Biochimica et biophysica acta. Molecular basis of disease最新文献_第6页

TFEB activator protects against ethanol toxicity-induced cardiac injury by restoring mitophagy and autophagic flux TFEB激活剂通过恢复线粒体自噬和自噬通量来保护乙醇毒性诱导的心脏损伤。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-11 DOI: 10.1016/j.bbadis.2025.167668

Mengxue Zhao , Ruocheng Zhang , Xiuzhu Chen , Peixuan Li , Hui Yang , Bin Gao , Baoxin Li , Weina Zhou , Yuanyuan Wang , Yunliang Zhang , Li Zhong , Rui Guo

Excessive alcohol consumption is a major cause of alcoholic cardiomyopathy (ACM) and myocardial injury. This study aims to investigate the role of transcription factor EB (TFEB) in ethanol-induced cardiac anomalies using a murine model, AC16 human cardiomyocytes, and human plasma. Wild-type mice treated with a TFEB activator (Compound 1) or vehicle (25 mg/kg/d) were challenged with or without ethanol (3 g/kg/d, i.p.) for three consecutive days. Cardiac geometry and function were evaluated by echocardiography. The expressions of TFEB, molecules related to mitochondria, markers of apoptosis, mitophagy and lysosomes were examined in heart tissues and AC16 cardiomyocytes. Mitochondrial function, lysosome activity, and their localizations were measured in AC16 cardiomyocytes. Levels of TFEB and autophagic markers were also detected in human serum from healthy individuals and patients with ACM. Ethanol administration in mice induced severe cardiac dysfunction accompanied by upregulated P62 and LC3B, downregulated TFEB, lysosomal markers and mitophagy-associated receptors in heart tissues. Ethanol toxicity also led to reduced mitochondrial and lysosomal activity. Interestingly, TFEB activation mitigated the detrimental effects caused by ethanol. Inhibition of autophagy abolished the anti-apoptotic effect of TFEB in AC16 cells. In conclusion, TFEB is beneficial in ethanol-induced cardiac anomalies by reducing apoptosis, recovering lysosomal activity, and restoring proper mitophagy and autophagic flux.

过量饮酒是酒精性心肌病（ACM）和心肌损伤的主要原因。本研究旨在通过小鼠模型、AC16人心肌细胞和人血浆研究转录因子EB （TFEB）在乙醇诱导的心脏异常中的作用。用TFEB激活剂（化合物1）或对照剂（25 mg/kg/d）处理野生型小鼠，连续3天用或不用乙醇（3 g/kg/d, i.p）刺激。超声心动图评价心脏几何形状和功能。检测心肌组织和AC16心肌细胞中TFEB、线粒体相关分子、凋亡标志物、线粒体自噬和溶酶体的表达。测定AC16心肌细胞的线粒体功能、溶酶体活性及其定位。在健康个体和ACM患者的血清中也检测了TFEB和自噬标志物的水平。乙醇给药小鼠可诱导严重心功能障碍，并伴有P62和LC3B上调，TFEB、溶酶体标志物和心脏组织中有丝分裂相关受体下调。乙醇毒性也导致线粒体和溶酶体活性降低。有趣的是，TFEB激活减轻了乙醇引起的有害影响。自噬抑制可消除TFEB在AC16细胞中的抗凋亡作用。综上所述，TFEB通过减少细胞凋亡，恢复溶酶体活性，并通过打开线粒体自噬通量来恢复适当的线粒体自噬，从而有利于乙醇诱导的心脏异常。

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引用次数: 0

GIMAP1 interacts with TMX1 to improve lung adenocarcinoma prognosis by influencing tumor immune microenvironment GIMAP1与TMX1相互作用，通过影响肿瘤免疫微环境改善肺腺癌预后。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-11 DOI: 10.1016/j.bbadis.2025.167661

Pinglang Ruan , Jiani Li , Khalid A. Abdelhalim , Zhongxiang Tang , Weitong Tan , Jiaoyang Yao , Yurong Tan , Lili Wang

