphenol, is widely used as a functional food additive and food preservative due to its antioxidant and anti-inflammatory properties. However, its protective role against drug-induced organ damage, particularly colistin-induced nephrotoxicity (CIN), remains underexplored. This study investigated Res's protective effects and mechanisms against CIN in rat and NRK-52E cells. In vivo, Res (5-20 mg/kg) significantly improved renal function, alleviated histopathological damage, and restored antioxidant status. Mechanistically, Res modulated the Keap1/Nrf2 axis, suppressing excessive Nrf2 activation and its downstream enzymes. Concurrently, Res inhibited ferroptosis by reducing iron accumulation and modulating key ferroptosis markers (GPX4, ACSL4). In vitro, Res (20 μM) reversed CS- and RSL3-induced cytotoxicity, lipid peroxidation, and ferrous iron overload; Nrf2 siRNA abrogated these effects, confirming Nrf2's essential role. These findings highlight Res as a promising strategy to enhance colistin's clinical safety through precise Nrf2 modulation and ferroptosis inhibition, underscoring the therapeutic potential of natural food compounds.

白藜芦醇(Resveratrol, Res)是一种天然多酚,由于其抗氧化和抗炎的特性,被广泛用作功能性食品添加剂和食品防腐剂。然而,其对药物性器官损伤的保护作用,特别是粘菌素引起的肾毒性(CIN),仍未得到充分研究。本研究探讨了Res对大鼠和NRK-52E细胞抗CIN的保护作用及其机制。在体内,Res (5-20 mg/kg)可显著改善肾功能,减轻组织病理损伤,恢复抗氧化状态。在机制上,Res调节Keap1/Nrf2轴,抑制过度的Nrf2激活及其下游酶。同时,Res通过减少铁积累和调节关键铁下垂标志物(GPX4, ACSL4)来抑制铁下垂。在体外,Res (20 μM)可逆转CS-和rsl3诱导的细胞毒性、脂质过氧化和亚铁超载;Nrf2 siRNA消除了这些影响,证实了Nrf2的重要作用。这些发现突出了Res作为一种有希望的策略,通过精确调节Nrf2和抑制铁下沉来提高粘菌素的临床安全性,强调了天然食品化合物的治疗潜力。
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引用次数: 0
MOTS-c attenuates cardiac dysfunction following high altitude exposure by promoting mitophagy. MOTS-c通过促进线粒体自噬来减轻高海拔暴露后的心功能障碍。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-05 DOI: 10.1016/j.freeradbiomed.2026.01.064
Zihang Feng, Yuan Xing, Jing Lou, Han Li, Ziang Zhang, Min Li, Qing Zhu, Yang Cui, Jia Li, Feng Gao, Wei Yi, Yang Sun, Xing Zhang

Prolonged exposure to high altitude (HA) results in a range of systemic changes, some of which, specifically for the heart, particularly cardiac changes, remain difficult to reverse after returning to low altitude. Cardiac de-acclimatization after HA exposure and its underlying mechanisms remain unclear. In this study, mice were subjected to a decompression chamber to simulate a 6000-m altitude exposure for 10 days, followed by the other 10-day de-acclimatization period at a lower altitude of 400 m. The cardiac dysfunction induced by HA exposure persisted throughout the de-acclimatization, accompanied with sustained mitochondrial dysfunction and the short peptide mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-c) deficiency. Exogenous supplementation of MOTS-c during de-acclimatization effectively alleviated the cardiac dysfunction post HA exposure. Mechanistically, MOTS-c activated the PTEN-induced putative kinase 1 (Pink1) / Parkin pathway, promoting mitophagy and improving mitochondrial quality. Silencing Pink1 abolished the protective effects of MOTS-c during de-acclimatization. Additionally, reduced circulating MOTS-c levels were observed in patients with high altitude heart disease and acute coronary syndrome. These results suggest that HA exposure leaves a memory of cardiac dysfunction upon return to lower altitude. This is attributed to a sustained deficiency in MOTS-c. MOTS-c maintains mitochondrial quality through promoting mitophagy, highlighting its therapeutic potential for treating HA-induced cardiac dysfunction during de-acclimatization.

