Biochimica et biophysica acta. Molecular basis of disease最新文献_第4页

Exercise-induced irisin attenuates ferroptosis in polycystic ovary syndrome by modulating the NCOA4-FTH pathway 运动诱导的鸢尾素通过调节NCOA4-FTH通路减轻多囊卵巢综合征的铁下垂。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-11-12 DOI: 10.1016/j.bbadis.2025.168108

Yaling Zhang , Yi Zhang , Daojuan Wang , Yajing Weng , Shanmei Shen , Yanting Wen , Jianguo Ruan , Yong Wang

Objective

Hyperandrogenism is a central pathological feature of polycystic ovary syndrome (PCOS) that disrupts granulosa cell function. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, may contribute to ovarian injury. This study aimed to clarify the pathways of hyperandrogenic-induced granulosa cells ferroptosis, elucidating the molecular mechanism of exercise and its secretory factor, irisin, through the NCOA4-FTH pathway.

Methods

DHEA-induced PCOS model and in vitro granulosa cells were constructed to systematically evaluate the effects of exercise and irisin on ovarian function and ferroptosis. In vivo experiments included treadmill training in PCOS mice, assessment of estrous cycles, glucose/insulin tolerance, ovarian morphology, oxidative stress, ferroptosis, and NCOA4-FTH pathway proteins. In vitro, granulosa cells were treated with DHT and co-exposed to irisin or the ferroptosis inhibitor Ferrostatin-1 (Fer-1), with siRNA-mediated NCOA4 knockdown for functional verification.

Results

DHEA-induced PCOS mice exhibited disrupted estrous cycles, abnormal follicular morphology, glucose intolerance, insulin resistance, and ferroptosis activation, characterized by oxidative stress, Fe²⁺ overload, and dysregulated ferroptosis-related proteins. Fer-1 reversed DHT-induced GPX4 downregulation, suggesting ferroptosis involvement. Eight-week aerobic exercise improved metabolic parameters and ovarian morphology, suppressed ferroptosis by modulating NCOA4 and GPX4 expression, and alleviated oxidative stress. Mechanistically, exercise-induced irisin inhibited ferritinophagy and restored iron metabolism via the NCOA4-FTH pathway. NCOA4 knockdown further validated its central role in regulating ferritinophagy.

Conclusion

Hyperandrogenism triggers granulosa cells ferroptosis in PCOS, while exercise and irisin protect ovarian function by regulating the NCOA4–FTH pathway, suggesting a potential therapeutic target for PCOS.

目的：雄激素分泌过多是多囊卵巢综合征（PCOS）的中心病理特征，可破坏颗粒细胞功能。铁下垂是一种由脂质过氧化引起的铁依赖性细胞死亡形式，可能导致卵巢损伤。本研究旨在阐明高雄激素诱导的颗粒细胞铁下垂的途径，通过NCOA4-FTH途径阐明运动及其分泌因子鸢尾素的分子机制。方法：构建dhea诱导的PCOS模型和体外颗粒细胞，系统评价运动和鸢尾素对卵巢功能和铁下垂的影响。体内实验包括PCOS小鼠的跑步机训练、动情周期、葡萄糖/胰岛素耐量、卵巢形态、氧化应激、铁下垂和NCOA4-FTH途径蛋白的评估。在体外，用DHT处理颗粒细胞，并共同暴露于鸢尾素或铁凋亡抑制剂铁抑素-1 (ferl -1)，并通过sirna介导的NCOA4敲低进行功能验证。结果：dhea诱导的PCOS小鼠表现出发色周期中断、卵泡形态异常、葡萄糖耐受不良、胰岛素抵抗和铁凋亡激活，其特征是氧化应激、铁2+过载和铁凋亡相关蛋白失调。fer1逆转dht诱导的GPX4下调，提示铁下垂参与。8周有氧运动改善代谢参数和卵巢形态，通过调节NCOA4和GPX4表达抑制铁下垂，减轻氧化应激。机制上，运动诱导的鸢尾素通过NCOA4-FTH途径抑制铁蛋白自噬并恢复铁代谢。NCOA4敲低进一步证实了其在调节铁蛋白自噬中的核心作用。结论：高雄激素导致PCOS患者颗粒细胞铁下垂，而运动和鸢尾素通过调节NCOA4-FTH通路保护卵巢功能，提示PCOS的潜在治疗靶点。

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引用次数: 0

Vitamin D attenuates PCSK9-driven phenotypic switch of vascular smooth muscle cells and neointimal hyperplasia via SIRT6 activation 维生素D通过SIRT6激活减弱pcsk9驱动的血管平滑肌细胞表型开关和内膜增生。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-12-12 DOI: 10.1016/j.bbadis.2025.168135

Sushmitha Duddu , Yash T. Katakia , Nivedha Suresh , Rituparna Chakrabarti , Syamantak Majumder , Praphulla Chandra Shukla