Recent studies have indicated that the GIMAP family is downregulated in lung cancer and correlates with poor prognosis, although the underlying mechanisms remain unclear. This study aimed to elucidate the mechanism behind GIMAP1 downregulation in lung cancer. Bioinformatics tools were employed to assess the correlation between the GIMAP family and various cancers. Specifically, GIMAP1 was selected for further investigation, and its role in lung adenocarcinoma was confirmed through RNA sequencing analysis, Gene Set Enrichment Analysis (GSEA) of differentially expressed genes, correlation analysis with immune cell infiltration, and assay of the GIMAP1-TMX1 interaction. Based on bioinformatics analysis and real-world cohort studies, it was found that GIMAP1 was underexpressed in lung cancer tissues but exhibited elevated expression following immunotherapy. Overexpression of GIMAP1 was shown to influence several immune signaling pathways. In patients with high GIMAP1 expression, there was a significant increase in the infiltration of CD8⁺ T cells, activated memory CD4⁺ T cells, monocytes, and M1 macrophages; conversely, infiltration by M0 macrophages, resting dendritic cells (DCs), and plasma cells was significantly reduced. In vitro experiments showed that high levels of GIMAP1 increased the percentage of Treg, NK, and NKT cells. Additionally, GIMAP1 directly interacted with TMX1 and modulated the expression of downstream immune-related genes including CMTM5, IL17F, TRAV34, and XCR1. Therefore, GIMAP1 may serve as a promising therapeutic target in lung cancer, influencing both disease initiation and progression.

最近的研究表明，GIMAP家族在肺癌中下调并与不良预后相关，尽管其潜在机制尚不清楚。本研究旨在阐明GIMAP1在肺癌中下调的机制。使用生物信息学工具评估GIMAP家族与各种癌症之间的相关性。具体而言，我们选择GIMAP1作为进一步研究对象，通过RNA测序分析、差异表达基因的基因集富集分析（GSEA）、与免疫细胞浸润的相关性分析、GIMAP1- tmx1相互作用分析，证实了GIMAP1在肺腺癌中的作用。基于生物信息学分析和现实世界队列研究，我们发现GIMAP1在肺癌组织中表达不足，但在免疫治疗后表达升高。GIMAP1过表达可影响多种免疫信号通路。GIMAP1高表达患者CD8+ T细胞、活化记忆CD4+ T细胞、单核细胞、M1巨噬细胞的浸润明显增加；相反，M0巨噬细胞、静息树突状细胞（dc）和浆细胞的浸润明显减少。体外实验表明，高水平的GIMAP1增加了Treg、NK和NKT细胞的百分比。此外，GIMAP1直接与TMX1相互作用，调节下游免疫相关基因CMTM5、IL17F、TRAV34和XCR1的表达。因此，GIMAP1可能作为一个有希望的肺癌治疗靶点，影响疾病的发生和进展。

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引用次数: 0

Multi-omics analyses of early-onset familial Alzheimer's disease and Sanfilippo syndrome zebrafish models reveal commonalities in disease mechanisms 早发性家族性阿尔茨海默病和圣菲利波综合征斑马鱼模型的多组学分析揭示了疾病机制的共性。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-09 DOI: 10.1016/j.bbadis.2024.167651

Karissa Barthelson , Rachael A. Protzman , Marten F. Snel , Kim Hemsley , Michael Lardelli

