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Bone Organ-on-a-Chip Uncovers That TPD52L1 Enhances Osteogenic Differentiation of MSCs and Contributes to Osteoporosis Repair 骨器官芯片揭示TPD52L1增强MSCs成骨分化并促进骨质疏松修复
IF 4.2 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-07 DOI: 10.1096/fj.202503575RR
Zhewen Liu, Weina Ju, Fukun Lin, Yiming Liu, Baochang Qi

This study aims to develop a novel therapeutic strategy for osteoporosis (OP) by enhancing the osteogenic differentiation potential of mesenchymal stem cells (MSCs). A three-channel biomimetic bone organ-on-a-chip model was constructed. Through bioinformatics analysis, TPD52L1, a key upregulated gene involved in the osteogenic differentiation of MSCs, was identified. Molecular experiments were conducted to verify the effects of its overexpression on the Wnt/β-catenin pathway. Critically, systematic knockdown experiments were performed to validate its necessity in mechanotransduction. Subsequently, functional experiments were performed to evaluate its role in the osteogenic and adipogenic differentiation of MSCs in a GIOP model. Safety assessments for TPD52L1-overexpressing MSCs covered subcellular localization, proliferation, anchorage-independent growth, oncogene expression, and short-term in vivo tumorigenicity. TPD52L1 overexpression activated the Wnt/β-catenin pathway and promoted osteogenic differentiation of MSCs. Its knockdown blocked mechanical stimulation-induced pathway activation and osteogenic marker upregulation, confirming its necessity in mechano-osteogenic conversion. TPD52L1 upregulated osteoblast markers osteocalcin (OCN) and alkaline phosphatase (ALP), downregulated the osteoclast marker tartrate-resistant acid phosphatase (TRAP), and reversed the osteoporosis phenotype. When combined with cyclic mechanical force stimulation in the organ-on-a-chip system, a synergistic effect was observed, enhancing bone repair. TPD52L1 was localized in the cytoplasm, and its endogenous expression was upregulated by mechanical stimulation, indicating mechanosensitivity. TPD52L1 overexpression did not affect MSCs' proliferation, anchorage-independent growth, or oncogene expression. Subcutaneous transplantation experiments confirmed that it did not induce tumor formation or significant pathological changes, demonstrating favorable biosafety. TPD52L1 serves as a key target for promoting the osteogenic differentiation of MSCs.

本研究旨在通过增强间充质干细胞(MSCs)的成骨分化潜能,开发一种治疗骨质疏松症(OP)的新策略。构建了三通道仿生骨器官芯片模型。通过生物信息学分析,确定了参与MSCs成骨分化的关键上调基因TPD52L1。通过分子实验验证其过表达对Wnt/β-catenin通路的影响。重要的是,进行了系统的敲除实验来验证其在机械转导中的必要性。随后,在GIOP模型中进行功能实验以评估其在MSCs成骨和成脂分化中的作用。tpd52l1过表达MSCs的安全性评估包括亚细胞定位、增殖、非锚定生长、癌基因表达和短期体内致瘤性。TPD52L1过表达激活Wnt/β-catenin通路,促进MSCs成骨分化。其敲低阻断了机械刺激诱导的通路激活和成骨标志物上调,证实了其在机械成骨转化中的必要性。TPD52L1上调成骨细胞标志物骨钙素(OCN)和碱性磷酸酶(ALP),下调破骨细胞标志物酒石酸抗性酸性磷酸酶(TRAP),逆转骨质疏松表型。当在器官芯片系统中结合循环机械力刺激时,观察到协同效应,增强骨修复。TPD52L1定位于细胞质中,其内源性表达在机械刺激下上调,表明机械敏感性。TPD52L1过表达不影响MSCs的增殖、非锚定生长或癌基因表达。皮下移植实验证实其不诱导肿瘤形成或明显的病理改变,具有良好的生物安全性。TPD52L1是促进MSCs成骨分化的关键靶点。
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引用次数: 0
Loss of Kinesin KIF16B Disrupts Organelle Dynamics for Developmental Potential in Oocytes 激酶蛋白KIF16B的缺失破坏卵母细胞发育潜能的细胞器动力学。
IF 4.2 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-07 DOI: 10.1096/fj.202504857R
Meng-Xiang Li, Zi-Jian Wu, Kun-Huan Zhang, Yuan-Jing Zou, Ping-Shuang Lu, Shuo-Cheng Fan, Xuan Wu, Shao-Chen Sun, Yue Wang