长时间暴露于高海拔(HA)会导致一系列全身变化,其中一些,特别是心脏,特别是心脏的变化,在返回低海拔后仍然难以逆转。羟基磷灰石暴露后的心脏去环境适应及其潜在机制尚不清楚。在本研究中,小鼠在减压室中模拟海拔6000米的暴露10天,然后在海拔400米的较低海拔进行10天的适应期。HA暴露引起的心功能障碍在去环境化过程中持续存在,并伴有持续的线粒体功能障碍和12S核糖体RNA -c型(MOTS-c)缺失的短肽线粒体开放阅读框。在适应环境过程中外源性补充MOTS-c可有效缓解HA暴露后的心功能障碍。在机制上,MOTS-c激活了pten诱导的激酶1 (Pink1) / Parkin通路,促进线粒体自噬并改善线粒体质量。Pink1的沉默消除了MOTS-c在脱驯化过程中的保护作用。此外,在高原心脏病和急性冠状动脉综合征患者中观察到循环MOTS-c水平降低。这些结果表明,HA暴露会在返回低海拔地区时留下心功能障碍的记忆。这是由于MOTS-c持续缺乏造成的。MOTS-c通过促进线粒体自噬来维持线粒体质量,这突出了其治疗ha在适应环境过程中引起的心功能障碍的治疗潜力。
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引用次数: 0
What Lies Beyond Thioredoxin Reductase? Cyclometallated gold Compounds Reveal Sec Selectivity in Glutathione Peroxidases. 硫氧还蛋白还原酶之外还有什么?环金属化金化合物在谷胱甘肽过氧化物酶中显示出选择性。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-05 DOI: 10.1016/j.freeradbiomed.2026.02.007
Ioannis Kanavos, Douglas H Nakahata, Madeleine S Barrett, Ancély F Dos Santos, Maria Zubiria-Ulacia, German E Pieslinger, Ana Beatriz da Silva Teixeira, Isadora Medeiros, Clarissa Ribeiro Reily Rocha, Jonas Eberle, Ryszard Lobinski, Jon Mattin Matxain, Matthew D Hall, José P Friedmann Angeli, Elias S J Arnér, Luisa Ronga, Raphael E F de Paiva

Cyclometallated gold(III) compounds were evaluated for their chemoselective capability to promote C-Se coupling reactions under biocompatible conditions. Competitive reactions with selenium and sulfur substrates highlighted the preference for selenium, and this selectivity was further confirmed in selenopeptide models mimicking the GPx active site. Given that thioredoxin reductase (TXNRD1) is a canonical target for gold compounds, we confirmed that our complexes also inhibit this enzyme, with the two six-membered metallacycles exhibiting a higher potency than auranofin. Expanding beyond TXNRD1, the compounds were further investigated as inhibitors of other selenoenzymes, specifically glutathione peroxidase isoenzymes (GPx1, GPx4). The metallacycles were potent inhibitors of GPx1, while in vitro GPx4 inhibition was overall less pronounced, with LC/MS studies identifying selenocysteine (Sec51) as the primary arylation site on GPx1. We demonstrated that this chemoselectivity could be translated to an intracellular setting. The selectivity towards Se was further explored using A375 GPx4 WT and A375 GPx4 U46C mutant cell lines, where proliferation assays showed a greater effect in the GPx4 WT cells. By integrating structural and functional insights across selenoenzyme families, this study reveals glutathione peroxidases as pivotal molecular targets of cyclometallated gold(III) compounds and lays the groundwork for designing selective Sec-targeting metallodrugs, an approach with untapped potential in anticancer therapy.

研究了环金属化金(III)化合物在生物相容性条件下促进C-Se偶联反应的化学选择能力。与硒和硫底物的竞争反应突出了硒的选择性,这种选择性在模拟GPx活性位点的硒肽模型中得到进一步证实。考虑到硫氧还蛋白还原酶(TXNRD1)是金化合物的典型靶标,我们证实我们的配合物也抑制该酶,两个六元金属环表现出比金酰fin更高的效力。除了TXNRD1之外,这些化合物还被进一步研究作为其他硒酶的抑制剂,特别是谷胱甘肽过氧化物酶同工酶(GPx1, GPx4)。金属环是GPx1的有效抑制剂,而GPx4的体外抑制总体上不太明显,LC/MS研究鉴定硒代半胱氨酸(Sec51)是GPx1的主要芳基化位点。我们证明,这种化学选择性可以翻译到细胞内设置。在A375 GPx4 WT和A375 GPx4 U46C突变细胞系中进一步研究了硒的选择性,增殖实验显示GPx4 WT细胞对硒的选择性更强。通过整合硒酶家族的结构和功能,本研究揭示了谷胱甘肽过氧化物酶是环金属化金(III)化合物的关键分子靶点,并为设计选择性的sec靶向金属药物奠定了基础,这一方法在抗癌治疗中具有未开发的潜力。
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引用次数: 0
HO-1/Nrf2 activation orchestrates protection in sepsis-induced lung injury by suppressing CCR2hi monocyte recruitment and MAPK-driven inflammation. HO-1/Nrf2激活通过抑制CCR2hi单核细胞募集和mapk驱动的炎症来协调脓毒症诱导的肺损伤的保护。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-04 DOI: 10.1016/j.freeradbiomed.2026.02.004
Jing Yang, Li Zhang, Huirong An, Xin Guan, Yuan Zhang, Junlong Zhang, Shasha Liu, Shihan Du, Jia Shi, Yan Guo, Jianbo Yu

