Biochimica et biophysica acta. Molecular basis of disease最新文献_第2页

Multimodal psychological intervention improves psychological well-being and inflammatory profiles in patients with diabetic nephropathy 多模式心理干预改善糖尿病肾病患者的心理健康和炎症概况。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-04-01 Epub Date: 2026-01-22 DOI: 10.1016/j.bbadis.2026.168171

Hangyan Tang , Shengquan Liu

Patients with diabetic nephropathy (DN) often experience negative emotions and a decline in quality of life, conditions in which the neuro–endocrine–immune axis plays a crucial role. In this study, we explored the effects of an eight-week multimodal psychological intervention, incorporating cognitive behavioral therapy, mindfulness meditation, and relaxation training, on DN patients. Ninety participants were randomly assigned to an intervention group, a sham intervention group, or a control group. The sham intervention group received nonspecific contact of equivalent duration, while the control group received routine care only. Psychological outcomes were evaluated using HADS and SF-36 scales, and serum levels of cortisol, CRH, ACTH, IL-6, IL-1β, and TNF-α were measured by enzyme-linked immunosorbent assay. Bioinformatic analyses, including Gene Ontology/Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis and protein-protein interaction network mapping, were employed to identify key molecular mechanisms. Results demonstrated that the intervention group exhibited significant improvements in emotional well-being and quality of life, accompanied by reductions in neuroendocrine hormones and inflammatory cytokines. Bioinformatic data further revealed the central role of IL-6 within the inflammatory regulatory network in DN. These findings suggest that multimodal psychological intervention can effectively improve psychological outcomes and inflammatory profiles in DN patients by targeting the neuro–endocrine–immune axis, with IL-6 acting as a pivotal mediator. This work provides novel evidence supporting the integration of psychological interventions into the management of DN and highlights IL-6 as a potential therapeutic target.

糖尿病肾病（DN）患者经常经历负面情绪和生活质量下降，其中神经内分泌免疫轴起着至关重要的作用。在这项研究中，我们探讨了一项为期八周的多模式心理干预，包括认知行为疗法、正念冥想和放松训练，对DN患者的影响。90名参与者被随机分配到干预组、假干预组和对照组。假干预组给予同等时间的非特异性接触，对照组只给予常规护理。采用HADS和SF-36量表评估心理结果，采用酶联免疫吸附法测定血清皮质醇、CRH、ACTH、IL-6、IL-1β和TNF-α水平。生物信息学分析，包括基因本体/京都基因与基因组百科全书功能富集分析和蛋白质-蛋白质相互作用网络定位，以确定关键的分子机制。结果表明，干预组在情绪健康和生活质量方面表现出显著改善，同时神经内分泌激素和炎症细胞因子也有所减少。生物信息学数据进一步揭示了IL-6在DN炎症调节网络中的核心作用。这些发现表明，多模式心理干预可以有效改善DN患者的心理结局和炎症特征，以神经-内分泌-免疫轴为靶点，IL-6作为关键介质。这项工作提供了新的证据，支持将心理干预整合到DN的管理中，并强调IL-6是一个潜在的治疗靶点。

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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 : 2026-04-01 Epub 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

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 : 2026-04-01 Epub 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

ATP6V0d2 alleviates acute liver injury via promoting hepatocyte autophagy ATP6V0d2通过促进肝细胞自噬减轻急性肝损伤

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-04-01 Epub Date: 2026-01-27 DOI: 10.1016/j.bbadis.2026.168170

Mengxia Zhang , Zhemin Shi , Yi Yang , Yue Huang , Kefei Guo , Yuying Sun , Jianan Gao , Jiajun Wang , Yanjun Li , Wei Hong , Tao Han , Kun Zhang

Liver injury is the pathological basis of various liver diseases, and severe acute liver injury can progress to acute liver failure with a high mortality. Although continuous progress has been made over the past few decades, the molecular mechanism underlying the progress of acute liver injury is still unclear. ATP6V0d2, a subunit of the vacuolar ATPase (V-ATPase) complex, is implicated in organelle acidification and intracellular degradation processes. In this study, three liver injury datasets were analyzed to screen the differentially expressed genes (DEGs) and identify Atp6v0d2, which was initially downregulated, and then upregulated to slightly higher than normal levels in both hepatocytes (HCs) and liver tissues in carbon tetrachloride (CCl₄)-induced acute liver injury, with the most significant downregulation observed 24 h after CCl₄ injection. Moreover, hepatocyte-specific overexpression of ATP6V0d2 alleviated CCl₄, concanavalin A (ConA) and acetaminophen (APAP)-induced acute liver injury by promoting hepatocyte autophagy, while silencing ATP6V0d2 inhibited hepatocyte autophagy and aggravated liver injury in vivo. In addition, consistent with the results of gene enrichment analysis, in vitro data demonstrated that ATP6V0d2 promoted hepatocyte autophagy mainly via facilitating the formation of autophagosomes. In conclusion, our results demonstrated that ATP6V0d2 played a protective role in acute liver injury by facilitating hepatocyte autophagy, which may provide a theoretical basis for the treatment and prognosis of acute liver injury.