Kinesin KIF16B, as a molecular motor protein within cells, primarily utilizes energy derived from ATP hydrolysis to transport intracellular cargo along microtubules, thereby participating in material transport, organelle dynamics, and cytoskeletal organization. However, the mechanism by which KIF16B regulates the maturation process of cytoplasm in mouse oocytes remains unclear. This study was to investigate the potential role of KIF16B in modulating organelle dynamics in mouse oocytes. Our findings suggest that depletion of KIF16B impairs oocyte developmental competence following parthenogenesis, implying potential abnormalities in oocyte maturation. We observed that oocytes with diminished KIF16B exhibited disrupted mitochondrial distribution and function, and further analysis revealed that this may be due to KIF16B involvement in p-Drp1 and Fis1-mediated mitochondrial fission. Besides, impaired mitochondrial function also resulted in oxidative stress. Additionally, abnormal distribution of the ER and ER stress were observed in oocytes lacking KIF16B. This was accompanied by elevated expression of ER stress-related genes CHOP and ATF4. Concurrently, KIF16B knockdown affected the distribution and function of the Golgi apparatus, leading to abnormalities in Golgi-based vesicular transport processes. In summary, our data suggest that the kinesin KIF16B modulates organelle dynamics during oocyte maturation.

Kinesin KIF16B是细胞内的一种分子运动蛋白,主要利用ATP水解产生的能量沿微管运输细胞内货物,从而参与物质运输、细胞器动力学和细胞骨架组织。然而,KIF16B调控小鼠卵母细胞细胞质成熟过程的机制尚不清楚。本研究旨在探讨KIF16B在调节小鼠卵母细胞细胞器动力学中的潜在作用。我们的研究结果表明,KIF16B的缺失会损害孤雌生殖后的卵母细胞发育能力,这意味着卵母细胞成熟的潜在异常。我们观察到,KIF16B减少的卵母细胞表现出线粒体分布和功能的破坏,进一步的分析表明,这可能是由于KIF16B参与p-Drp1和fis1介导的线粒体裂变。此外,线粒体功能受损也导致氧化应激。此外,在缺乏KIF16B的卵母细胞中,ER分布异常,ER应激异常。这伴随着内质网应激相关基因CHOP和ATF4的表达升高。同时,KIF16B基因敲低影响高尔基体的分布和功能,导致高尔基体基础的囊泡运输过程异常。总之,我们的数据表明,激酶KIF16B调节卵母细胞成熟过程中的细胞器动力学。
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引用次数: 0
Attenuation of Transforming Growth Factor-β Signaling Promotes Complete Recovery of Trabecular Bone Structure Following Immobilization With Traumatic Spinal Cord Injury 转化生长因子-β信号的衰减促进创伤性脊髓损伤固定后小梁骨结构的完全恢复。
IF 4.2 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-07 DOI: 10.1096/fj.202504448R
Karim Sahbani, Jeffry S. Nyman, Margo Button, Michael Hadjiargyrou, William A. Bauman, Hesham A. Tawfeek