Pathologically activated vascular smooth muscle cells (VSMCs) upregulate proprotein convertase subtilisin/kexin type 9 (PCSK9), contributing to vascular inflammation and remodeling. Although both PCSK9 and 25-hydroxyvitamin D (25OHD), the active form of Vitamin D, are linked to inflammatory regulation, their interaction in modulating VSMC phenotype remains unclear. Here, we investigated the effect of 25OHD on PCSK9 expression in human aortic SMCs (HASMCs) under lipopolysaccharide (LPS)-induced inflammatory stress. LPS stimulation increased PCSK9 mRNA >2-fold, while 25OHD pre-treatment significantly reduced this induction and restored expression of contractile markers (Acta2, Cnn1, Myocd, Tagln). Functional assays revealed that both 25OHD and PCSK9 knockdown attenuated LPS-induced proliferation and migration in HASMCs. In vivo, 25OHD supplementation in C57BL/6 mice for six weeks prior to partial carotid artery ligation suppressed injury-induced PCSK9 expression in SMCs and reduced neointimal hyperplasia. Supporting these findings, reanalysis of RNA-seq data revealed that airway SMCs (ASMCs) derived from asthma patients and treated with Vitamin D exhibited lower PCSK9 expression and concomitantly elevated sirtuin expression relative to untreated asthmatic controls. Mechanistically, 25OHD enhanced SIRT6 activation, and inhibition of SIRT6 with nicotinamide reversed 25OHD-mediated PCSK9 downregulation, identifying SIRT6 as a key regulator. Together, these findings reveal a novel SIRT6-dependent mechanism by which Vitamin D suppresses PCSK9-driven VSMC phenotypic switching, exerting protective effects against vascular inflammation and remodeling.

News and Noteworthy: This study highlights the crucial role of PCSK9 in the inflammation and phenotypic modulation of VSMCs. The active Vitamin D metabolite, 25OHD, suppresses inflammation-induced PCSK9 expression and restores contractile gene markers in HASMCs. In vivo, Vitamin D supplementation reduces PCSK9 levels and neointimal hyperplasia following flow-mediated vascular injury. Mechanistically, 25OHD activates SIRT6, establishing a novel 25OHD–SIRT6–PCSK9 regulatory axis with promising therapeutic implications for vascular inflammation and remodeling.

病理激活的血管平滑肌细胞（VSMCs）上调枯草素/键合蛋白9型（PCSK9）蛋白转化酶，参与血管炎症和重塑。尽管PCSK9和25-羟基维生素D（25 -羟基维生素D，维生素D的活性形式）都与炎症调节有关，但它们在调节VSMC表型中的相互作用尚不清楚。在此，我们研究了在脂多糖（LPS）诱导的炎症应激下，25OHD对人主动脉smc （HASMCs）中PCSK9表达的影响。LPS刺激使PCSK9 mRNA的表达增加了2倍，而25OHD预处理显著降低了这种诱导作用，恢复了收缩标志物（Acta2、Cnn1、心肌、Tagln）的表达。功能分析显示，25OHD和PCSK9敲低均能减弱lps诱导的HASMCs的增殖和迁移。在体内，在部分颈动脉结扎前6周，在C57BL/6小鼠中补充25OHD可抑制损伤诱导的SMCs中PCSK9的表达，并减少新生内膜增生。支持这些发现的是，RNA-seq数据的再分析显示，与未治疗的哮喘对照组相比，来自哮喘患者并接受维生素D治疗的气道SMCs （ASMCs）表现出较低的PCSK9表达和伴随的sirtuin表达升高。在机制上，25OHD增强了SIRT6的激活，而烟酰胺抑制SIRT6逆转了25OHD介导的PCSK9下调，表明SIRT6是一个关键的调节因子。总之，这些发现揭示了一种新的sirt6依赖机制，通过该机制，维生素D抑制pcsk9驱动的VSMC表型转换，对血管炎症和重塑发挥保护作用。新闻和值得注意的是：这项研究强调了PCSK9在VSMCs的炎症和表型调节中的关键作用。活性维生素D代谢物25OHD抑制炎症诱导的PCSK9表达，恢复HASMCs中的收缩基因标记。在体内，补充维生素D可降低PCSK9水平和血流介导的血管损伤后的新生内膜增生。在机制上，25OHD激活SIRT6，建立了一个新的25OHD-SIRT6- pcsk9调控轴，对血管炎症和重构具有良好的治疗意义。

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引用次数: 0

Neutrophil-derived thrombospondin-1 (THBS1) drives type 2 diabetes-induced osteoporosis via CD36-PPARγ-POU2F2 signaling 中性粒细胞衍生的血栓反应蛋白-1 （THBS1）通过CD36-PPARγ-POU2F2信号驱动2型糖尿病诱导的骨质疏松症。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-12-15 DOI: 10.1016/j.bbadis.2025.168139

Weibo Huang , Chenghao Zhou , Rong Wu , Kangcheng Zhao , Jianfeng Wu , Dianwen Song

Objective

Type 2 diabetes (T2D) is associated with osteoporosis. Although chronic inflammation and immune dysregulation are implicated in T2D-induced bone loss, the specific roles of immune cells remain poorly understood. This study aimed to investigate how neutrophils in T2D contribute to osteoporosis and to identify the underlying molecular mechanisms and potential therapeutic targets.