Sanfilippo syndrome (mucopolysaccharidosis type III, MPSIII) causes childhood dementia, while Alzheimer's disease is the most common type of adult-onset dementia. There is no cure for either of these diseases, and therapeutic options are extremely limited. Increasing evidence suggests commonalities in the pathogenesis of these diseases. However, a direct molecular-level comparison of these diseases has never been performed. Here, we exploited the power of zebrafish reproduction (large families of siblings from single mating events raised together in consistent environments) to conduct sensitive, internally controlled, comparative transcriptome and proteome analyses of zebrafish models of early-onset familial Alzheimer's disease (EOfAD, psen1^Q96_K97del/+) and MPSIIIB (naglu^{A603fs/A603fs}) within single families. We examined larval zebrafish (7 days post fertilisation), representing early disease stages. We also examined the brains of 6-month-old zebrafish, which are approximately equivalent to young adults in humans. We identified substantially more differentially expressed genes and pathways in MPS III zebrafish than in EOfAD-like zebrafish. This is consistent with MPS III being a rapidly progressing and earlier onset form of dementia. Similar changes in expression were detected between the two disease models in gene sets representing extracellular matrix receptor interactions in larvae, and the ribosome and lysosome pathways in 6-month-old adult brains. Cell type-specific changes were detected in MPSIIIB brains at 6 months of age, likely reflecting significant disturbances of oligodendrocyte, neural stem cell, and inflammatory cell functions and/or numbers. Our ‘omics analyses have illuminated similar disease pathways between EOfAD and MPS III indicating where efforts to find mutually effective therapeutic strategies can be targeted.

三菲利波综合征（粘多糖病III型，MPSIII）导致儿童痴呆，而阿尔茨海默病是最常见的成人发病痴呆类型。这两种疾病都无法治愈，治疗选择也极为有限。越来越多的证据表明这些疾病的发病机制具有共性。然而，从未对这些疾病进行过直接的分子水平比较。在这里，我们利用斑马鱼的繁殖能力（在一致的环境中共同培养的单次交配事件的兄弟姐妹大家庭），对单个家族中早发性家族性阿尔茨海默病（EOfAD, psen1Q96_K97del/+）和MPSIIIB （nagluA603fs/A603fs）的斑马鱼模型进行敏感的，内部控制的，比较转录组和蛋白质组分析。我们检查了斑马鱼幼虫（受精后7 天），代表早期疾病阶段。我们还检查了6个月大的斑马鱼的大脑，其大致相当于人类的年轻成年人。我们在MPS III型斑马鱼中发现了比eofad样斑马鱼更多的差异表达基因和途径。这与MPS III是一种快速进展和早期发病的痴呆形式是一致的。在两种疾病模型中，在代表幼虫细胞外基质受体相互作用的基因集以及6个月大的成人大脑中的核糖体和溶酶体途径中检测到类似的表达变化。在6 月龄时，MPSIIIB大脑中检测到细胞类型特异性变化，可能反映了少突胶质细胞、神经干细胞和炎症细胞功能和/或数量的显著紊乱。我们的组学分析已经阐明了EOfAD和MPS III之间相似的疾病途径，这表明在哪里可以找到相互有效的治疗策略。

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引用次数: 0

Knockdown of LAMA3 enhances the sensitivity of colon cancer to oxaliplatin by regulating the Hippo-YAP pathway 下调LAMA3可通过调节Hippo-YAP通路增强结肠癌对奥沙利铂的敏感性。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-09 DOI: 10.1016/j.bbadis.2025.167665

Jiqiang Li , Yahui Yu , Rong Zeng, Yujiao Zou, Junguo Bu

Background

Oxaliplatin is the first-line chemotherapy for patients with colon cancer (CC). However, its resistance limits its therapeutic efficacy.

Methods

Oxaliplatin resistance-associated differentially expressed genes (DEGs) in the GSE42387 and GSE227315 datasets were identified through bioinformatics methods. Functional experiments were conducted both in vitro and in vivo to evaluate the roles of laminin subunit alpha 3 (LAMA3) in drug resistance and tumorigenesis. The downstream molecular mechanisms were explored using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and western blot.