肝损伤是各种肝脏疾病的病理基础，严重的急性肝损伤可发展为急性肝衰竭，死亡率高。虽然在过去的几十年里取得了不断的进展，但急性肝损伤进展的分子机制仍不清楚。ATP6V0d2是液泡atp酶（v - atp酶）复合物的一个亚基，参与细胞器酸化和细胞内降解过程。本研究通过对3组肝损伤数据进行分析，筛选差异表达基因（DEGs），鉴定出Atp6v0d2，在四氯化碳（CCl4）诱导的急性肝损伤中，Atp6v0d2在肝细胞（hc）和肝组织中均呈先下调后上调至略高于正常水平，且在注射CCl4 24 h后下调最为显著。此外，肝细胞特异性过表达ATP6V0d2通过促进肝细胞自噬，减轻CCl4、豆豆蛋白A （ConA）和对乙酰氨基酚（APAP）诱导的急性肝损伤，而在体内沉默ATP6V0d2抑制肝细胞自噬，加重肝损伤。此外，与基因富集分析结果一致，体外实验数据表明，ATP6V0d2主要通过促进自噬体的形成来促进肝细胞自噬。综上所述，我们的研究结果表明，ATP6V0d2通过促进肝细胞自噬在急性肝损伤中发挥保护作用，这可能为急性肝损伤的治疗和预后提供理论依据。

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引用次数: 0

Urinary microbiome and metabolomic profiling reveal propionic acid as an enhancer of BCG immunotherapy in bladder cancer 尿微生物组学和代谢组学分析显示丙酸作为卡介苗免疫治疗膀胱癌的增强剂

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-04-01 Epub Date: 2026-02-12 DOI: 10.1016/j.bbadis.2026.168192

Jing Liu , Yizhao Luo , Lu Chen , Wei Xiong , Yu An , Zhiwei Ma , Dan Zhang

Bladder cancer (BC) is the tenth most common malignancy worldwide, with non-muscle invasive bladder cancer (NMIBC) accounting for approximately 75% of cases, and Bacillus Calmette-Guérin (BCG) remaining the standard intravesical therapy. In light of global BCG shortages, this study aimed to identify potential strategies to enhance BCG efficacy by integrating urinary microbiome profiling with targeted short-chain fatty acid (SCFA) metabolomics. Urine samples collected from BC patients before and after BCG instillation were analyzed to determine BCG-associated microbial and metabolic changes, and the functional role of the key metabolite propionic acid (PA) was evaluated through in vitro experiments using MB49 and MBT2 murine BC cell lines and in vivo mouse BC models treated with BCG plus PA. Flow cytometry was used to quantify tumor-infiltrating CD4⁺ and CD8⁺ T cells to elucidate immune-related mechanisms. BCG treatment significantly reshaped urinary microbial composition, dominant flora, and fatty acid metabolic patterns, and notably increased urinary PA levels. Functional assays demonstrated that PA markedly augmented the antitumor activity of BCG, potentially by promoting CD4⁺/CD8⁺ T-cell infiltration into tumor tissues. Collectively, these findings indicate that BCG modulates the urinary microbiome and SCFA metabolic landscape in BC patients, and that PA enhances BCG efficacy by boosting T-cell-mediated immune responses, highlighting PA-BCG combination therapy as a promising therapeutic strategy for BC.