Methods

We utilized a combination of in vivo and in vitro approaches, including T2D and control mouse models, primary cell cultures, and publicly available single-cell RNA sequencing data from the GEO database. Osteoporosis was assessed through TRAP staining, micro-CT imaging, and quantitative PCR. Molecular interactions were examined using Western blotting, chromatin immunoprecipitation followed by qPCR, and flow cytometry. Additionally, virtual screening was employed to identify potential inhibitors of thrombospondin-1(THBS1).

Results

Neutrophils isolated from T2D mice promoted osteoclast activity and bone loss when transferred into wild-type mice, as evidenced by increased TRAP-positive cells and deteriorated bone microarchitecture. We identified THBS1, a glycoprotein secreted at higher levels by T2D neutrophils, as a mediator of osteoclast differentiation. THBS1 engaged the CD36 receptor on macrophages, activating PPARγ, which transcriptionally upregulates POU2F2—a transcription factor that enhances osteoclastogenesis via c-FOS induction. Genetic ablation of THBS1 attenuated osteoclast formation and bone loss in T2D mice. Virtual screening identified nasunin as a potent THBS1 inhibitor. Treatment with nasunin suppressed the CD36–PPARγ–POU2F2–c-FOS axis, reduced osteoclast differentiation in vitro, and ameliorated T2D-induced osteoporosis in vivo.

Conclusion

Our findings reveal a novel pathway through which neutrophil-derived THBS1 exacerbates diabetic osteoporosis by promoting osteoclastogenesis via CD36–PPARγ–POU2F2 signaling.

目的：2型糖尿病（T2D）与骨质疏松有关。尽管慢性炎症和免疫失调与t2d诱导的骨质流失有关，但免疫细胞的具体作用仍然知之甚少。本研究旨在探讨T2D中性粒细胞如何促进骨质疏松症，并确定潜在的分子机制和潜在的治疗靶点。方法：我们结合了体内和体外方法，包括T2D和对照小鼠模型，原代细胞培养，以及GEO数据库中公开的单细胞RNA测序数据。通过TRAP染色、显微ct成像和定量PCR评估骨质疏松症。分子间相互作用采用Western blotting、染色质免疫沉淀（随后采用qPCR）和流式细胞术检测。此外，虚拟筛选用于确定血栓反应蛋白-1（THBS1）的潜在抑制剂。结果：从T2D小鼠中分离的中性粒细胞在转移到野生型小鼠时促进破骨细胞活性和骨质流失，表现为trap阳性细胞增加和骨微结构恶化。我们发现THBS1是一种由T2D中性粒细胞分泌的较高水平的糖蛋白，是破骨细胞分化的介质。THBS1参与巨噬细胞上的CD36受体，激活PPARγ，其转录上调pou2f2 -一种通过c-FOS诱导促进破骨细胞发生的转录因子。THBS1基因消融术可减轻T2D小鼠破骨细胞的形成和骨质流失。虚拟筛选证实nasunin是一种有效的THBS1抑制剂。纳苏宁治疗抑制CD36-PPARγ-POU2F2-c-FOS轴，减少体外破骨细胞分化，改善体内t2d诱导的骨质疏松症。结论：我们的研究结果揭示了中性粒细胞来源的THBS1通过CD36-PPARγ-POU2F2信号通路促进破骨细胞生成，从而加剧糖尿病骨质疏松症的新途径。

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引用次数: 0

Swimming exercise attenuates diabetic myopathy and is associated with histological and mitochondrial changes in pregnant rats (Rattus norvegicus) 游泳运动减轻妊娠大鼠糖尿病性肌病，并与组织学和线粒体变化有关（褐家鼠）

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-11-25 DOI: 10.1016/j.bbadis.2025.168126

Bruna Bologna Catinelli , Angélica Mércia Pascon Barbosa , Aline Medolago Carr , Rafael Guilen de Oliveira , Fernanda Cristina Bergamo Alves , Franciele Mosele , Agnaldo Bruno Chies , Sérgio Luis Felisbino , Luis Sobrevia , Patrícia de Souza Rossignoli , Marilza Vieira Cunha Rudge , Diamater Study Group

Aim

Diabetic-induced myopathy (DiM) is reversed by swimming exercise (SE) in diabetic pregnant rats. This study aims to characterise the role of muscle stem cells (MuSCs), mitochondrial adaptations, and inflammation in this process.

