Biochimica et biophysica acta. Molecular basis of disease最新文献_第3页

Placental aberrant inflammation and spatial-specific lipid metabolism contribute to hypertensive disorder of pregnancy susceptibility in preeclampsia offspring 胎盘异常炎症和空间特异性脂质代谢有助于子痫前期子代妊娠易感性高血压障碍。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-01-19 DOI: 10.1016/j.bbadis.2026.168168

Pei-ran Hu , Jing-hui Xu , Yan Shi , Ying Zhu , Gao-chen Zhang , Jie-ru Yang , Yue Xu , Ming-hao Li , Xian-hua Lin , Yu Zhang , He-feng Huang

Epidemiological studies have demonstrated that daughters of preeclamptic mothers have an increased risk of hypertensive disorders of pregnancy (HDP), but the underlying mechanisms remain unclear. To investigate the molecular changes underlying this HDP intergenerational transmission, we established an L-NAME-induced PE model in pregnant mice (F0) and examined female offspring (F1) during their pregnancies. F1 females developed gestational hypertension in late pregnancy, accompanied by enlarged placental labyrinthine areas and elevated VGFR1 expression, despite normal circulating sFlt1 levels. Across gestation, F2 placentas exhibited sustained impairment of apolipoprotein-mediated lipid transport beginning at mid-gestation, while inflammatory and HIF1α pathways were mainly activated at late gestation. Spatial transcriptomic data further showed that apolipoproteins were predominantly localized to yolk sac regions, whereas inflammatory factors exhibited widespread distribution. Importantly, F1 maternal lipid profiles remained normal before conception but manifested elevated serum triglyceride levels during pregnancy, concurrent with placental lipid accumulation. This pregnancy-specific dyslipidemia suggests that placental lipid metabolism dysfunction may contribute to maternal lipid dysregulation. Clinical validation in 28,117 women further confirmed that elevated mid-gestation triglyceride levels were strongly associated with HDP risk, consistent with the dyslipidemia observed in our mouse model. Together, these findings demonstrate that pregnancy-specific lipid dysregulation represents a conserved mechanism linking placental dysfunction to HDP susceptibility. Our study provides mechanistic insights into the intergenerational transmission of PE and identifies mid-gestation maternal lipid profiles as potential predictive biomarkers, offering a basis for early risk assessment and future therapeutic targeting.

流行病学研究表明，先兆子痫母亲的女儿患妊娠高血压疾病（HDP）的风险增加，但其潜在机制尚不清楚。为了研究HDP代际传递背后的分子变化，我们在怀孕小鼠（F0）中建立了l - name诱导的PE模型，并对怀孕期间的雌性后代（F1）进行了检测。F1女性在妊娠后期出现妊娠高血压，伴随着胎盘迷路面积增大和VGFR1表达升高，尽管循环sFlt1水平正常。在整个妊娠期间，F2胎盘从妊娠中期开始表现出载脂蛋白介导的脂质转运持续受损，而炎症和HIF1α途径主要在妊娠后期被激活。空间转录组学数据进一步表明，载脂蛋白主要集中在卵黄囊区域，而炎症因子则分布广泛。重要的是，F1孕妇的血脂在受孕前保持正常，但在怀孕期间表现出血清甘油三酯水平升高，同时伴有胎盘脂质积累。这种妊娠期特异性血脂异常提示胎盘脂质代谢功能障碍可能导致母体脂质失调。28,117名妇女的临床验证进一步证实妊娠中期甘油三酯水平升高与HDP风险密切相关，与我们在小鼠模型中观察到的血脂异常一致。总之，这些发现表明，妊娠特异性脂质失调代表了一种将胎盘功能障碍与HDP易感性联系起来的保守机制。我们的研究为PE的代际传播提供了机制见解，并确定了妊娠中期母亲脂质谱作为潜在的预测性生物标志物，为早期风险评估和未来的治疗靶向提供了基础。

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引用次数: 0

Berbamine attenuates acetaminophen-induced liver injury by engaging GCLC and enhancing ferroptosis-regulatory antioxidant pathways 小檗碱通过参与GCLC和增强铁凋亡调节抗氧化途径减轻对乙酰氨基酚诱导的肝损伤

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-01-14 DOI: 10.1016/j.bbadis.2026.168154

Mengli Tao , Jiayi Shi , Yingying Zhang , Yigang Zheng , Yufen Zhao , Huabin Ma , Long Li

Objective

Acetaminophen (APAP)-induced liver injury (ALI), the major cause of acute drug-induced hepatotoxicity, lacks effective therapies. Berbamine (BBM), a bisbenzylisoquinoline alkaloid derived from the genus Berberis, exhibits diverse pharmacological properties but its efficacy against ALI and involvement in ferroptosis remains unexplored. This study aims to investigate the hepatoprotective effects and mechanisms of BBM against ALI and ferroptosis.