Results

Six hub genes associated with oxaliplatin resistance were identified, including LAMB3, ITGA3, COL4A6, COL12A1, LAMA3, and LAMC2, all of which were highly expressed in oxaliplatin-resistant CC cell lines. LAMA3 knockdown sensitized CC cells to oxaliplatin treatment, resulting in further inhibition of proliferation, migration, and invasion, as well as an increase in apoptosis in CC cells. Additionally, LAMA3 knockdown promoted the therapeutic efficacy of oxaliplatin in the CC xenograft tumor models. Mechanistically, overexpression of YAP notably counteracted the enhanced sensitivity to oxaliplatin caused by LAMA3 knockdown, indicating that LAMA3 modulates oxaliplatin sensitivity in CC through the Hippo-YAP pathway.

Conclusion

LAMA3 knockdown promotes CC sensitivity to oxaliplatin via modulating the Hippo-YAP pathway, providing new therapeutic targets for the CC treatment.

背景：奥沙利铂是结肠癌（CC）患者的一线化疗药物。然而，其耐药性限制了其治疗效果。方法：通过生物信息学方法鉴定GSE42387和GSE227315数据集中的奥沙利铂耐药相关差异表达基因（DEGs）。通过体外和体内功能实验，探讨层粘连蛋白亚单位α 3 （LAMA3）在耐药和肿瘤发生中的作用。利用京都基因与基因组百科全书（KEGG）途径富集分析和western blot对下游分子机制进行了探索。结果：共鉴定出6个与奥沙利铂耐药相关的枢纽基因，包括LAMB3、ITGA3、COL4A6、COL12A1、LAMA3和LAMC2，这些基因均在奥沙利铂耐药CC细胞系中高表达。LAMA3敲低使CC细胞对奥沙利铂治疗增敏，进一步抑制CC细胞的增殖、迁移和侵袭，增加凋亡。此外，LAMA3敲低可促进奥沙利铂在CC异种移植肿瘤模型中的治疗效果。在机制上，YAP的过表达显著抵消了LAMA3敲低引起的对奥沙利铂敏感性增强，表明LAMA3通过希波-YAP途径调节CC中奥沙利铂敏感性。结论：LAMA3敲低可通过调节Hippo-YAP通路促进CC对奥沙利铂的敏感性，为CC治疗提供新的治疗靶点。

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引用次数: 0

Insights on post-translational modifications in fatty liver and fibrosis progression 脂肪肝和纤维化进展的翻译后修饰见解。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-07 DOI: 10.1016/j.bbadis.2025.167659

Chithra Raju, Kavitha Sankaranarayanan

Metabolic dysfunction-associated steatotic liver disease [MASLD] is a pervasive multifactorial health burden. Post-translational modifications [PTMs] of amino acid residues in protein domains demonstrate pivotal roles for imparting dynamic alterations in the cellular micro milieu. The crux of identifying novel druggable targets relies on comprehensively studying the etiology of metabolic disorders. This review article presents how different chemical moieties of various PTMs like phosphorylation, methylation, ubiquitination, glutathionylation, neddylation, acetylation, SUMOylation, lactylation, crotonylation, hydroxylation, glycosylation, citrullination, S-sulfhydration and succinylation presents the cause-effect contribution towards the MASLD spectra. Additionally, the therapeutic prospects in the management of liver steatosis and hepatic fibrosis via targeting PTMs and regulatory enzymes are also encapsulated. This review seeks to understand the function of protein modifications in progression and promote the markers discovery of diagnostic, prognostic and drug targets towards MASLD management which could also halt the progression of a catalogue of related diseases.

代谢功能障碍相关的脂肪变性肝病[MASLD]是一种普遍的多因素健康负担。蛋白质结构域氨基酸残基的翻译后修饰（PTMs）在细胞微环境的动态变化中起着关键作用。寻找新的药物靶点的关键在于对代谢紊乱的病因学进行全面研究。本文综述了各种PTMs的不同化学成分，如磷酸化、甲基化、泛素化、谷胱甘肽化、类脲化、乙酰化、sumo酰化、乳酸化、巴豆酰化、羟化、糖基化、瓜氨酸化、s -巯基化和琥珀酰化对MASLD光谱的因果贡献。此外，通过靶向PTMs和调节酶治疗肝脂肪变性和肝纤维化的治疗前景也被概括。本综述旨在了解蛋白修饰在进展中的功能，并促进对MASLD治疗的诊断、预后和药物靶点的标记物发现，这也可能阻止一系列相关疾病的进展。