膀胱癌（BC）是世界上第十大最常见的恶性肿瘤，非肌肉浸润性膀胱癌（NMIBC）约占75%的病例，卡介苗（BCG）仍然是标准的膀胱内治疗方法。鉴于全球卡介苗短缺，本研究旨在通过整合尿微生物组分析和靶向短链脂肪酸（SCFA）代谢组学来确定提高卡介苗疗效的潜在策略。对BCG灌注前后的BC患者尿液样本进行分析，以确定BCG相关的微生物和代谢变化，并通过MB49和MBT2小鼠BC细胞系以及BCG + PA处理的小鼠BC模型进行体外实验，评估关键代谢物丙酸（PA）的功能作用。流式细胞术用于定量肿瘤浸润的CD4+和CD8+ T细胞，以阐明免疫相关机制。BCG治疗显著重塑了尿微生物组成、优势菌群和脂肪酸代谢模式，并显著提高了尿PA水平。功能实验表明，PA能显著增强BCG的抗肿瘤活性，可能是通过促进CD4+/CD8+ t细胞向肿瘤组织的浸润。总之，这些研究结果表明，卡介苗调节BC患者的尿微生物组和SCFA代谢景观，PA通过增强t细胞介导的免疫反应来增强卡介苗的疗效，强调PA-BCG联合治疗是BC的一种有前景的治疗策略。

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引用次数: 0

Vesicular nucleotide transporter (VNUT)-dependent ATP secretion by hepatic stellate cells promotes liver fibrosis 肝星状细胞分泌囊泡核苷酸转运蛋白（VNUT）依赖性ATP促进肝纤维化。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-04-01 Epub Date: 2026-02-04 DOI: 10.1016/j.bbadis.2026.168180

Masaharu Kabashima , Nao Hasuzawa , Lixiang Wang , Junjiro Rikitake , Seiji Nomura , Tomohiro Niimoto , Rie Tokubuchi , Sawako Moriyama , Mizuki Gobaru , Yukihiro Inoguchi , Ayako Nagayama , Kenji Ashida , Keisuke Ohta , Yoshinori Moriyama , Masatoshi Nomura

Although liver fibrosis presents a substantial global health challenge, therapeutic options that directly target liver fibrosis remain limited. Hepatic stellate cells (HSCs) are key contributors to fibrosis through extracellular matrix production. This study uncovers a previously unrecognized function of HSCs: ATP secretion. We found that HSCs express the vesicular nucleotide transporter (VNUT) on secretory vesicles and actively release ATP. In mouse HSCs, VNUT is localized to the cytosol and around lipid droplets. In a thioacetamide-induced liver fibrosis model, VNUT inhibition with clodronate suppressed HSC proliferation and fibrosis progression, while restoring AMPK phosphorylation. In human hepatic stellate LX-2 cells, VNUT colocalized with v-SNARE proteins VAMP3 and VAMP7 and the vesicular proton pump V-ATPase. ATP secretion from LX-2 cells was observed upon stimulation with the Ca²⁺ ionophore ionomycin and was inhibited by Ca²⁺ chelation or low temperature, supporting an exocytotic mechanism. Clodronate and VNUT-targeting siRNA significantly reduced ATP release. Thapsigargin, an inducer of endoplasmic reticulum Ca²⁺ release, upregulated VNUT expression, suggesting a transcriptional regulation of VNUT-dependent ATP release by Ca²⁺ signaling. TGF-β1 stimulation also upregulated VNUT expression, suggesting its involvement in TGF-β1–induced fibrogenesis pathway. Additionally, serotonin was identified as an ATP secretion stimulator in LX-2 cells, and this effect was blocked by clodronate. Platelets—a major peripheral serotonin source—were increased in TAA-treated liver and found adjacent to serotonin receptor 5-HT2B-positive HSCs. Clodronate treatment reduced CD41-positive platelets in liver tissue. These findings highlight VNUT-mediated ATP secretion as a key regulator of HSC function and a potential therapeutic target for liver fibrosis.