Methods

The in vivo model of ALI and the in vitro ferroptosis models were established using APAP and RSL3, respectively. Models received BBM or Ferrostatin-1 (Fer-1) treatment. The direct target of BBM was identified through molecular docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) assays.

Results

In vivo, BBM pretreatment dose-dependently alleviated APAP-induced hepatic damage, inflammation, and ferroptosis markers, including lipid peroxidation, GSH depletion, and PTGS2 upregulation, while upregulating GPX4. Meanwhile, the hepatoprotective effects of BBM against ALI matched Fer-1, confirming ferroptosis as an ALI driver. In vitro, BBM inhibited RSL3-induced ferroptosis, reducing ROS, lipid peroxidation, and mitochondrial dysfunction. These effects were mediated by NRF2/GCLC/GPX4 axis activation and FSP1 upregulation. Crucially, BBM directly bound GCLC confirmed by Molecular docking, CETSA, and DARTS.

Conclusion

BBM protects against ALI by mitigating ferroptosis, oxidative stress, and inflammation, in part through direct modulation of GCLC and coordinated activation of the NRF2/GCLC/GPX4 axis together with FSP1. These findings provide pharmacological evidence supporting the potential of BBM as a promising therapeutic candidate for ALI.

目的对乙酰氨基酚（APAP）致肝损伤（ALI）是急性药物性肝毒性的主要原因，缺乏有效的治疗方法。小檗碱（BBM）是一种从小檗属植物中提取的双苄基异喹啉类生物碱，具有多种药理特性，但其对ALI的疗效和对铁下垂的影响尚不清楚。本研究旨在探讨BBM对ALI和铁下沉的肝保护作用及其机制。方法采用APAP和RSL3分别建立ALI体内模型和体外铁下垂模型。模型接受BBM或铁他汀-1 （ferr -1）治疗。通过分子对接、细胞热移测定（CETSA）和药物亲和反应靶稳定性（DARTS）测定确定BBM的直接靶点。结果在体内，BBM预处理剂量依赖性地减轻了apap诱导的肝损伤、炎症和铁死亡标志物，包括脂质过氧化、GSH耗竭和PTGS2上调，同时上调GPX4。同时，BBM对ALI的肝保护作用与fe -1相匹配，证实了铁下沉是ALI的驱动因素。在体外，BBM抑制rsl3诱导的铁下垂，减少ROS、脂质过氧化和线粒体功能障碍。这些作用是由NRF2/GCLC/GPX4轴激活和FSP1上调介导的。至关重要的是，BBM直接结合了经分子对接、CETSA和dart证实的GCLC。结论bbm通过直接调节GCLC和NRF2/GCLC/GPX4轴与FSP1的协同激活，减轻铁下沉、氧化应激和炎症，从而对ALI具有保护作用。这些发现提供了药理学证据，支持BBM作为ALI的有希望的治疗候选药物的潜力。

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引用次数: 0

SIRT5 promotes vascular regeneration in peripheral muscle ischemia by regulating malonylation and glycolysis SIRT5通过调节丙二醛化和糖酵解促进外周肌肉缺血血管再生。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-01-12 DOI: 10.1016/j.bbadis.2026.168163

Kanghui Chen , Hang Chen , Peng Wang , Yueyi Pan , Heng Yang , Aijun Sun , Junbo Ge , Xueying Chen , Lei Xu , Xiaolei Sun