Sepsis-induced acute lung injury (ALI) remains a devastatingly lethal clinical syndrome driven by aberrant inflammatory dysregulation, wherein monocytes play critical roles in disease pathogenesis. This study elucidates the mechanistic basis by which the HO-1 inducer Hemin alleviates ALI by activating the HO-1/Nrf2 pathway to target pro-inflammatory monocytes. RNA-seq analysis revealed that the most prominently dysregulated genes in LPS-stimulated human THP-1 monocytes (relative to untreated controls) were predominantly enriched in pathways governing inflammatory responses and oxidative stress. In vitro experiments revealed that Hemin suppressed the p38-MAPK/mTOR pathways in human monocytes, inhibiting inflammatory activation, differentiation, and LPS-induced cell death while preserving phagocytosis. The murine ALI model was established in WT, CCR2-/-, and Nrf2-/- mice via tail vein injection of LPS, with assessments conducted 12 hours later. In LPS-challenged mice, Hemin pretreatment selectively inhibited the recruitment of CCR2hi monocytes (but not CCR2lo monocytes or neutrophils) into the lungs, thereby attenuating histopathological injury, reducing TNF-α and IL-6 levels, and diminishing monocyte-derived macrophages and their M1/M2 polarization. CCR2 deficiency not only abrogated the therapeutic efficacy of Hemin in ALI, evidenced by the failure to prevent the LPS-induced increase in the proportion of monocyte-derived macrophages and the elevation of macrophage polarization, but also paradoxically elevated pulmonary TNF-α concentrations. Furthermore, experiments using Nrf2-/- mice revealed that the protective benefits of Hemin are strictly Nrf2-dependent. Nrf2 deficiency prevented Hemin from restoring the redox balance (GSH/GSSG ratio) and abolished its systemic and pulmonary anti-inflammatory effects, along with its suppression of CCR2hi subsets and inhibition of macrophages polarization. Collectively, our findings establish that activation of the HO-1/Nrf2 pathway mitigates ALI by selectively targeting CCR2hi pro-inflammatory monocytes, positioning Hemin as a promising therapeutic candidate for ALI and identifying the proportion of CCR2hi monocyte and Nrf2-mediated redox markers as potential biomarkers to guide precision medicine strategies for ALI management.

脓毒症诱导的急性肺损伤(ALI)仍然是一种由异常炎症失调驱动的致命临床综合征,其中单核细胞在疾病发病机制中起关键作用。本研究阐明了HO-1诱导剂Hemin通过激活HO-1/Nrf2通路靶向促炎单核细胞减轻ALI的机制基础。RNA-seq分析显示,在lps刺激的人THP-1单核细胞中(相对于未处理的对照组),最显著的失调基因主要富集在控制炎症反应和氧化应激的途径中。体外实验显示,Hemin抑制人单核细胞p38-MAPK/mTOR通路,抑制炎症激活、分化和lps诱导的细胞死亡,同时保持吞噬功能。通过尾静脉注射LPS建立WT、CCR2-/-、Nrf2-/-小鼠ALI模型,12小时后进行评估。在lps刺激小鼠中,Hemin预处理选择性地抑制CCR2hi单核细胞(但不包括CCR2lo单核细胞或中性粒细胞)向肺的募集,从而减轻组织病理学损伤,降低TNF-α和IL-6水平,减少单核细胞来源的巨噬细胞及其M1/M2极化。CCR2缺乏不仅削弱了Hemin在ALI中的治疗效果,不能阻止lps诱导的单核细胞来源的巨噬细胞比例增加和巨噬细胞极化的升高,而且还矛盾地升高了肺TNF-α浓度。此外,对Nrf2-/-小鼠的实验表明,Hemin的保护作用严格依赖于Nrf2。Nrf2缺乏阻止Hemin恢复氧化还原平衡(GSH/GSSG比值),取消其全身和肺部抗炎作用,以及其抑制CCR2hi亚群和抑制巨噬细胞极化的作用。总的来说,我们的研究结果表明,HO-1/Nrf2通路的激活通过选择性靶向CCR2hi促炎单核细胞来减轻ALI,将Hemin定位为ALI的有希望的治疗候选药物,并确定CCR2hi单核细胞和Nrf2介导的氧化还原标记物的比例作为潜在的生物标记物来指导ALI管理的精准医学策略。
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引用次数: 0
Inhibiting Endoplasmic Reticulum/Plasma Membrane Contact Ameliorates Endometrial Fibrosis by Preventing Senescence in Endometrial Epithelial Cells. 抑制内质网/质膜接触通过防止子宫内膜上皮细胞衰老改善子宫内膜纤维化。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-04 DOI: 10.1016/j.freeradbiomed.2026.01.059
Huan Yang, Yi Zhang, Mengxiong Li, Kaixuan Zeng, Yaoyao Xu, Ruohong Pan, Jiayu Huang, Lu Sun, Yuqing Yao, Jin Luo, Tian Li

Intrauterine adhesion (IUA) is characterized by the formation of endometrial fibrosis within the uterine cavity, which can lead to thin endometrium, hypomenorrhea, infertility, and recurrent abortion, exerting a detrimental impact on women's physical and psychological health. Currently, its pathogenesis is not fully elucidated, absence of effective therapies and coupled with a high recurrence rate. In this study, single-cell RNA sequencing was applied for the first time to a mouse IUA model, revealing significant changes in the expression of senescence markers in endometrial epithelial cells (EECs). Specifically, upregulation of Cdkn1a, and Il6, and downregulation of Lamin B1. Further bioinformatic analysis showed significant enrichment of gene sets related to calcium overload, ER stress, and Endoplasmic Reticulum/Plasma Membrane (ER/PM) contacts in the EECs of IUA mice. Mechanistically, ER/PM contacts in IUA activates the STIM1/Orai1 channel complex, leading to ER stress and intracellular calcium overload, which induces cellular senescence in EECs and ultimately drives IUA progression. Intrauterine administration of the STIM1/Orai1 channel inhibitor BTP2 significantly suppressed ER/PM contacts-induced senescence in EECs and effectively alleviated endometrial fibrosis in the mouse IUA model. In conclusion, targeting the STIM1/Orai1 calcium channel dependent on ER/PM contact sites significantly ameliorates endometrial fibrosis, offering a promising therapeutic strategy for IUA.