尽管肝纤维化是一个重大的全球健康挑战，但直接针对肝纤维化的治疗选择仍然有限。肝星状细胞（hsc）是通过细胞外基质产生纤维化的关键贡献者。这项研究揭示了造血干细胞以前未被认识到的功能：ATP分泌。我们发现造血干细胞在分泌囊泡上表达囊泡核苷酸转运蛋白（VNUT），并积极释放ATP。在小鼠造血干细胞中，VNUT定位于细胞质溶胶和脂滴周围。在硫代乙酰胺诱导的肝纤维化模型中，氯膦酸钠抑制VNUT抑制HSC增殖和纤维化进展，同时恢复AMPK磷酸化。在人肝星状LX-2细胞中，VNUT与v-SNARE蛋白VAMP3和VAMP7以及泡状质子泵v- atp酶共定位。LX-2细胞的ATP分泌在Ca2+离子离子离子离子素刺激下被观察到，并被Ca2+螯合或低温抑制，支持胞外机制。氯膦酸钠和vnut靶向siRNA显著减少ATP释放。Thapsigargin是一种内质网Ca2+释放的诱导剂，上调VNUT的表达，提示通过Ca2+信号对VNUT依赖的ATP释放进行转录调节。TGF-β1刺激也上调了VNUT的表达，提示其参与TGF-β1诱导的纤维形成途径。此外，血清素在LX-2细胞中被鉴定为ATP分泌刺激物，这种作用被氯膦酸盐阻断。血小板——一种主要的外周血清素来源——在taa处理的肝脏中增加，并在血清素受体5- ht2b阳性的hsc附近发现。氯膦酸钠治疗可减少肝组织中cd41阳性血小板。这些发现强调了vnut介导的ATP分泌是HSC功能的关键调节因子，也是肝纤维化的潜在治疗靶点。

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引用次数: 0

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 : 2026-04-01 Epub 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 : 2026-04-01 Epub 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

Oncogenic epigenetic factor EP300 is a potential therapeutic target for bladder carcinoma 致癌表观遗传因子EP300是膀胱癌的潜在治疗靶点。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-04-01 Epub Date: 2026-02-06 DOI: 10.1016/j.bbadis.2026.168182

Qing Zhang , Yingzhou Hong , Chongjie He , Rui Guo , Xianbin Duan , Chenxi Mo , Tao Huang , Junwei He , Shi Fu , Shuangsheng Deng , Cheng Peng , Haifeng Wang , Chunming Guo

Bladder cancer remains a major cause of global mortality with limited therapies. Here, we reported that epigenetic regulator EP300 acts as oncogenic role in bladder cancer. Public data show EP300 mutations correlated with better prognosis, while high EP300 expression predicted poor outcomes. Our clinical cohort demonstrated that EP300 expressed higher in tumors rather than adjacent tissues. Functionally, impairing of EP300 decreased both cell viability and organoids growth in bladder cancer cells. The selective EP300 inhibitor A485 similarly reduced bladder cancer cell growth in vitro and in vivo. Long-term treatment of A485 alleviated tumor invasion in a BBN-induced spontaneous bladder cancer mouse model. Bioinformatic analysis evaluated both basal/squamous-like markers and papillary-like markers were decreased in A485 treatment. Furthermore, downregulated genes by A485 are mainly related to cell cycle regulation. Mechanistically, A485 decreased the levels of EP300 and H3K27ac upon MYC enhancer, consequently inhibited MYC expression. Additionally, the MYC inhibitor demonstrated similar effects as A485 to decrease cell viability and organoid growth. Critically, in patient-derived organoids (PDOs), A485 selectively attenuated tumor organoid growth and reduced MKI67⁺ and CD44⁺ cell populations, sparing adjacent normal tissue organoids. Collectively, EP300 promotes bladder cancer progression by sustaining proliferation through MYC regulation, and its inhibitor A485 represents a promising targeted therapeutic candidate.

膀胱癌仍然是全球死亡的主要原因，治疗方法有限。在这里，我们报道了表观遗传调控因子EP300在膀胱癌中起致癌作用。公开数据显示，EP300突变与预后较好相关，而高表达EP300则预示预后较差。我们的临床队列表明，EP300在肿瘤中的表达高于邻近组织。功能上，EP300的损伤降低了膀胱癌细胞的细胞活力和类器官的生长。选择性EP300抑制剂A485在体外和体内同样降低了膀胱癌细胞的生长。在bbn诱导的自发性膀胱癌小鼠模型中，长期治疗A485可减轻肿瘤侵袭。生物信息学分析评估了A485治疗后基底/鳞状样标记物和乳头状标记物的减少。此外，A485下调的基因主要与细胞周期调控有关。机制上，A485降低MYC增强子上EP300和H3K27ac的水平，从而抑制MYC的表达。此外，MYC抑制剂显示出与A485相似的降低细胞活力和类器官生长的作用。关键是，在患者源性类器官（PDOs）中，A485选择性地减弱肿瘤类器官生长，减少MKI67+和CD44+细胞群，保留邻近的正常组织类器官。总的来说，EP300通过MYC调控来维持膀胱癌的增殖，从而促进膀胱癌的进展，其抑制剂A485代表了一种有前景的靶向治疗候选药物。