Peripheral artery disease (PAD) is a prominent contributor to the global prevalence and mortality of cardiovascular diseases, yet the therapeutic strategies remain limited and urgently to explore the new methods of promoting vascular regeneration. Metabolism involves numerous aspects of angiogenesis, including the energetics, proliferation, signal transduction and gene expression of endothelial cells (ECs). Sirtuin (SIRT) family play an important role in regulating numerous metabolic processes due to its protein modification activity. Herein, the effect of SIRTs on regulating muscle vascular regeneration of PAD patients was demonstrated. We reanalyzed the SIRTs family by using the reported data of single-nuclei atlas of human PAD limb muscle and found that SIRT5 expression in ECs was significantly downregulated. Then the dynamic changes of SIRTs in ischemic hindlimb of mice and hypoxia-induced HUVECs were observed, among which, SIRT5 showed the most sensitive and significant change in responding to ischemia. Deletion of SIRT5 inhibited the blood flow perfusion recovery and consequently aggravated ischemic hindlimb injury in mice. SIRT5 knock down in vitro inhibited the proliferation, migration and angiogenesis of HUVECs both under normoxia and hypoxia. The mechanism was involved in significantly decreased expression of glycolytic enzymes and increased malonylation of proteins, especially GAPDH, in HUVECs with SIRT5 knock down. In conclusion, SIRT5 controlled the vascular regeneration capacity of lower limb muscles by regulating glycolysis and malonylation modification. Regulating SIRT5 activity might be novel therapeutic target for PAD patients.

外周动脉疾病（PAD）是全球心血管疾病患病率和死亡率的重要因素，但治疗策略仍然有限，迫切需要探索促进血管再生的新方法。代谢涉及血管生成的许多方面，包括内皮细胞（ECs）的能量学、增殖、信号转导和基因表达。Sirtuin （SIRT）家族由于其蛋白修饰活性在调节多种代谢过程中发挥重要作用。本研究证明了SIRTs对PAD患者肌肉血管再生的调节作用。我们利用已报道的人类PAD肢体肌肉单核图谱数据重新分析了SIRT5家族，发现SIRT5在ECs中的表达显著下调。然后观察小鼠后肢缺血和缺氧诱导HUVECs中SIRTs的动态变化，其中SIRT5在响应缺血时表现出最敏感、最显著的变化。SIRT5的缺失抑制了血流灌注恢复，从而加重了小鼠后肢缺血性损伤。SIRT5基因敲低在常氧和缺氧条件下均能抑制HUVECs的增殖、迁移和血管生成。其机制涉及SIRT5敲低的HUVECs中糖酵解酶的表达显著降低，丙二醛化蛋白（尤其是GAPDH）的表达增加。综上所述，SIRT5通过调节糖酵解和丙二醛化修饰来控制下肢肌肉的血管再生能力。调节SIRT5活性可能是PAD患者新的治疗靶点。

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引用次数: 0

CCAT1 attenuates intermittent hypoxia associated endothelial cell pyroptosis through STAU1-mediated IRF1 mRNA degradation CCAT1通过stau1介导的IRF1 mRNA降解来减弱间歇性缺氧相关的内皮细胞焦亡。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-01-09 DOI: 10.1016/j.bbadis.2026.168155

Wen Liu , Xinxin Li , Qing Zhu , Kaixin Wang , Chen Zhao , Xun Qi , Cuiting Zhao , Zhishuang Dong , Chunyan Ma

Background

Previous studies have established that vascular endothelial dysfunction is prevalent among obstructive sleep apnea (OSA) patients. Nonetheless, the mechanism by which intermittent hypoxia (IH) contributes to endothelial dysfunction remains unclear.

Methods

Bioinformatics analysis was conducted to identify the key molecules implicated in IH. The correlation between serum lncRNA CCAT1 and GSDMD levels with endothelial function in OSA patients was evaluated. IH-induced HUVECs were used as an in vitro OSA model. We assessed the expression and interaction of CCAT1 and IRF1, and their effects on endothelial cell pyroptosis and dysfunction to investigate the mechanism of CCAT1/IRF1/GSDMD in IH-induced HUVECs.

Findings

Bioinformatic analysis revealed the crucial role of pyroptotic pathway after IH. OSA patients exhibited elevated serum GSDMD levels, however, CCAT1 expression was decreased. There was a correlation between OSA severity, endothelial function, GSDMD and CCAT1 levels. CCAT1 was downregulated and IRF1 was upregulated in IH-induced HUVECs. Low CCAT1 and high IRF1 expression were associated with exacerbated GSDMD-mediated pyroptosis and impaired endothelial function. CCAT1 overexpression facilitated IRF1 mRNA degradation of via SMD pathway, mitigating GSDMD-mediated pyroptosis and endothelial dysfunction.

Interpretation

CCAT1 attenuates IH-induced endothelial cell pyroptosis through STAU1-mediated IRF1 mRNA degradation, suggesting its potential therapeutic value in OSA-related endothelial dysfunction.