宫腔内粘连(Intrauterine adhesion, IUA)的特点是宫腔内形成子宫内膜纤维化,可导致子宫内膜变薄、月经减少、不孕症和反复流产,对女性的身心健康产生不利影响。目前,其发病机制尚未完全阐明,缺乏有效的治疗方法,且复发率高。本研究首次将单细胞RNA测序应用于小鼠IUA模型,发现子宫内膜上皮细胞(endometrial epithelial cells, EECs)中衰老标志物的表达发生了显著变化。具体来说,Cdkn1a和Il6上调,Lamin B1下调。进一步的生物信息学分析显示,在IUA小鼠的EECs中,与钙超载、内质网应激和内质网/质膜(ER/PM)接触相关的基因组显著富集。在机制上,IUA中的ER/PM接触激活STIM1/Orai1通道复合物,导致内质网应激和细胞内钙超载,从而诱导EECs细胞衰老,最终推动IUA进展。子宫内给予STIM1/Orai1通道抑制剂BTP2可显著抑制ER/PM接触引起的EECs衰老,并有效缓解小鼠IUA模型的子宫内膜纤维化。总之,靶向依赖于ER/PM接触位点的STIM1/Orai1钙通道可显著改善子宫内膜纤维化,为IUA提供了一种有前景的治疗策略。
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引用次数: 0
D-Ribose-Induced Cytotoxicity in K562 Cells: RBKS-Dependent Disruption of Copper Homeostasis and Mitochondrial Function. d -核糖诱导的K562细胞毒性:rbks依赖性铜稳态和线粒体功能的破坏。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-04 DOI: 10.1016/j.freeradbiomed.2026.01.062
Wang Zeying, Li Houyu, Yang Zhongbin, Tai Yu, He Qi, Hou Kun, He Qihang, Zhou Yingnan, Liu Zhi, Li Xiaojing, Zhang Xueming, Ma Qiang, Zhou Jingye, Shi Caixia, He Liran, Jin Jing, Su Yan

Background: D-ribose, a highly reducing pentose sugar, can be phosphorylated by ribokinase (RBKS) to form ribose-5-phosphate (R-5-P). Elevated urinary D-ribose levels have been reported in patients with type 2 diabetes mellitus (T2DM) and Alzheimer's disease, implicating its potential role in disease pathogenesis. Previous investigations into D-ribose cytotoxicity have primarily focused on its non-enzymatic glycation activity, while alternative mechanisms remain underexplored. Since hemoglobin is a major in vivo target of glycation, this study utilized K562 cells-which retain inducible hemoglobin expression-to examine additional cytotoxic mechanisms of D-ribose.

Methods and results: CCK-8 assays demonstrated that D-ribose inhibited K562 cell proliferation in a concentration- and time-dependent manner, and this inhibitory effect was significantly enhanced in hemin-induced differentiated K562 cells. Conversely, RBKS overexpression promoted proliferation and alleviated oxidative stress in K562 cells. Transcriptomic analysis revealed that differentially expressed genes in D-ribose-treated cells were enriched in mineral absorption and oxidative phosphorylation pathways (KEGG), as well as in biological processes related to copper ion homeostasis (GO). RT-qPCR confirmed that both D-ribose treatment and RBKS knockout downregulated key copper homeostasis genes (e.g., SLC31A1, MT1F, ATOX1) and mitochondrial respiratory chain genes (e.g., COX17, COX11, MTATP8, MTND6), and were accompanied by a significant reduction in intracellular free copper levels.

Conclusions: These findings reveal a novel cytotoxic mechanism mediated by the RBKS-copper-oxidative phosphorylation axis in D-ribose-treated K562 cells, providing key insights into the intracellular role of D-ribose.