Methods

A mild hyperglycaemic pregnant rat model was created by administering 100 mg/kg streptozotocin to Wistar female newborns on the first day of life. In adulthood, after mating, the rats were assigned to either a sedentary or exercise group. The SE protocol involved 60 min of daily swimming, 6 days per week, from gestational day 0 to 20. On gestational day 21, blood samples, rectus abdominis muscle (RAM), and soleus muscle were collected for analysis of fiber type, MuSCs count, mitochondrial adaptations, and inflammation markers.

Results

The diabetic group showed a lower number of fast and slow-twitch fibers. SE increased the number of MuSCs, the MuSCs/myonuclei ratio, mitochondrial area, and count, and restored citrate synthase activity. SE also increased the MuSCs/fiber and myonuclei/fiber ratios, as well as the mitochondria number/fiber and mitochondria area/fiber ratios, showing a positive relationship between mitochondrial count and fiber number in the diabetic group. Inflammation analysis revealed no differences in pro-inflammatory marker expression or quantification.

Conclusion

These results highlight a new combined effect of SE, increasing MuSCs and mitochondrial number and area, as well as restoring citrate synthase activity, suggesting that changes in muscle histology, MuSCs abundance, and mitochondrial adaptations with SE in diabetic animals may be key mechanisms in attenuating RAM DiM in diabetic pregnant rats.

目的通过游泳运动（SE）逆转糖尿病妊娠大鼠糖尿病性肌病（DiM）。本研究旨在描述肌肉干细胞（MuSCs）、线粒体适应和炎症在这一过程中的作用。方法Wistar雌性新生儿出生第一天给予100 mg/kg链脲佐菌素，建立轻度高血糖妊娠大鼠模型。成年后，交配后，老鼠被分配到久坐组或运动组。SE方案包括每天游泳60分钟，每周6天，从妊娠第0天到第20天。在妊娠第21天，采集血液样本、腹直肌（RAM）和比目鱼肌，分析纤维类型、musc计数、线粒体适应性和炎症标志物。结果糖尿病组快、慢肌纤维数量明显减少。SE增加了MuSCs数量、MuSCs/myonuclei比值、线粒体面积和数量，恢复了柠檬酸合成酶活性。SE还增加了糖尿病组MuSCs/fiber和myonuclei/fiber比值，以及线粒体数目/fiber和线粒体面积/fiber比值，表明线粒体数目和纤维数目呈正相关。炎症分析显示，促炎标志物的表达和定量没有差异。结论SE对糖尿病妊娠大鼠的RAM DiM有新的联合作用，增加了MuSCs和线粒体的数量和面积，恢复了柠檬酸合酶的活性，提示SE对糖尿病动物肌肉组织学、MuSCs丰度和线粒体适应性的改变可能是糖尿病妊娠大鼠RAM DiM减轻的关键机制。

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引用次数: 0

Vitexin targets USP49-GRPR deubiquitination axis in medullary thyroid carcinoma therapy 牡荆素靶向USP49-GRPR去泛素化轴治疗甲状腺髓样癌

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-12-04 DOI: 10.1016/j.bbadis.2025.168128

Qing Xia , Shuai Dong , Wenjun Xu , Qinmei Lai , Hanlin Song , Wei Zhang

Medullary thyroid carcinoma (MTC) is a rare, aggressive neuroendocrine malignancy with limited therapeutic options, often exhibiting resistance to targeted therapies. This study demonstrates that the natural flavonoid vitexin suppresses MTC progression by disrupting the deubiquitination axis involving USP49 and the gastrin-releasing peptide receptor (GRPR). GRPR, known to drive tumor growth in neuroendocrine cancers, promotes cell survival via the PI3K/AKT signaling pathway. We identified USP49 as a key regulator of GRPR protein stability in MTC, a previously unrecognized interaction where USP49 counteracts GRPR ubiquitination. Vitexin inhibits USP49, destabilizing GRPR. Consequently, vitexin treatment significantly reduced MTC cell proliferation, enhanced apoptosis, and impaired migration and invasion in vitro. Furthermore, vitexin markedly inhibited tumor growth in nude mouse xenograft models, correlating with decreased Ki67 expression and increased apoptotic markers (Tunel). Mechanistically, USP49 stabilizes GRPR by preventing its ubiquitin-mediated degradation; inhibiting USP49 with vitexin resensitizes tumors to apoptosis by destabilizing GRPR. These findings highlight the therapeutic potential of targeting post-translational modification pathways, specifically deubiquitination, in MTC. Vitexin represents a promising candidate agent for overcoming therapeutic resistance by disrupting GRPR-driven survival mechanisms. This work underscores the critical role of deubiquitination in MTC progression and offers a rationale for utilizing natural compounds to modulate GPCR stability in aggressive cancers.