Marked trabecular bone loss of the distal femoral and proximal tibial regions is one of the most common and devastating complications of spinal cord injury (SCI) with highest incidence of fracture and no efficacious treatment to date. Osteocytes exhibit increased transforming growth factor-β (TGF-β) signaling 5 weeks after SCI. Whether reducing TGF-β signaling will restore trabecular bone structure after development of bone loss with SCI has not been tested. To address this, male mice underwent laminectomy (sham) or thoracic (T10) contusion SCI resulting in complete hindlimb paralysis. Five weeks later, sham and SCI mice received either control (IgG) or anti-TGF-β neutralizing (ID11) antibody (10 mg/kg/day, twice weekly) for 5 weeks before sacrifice. Micro-computed tomography (micro-CT) analysis of the distal femoral region showed that, compared to sham-IgG animals, treatment with ID11 significantly (p < 0.05) restored trabecular fractional bone volume (107% SCI-ID11 vs. 65% SCI-IgG), thickness (109% SCI-ID11 vs. 88% SCI-IgG), connectivity (99% SCI-ID11 vs. 78% SCI-IgG), and structure model index (101% SCI-ID11 vs. 118% SCI-IgG). In contrast, analysis of femoral mid-shaft regions showed that both SCI-1D11 and SCI-IgG mice exhibited reduced cortical thickness (91% vs. 84%). Histomorphometric analysis revealed no differences in indices of osteoblast or osteoclast numbers or surfaces between SCI-IgG, SCI-1D11, and sham-IgG groups. Similarly, analysis of femoral bone marrow supernatants demonstrated no significant difference in levels of procollagen type 1 intact N-terminal propeptide (P1NP) or tartrate-resistant acid phosphatase 5b (TRAcP-5b). Thus, TGF-β signaling may be a promising therapeutic target to regain trabecular bone architecture and prevent fractures after SCI.

股骨远端和胫骨近端明显的骨小梁丢失是脊髓损伤(SCI)最常见和最具破坏性的并发症之一,骨折发生率最高,迄今为止没有有效的治疗方法。骨细胞在脊髓损伤后5周表现出TGF-β信号的增加。减少TGF-β信号是否会恢复脊髓损伤骨质流失后的骨小梁结构尚未得到验证。为了解决这个问题,雄性小鼠接受了椎板切除术(假)或胸椎挫伤(T10),导致后肢完全瘫痪。5周后,假手术小鼠和脊髓损伤小鼠分别接受对照(IgG)或抗tgf -β中和(ID11)抗体(10 mg/kg/天,每周2次),连续5周后处死。股骨远端区域的微计算机断层扫描(micro-CT)分析显示,与假igg动物相比,ID11治疗显著(p
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引用次数: 0
Establishment and Functional Characterization of Bovine Endometrial Epithelial Organoids 牛子宫内膜上皮类器官的建立及功能表征。
IF 4.2 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-07 DOI: 10.1096/fj.202503351R
Iebu Devkota, Zachary L. Bonomo, Dailin M. Fuego, Yuxia Li, Xujia Zhang, Shavahn C. Loux, Charles R. Looney, Ana I. V. Maia, Fabrizio Donnarumma, Antonios Matsakas, Anastasios Vourekas, Philip H. Elzer, Xing Fu, Kenneth R. Bondioli, John J. Bromfield, Pablo Bermejo-Álvarez, Constantine A. Simintiras

Pre-implantation embryonic loss constitutes a major barrier to reproductive efficiency in livestock, yet the extrinsic determinants of embryonic survival remain poorly defined. Intra-organoid fluid (IOF) faithfully recapitulates native tissue secretions across multiple organ systems. We hypothesized that bovine endometrial epithelial organoids (BEEO) would produce IOF that mirrored in vivo uterine luminal fluid composition and extend embryo culture duration in vitro. We pursued three objectives: (a) establish and morphologically characterize BEEO, (b) define BEEO transcriptomic and secretory responses to 17β-estradiol (E2), medroxyprogesterone acetate (MPA), and interferon-tau (IFNτ), and (c) determine whether BEEO-derived IOF can support in vitro embryonic development beyond Day 8 (hatched blastocyst stage) under conventional culture conditions. BEEO were established from primary endometrial tissue (n = 4) and maintained a stable epithelial phenotype through multiple passages. Transcriptomic profiling revealed robust responses to stimulation, with E2, MPA, and IFNτ inducing distinct gene expression programs consistent with in vivo effects. IOF metabolomic analysis confirmed hormone-dependent regulation of IOF secretory output, with E2 + MPA (diestrus mimic) enhancing the production of metabolites implicated in conceptus development. Remarkably, IOF from diestrus mimic-stimulated BEEO, despite being diluted approximately seven-fold in PBS, maintained embryo survival rates comparable to optimized commercial medium and exceeded PBS-only controls. These findings position BEEO as a physiologically relevant model for dissecting maternal-embryo interactions in vitro and identifying targets to improve fertility in cattle and other livestock.