背景：先前的研究已经证实，血管内皮功能障碍在阻塞性睡眠呼吸暂停（OSA）患者中普遍存在。尽管如此，间歇性缺氧（IH）导致内皮功能障碍的机制仍不清楚。方法：采用生物信息学分析方法，鉴定与IH相关的关键分子。评估OSA患者血清lncRNA CCAT1和GSDMD水平与内皮功能的相关性。以ih诱导的huvec作为体外OSA模型。我们通过检测CCAT1和IRF1的表达、相互作用及其对内皮细胞焦亡和功能障碍的影响，探讨CCAT1/IRF1/GSDMD在ih诱导的huvec中的作用机制。结果：生物信息学分析揭示了IH后热噬通路的关键作用。OSA患者血清GSDMD水平升高，而CCAT1表达降低。OSA严重程度、内皮功能、GSDMD与CCAT1水平存在相关性。在ih诱导的HUVECs中，CCAT1下调，IRF1上调。低CCAT1和高IRF1表达与gsdmd介导的焦亡加剧和内皮功能受损相关。CCAT1过表达促进IRF1 mRNA通过SMD途径降解，减轻gsdmd介导的焦亡和内皮功能障碍。解释：CCAT1通过stau1介导的IRF1 mRNA降解，减弱ih诱导的内皮细胞焦亡，提示其在osa相关内皮功能障碍中的潜在治疗价值。

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引用次数: 0

Oncostatin M promotes versican expression in cardiac fibroblasts to facilitate extracellular matrix remodeling Oncostatin M促进心肌成纤维细胞中versican的表达，促进细胞外基质重塑。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-01-07 DOI: 10.1016/j.bbadis.2026.168153

Yunxiaoxiao Wu , Ziyu Zeng , Chenying Xiang , Xinou Jiang , Yu Nie , Yanlu Xu , Jie Feng

Myocardial injury is accompanied by an acute inflammatory response. Our previous work identified Oncostatin M as a key cytokine promoting heart regeneration through stimulating cardiomyocyte proliferation, while its effects on fibroblasts cannot be ignored. Cytokines are generally recognized to activate profibrotic gene programs in cardiac fibroblasts, a process traditionally regarded as detrimental to functional repair. Here, we showed that OSM enhanced cardiac fibroblasts to express versican, a pro-regenerative ECM component in the heart, through activating gp130/JAK/STAT3 signaling pathway. We determined that OSM steered fibroblasts toward a pro-regenerative state by promoting regenerative extracellular matrix remodeling.

心肌损伤伴有急性炎症反应。我们之前的工作发现，Oncostatin M是通过刺激心肌细胞增殖促进心脏再生的关键细胞因子，而其对成纤维细胞的作用也不容忽视。细胞因子通常被认为可以激活心脏成纤维细胞中的纤维化基因程序，这一过程传统上被认为不利于功能修复。在这里，我们发现OSM通过激活gp130/JAK/STAT3信号通路，增强心脏成纤维细胞表达versican，这是心脏中促进再生的ECM成分。我们确定OSM通过促进再生细胞外基质重塑，将成纤维细胞导向促再生状态。

引用次数: 0

HMGA2 inhibits Pink1-mediated mitophagy and promotes vascular calcification HMGA2抑制pink1介导的有丝分裂并促进血管钙化。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-01-06 DOI: 10.1016/j.bbadis.2025.168149

Shengjue Xiao , Zhengdong Chen , Yiqing Yang , Liqun Ren , Yuyu Yao , Naifeng Liu