甲状腺髓样癌（MTC）是一种罕见的侵袭性神经内分泌恶性肿瘤，治疗选择有限，通常表现出对靶向治疗的抵抗。本研究表明，天然黄酮类牡荆素通过破坏涉及USP49和胃泌素释放肽受体（GRPR）的去泛素化轴来抑制MTC的进展。GRPR，已知在神经内分泌癌中驱动肿瘤生长，通过PI3K/AKT信号通路促进细胞存活。我们发现USP49是MTC中GRPR蛋白稳定性的关键调节因子，这是一种以前未被认识到的相互作用，其中USP49抵消GRPR泛素化。牡荆素抑制USP49，破坏GRPR稳定。因此，牡荆素处理显著降低了MTC细胞的增殖，增强了凋亡，并损害了体外迁移和侵袭。此外，牡荆素在裸鼠异种移植模型中显著抑制肿瘤生长，与Ki67表达降低和凋亡标志物增加相关（Tunel）。在机制上，USP49通过阻止其泛素介导的降解来稳定GRPR；用牡荆素抑制USP49通过破坏GRPR使肿瘤重致凋亡。这些发现强调了靶向MTC翻译后修饰途径的治疗潜力，特别是去泛素化。牡荆素是一种很有前途的候选药物，可以通过破坏grpr驱动的生存机制来克服治疗耐药性。这项工作强调了去泛素化在MTC进展中的关键作用，并为利用天然化合物调节侵袭性癌症中GPCR的稳定性提供了理论依据。

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引用次数: 0

Inhibition of BRG1 suppresses the progression of glioblastoma via repressing oligodendrocyte genes 抑制BRG1通过抑制少突胶质细胞基因来抑制胶质母细胞瘤的进展。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-11-14 DOI: 10.1016/j.bbadis.2025.168118

Huanwen Rui , Bo Chen , Min Wang , Xing Xue , Yangyang Ma , Chenyang Zhang , Ying Xu , Zai Song , Feifei Ji , Weijun Feng , Hao Li

Glioblastoma, the most lethal and pervasive subtype of glioma, has been classified according to both molecular signatures and cell identity. However, the promise of subtype-specific therapy for GBM has yet to be realized. We hypothesize that epigenetic compounds could be effective due to the crucial role of epigenetic regulation in maintaining individual GBM subtypes. We establish a mouse GBM model by expressing AKT3, DN-p53 and PDGFB (ADP) in cortical neural progenitor cells via in utero electroporation. Gene expression analysis demonstrate that ADP glioma exhibits the oligodendrocyte precursor cell (OPC) signature. A small-scale compound screening conducted in cultured ADP tumor cells identify BRM014 (dual ATPase inhibitor of chromatin remodelers BRM/BRG1) as an effective compound. Mechanistically, acute treatment of ADP tumor cells with BRM014 specifically inhibits chromatin accessibility and the expression of oligodendrocyte genes. Importantly, genetic depletion of Brg1 significantly delays tumor progression and prolongs the survival of ADP glioma-bearing mice. Importantly, BRM014 treatment selectively inhibits the growth of human GBM cells with the OPC signature. In sum, our findings demonstrate that the inhibition of ATPase activity of BRG1 is a promising epigenetic therapy for OPC-like GBM.

胶质母细胞瘤是胶质瘤中最致命和最普遍的亚型，根据分子特征和细胞特性进行分类。然而，亚型特异性治疗GBM的前景尚未实现。我们假设，由于表观遗传调控在维持单个GBM亚型中的关键作用，表观遗传化合物可能是有效的。我们通过子宫内电穿孔在小鼠皮层神经祖细胞中表达AKT3、DN-p53和PDGFB (ADP)，建立小鼠GBM模型。基因表达分析表明ADP胶质瘤具有少突胶质前体细胞（OPC）特征。在培养的ADP肿瘤细胞中进行的小规模化合物筛选发现BRM014（染色质重塑者BRM/BRG1的双atp酶抑制剂）是一种有效的化合物。机制上，BRM014急性治疗ADP肿瘤细胞特异性抑制染色质可及性和少突胶质细胞基因的表达。重要的是，Brg1基因缺失可显著延缓ADP胶质瘤小鼠的肿瘤进展，延长其生存期。重要的是，BRM014治疗选择性地抑制具有OPC特征的人GBM细胞的生长。总之，我们的研究结果表明，抑制BRG1的atp酶活性是一种很有希望的opc样GBM的表观遗传学治疗方法。

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引用次数: 0

High-fat diet does not exacerbate aortic pathology and enhances metabolic function in Marfan syndrome Fbn1C1041G/+ mice 高脂肪饮食不会加重马凡综合征Fbn1C1041G/+小鼠的主动脉病理，并能增强代谢功能。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-11-11 DOI: 10.1016/j.bbadis.2025.168107

Carmen Yap , Myrthe E. Hoogeland , Siyu Li , Iris Bakker , Ela Yalcin , Roelof Ottenhoff , Maria P. Clemente-Olivo , Sander Kooijman , Yousef Morcos , Gerhard Sengle , Vivian de Waard

Background and aims

Marfan syndrome (MFS) is a systemic disorder, caused by different pathogenic variants in the fibrillin-1 gene (FBN1). Interestingly, patients with MFS are often characterized with an asthenic body type, most likely associated with systemic metabolic alterations. We evaluate the effects of a high-fat diet (HFD) on aortic pathology and metabolism in a mouse model of MFS.