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引用次数: 0

Goosecoid promotes hepatic stellate cell epithelial-mesenchymal transition via transcriptional activation of serum- and glucocorticoid-induced protein kinase 1 in liver fibrosis 鹅样蛋白通过激活血清和糖皮质激素诱导的蛋白激酶1在肝纤维化中促进肝星状细胞上皮-间质转化

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-04-01 Epub Date: 2026-01-24 DOI: 10.1016/j.bbadis.2026.168169

Yongjuan Wang , Xiaoli Xie , Jiajun Tian , Xiaoyu Jiang , Huiqing Jiang

Background

Goosecoid (GSC) is a transcription factor implicated in epithelial-mesenchymal transition (EMT) during embryogenesis and cancer, but its function in organ fibrosis remains poorly understood. This study investigates the role and mechanistic targets of GSC in hepatic stellate cell (HSC) EMT during liver fibrogenesis.

Methods

We analyzed GSC and EMT marker expression in primary HSCs isolated from murine liver fibrosis models induced by carbon tetrachloride (CCl₄) or bile duct ligation (BDL), and in TGF-β-stimulated LX-2 cells. The functional role of GSC was validated via in vitro and in vivo GSC knockdown, while chromatin immunoprecipitation sequencing (ChIP-seq) combined with experimental verification was used to identify its target genes and regulatory mechanisms.

Results

GSC expression was significantly upregulated in activated HSCs from fibrotic mouse models and TGF-β-induced LX-2 cells, which was closely associated with enhanced EMT (downregulation of epithelial markers, upregulation of mesenchymal markers). Functional assays confirmed that GSC knockdown suppressed HSC EMT in vitro and ameliorated liver fibrosis in vivo via AAV-mediated HSC-specific GSC silencing. Mechanistically, we found that GSC undergoes increased nuclear translocation during HSC activation. ChIP-seq analysis identified Serum- and glucocorticoid-induced protein kinase 1 (SGK1) as a direct transcriptional target of GSC. Further validation revealed that SGK1, in turn, promotes HSC EMT by activating the NF-κB signaling pathway.

Conclusion

This study uncovers a novel mechanism by which GSC promotes HSC EMT and liver fibrosis through direct transcriptional activation of SGK1, followed by downstream NF-κB pathway activation.

Summary

GSC is markedly upregulated in activated HSCs from murine fibrosis models (CCl₄/BDL) and during TGF-β-induced EMT. HSC-specific GSC knockdown attenuated liver fibrosis progression. Mechanistically, GSC translocates to the nucleus where it binds the SGK1 promoter to enhance transcription, subsequently driving HSC EMT and promoting fibrogenesis through the NF-κB signaling pathway.

goosecoid （GSC）是一种涉及胚胎发生和癌症期间上皮-间充质转化（EMT）的转录因子，但其在器官纤维化中的功能尚不清楚。本研究探讨了GSC在肝纤维化过程中肝星状细胞（HSC） EMT中的作用及其机制靶点。方法分析四氯化碳（CCl₄）或胆管结扎（BDL）诱导的小鼠肝纤维化模型中分离的原代hsc和TGF-β刺激的LX-2细胞中GSC和EMT标志物的表达。通过体外和体内GSC敲低验证了GSC的功能作用，并利用染色质免疫沉淀测序（ChIP-seq）结合实验验证鉴定了其靶基因和调控机制。结果在纤维化小鼠模型和TGF-β诱导的LX-2细胞活化的hsc中，gsc表达显著上调，这与EMT（上皮标记下调，间充质标记上调）增强密切相关。功能分析证实，GSC敲除在体外抑制HSC EMT，并通过aav介导的HSC特异性GSC沉默在体内改善肝纤维化。在机制上，我们发现在HSC激活过程中，GSC经历了核易位的增加。ChIP-seq分析发现血清和糖皮质激素诱导的蛋白激酶1 （SGK1）是GSC的直接转录靶点。进一步的验证表明，SGK1反过来通过激活NF-κB信号通路促进HSC EMT。结论本研究揭示了GSC通过直接转录激活SGK1，进而激活下游NF-κB通路促进HSC EMT和肝纤维化的新机制。小鼠纤维化模型（CCl₄/BDL）和TGF-β诱导的EMT中活化的hsc中gsc明显上调。hsc特异性GSC敲除可减轻肝纤维化进展。在机制上，GSC易位到细胞核，在那里它结合SGK1启动子来增强转录，随后通过NF-κB信号通路驱动HSC EMT并促进纤维形成。

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引用次数: 0