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引用次数: 0

Ubiquitin-specific peptidase 10 promotes renal interstitial fibrosis progression through deubiquitinating and stabilizing P53 protein 泛素特异性肽酶10通过去泛素化和稳定P53蛋白促进肾间质纤维化进展。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-07 DOI: 10.1016/j.bbadis.2025.167660

Suwen Liu , Yunwen Yang , Qian Li , Lichun Yu , Zihan Zong , Ruixian Zang , Wentao Ji , Shuzhen Sun

Renal interstitial fibrosis is the main factor determining chronic kidney disease (CKD) progression, and renal tubular epithelial cells are the key drivers of this pathological process. Herein, we revealed significantly increased ubiquitin-specific peptidase 10 (USP10) expression in the kidney tissues of both patients with CKD and mice induced by unilateral ureteral obstruction, as well as in transforming growth factor-beta 1 (TGFβ1)-induced renal tubular epithelial cells. In vivo, treatment with the USP10 small molecule inhibitor Spautin-1, which inhibits its deubiquitinating activity, weakened renal interstitial fibrosis progression and alleviated the subsequent inflammatory response and oxidative stress in male mice. In vitro, knocking down USP10 or inhibiting its deubiquitinating activity through Spautin-1 significantly reduced fibronectin expression and ameliorated TGFβ1-induced renal tubular epithelial cell dedifferentiation. Additionally, our results revealed that USP10 directly binds to P53 and removes the K48-linked polyubiquitin chains from P53, thereby affecting its ubiquitination, stability, and nuclear translocation, which subsequently leads to the upregulation of P21 and promotes fibrotic gene expression in injured renal tubular epithelial cells, ultimately exacerbating renal interstitial fibrosis. In conclusion, USP10 is inhibited through the P53 signaling pathway to alleviate the progression of renal interstitial fibrosis and serve as a potential target for treating CKD.

肾间质纤维化是决定慢性肾病（CKD）进展的主要因素，肾小管上皮细胞是这一病理过程的关键驱动因素。本研究发现，在CKD患者和单侧输尿管梗阻小鼠的肾脏组织中，以及在转化生长因子- β1 （tgf - β1）诱导的肾小管上皮细胞中，泛素特异性肽酶10 （USP10）的表达显著增加。在体内，用USP10小分子抑制剂Spautin-1治疗，抑制其去泛素化活性，减弱雄性小鼠肾间质纤维化进展，减轻随后的炎症反应和氧化应激。在体外，通过Spautin-1敲低USP10或抑制其去泛素化活性可显著降低纤维连接蛋白的表达，改善tgf - β1诱导的肾小管上皮细胞去分化。此外，我们的研究结果表明，USP10直接与P53结合，去除P53上k48连接的多泛素链，从而影响其泛素化、稳定性和核易位，进而导致P21上调，促进损伤肾小管上皮细胞中纤维化基因表达，最终加重肾间质纤维化。综上所述，USP10通过P53信号通路受到抑制，可缓解肾间质纤维化的进展，是治疗CKD的潜在靶点。

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引用次数: 0

Chlorophyllides repress gain-of-function p53 mutated HNSCC cell proliferation via activation of p73 and repression of p53 aggregation in vitro and in vivo 在体外和体内，叶绿素内酯通过激活p73和抑制p53聚集抑制功能获得型p53突变的HNSCC细胞增殖。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-07 DOI: 10.1016/j.bbadis.2025.167662

Bi-He Cai , Yi-Ting Wang , Chia-Chi Chen , Fang-Yu Yeh , Yu-Rou Lin , Ying-Chen Lin , Tze-You Wu , Kuan-Yo Wu , Ching-Feng Lien , Yu-Chen Shih , Jei-Fu Shaw