Methods and results

Male Fbn1^C1041G/+ MFS mice and wild-type littermates were fed a chow or a HFD for 13 weeks. Compared to chow, HFD-fed mice show increased body weight and white adipose tissue, developed glucose intolerance and increased the use of fat as a fuel source indicated by lower respiratory exchange ratio, independent of genotype. MFS mice showed an increased heart tissue weight, increase in aortic root diameter, and higher number of elastin breaks in the aorta compared to wild-type mice when fed a chow diet. The aortic diameter did not further increase upon HFD feeding in MFS mice, while HFD did promote aortic dilation of the ascending aorta of wild-type mice. In most examined tissues, the mitochondrial gene expression profile is altered in MFS mice on a chow diet. Especially Sirt1 was reduced in all tissues, with HFD normalizing the MFS profile towards a wild-type profile. The latter may contribute to the observed increase in energy expenditure upon HFD in MFS mice.

Conclusion

In conclusion, Fbn1^C1041G/+ MFS aortic pathology is not aggravated by the HFD, most likely due to the increase of mitochondrial gene expression upon HFD in MFS mice.

背景与目的：马凡氏综合征（Marfan syndrome， MFS）是一种由纤维蛋白1基因（FBN1）的不同致病变异引起的全身性疾病。有趣的是，MFS患者通常以虚弱的身体类型为特征，很可能与全身代谢改变有关。我们评估了高脂肪饮食（HFD）对MFS小鼠模型主动脉病理和代谢的影响。方法与结果：雄性Fbn1C1041G/+ MFS小鼠和野生型仔鼠分别饲喂鼠粮或HFD 13 周。与饲料相比，饲喂hfd的小鼠表现出体重和白色脂肪组织的增加，出现葡萄糖耐受不良，并且增加了脂肪作为燃料来源的使用，这表明呼吸交换率较低，与基因型无关。与野生型小鼠相比，MFS小鼠的心脏组织重量增加，主动脉根直径增加，主动脉弹性蛋白断裂数量增加。饲喂HFD后，MFS小鼠主动脉直径没有进一步增大，而饲喂HFD后，野生型小鼠升主动脉扩张明显。在大多数被检查的组织中，线粒体基因表达谱在鼠粮中被改变。特别是Sirt1在所有组织中都减少，HFD使MFS谱正常化到野生型谱。后者可能有助于观察到MFS小鼠在HFD时能量消耗的增加。结论：综上所述，Fbn1C1041G/+ MFS主动脉病变不因HFD而加重，很可能是由于MFS小鼠在HFD上线粒体基因表达增加所致。

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引用次数: 0

MAIT cells accumulated via CXCL12-CXCR4 chemotaxis are involved in pathologic gastric inflammation among Helicobacter pylori-infected patients 通过CXCL12-CXCR4趋化积累的MAIT细胞参与了幽门螺杆菌感染患者的病理性胃炎症。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2026-01-03 DOI: 10.1016/j.bbadis.2025.168151

Fang Zhang , Youjian Zhou , Tingting Xia , Yue Xu , Taojun He , Bin Li , Shasha Yang , Ying Chen , Honglei Chen , Chao Wu

Background

Helicobacter pylori can cause gastritis, peptic ulcers, and even gastric cancer. In addition to conventional T cells, mucosal-associated invariant T (MAIT) cells may have an important immunologic role in mucosal infectious diseases. However, the phenotypic and effector characteristics of gastric MAIT cells and the relationship between mucosal MAIT cells and H. pylori-related diseases have not been established.

Methods

We analyzed the phenotypes and cytokines of gastric and peripheral MAIT cells from H. pylori-infected patients by flow cytometry. CXCL12-mediated chemotaxis of MAIT cells was measured by Transwell assay. Relationship between MAIT cells and inflammation of H. pylori-infected gastric diseases was assessed with immunofluorescence staining and histopathological score.

Results

The number of gastric MAIT cells was significantly increased but the frequency of peripheral MAIT cells were decreased in patients with H. pylori infections. The gastric MAIT cells were activated with high expression of CD69 and CD38, and produced several pro-inflammatory cytokines. Furthermore, we observed the expression of CXCR4 and CXCL12 were upregulated in H. pylori-infected stomachs. CXCL12 promoted MAIT cells to migrate, which was blocked by a CXCR4 antagonist. Finally, we demonstrated that the number of gastric MAIT cells was positively correlated with severe inflammation in H. pylori-infected stomachs.