背景:d -核糖是一种高还原性戊糖,可被核糖激酶(RBKS)磷酸化形成核糖-5-磷酸(R-5-P)。尿d -核糖水平升高在2型糖尿病(T2DM)和阿尔茨海默病患者中有报道,暗示其在疾病发病机制中的潜在作用。先前对d -核糖细胞毒性的研究主要集中在其非酶糖基化活性上,而其他机制仍未得到充分探索。由于血红蛋白是体内糖基化的主要靶点,本研究利用K562细胞-保留可诱导的血红蛋白表达-来研究d -核糖的其他细胞毒性机制。方法和结果:CCK-8实验表明,d -核糖对K562细胞增殖的抑制作用呈浓度依赖性和时间依赖性,并且这种抑制作用在hemin诱导的分化K562细胞中显著增强。相反,RBKS过表达可促进K562细胞增殖,减轻氧化应激。转录组学分析显示,d -核糖处理细胞中的差异表达基因在矿物质吸收和氧化磷酸化途径(KEGG)以及与铜离子稳态(GO)相关的生物过程中富集。RT-qPCR证实,d -核糖处理和RBKS敲除均下调了关键的铜稳态基因(如SLC31A1、MT1F、ATOX1)和线粒体呼吸链基因(如COX17、COX11、MTATP8、MTND6),并伴有细胞内游离铜水平的显著降低。结论:这些发现揭示了d -核糖处理的K562细胞中rbks -铜-氧化磷酸化轴介导的一种新的细胞毒性机制,为d -核糖在细胞内的作用提供了关键的见解。
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引用次数: 0
PGAM1-dependent VDAC1 oligomerization disrupts mitochondrial quality control to drive doxorubicin cardiotoxicity via the cGAS-STING-ferroptosis axis. pgam1依赖性VDAC1寡聚化破坏线粒体质量控制,通过cgas - sting -铁下垂轴驱动阿霉素心脏毒性。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-04 DOI: 10.1016/j.freeradbiomed.2026.01.065
Yukun Li, Sicheng Zheng, Haowen Zhuang, Ji Wu, Junyan Wang, Xing Chang

Objectives: Doxorubicin (Dox) is a potent chemotherapeutic agent whose clinical use is limited by severe cardiotoxicity. The underlying molecular mechanisms remain incompletely understood. This study aimed to investigate the role of the phosphoglycerate mutase 1 (PGAM1)/voltage-dependent anion channel 1 (VDAC1) axis in early-stage Dox-induced cardiotoxicity, focusing on its impact on mitochondrial quality control (MQC), endoplasmic reticulum (ER) stress, and the subsequent activation of innate immune signaling.

Methods: We established a short-term cumulative Dox-induced cardiomyopathy model using wild-type and cardiomyocyte-specific PGAM1 knockout (PGAM1-CKO) mice. Cardiac function was assessed by echocardiography. In vitro experiments were performed on neonatal mouse cardiomyocytes (NMCMs) and HL-1 cells. Molecular techniques including Western blotting, immunofluorescence, co-immunoprecipitation, and quantitative PCR were used to dissect the signaling pathway. Key pathway components were validated using specific pharmacological inhibitors and activators.

Results: Dox treatment significantly upregulated PGAM1 expression in cardiomyocytes. PGAM1-CKO mice were protected from Dox-induced cardiac dysfunction, fibrosis, and inflammation. Mechanistically, Dox-induced PGAM1 promoted the pathological oligomerization of VDAC1. This PGAM1-VDAC1 interaction triggered the collapse of MQC and induced ER stress, leading to the leakage of mitochondrial DNA (mtDNA) into the cytosol. The released cytosolic mtDNA subsequently activated the cGAS-STING innate immune pathway, which we identified as a critical upstream driver of cardiomyocyte ferroptosis. Pharmacological induction of VDAC1 oligomerization or STING activation abolished the cardioprotective effects observed in PGAM1-CKO mice.

Conclusion: Our findings reveal a novel PGAM1/VDAC1 signaling axis that triggers early Dox-induced cardiotoxicity. This axis disrupts mitochondrial homeostasis, leading to mtDNA release, which activates the cGAS-STING pathway and ultimately culminates in cardiomyocyte ferroptosis. Targeting the PGAM1/VDAC1 interaction presents a promising therapeutic strategy to mitigate Dox-induced cardiac injury.

目的:阿霉素是一种有效的化疗药物,其临床应用受到严重心脏毒性的限制。潜在的分子机制仍然不完全清楚。本研究旨在探讨磷酸甘油酸突变酶1 (PGAM1)/电压依赖性阴离子通道1 (VDAC1)轴在早期dox诱导的心脏毒性中的作用,重点关注其对线粒体质量控制(MQC)、内质网(ER)应激以及随后的先天免疫信号激活的影响。方法:利用野生型和心肌细胞特异性PGAM1敲除(PGAM1- cko)小鼠建立短期累积性dox诱导的心肌病模型。超声心动图评估心功能。体外实验采用新生小鼠心肌细胞(NMCMs)和HL-1细胞进行。分子技术包括Western blotting,免疫荧光,共免疫沉淀和定量PCR来解剖信号通路。使用特定的药理学抑制剂和激活剂验证了关键途径成分。结果:阿霉素显著上调心肌细胞PGAM1表达。PGAM1-CKO小鼠不受dox诱导的心功能障碍、纤维化和炎症的影响。在机制上,dox诱导的PGAM1促进了VDAC1的病理寡聚化。这种PGAM1-VDAC1相互作用触发MQC崩溃,诱导内质网应激,导致线粒体DNA (mtDNA)渗漏到细胞质中。释放的细胞质mtDNA随后激活了cGAS-STING先天免疫途径,我们发现这是心肌细胞铁凋亡的关键上游驱动因素。药理诱导VDAC1寡聚化或STING激活可消除PGAM1-CKO小鼠的心脏保护作用。结论:我们的研究结果揭示了一种新的PGAM1/VDAC1信号轴,可触发早期dox诱导的心脏毒性。该轴破坏线粒体稳态,导致mtDNA释放,激活cGAS-STING途径,最终导致心肌细胞铁下垂。靶向PGAM1/VDAC1相互作用是减轻dox诱导的心脏损伤的一种有前景的治疗策略。
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引用次数: 0
SEASONAL FLUCTUATIONS IN AMBIENT PARTICULATE MATTER2.5 EXPOSURE DIFFERENTIALLY REGULATE JAK2/STAT3 SIGNALING IN NEVER SMOKING RURAL AND URBAN COHORTS. 在从不吸烟的农村和城市人群中,环境颗粒物2.5暴露的季节性波动对jak2 / stat3信号的调节存在差异。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-04 DOI: 10.1016/j.freeradbiomed.2026.02.006
Sukanya Ghosh, Rupa Chaudhuri, Meghna Mukherjee, Anurima Samanta, Priyanka Saha, Lucas R F Henneman, Deepanjan Majumdar, Mita Ray Sengupta, Anindita Chakraborty, Bidisha Maiti, Supratim Ghosh, Avik Biswas, Dona Sinha