Mitochondrial dysfunction is implicated in the development of vascular calcification, whereas protective mitophagy helps to hinder its progression. HMGA2 plays a pivotal role in regulating mitochondrial integrity and mitophagy. However, the precise impact of HMGA2-controlled mitophagy on vascular calcification remains unclear. In our study, we observed elevated HMGA2 expression during both Vitamin D3-induced aortic calcification in mice and β-GP-induced calcification of mouse aortic vascular smooth muscle (MOVAS). Additionally, we identified dynamic changes in mitophagy in MOVAS and demonstrated that HMGA2 knockdown promoted mitophagy, exerting a protective effect against vascular calcification in both in vivo and in vitro settings. Preconditioning with the autophagy inhibitor chloroquine diminished the protective effect of HMGA2 knockdown on aortic calcification in mice by inhibiting mitophagy. Furthermore, we observed an increase in cytoplasmic HMGA2 levels in MOVAS following vascular calcification, along with its binding to PTEN induced kinase 1 (Pink1) in the cytoplasm. This affects the distribution of Pink1, which cannot be transferred to the mitochondrial outer membrane to initiate mitophagy. Subsequently, silencing Pink1 exacerbated mitochondrial damage and apoptosis by inhibiting mitophagy, thereby promoting vascular calcification in β-GP-treated MOVAS. Our results indicated that cytosolic HMGA2 bound to Pink1, inhibiting mitophagy by impeding Pink1's relocation from the cytosol to the mitochondria, thereby reducing mitophagy activation, inducing apoptosis, ultimately accelerating the transition of MOVAS to an osteoblastic phenotype and calcium deposition. In conclusion, inducing mitophagy pharmacologically by targeting HMGA2 may represent a promising therapeutic approach for managing vascular calcification.

线粒体功能障碍涉及血管钙化的发展，而保护性线粒体自噬有助于阻碍其进展。HMGA2在调节线粒体完整性和线粒体自噬中起关键作用。然而，hmga2控制的线粒体自噬对血管钙化的确切影响尚不清楚。在我们的研究中，我们观察到在维生素d3诱导的小鼠主动脉钙化和β- gp诱导的小鼠主动脉血管平滑肌（MOVAS）钙化过程中HMGA2的表达升高。此外，我们确定了MOVAS中线粒体自噬的动态变化，并证明HMGA2敲低可促进线粒体自噬，在体内和体外均对血管钙化发挥保护作用。自噬抑制剂氯喹预处理可通过抑制线粒体自噬来减弱HMGA2基因敲低对小鼠主动脉钙化的保护作用。此外，我们观察到MOVAS血管钙化后细胞质HMGA2水平增加，并与细胞质中PTEN诱导的激酶1 （Pink1）结合。这影响了Pink1的分布，Pink1不能转移到线粒体外膜来启动线粒体自噬。随后，沉默Pink1通过抑制线粒体自噬加剧线粒体损伤和凋亡，从而促进β- gp处理的MOVAS血管钙化。我们的研究结果表明，胞质HMGA2与Pink1结合，通过阻碍Pink1从胞质溶胶到线粒体的重新定位来抑制线粒体自噬，从而减少线粒体自噬激活，诱导细胞凋亡，最终加速MOVAS向成骨细胞表型的转变和钙沉积。总之，通过靶向HMGA2诱导线粒体自噬可能是一种很有前途的治疗血管钙化的方法。

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引用次数: 0

ZFP36L1-mediated PRDM1 mRNA degradation inhibits inflammatory activation of Kupffer cells and ameliorates DCD liver ischemic-reperfusion injury zfp36l1介导的PRDM1 mRNA降解抑制Kupffer细胞的炎症激活，改善DCD肝缺血-再灌注损伤。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-01-04 DOI: 10.1016/j.bbadis.2025.168152

Peng Du , Meng Deng , Xin Ge , Wendong Wang , Mingfang Zhang , Panliang Wang

Background

Ischemia-reperfusion injury (IRI) represents a significant and unavoidable clinical challenge in donation after cardiac death (DCD) liver transplantation. Excessive sterile inflammation plays a critical role in the pathogenesis of liver IRI. This study, guided by bioinformatics insights, investigates the function of ZFP36 ring finger protein like 1 (ZFP36L1) in the activation of Kupffer cells (KCs) in IRI in DCD liver transplantation.

Methods

A rat DCD liver transplantation model and a lipopolysaccharide (LPS)-induced KCs inflammation model were established. Models were pretreated with ZFP36L1 and/or PR/SET domain 1 (PRDM1) gene overexpression vectors for functional and mechanistic examination.

Results

ZFP36L1 was downregulated in KCs in both the rats with the DCD liver transplantation model and human DCD liver transplantation specimens. Overexpression of ZFP36L1 in rat KCs ameliorated liver injury, reduced the secretion of inflammatory cytokines, alleviated oxidative stress, inhibited cell apoptosis, and suppressed the inflammatory activation of KCs. Parallel anti-inflammatory effects of ZFP36L1 were observed in LPS-treated mouse KCs in vitro. As an RNA-binding protein, ZFP36L1 promoted the degradation of PRDM1 mRNA by specifically binding to AU-rich elements within its 3′-untranslated region (3′-UTR). Overexpression of PRDM1 effectively counteracted the regulatory effects of ZFP36L1, thereby reversing the suppression of inflammatory activation in KCs and exacerbating liver IRI.