Conclusions

Gastric MAIT cells were accumulated and activated in H. pylori-infected stomachs, which may be involved in the pathologic inflammation of H. pylori-related gastric diseases.

背景：幽门螺杆菌可引起胃炎、消化性溃疡，甚至胃癌。除常规T细胞外，粘膜相关不变性T细胞（MAIT）可能在粘膜感染性疾病中起重要的免疫作用。然而，胃MAIT细胞的表型和效应特性以及粘膜MAIT细胞与幽门螺杆菌相关疾病的关系尚未确定。方法：采用流式细胞术分析幽门螺杆菌感染患者胃和外周血MAIT细胞的表型和细胞因子。Transwell法检测cxcl12介导的MAIT细胞趋化性。采用免疫荧光染色和组织病理学评分评估MAIT细胞与幽门螺杆菌感染胃病炎症的关系。结果：幽门螺杆菌感染患者胃MAIT细胞数量明显增加，外周MAIT细胞频率明显降低。胃MAIT细胞被激活，CD69和CD38高表达，并产生多种促炎细胞因子。此外，我们观察到CXCR4和CXCL12在幽门螺旋杆菌感染的胃中表达上调。CXCL12促进MAIT细胞迁移，这一作用被CXCR4拮抗剂阻断。最后，我们证明了胃MAIT细胞的数量与幽门螺旋杆菌感染胃的严重炎症呈正相关。结论：胃MAIT细胞在幽门螺杆菌感染的胃中积累并活化，可能参与幽门螺杆菌相关胃疾病的病理性炎症。

{"title":"MAIT cells accumulated via CXCL12-CXCR4 chemotaxis are involved in pathologic gastric inflammation among Helicobacter pylori-infected patients","authors":"Fang Zhang , Youjian Zhou , Tingting Xia , Yue Xu , Taojun He , Bin Li , Shasha Yang , Ying Chen , Honglei Chen , Chao Wu","doi":"10.1016/j.bbadis.2025.168151","DOIUrl":"10.1016/j.bbadis.2025.168151","url":null,"abstract":"<div><h3>Background</h3><div><em>Helicobacter pylori</em> can cause gastritis, peptic ulcers, and even gastric cancer. In addition to conventional T cells, mucosal-associated invariant T (MAIT) cells may have an important immunologic role in mucosal infectious diseases. However, the phenotypic and effector characteristics of gastric MAIT cells and the relationship between mucosal MAIT cells and <em>H. pylori</em>-related diseases have not been established.</div></div><div><h3>Methods</h3><div>We analyzed the phenotypes and cytokines of gastric and peripheral MAIT cells from <em>H. pylori</em>-infected patients by flow cytometry. CXCL12-mediated chemotaxis of MAIT cells was measured by Transwell assay. Relationship between MAIT cells and inflammation of <em>H. pylori</em>-infected gastric diseases was assessed with immunofluorescence staining and histopathological score.</div></div><div><h3>Results</h3><div>The number of gastric MAIT cells was significantly increased but the frequency of peripheral MAIT cells were decreased in patients with <em>H. pylori</em> infections. The gastric MAIT cells were activated with high expression of CD69 and CD38, and produced several pro-inflammatory cytokines. Furthermore, we observed the expression of CXCR4 and CXCL12 were upregulated in <em>H. pylori</em>-infected stomachs. CXCL12 promoted MAIT cells to migrate, which was blocked by a CXCR4 antagonist. Finally, we demonstrated that the number of gastric MAIT cells was positively correlated with severe inflammation in <em>H. pylori</em>-infected stomachs.</div></div><div><h3>Conclusions</h3><div>Gastric MAIT cells were accumulated and activated in <em>H. pylori</em>-infected stomachs, which may be involved in the pathologic inflammation of <em>H. pylori</em>-related gastric diseases.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168151"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907225","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

Prolyl-hydroxylase domain inhibition enhances collagen levels in oral mucosa-derived fibroblasts 脯氨酸羟化酶结构域抑制可提高口腔粘膜源性成纤维细胞中的胶原水平。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-11-29 DOI: 10.1016/j.bbadis.2025.168124

Sivan Najar Hasson , Itay Kilimnik , Bar Shahar , Lucia Adriana Lifshits , Marina Sova , Daniel Zvi Bar , Lihi Adler-Abramovich , Evgeny Weinberg , Maayan Gal