Ambient particulate matter ≤ 2.5 μm in aerodynamic diameter (PM2.5) is a major environmental carcinogen, yet alterations in the pro-carcinogenic signaling pathways in asymptomatic never smokers remain poorly defined. This study examined the effect of seasonal fluctuations of PM2.5 on genotoxic stress and pro-oncogenic signaling in rural (RU) and urban (UR) cohorts from West Bengal, India. Environmental monitoring revealed high PM2.5 and associated benzo[α]pyrene in UR, during winter, induced genotoxic stress in sputum-derived airway cells and peripheral blood mononuclear cells as evidenced from comet assay and 8-hydroxy-2' -deoxyguanosine analysis. RNA sequencing, real-time polymerase chain reaction, indirect enzyme-linked immunosorbent assay and immunoblotting identified activation of the interleukin-6/epidermal growth factor receptor-driven Janus kinase (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling and associated crosstalk with the rat sarcoma /rapidly accelerated fibrosarcoma /mitogen-activated protein kinase pathways in airway cells and leukocytes of UR cohort. This signaling activation coincided with upregulation of pro-survival effectors (B-cell lymphoma-2, myeloid cell leukemia-1, MYC proto-oncogene, Cyclin D1) and repression of apoptosis regulator, BCL2-associated X, p21 and endogenous JAK/STAT pathway inhibitors (protein inhibitor of activated STAT 2 and suppressor of cytokine signaling 2). Linear mixed-effects regression models linked winter PM2.5 surges with increased genotoxic damage and altered JAK2/STAT3 cues in UR cohort. Risk modeling further predicted higher PM2.5-attributed lung cancer mortality in UR populations. Collectively, these findings indicated that elevated PM2.5 exposure was associated with early genotoxic and JAK2/STAT3-associated pro-carcinogenic alterations in airway cells and leukocytes of asymptomatic individuals, reflecting heightened biological sensitivity in urban populations.