胚胎着床前胚胎丢失是牲畜繁殖效率的主要障碍,但胚胎存活的外在决定因素仍不明确。类器官内液(IOF)忠实地概括了跨多个器官系统的天然组织分泌物。我们假设牛子宫内膜上皮类器官(BEEO)可以产生反映体内子宫腔液组成的IOF,并延长胚胎体外培养时间。我们追求三个目标:(a)建立BEEO并对其进行形态学表征,(b)确定BEEO对17β-雌二醇(E2)、醋酸甲孕酮(MPA)和干扰素-tau (IFNτ)的转录组学和分泌反应,以及(c)确定BEEO衍生的IOF是否能在常规培养条件下支持体外胚胎发育超过第8天(孵化囊胚期)。BEEO从原发性子宫内膜组织(n = 4)中建立,并通过多次传代保持稳定的上皮表型。转录组学分析显示,E2、MPA和IFNτ诱导的不同基因表达程序与体内效应一致,对刺激有强大的反应。IOF代谢组学分析证实了IOF分泌量的激素依赖性调节,E2 + MPA (distrus mimic)增强了与受孕发育有关的代谢物的产生。值得注意的是,尽管在PBS中稀释了大约7倍,但来自模拟猪瘟的BEEO的IOF保持了与优化的商业培养基相当的胚胎存活率,并且超过了仅PBS的对照组。这些发现将BEEO定位为一个生理学相关的模型,用于解剖体外母胚相互作用,并确定提高牛和其他牲畜生育能力的目标。
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引用次数: 0
SPP1+ Macrophage-POSTN+ Fibroblast-Endothelial Triad Dictates Immunotherapy Response in Bladder Cancer SPP1+巨噬细胞-后n +成纤维细胞内皮三联体决定膀胱癌的免疫治疗反应。
IF 4.2 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-07 DOI: 10.1096/fj.202504456RR
Hualin Chen, Yueqiang Peng, Zhigang Ji, Jie Dong

Although immunotherapy has shown promise in improving outcomes for bladder cancer (BCa) patients, treatment responses remain highly variable. A comparative examination of the tumor microenvironment (TME) between responders and non-responders may reveal key resistance mechanisms and identify potential therapeutic targets. We integrated spatial transcriptomics, single-cell RNA sequencing, and multiplexed immunofluorescence to characterize spatial structures within the TME that influence response to anti-PD-1 therapy in BCa patients. In non-responders, we observed an accumulation of stem-like malignant epithelial cells with high MYBL2 expression near the tumor boundary. Furthermore, we identified a spatial triad structure—composed of SPP1+ tumor-associated macrophages (TAMs), POSTN+ cancer-associated fibroblasts (CAFs), and endothelial cells—located at the tumor periphery. This structure was associated with T-cell exclusion and reduced efficacy of immune checkpoint blockade. In a preclinical model, inhibiting SPP1 enhanced the response to anti-PD-1 therapy, resulting in reduced CAF infiltration and increased recruitment of cytotoxic T cells. Our study reveals a triad cellular structure mediated by SPP1+ TAMs, POSTN+ CAFs, and endothelial cells that contribute to immunotherapy resistance in BCa. Targeting this structure, particularly through SPP1 blockade, represents a promising strategy to augment the efficacy of immune checkpoint inhibitors.