Fibroblast cells are a primary source of collagen, playing a vital role in maintaining the structural integrity of the oral mucosa. Given that hypoxia upregulates collagen levels in oral mucosa-derived fibroblasts (OMDFs), this study aims to investigate the effect of inhibiting prolyl-hydroxylase domain (PHD) enzymes, negative regulators of the transcription factor hypoxia-inducible factor (HIF), on collagen-I levels under normal oxygen levels. We examined three PHD inhibitors, IOX4, Enarodustat, and Daprodustat, for their effect on collagen levels in keratinized OMDFs. While IOX4 exhibited cellular cytotoxicity, Enarodustat and Daprodustat did not affect cell viability. Further treatment with Daprodustat at 12.5 or 25 μM significantly increased collagen I level more than twofold compared to non-treated cells, whereas Enarodustat had no significant effect. Additional mechanistic studies revealed that Daprodustat treatment induced the accumulation and nuclear translocation of HIF-1α and upregulated transcripts of key collagen-modifying enzymes, including P4HA1 and P4HA2, by more than twofold. This study demonstrates that direct PHD inhibition effectively enhances collagen biosynthesis in OMDFs. The mechanism involves HIF-1α-mediated upregulation of collagen-modifying enzymes. These findings highlight the potential of repurposing clinically approved PHD inhibitors as therapeutic agents for promoting the healing and regeneration of damaged gingiva and additional tissues.

成纤维细胞是胶原蛋白的主要来源，在维持口腔黏膜结构完整性方面起着至关重要的作用。鉴于缺氧可上调口腔粘膜源性成纤维细胞（OMDFs）中的胶原水平，本研究旨在探讨在正常氧水平下，抑制脯氨酸羟化酶结构域（PHD）酶（转录因子缺氧诱导因子（HIF）的负调节因子）对胶原-i水平的影响。我们检测了三种PHD抑制剂IOX4、Enarodustat和Daprodustat对角化omdf中胶原水平的影响。IOX4表现出细胞毒性，Enarodustat和Daprodustat不影响细胞活力。在12.5或25 μM下进一步使用Daprodustat，与未处理的细胞相比，胶原I水平显著增加了两倍以上，而Enarodustat没有显著影响。其他机制研究表明，Daprodustat处理诱导HIF-1α的积累和核易位，并上调关键胶原修饰酶（包括P4HA1和P4HA2）的转录本，增加了两倍以上。本研究表明，直接抑制PHD可有效促进OMDFs中胶原蛋白的生物合成。其机制涉及hif -1α-介导的胶原修饰酶上调。这些发现强调了重新利用临床批准的PHD抑制剂作为促进受损牙龈和其他组织愈合和再生的治疗剂的潜力。

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引用次数: 0

Lactate-induced mitochondrial magnesium uptake and its metabolic implications in the McArdle disease model 乳酸诱导的线粒体镁摄取及其在mccardle病模型中的代谢意义

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-12-11 DOI: 10.1016/j.bbadis.2025.168130

Thiruvelselvan Ponnusamy , Jeremy Mehta , Haris Waseem , Marianne Assogba , Asha Parveen Sakkarai Mohamed , Shibani Kudchadkar , Paul Herold , Kalimuthusamy Natarajaseenivasan , Santhanam Shanmughapriya

McArdle disease, caused by mutations in the pygm encoding myophosphorylase, impairs muscle glycogenolysis and lactate production during exercise, leading to severe energy deficits. Here, we report that the decreased lactate production in McArdle disease regulates mitochondrial magnesium (mMg²⁺) uptake, with major metabolic consequences in skeletal muscle. Using a CRISPR/Cas9-generated pygm knockout (KO) rat model, we demonstrate that KO rats fail to elevate lactate during static muscle contraction and exhibit diminished mMg²⁺ uptake, disrupted ATP synthesis, and impaired mitochondrial respiration. In vitro, caffeine-stimulated KO myotubes showed preserved Ca²⁺ oscillations but lacked lactate production and mMg²⁺ uptake. Restoration of lactate levels via glucose supplementation rescued mMg²⁺ transport and improved metabolic output. These findings underscore the significance of lactate as a crucial regulator of mMg²⁺ homeostasis and provide valuable mechanistic insights into the metabolic dysfunction observed in McArdle disease.

mccardle病，由编码肌磷酸化酶的pygm基因突变引起，在运动过程中损害肌肉糖原分解和乳酸生成，导致严重的能量不足。在这里，我们报告了McArdle病中乳酸生成的减少调节线粒体镁（mMg2+）的摄取，对骨骼肌产生主要的代谢后果。使用CRISPR/ cas9生成的pygm敲除（KO）大鼠模型，我们证明KO大鼠在静态肌肉收缩期间不能升高乳酸，并且表现出mMg2+摄取减少，ATP合成中断和线粒体呼吸受损。在体外，咖啡因刺激的KO肌管显示保留Ca2+振荡，但缺乏乳酸生成和mMg2+摄取。通过补充葡萄糖恢复乳酸水平可挽救mMg2+运输并改善代谢输出。这些发现强调了乳酸作为mMg2+稳态的关键调节因子的重要性，并为mccardle病中观察到的代谢功能障碍提供了有价值的机制见解。

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引用次数: 0