空气动力学直径≤2.5 μm的环境颗粒物(PM2.5)是一种主要的环境致癌物,但在无症状从不吸烟者中,促致癌信号通路的变化仍不明确。本研究考察了PM2.5的季节性波动对印度西孟加拉邦农村(RU)和城市(UR)队列中遗传毒性应激和促癌信号传导的影响。彗星试验和8-羟基-2′-脱氧鸟苷分析结果显示,冬季尿毒区高PM2.5和相关苯并[α]芘可引起痰源性气道细胞和外周血单核细胞的基因毒性应激。RNA测序、实时聚合酶链反应、间接酶联免疫吸附试验和免疫印迹技术鉴定了白细胞介素-6/表皮生长因子受体驱动的Janus激酶(JAK2)/信号转导和转录激活因子3 (STAT3)信号通路的激活以及与UR队列大鼠肉瘤/快速纤维肉瘤/丝裂原激活的蛋白激酶途径相关的串音。这种信号激活与促生存效应因子(b细胞淋巴瘤-2、髓细胞白血病-1、MYC原癌基因、Cyclin D1)的上调和凋亡调节因子、bcl2相关X、p21和内源性JAK/STAT通路抑制剂(活化STAT 2的蛋白抑制剂和细胞因子信号传导2的抑制因子)的抑制相一致。线性混合效应回归模型将冬季PM2.5激增与UR队列中基因毒性损伤的增加和JAK2/STAT3线索的改变联系起来。风险模型进一步预测,在尿路人群中,pm2.5导致的肺癌死亡率更高。总的来说,这些发现表明,PM2.5暴露升高与无症状个体气道细胞和白细胞的早期基因毒性和JAK2/ stat3相关的前致癌性改变有关,反映了城市人群生物敏感性增高。
{"title":"SEASONAL FLUCTUATIONS IN AMBIENT PARTICULATE MATTER<sub>2.5</sub> EXPOSURE DIFFERENTIALLY REGULATE JAK2/STAT3 SIGNALING IN NEVER SMOKING RURAL AND URBAN COHORTS.","authors":"Sukanya Ghosh, Rupa Chaudhuri, Meghna Mukherjee, Anurima Samanta, Priyanka Saha, Lucas R F Henneman, Deepanjan Majumdar, Mita Ray Sengupta, Anindita Chakraborty, Bidisha Maiti, Supratim Ghosh, Avik Biswas, Dona Sinha","doi":"10.1016/j.freeradbiomed.2026.02.006","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.02.006","url":null,"abstract":"<p><p>Ambient particulate matter ≤ 2.5 μm in aerodynamic diameter (PM<sub>2.5</sub>) is a major environmental carcinogen, yet alterations in the pro-carcinogenic signaling pathways in asymptomatic never smokers remain poorly defined. This study examined the effect of seasonal fluctuations of PM<sub>2.5</sub> on genotoxic stress and pro-oncogenic signaling in rural (RU) and urban (UR) cohorts from West Bengal, India. Environmental monitoring revealed high PM<sub>2.5</sub> and associated benzo[α]pyrene in UR, during winter, induced genotoxic stress in sputum-derived airway cells and peripheral blood mononuclear cells as evidenced from comet assay and 8-hydroxy-2' -deoxyguanosine analysis. RNA sequencing, real-time polymerase chain reaction, indirect enzyme-linked immunosorbent assay and immunoblotting identified activation of the interleukin-6/epidermal growth factor receptor-driven Janus kinase (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling and associated crosstalk with the rat sarcoma /rapidly accelerated fibrosarcoma /mitogen-activated protein kinase pathways in airway cells and leukocytes of UR cohort. This signaling activation coincided with upregulation of pro-survival effectors (B-cell lymphoma-2, myeloid cell leukemia-1, MYC proto-oncogene, Cyclin D1) and repression of apoptosis regulator, BCL2-associated X, p21 and endogenous JAK/STAT pathway inhibitors (protein inhibitor of activated STAT 2 and suppressor of cytokine signaling 2). Linear mixed-effects regression models linked winter PM<sub>2.5</sub> surges with increased genotoxic damage and altered JAK2/STAT3 cues in UR cohort. Risk modeling further predicted higher PM<sub>2.5</sub>-attributed lung cancer mortality in UR populations. Collectively, these findings indicated that elevated PM<sub>2.5</sub> exposure was associated with early genotoxic and JAK2/STAT3-associated pro-carcinogenic alterations in airway cells and leukocytes of asymptomatic individuals, reflecting heightened biological sensitivity in urban populations.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Taurine Restores Oocyte Quality by Enhancing Mitochondrial Function in Mice Exposed to Dibutyl Phthalate during Adolescence. 牛磺酸通过增强青春期暴露于邻苯二甲酸二丁酯的小鼠的线粒体功能恢复卵母细胞质量。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-04 DOI: 10.1016/j.freeradbiomed.2026.01.046
Yidan Ma, Liping Yan, Yan Zhang, Yanqing Geng, Xin Yin, Rufei Gao, Xinyi Mu, Xiaoqing Liu, Junlin He

Adolescence represents a vulnerable window for ovarian development, during which oocytes rely heavily on mitochondrial bioenergetics and redox homeostasis. Dibutyl phthalate (DBP) is a widely used plasticizer recognized for its endocrine-disrupting properties. It can compromise oocyte integrity during these sensitive developmental stages. We found that adolescent DBP exposure impairs oocyte quality in mice, causing fragmentation, meiotic arrest, spindle disorganization, and chromosome misalignment. Smart RNA-seq analysis of DBP-exposed oocytes revealed that these defects are associated with mitochondrial dysfunction, particularly impairment of respiratory chain complex I. Consistently, DBP exposure induced mitochondrial clustering, excessive ROS production, loss of membrane potential, ATP depletion, and suppression of complex I activity, which could be recapitulated by in vitro administration of MBP, a bioactive DBP metabolite. Inhibition of complex I with rotenone reduced oocyte maturation and mitochondrial membrane potential, supporting complex I as a primary target of DBP-induced injury. Mechanistically, DBP reduced 5-taurinomethyluridine (τm5U) modification of mitochondrial tRNAs and decreased the protein level of the mitochondrially encoded complex I subunit MT-ND1, leading to impaired complex I activity. Systemic taurine availability was also reduced. Notably, taurine supplementation restored τm5U modification and enhanced MT-ND1 translation, thereby rescuing complex I activity and reestablishing mitochondrial function. These improvements mitigated DNA damage and apoptosis, corrected meiotic defects, and rescued oocyte maturation, embryonic development, and fertility. Together, our findings indicate that DBP disrupts oocyte development by impairing mitochondrial redox homeostasis in mice, and suggest that taurine supplementation can restore mitochondrial function and preserve female fertility under environmental insults.