尽管免疫疗法已显示出改善膀胱癌(BCa)患者预后的希望,但治疗反应仍然高度可变。对有应答者和无应答者之间的肿瘤微环境(TME)进行比较检查可能揭示关键的耐药机制并确定潜在的治疗靶点。我们整合了空间转录组学、单细胞RNA测序和多重免疫荧光来表征影响BCa患者抗pd -1治疗反应的TME内的空间结构。在无应答者中,我们在肿瘤边界附近观察到MYBL2高表达的干细胞样恶性上皮细胞的积累。此外,我们发现了一个位于肿瘤周围的空间三元结构,由SPP1+肿瘤相关巨噬细胞(tam), POSTN+癌症相关成纤维细胞(CAFs)和内皮细胞组成。这种结构与t细胞排斥和免疫检查点阻断的有效性降低有关。在临床前模型中,抑制SPP1增强了对抗pd -1治疗的反应,导致CAF浸润减少,细胞毒性T细胞募集增加。我们的研究揭示了由SPP1+ tam、POSTN+ CAFs和内皮细胞介导的三合一细胞结构有助于BCa的免疫治疗抵抗。针对这种结构,特别是通过SPP1阻断,代表了一种有希望的策略来增强免疫检查点抑制剂的功效。
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引用次数: 0
Cholesterol Lowering Alone Fails to Reverse Atherosclerotic Plaque Necrosis, Granulopoiesis, and Neurovascular Neutrophils in Middle-Aged Mice 单独降低胆固醇不能逆转中年小鼠动脉粥样硬化斑块坏死、颗粒生成和神经血管中性粒细胞。
IF 4.2 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-07 DOI: 10.1096/fj.202503638RR
Olivia Gannon, Allison Rahtes, Jesse L. Bonin, Ignacia Salfate del Rio, Jessica Partridge, Christina Nickerson, Sayeed Khan, Ariana Nobles, Gideon R. Covert, Amber Bahr, Ramon Bossardi Ramos, Katherine C. MacNamara, Gabrielle Fredman

Cholesterol lowering through diet, lifestyle, and pharmacologic therapy remains central for limiting atherosclerosis and prevention of major adverse cardiovascular events. Yet, 33%–50% of individuals on lipid-lowering therapy continue to exhibit elevated inflammation. Middle age (MA) represents a critical window for disease acceleration, underscoring a need to better understand nonresolving inflammation in this time frame. Here, we rendered young (2 months) and MA mice (10 months) hypercholesterolemic with an AAV8-PCSK9 virus and western diet (WD). Following 20 weeks on WD, mice were switched to a chow diet for 6 weeks to induce lipid lowering. This design models dietary cholesterol reduction to dissect lipid-driven versus inflammation-driven pathways in atherosclerosis. At baseline atherosclerosis, we found that MA mice had increased plaque necrosis as well as increased circulating and bone marrow PMN compared to young mice. After chow switch, unlike in young mice, MA mice had increased plaque necrosis and reduced remodeling, as well as increased circulating white blood cells and bone marrow hematopoietic stem cell progenitors (HSPCs). In MA chow-switched mice, circulating neutrophils correlated with necrosis whereas young mice exhibited no correlation. Furthermore, MA atherosclerotic mice had bone marrow HSPCs and neutrophils that exhibited a more activated phenotype relative to young after chow switch. In addition, we observed elevated neutrophil–endothelial contacts in the hippocampal vasculature of MA mice after chow switch. While dietary intervention and lowered plasma cholesterol restrained atheroprogression in young, it was inadequate in MA mice, failing to reduce systemic inflammation and indicating the need for complementary therapies during this time frame.

通过饮食、生活方式和药物治疗降低胆固醇仍然是限制动脉粥样硬化和预防主要不良心血管事件的核心。然而,33%-50%接受降脂治疗的个体继续表现出炎症升高。中年(MA)是疾病加速的关键窗口期,强调需要在这个时间框架内更好地了解非消解性炎症。在这里,我们用AAV8-PCSK9病毒和西方饮食(WD)使幼年(2个月)和成年(10个月)小鼠高胆固醇血症。在WD治疗20周后,将小鼠改为鼠粮饮食6周,以诱导脂质降低。本设计模拟饮食胆固醇降低,以解剖动脉粥样硬化中脂质驱动与炎症驱动的途径。在基线动脉粥样硬化时,我们发现与年轻小鼠相比,MA小鼠斑块坏死增加,循环和骨髓PMN增加。换食后,与年轻小鼠不同,MA小鼠斑块坏死增加,重塑减少,循环白细胞和骨髓造血干细胞祖细胞(HSPCs)增加。在MA周转换小鼠中,循环中性粒细胞与坏死相关,而年轻小鼠则没有相关性。此外,MA动脉粥样硬化小鼠的骨髓HSPCs和中性粒细胞在换食后表现出比年轻小鼠更活化的表型。此外,我们还观察到,换食后,MA小鼠海马血管中中性粒细胞与内皮细胞的接触增加。虽然饮食干预和降低血浆胆固醇抑制了年轻小鼠的动脉粥样硬化进展,但在MA小鼠中是不够的,未能减少全身性炎症,表明需要在这段时间内进行补充治疗。
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引用次数: 0
Limonin Is a Novel Hexokinase 2 Inhibitor That Suppresses Hepatic Stellate Cell Activation and Histone Lactylation 柠檬苦素是一种抑制肝星状细胞活化和组蛋白乳酸化的新型己糖激酶2抑制剂。
IF 4.2 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-06 DOI: 10.1096/fj.202504035R
Tian Lan, Chen-chen Wang, Jun-jie Ying, Wen Wang, Xi-xi Zeng, Wei-li Mao, Tao Lu, Si-wei Wang