Conclusion

This study demonstrates that ZFP36L1 mitigates the inflammatory activation of KCs and alleviates DCD liver IRI by inducing PRDM1 mRNA degradation.

背景：缺血再灌注损伤（IRI）是心源性死亡（DCD）肝移植捐献中一个重要且不可避免的临床挑战。过度无菌性炎症在肝脏IRI的发病机制中起关键作用。本研究在生物信息学的指导下，探讨了ZFP36无名指蛋白样1 （ZFP36L1）在DCD肝移植IRI中库普弗细胞（KCs）激活中的功能。方法：建立大鼠DCD肝移植模型和脂多糖（LPS）诱导KCs炎症模型。用ZFP36L1和/或PR/SET domain 1 （PRDM1）基因过表达载体预处理模型，进行功能和机制检测。结果：在DCD肝移植模型大鼠和人DCD肝移植标本中，KCs中ZFP36L1表达下调。ZFP36L1在大鼠KCs中的过表达可改善肝损伤，减少炎症因子的分泌，减轻氧化应激，抑制细胞凋亡，抑制KCs的炎症活化。ZFP36L1在体外lps处理小鼠KCs中观察到平行抗炎作用。作为一种rna结合蛋白，ZFP36L1通过特异性结合PRDM1 mRNA的3'-非翻译区（3'-UTR）中的富au元素，促进了PRDM1 mRNA的降解。PRDM1的过表达有效地抵消了ZFP36L1的调节作用，从而逆转了KCs中对炎症激活的抑制，加剧了肝脏IRI。结论：本研究表明ZFP36L1通过诱导PRDM1 mRNA降解，减轻KCs的炎症激活，减轻DCD肝脏IRI。

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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 : 2026-01-03 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。

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引用次数: 0

Osteopontin aggravates myocardial fibrosis by promoting phenotypic transition of cardiac fibroblasts via Hippo-YAP pathway 骨桥蛋白通过Hippo-YAP通路促进心肌成纤维细胞表型转变，从而加重心肌纤维化

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-12-31 DOI: 10.1016/j.bbadis.2025.168150

Chen Liu , Wentao Liu , Yuan Wang , Chengzhi Jiang , Sheng Chen , Qianqian Huang , Xiaowei Xiong , Li Wang , Guohua Zeng , Qiren Huang

Osteopontin (OPN), a glycosylated protein ubiquitously in cellular matrix, exhibits a low expression in normal myocardial tissue but a high expression in fibrotic myocardial tissue. However, the action and mechanisms of OPN on the pathogenesis of myocardial fibrosis (MF) remain unclear. The purpose of the study is to investigate the action and mechanisms of OPN on the occurrence and development of MF, emphasizing abnormal activation of cardiac fibroblasts (CFs) and extracellular matrix (ECM) deposition. Both NIH-3T3 cells and C57BL/6 J mice were infected with OPN over-expression adenoviruses (Ad-Spp1). Cardiac function and fibrosis degree were evaluated in the presence and absence of angiotensin (AngII) (in vitro) or isoprenaline (ISO) (in vivo). Our data demonstrate that OPN over-expression results in myocardial injury and ECM accumulation under the physiological condition. Moreover, it exacerbates such effects under the pathological condition induced by AngII or ISO; in contrast, OPN knockdown attenuates the fibrotic response in vitro induced by AngII. Interestingly, OPN significantly promotes phenotypic conversion of CFs, characterized as elevated levels of α-SMA and Vimentin, with remarkable proliferation and migration in myocardial tissue. Mechanistically, our data indicate that such effects of OPN are mediated by nuclear translocation of YAP/TAZ via Hippo-YAP pathway, dependent of the membrane receptor integrin α_Vβ₃. Overall, OPN plays significant roles in the phenotypic transition of CFs via integrin-Hippo-YAP axis, ultimately leading to MF. The findings highlight the novel mechanisms of OPN triggering MF and would offer an early marker and potential targets for the prevention and treatment of MF.