青春期是卵巢发育的一个脆弱窗口,在此期间卵母细胞严重依赖线粒体生物能量和氧化还原稳态。邻苯二甲酸二丁酯(DBP)是一种广泛使用的增塑剂,具有内分泌干扰特性。在这些敏感的发育阶段,它会损害卵母细胞的完整性。我们发现青春期DBP暴露会损害小鼠卵母细胞的质量,导致分裂、减数分裂停滞、纺锤体解体和染色体失调。DBP暴露卵母细胞的智能RNA-seq分析显示,这些缺陷与线粒体功能障碍有关,特别是呼吸链复合体I的损伤。与此同时,DBP暴露诱导线粒体聚集、ROS过度产生、膜电位丧失、ATP消耗和复合体I活性抑制,这些可以通过体外给药MBP(一种生物活性DBP代谢物)来重现。鱼藤酮抑制复合物I降低卵母细胞成熟和线粒体膜电位,支持复合物I作为dbp诱导损伤的主要靶点。在机制上,DBP降低了线粒体trna的5-牛磺酸甲基尿嘧啶(τm5U)修饰,降低了线粒体编码的复合物I亚基MT-ND1的蛋白水平,导致复合物I活性受损。全身牛磺酸可用性也降低。值得注意的是,补充牛磺酸恢复了τm5U修饰,增强了MT-ND1的翻译,从而恢复了复合物I的活性,重建了线粒体功能。这些改进减轻了DNA损伤和细胞凋亡,纠正了减数分裂缺陷,挽救了卵母细胞成熟,胚胎发育和生育能力。总之,我们的研究结果表明,DBP通过损害小鼠线粒体氧化还原稳态来破坏卵母细胞的发育,并表明补充牛磺酸可以恢复线粒体功能,并在环境损害下保持女性的生育能力。
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引用次数: 0
Circulating Neuregulin-4 tracks acute hyperbaric and workload stress in human divers, preceding oxidative injury markers. 循环神经调节蛋白-4跟踪人类潜水员的急性高压和工作负荷压力,在氧化损伤标志物之前。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-02 DOI: 10.1016/j.freeradbiomed.2026.02.002
Claudia Di Biagio, Paola Giglio, Matteo Bordi, Giovanni Larotondo, Riccardo Turchi, Luigi Fattorini, Enrico Marchetti, Daniele Lettieri-Barbato, Costanza Montagna, Giuseppe Filomeni, Katia Aquilano

Acute hyperbaric stress during diving combines increased ambient pressure, hyperoxia, hemodynamic shifts, and often muscular workload. Identifying real-time blood biomarkers sensitive to these individual and combined physiological loads remains a challenge. Neuregulin-4 (NRG4), an adipokine secreted by thermogenic and subcutaneous white fat, responds to adrenergic stimulation and modulates redox homeostasis. We investigated NRG4 dynamics alongside oxidative protein carbonyls in divers in warm (thermoneutral) water (∼33.6 °C ambient water temperature) to avoid cold stress. Two field campaigns were conducted: a first depth response campaign involved divers exposed to 20, 30, or 40 m on separate days, without exercise, with serial blood sampling; a second physical effort study involved 15 m dives with or without slow-pedalling exercise. Serum NRG4 was quantified by ELISA and expressed as log2 fold change relative to baseline. Protein carbonyls were measured as markers of oxidative damage. Statistical analysis employed single-sample tests and false-discovery rate control. NRG4 exhibited a robust early increase at 30 m, significant after correction, and nominal elevations at 40 m, but remained unchanged at 20 m. Exercise at 15 m triggered a significant early NRG4 rise absent during passive dives at the same depth. Protein carbonyls remained stable in early post-emersion windows but increased significantly at later time points (180- and 240-min post-emersion) following dives to 40 m, indicating delayed oxidative burden. Our findings position NRG4 as a fast, pressure- and workload-responsive biomarker of diving stress, temporally distinct from classical oxidative injury markers that manifest later. This temporal dissociation underscores the potential of NRG4 for real-time monitoring of acute physiological load during hyperbaric exposure, integrating pressure- and workload-related stressors.

潜水时的急性高压应激包括环境压力增加、高氧、血流动力学变化和肌肉负荷。识别对这些个体和组合生理负荷敏感的实时血液生物标志物仍然是一个挑战。神经调节蛋白-4 (NRG4)是一种由热源性和皮下白色脂肪分泌的脂肪因子,可响应肾上腺素能刺激并调节氧化还原稳态。我们研究了潜水员在温暖(热中性)水中(环境水温约33.6°C)中NRG4和氧化蛋白羰基的动态变化,以避免冷应激。进行了两次现场活动:第一次深度反应活动涉及潜水员在不同的天暴露于20,30或40米,没有运动,并进行连续血液采样;第二项体力消耗研究涉及15米跳水,有或没有慢速蹬车锻炼。采用ELISA定量测定血清NRG4,表达量为相对于基线的log2倍变化。测定蛋白质羰基作为氧化损伤的标志物。统计分析采用单样本测试和错误发现率控制。NRG4在30 m处表现出强劲的早期上升,校正后显著,在40 m处名义海拔上升,但在20 m处保持不变。在15米深度的运动触发了显著的早期NRG4上升,而在相同深度的被动潜水中则没有。蛋白质羰基在早期恢复窗口保持稳定,但在潜水至40米后的较晚时间点(恢复后180和240分钟)显著增加,表明氧化负担延迟。我们的研究结果表明,NRG4是一种快速、压力和工作负荷响应的潜水应激生物标志物,与传统的氧化损伤标志物在时间上有所不同。这种时间分离强调了NRG4在高压暴露期间实时监测急性生理负荷、整合压力和工作负荷相关应激源方面的潜力。
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引用次数: 0
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Free Radical Biology and Medicine
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