Hexokinase 2 (HK2) is a pivotal enzyme in glycolytic metabolism and plays a crucial role in the activation of hepatic stellate cells (HSCs). Despite its importance, specific inhibitors targeting HK2 are still lacking in clinical practice. In this study, we utilized a human protein microarray to identify a significant interaction between limonin (Lim) and HK2. Subsequent analyses confirmed that Lim effectively inhibits HK2 activity and the modification of histone lactylation. Moreover, Lim's systemic effects include the downregulation of gene expression associated with HSC activation, which is closely linked to its modulation of HK2 and histone lactylation. Additionally, Lim exhibits anti-fibrotic properties, influencing the expression of genes involved in HSC activation and histone lactylation in vivo. These findings provide novel mechanistic insights into how Lim derivatives may mitigate hepatic fibrosis through the suppression of HK2 and targeted regulation of histone lactylation in activated HSCs.

己糖激酶2 (HK2)是糖酵解代谢的关键酶,在肝星状细胞(hsc)的激活中起着至关重要的作用。尽管它很重要,但在临床实践中仍缺乏针对HK2的特异性抑制剂。在这项研究中,我们利用人类蛋白质芯片来鉴定柠檬苦素(Lim)和HK2之间的显著相互作用。随后的分析证实Lim有效抑制HK2活性和组蛋白乳酸化修饰。此外,Lim的全身效应包括下调与HSC激活相关的基因表达,这与其对HK2和组蛋白乳酸化的调节密切相关。此外,Lim表现出抗纤维化特性,影响体内参与HSC活化和组蛋白乳酸化的基因表达。这些发现为Lim衍生物如何通过抑制HK2和靶向调节活化的hsc中的组蛋白乳酸化来减轻肝纤维化提供了新的机制见解。
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引用次数: 0
Cardiac Circ-ZNF609 Inhibition Attenuates Doxorubicin-Induced Cardiotoxicity Without Affecting the Chemotherapeutic Efficacy of Doxorubicin on Cancer in Female Mice 抑制心脏Circ-ZNF609可减轻阿霉素诱导的雌性小鼠心脏毒性,但不影响阿霉素对癌症的化疗效果。
IF 4.2 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-06 DOI: 10.1096/fj.202503974R
Shuang Zhang, Xiaotong Ding, Yunwei Xu, Caiyue Cui, Yuchao Yang, Yuhan Shao, Tianhui Wang, Yihua Bei, Lijun Wang, Jiahong Xu

The cardiac burden associated with doxorubicin (DOX) significantly limits its application in cancer treatment. Therefore, it is essential to identify effective strategies to protect the heart from cardiotoxic damage caused by chemotherapy. As sex is among the risk factors associated with DOX-induced cardiotoxicity, whether the cardiac beneficial effects observed from male mice can be applied to female mice remains unknown. We established a two-week DOX-induced cardiotoxicity model, in which the cumulative DOX dose administered to mice was comparable to that used in previous research. This model effectively induces cardiotoxicity and fibrosis while allowing for a sufficiently long monitoring period to evaluate the chemotherapeutic effects of DOX on tumors, without imposing an excessive physiological burden on the mice from prolonged tumor growth. Utilizing this tumor-bearing murine model, we employed TC-1 cancer cells, which express HPV16-E6 and HPV16-E7 proteins, to investigate the cardioprotective effects of circ-ZNF609 inhibition in DOX-treated tumor-bearing female mice. Our findings indicate that cardiac inhibition of circ-ZNF609 protects against DOX-induced cardiotoxicity without compromising the anti-tumor efficacy of DOX in females. These results suggest that targeting circ-ZNF609 in the heart may represent a promising and viable therapeutic strategy for preventing DOX-induced cardiotoxicity.