骨桥蛋白（Osteopontin， OPN）是一种普遍存在于细胞基质中的糖基化蛋白，在正常心肌组织中低表达，而在纤维化心肌组织中高表达。然而，OPN在心肌纤维化（MF）发病机制中的作用和机制尚不清楚。本研究旨在探讨OPN在MF发生发展中的作用和机制，重点研究OPN对心肌成纤维细胞（CFs）和细胞外基质（ECM）沉积的异常激活。用OPN过表达腺病毒（Ad-Spp1）感染NIH-3T3细胞和C57BL/6 J小鼠。在存在和不存在血管紧张素（AngII）（体外）或异丙肾上腺素（ISO）（体内）的情况下评估心功能和纤维化程度。我们的数据表明，在生理条件下，OPN过表达导致心肌损伤和ECM积累。且在AngII或ISO诱导的病理状态下，可加重上述作用；相反，OPN敲低可减弱AngII诱导的体外纤维化反应。有趣的是，OPN显著促进CFs的表型转化，表现为α-SMA和Vimentin水平升高，并在心肌组织中显著增殖和迁移。从机制上讲，我们的数据表明，OPN的这种作用是由YAP/TAZ通过希波-YAP途径的核易位介导的，依赖于膜受体整合素αVβ3。总的来说，OPN通过整合素-希波- yap轴在cf的表型转变中发挥重要作用，最终导致MF。这些发现强调了OPN触发MF的新机制，并将为MF的预防和治疗提供早期标记和潜在靶点。

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引用次数: 0

Type 5 diabetes: A comprehensive review to understand the basis of diabetes of poverty 5型糖尿病：了解贫困糖尿病基础的综合综述。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-12-26 DOI: 10.1016/j.bbadis.2025.168147

Jalal Taneera , Rania Saeed , Eglal Mahgoub , Zamzam Farhan , Abdalla Alobeidli , Mariyam Shoukat , Nael Shaat

Malnutrition-Related Diabetes Mellitus (MRDM) is a subtype of diabetes associated with chronic malnutrition, primarily observed in low- and middle-income countries (LMICs) and impoverished populations. The disease is characterized by onset in young, lean patients with a history of chronic undernutrition, insulin deficiency, persistent insulin sensitivity, and resistance to ketosis. MRDM was recognized by the World Health Organization (WHO) in 1985, then removed from classification in 1999 due to a lack of evidence. Emerging evidence has revealed a unique pathophysiology, prompting the International Diabetes Federation (IDF) to officially recognize MRDM as “Type 5 Diabetes” (T5D). This review synthesizes the evidence that validates T5D as a distinct endotype, which is mechanistically different from other diabetes types. It delineates the epidemiological patterns of T5D and focuses on the pathophysiological “blueprint” of the malnourished pancreas. It also integrates evidence showing how early-life nutritional deprivation, including protein and micronutrient deficiencies, programmatically reduces β-cell mass and function through mechanisms such as mitochondrial dysfunction, endoplasmic reticulum stress, oxidative damage, and persistent epigenetic modifications. Current management strategies and the distinct profile of long-term complications are highlighted. Finally, the review outlines pressing future directions, arguing that the formal recognition of T5D provides an opportunity for coordinated research and policy initiatives that address the root causes and consequences of this diabetes of poverty.

营养不良相关性糖尿病（MRDM）是一种与慢性营养不良相关的糖尿病亚型，主要见于低收入和中等收入国家（LMICs）和贫困人群。该病的特点是发病于年轻、瘦弱、有慢性营养不良、胰岛素缺乏、持续胰岛素敏感和酮症抵抗史的患者。MRDM于1985年被世界卫生组织（WHO）承认，但由于缺乏证据，于1999年从分类中删除。新出现的证据揭示了一种独特的病理生理学，促使国际糖尿病联合会（IDF）正式承认MRDM为“5型糖尿病”（T5D）。这篇综述综合了证实T5D是一种独特的内型的证据，它在机制上不同于其他类型的糖尿病。它描述了T5D的流行病学模式，并着重于营养不良胰腺的病理生理“蓝图”。它还整合了早期营养剥夺（包括蛋白质和微量营养素缺乏）如何通过线粒体功能障碍、内质网应激、氧化损伤和持续表观遗传修饰等机制程序性地减少β细胞质量和功能的证据。当前的管理策略和长期并发症的独特轮廓突出。最后，该综述概述了紧迫的未来方向，认为正式承认T5D为协调研究和政策举措提供了机会，以解决这种贫困糖尿病的根本原因和后果。

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