与阿霉素(DOX)相关的心脏负担显著限制了其在癌症治疗中的应用。因此,必须确定有效的策略来保护心脏免受化疗引起的心脏毒性损伤。由于性别是与dox诱导的心脏毒性相关的危险因素之一,因此在雄性小鼠中观察到的心脏有益效应是否适用于雌性小鼠尚不清楚。我们建立了一个为期两周的DOX诱导心脏毒性模型,其中小鼠的累积DOX剂量与先前研究中使用的剂量相当。该模型有效诱导心脏毒性和纤维化,同时允许足够长的监测周期来评估DOX对肿瘤的化疗效果,而不会因肿瘤生长时间延长而给小鼠带来过度的生理负担。利用这种荷瘤小鼠模型,我们利用表达HPV16-E6和HPV16-E7蛋白的TC-1癌细胞,研究了抑制circ-ZNF609对dox处理的荷瘤雌性小鼠的心脏保护作用。我们的研究结果表明,circ-ZNF609的心脏抑制可以防止DOX诱导的心脏毒性,而不会影响DOX在女性中的抗肿瘤功效。这些结果表明,在心脏中靶向circ-ZNF609可能是预防dox诱导的心脏毒性的一种有希望和可行的治疗策略。
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引用次数: 0
Correction to “Genomic Locus Tagged by Lung Function GWAS SNV rs12477314 (2q37.3) Acts as a Regulatory Region for a Systemic Inflammatory Phenotype” 更正“肺功能GWAS SNV rs12477314 (2q37.3)标记的基因组位点作为全身性炎症表型的调控区域”。
IF 4.2 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-06 DOI: 10.1096/fj.202600409

Grech, G.M., Fawcett, K.A., Hall, R.J., Grech, G., Ellul-Micallef, R., Hall, I.P. and Fenech, A.G. (2025), Genomic Locus Tagged by Lung Function GWAS SNV rs12477314 (2q37.3) Acts as a Regulatory Region for a Systemic Inflammatory Phenotype. The FASEB Journal 39 (2025): e70689, https://doi.org/10.1096/fj.202403208R.

In paragraph 2 of section 2.3 | PheWAS Analysis and Protein Association Analysis, the text “Association between rs12477314 C>T and protein levels were tested assuming an additive genetic model” should have read: “Association between rs12477314 C>T and protein levels were tested in individuals of European ancestry assuming an additive genetic model and adjusting for Olink batch, age, sex, genotyping array and the first 10 ancestry-based PCs.”

In the Acknowledgements section, we omitted:

“UK Biobank analyses were conducted using the UK Biobank Resource under Application Numbers 648 and 43027.”

We apologize for these errors.

Grech, G.M, Fawcett, K.A, Hall, R.J, Grech, G., Ellul-Micallef, R., Hall, I.P.和Fenech, A.G.(2025),肺功能基因位点标记的GWAS SNV rs12477314 (2q37.3)作为全身性炎症表型的调控区域。FASEB Journal 39 (2025): e70689, https://doi.org/10.1096/fj.202403208R.In第2.3 b|节第2段PheWAS分析和蛋白质关联分析,文本“rs12477314 C>;T和蛋白质水平之间的关联假设一个加性遗传模型被测试”应该是:“rs12477314 C>;T和蛋白质水平之间的关系在欧洲血统的个体中进行了测试,假设一个加性遗传模型,并根据Olink批次、年龄、性别、基因分型阵列和前10个基于祖先的pc进行了调整。”在致谢部分,我们省略了:“UK Biobank分析是使用UK Biobank资源进行的,申请号为648和43027。”我们为这些错误道歉。
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引用次数: 0
Characterization of Transcriptional, Epigenetic, and Phenotypic Plasticity and Discovery of Biomarkers in Acute and Chronic Murine Schistosomiasis Infection 急性和慢性小鼠血吸虫病感染中转录、表观遗传和表型可塑性的表征以及生物标志物的发现。
IF 4.2 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-05 DOI: 10.1096/fj.202502913R
Sheila de Andrade Penteado Corrêa, Cauã da Silva Oliveira Teodoro, João Paulo Luz da Silva, Fabio Queiroz, Tayná Dandara do Amaral, Silmara Marques Allegretti, Fernanda Silva de Oliveira, Rafaela Ferraz Teixeira, Lizandra Maia de Sousa, Sílvio Roberto Consonni, Matheus de Souza Gomes, Christoph Grunau, Fernanda Janku Cabral

Parasites can induce changes in their hosts, favoring the success of the infection and its development at each stage of their life cycle. The host minimizes the effects of the parasite's presence through its defense system, balancing the parasite–host relationship. The intricate parasite–host relationship provides physiological, immunological, and molecular cues that suggest interaction and mutual regulation of the transcriptome and epigenome, promoting phenotypic plasticity and survival in a changing environment. There has been a growing interest in the epigenetic mechanisms of Schistosoma mansoni, a parasite with remarkable phenotypic plasticity in response to signals from the environment and its hosts. Several studies emphasize the epigenetic mechanisms behind the phenotypic plasticity of Schistosoma. Regarding the host's gene expression in the face of infection, however, there is little evidence of which pathways are altered by the passage of the parasite through the lungs and by the pathogenesis in the hepatic portal system. In this work, we characterized S. mansoni infection in parasitological and biochemical aspects of the murine model in comparison with the profile of the initial, acute, and chronic phases of infection (3, 7, and 20 wpi (weeks postinfection), respectively). The biochemical and morphological results of the infection at 3, 7, and 20 wpi show the phenotypic changes of schistosomiasis in the murine model. ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) at 7 wpi shows a chromatin with higher accessibility for infected individuals, and Western blotting at 7 wpi shows an increase in histone marks H3K9ac and H3K9me3, indicating a change in chromatin status after infection. RNA-seq (RNA sequencing) for 7 wpi results show a differential profile of lipid metabolism genes that are negatively modulated, while immune system genes are positively modulated. It is interesting to note that the negative modulation of mRNA expression of lipid pathway genes causes the rates of these metabolites to appear decreased in the blood, while the increased expression of immune system defense genes is in accordance with liver histology data, which shows an inflammatory profile.

寄生虫可以诱导其宿主发生变化,在其生命周期的每个阶段有利于感染的成功及其发展。寄主通过其防御系统将寄生虫的影响降到最低,平衡寄主与寄主的关系。复杂的寄主关系提供了生理、免疫和分子线索,表明转录组和表观基因组的相互作用和相互调节,促进表型可塑性和在不断变化的环境中的生存。人们对曼氏血吸虫的表观遗传机制越来越感兴趣,曼氏血吸虫是一种对环境和宿主信号具有显著表型可塑性的寄生虫。一些研究强调了血吸虫表型可塑性背后的表观遗传机制。然而,关于宿主在感染时的基因表达,很少有证据表明寄生虫通过肺部和肝门静脉系统的发病机制改变了哪些途径。在这项工作中,我们在小鼠模型的寄生虫学和生化方面与感染的初始、急性和慢性期(分别为感染后3、7和20周)进行了比较。感染3、7、20 wpi时的生化和形态学结果显示了小鼠模型中血吸虫病的表型变化。7 wpi时的ATAC-seq(使用测序法检测转座酶可及染色质)显示,受感染个体的染色质可及性更高,7 wpi时的Western blotting显示组蛋白标记H3K9ac和H3K9me3增加,表明感染后染色质状态发生了变化。7个wpi的RNA-seq (RNA测序)结果显示脂质代谢基因的差异谱是负调节的,而免疫系统基因是正调节的。有趣的是,脂质通路基因mRNA表达的负调节导致这些代谢物在血液中出现下降,而免疫系统防御基因表达的增加与肝脏组织学数据一致,显示出炎症特征。
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