Head and neck squamous cell carcinoma (HNSCC) cells have a high p53 mutation rate, but there were rare reported about the p53 gain of function through the prion-like aggregated form in p53 mutated HNSCC cells. Thioflavin T (ThT) is used to stain prion-like proteins in cells. Previously, we found that ThT and p53 staining were co-localized in HNSCC cells (Detroit 562 cells) with homozygous p53 R175H mutation. NAMPT inhibitor can repress ThT staining in Detroit 562 cells. In our previous study, co-treatment with p73 activator NSC59984 and NAMPT inhibitor FK886 synergistically repressed Detroit 562 cell proliferation. In this study, we found that two heterozygous p53-R280T mutation HNSCC cell lines, TW01 and HONE-1, also have the ThT staining signal. Treatment with chlorophyllides and p73 activator or NAMPT inhibitor did not synergistically repress cell proliferation in either Detroit 562 or HONE-1 cells. Chlorophyllides reduced the ThT aggregation signal in both Detroit 562 and HONE-1 cells. Chlorophyllides also induced p73 and caspase 3/7 expression and repressed NAMPT expression in both Detroit 562 and HONE-1 cells. Chlorophyllides reduced tumor size in vivo in Detroit 562 cells injected into a xenograft nude mice model, but this in vivo tumor repression effect was not found in p73 knockdown Detroit 562 cells. Moreover, NAMPT was repressed by chlorophyllides independent of p73 status in vivo. We thus concluded that chlorophyllides have a dual anticancer function when applied to HNSCC cells with p53 gain-of-function mutation, via activation of p73 and repression of p53 aggregation.

头颈部鳞状细胞癌（HNSCC）细胞具有较高的p53突变率，但在p53突变的HNSCC细胞中，p53通过朊病毒样聚集形式获得功能的报道较少。硫黄素T （ThT）用于染色细胞中的朊病毒样蛋白。之前，我们发现ThT和p53染色在纯合子p53 R175H突变的HNSCC细胞（Detroit 562细胞）中共定位。NAMPT抑制剂能抑制底特律562细胞的ThT染色。在我们之前的研究中，p73激活剂NSC59984和NAMPT抑制剂FK886共同处理可协同抑制底特律562细胞的增殖。在本研究中，我们发现两个杂合p53-R280T突变HNSCC细胞系TW01和HONE-1也有ThT染色信号。叶绿素内酯和p73激活剂或NAMPT抑制剂对底特律562细胞或HONE-1细胞的增殖没有协同抑制作用。叶绿素内酯降低了底特律562细胞和HONE-1细胞的ThT聚集信号。在Detroit 562细胞和HONE-1细胞中，叶绿素内酯还能诱导p73和caspase 3/7的表达，抑制NAMPT的表达。叶绿素内酯在注入异种移植裸鼠模型的底特律562细胞中，体内肿瘤大小减小，但在p73敲除的底特律562细胞中，没有发现这种体内肿瘤抑制作用。此外，NAMPT在体内受到独立于p73状态的叶绿素内酯的抑制。因此，我们得出结论，当应用于p53功能获得突变的HNSCC细胞时，叶绿素内酯具有双重抗癌功能，通过激活p73和抑制p53聚集。

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引用次数: 0

Endoplasmic reticulum stress causes long bone shortening in P4hbC402R/+ mice: A mouse model exhibiting significant features of cole-carpenter syndrome driven by P4HB mutations 内质网应激导致P4hbC402R/+小鼠长骨缩短：P4HB突变驱动的cole-carpenter综合征小鼠模型

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-06 DOI: 10.1016/j.bbadis.2025.167663

Shuqin Xu , Yang Xu , Ziyuan Wang , Zhanying Wei , Yazhao Mei , Yangjia Cao , Baojie Li , Hao Zhang , Zhenlin Zhang

Cole-Carpenter syndrome (CCS) is a rare autosomal-dominant genetic disease characterized by craniosynostosis, ocular proptosis, hydrocephalus, distinctive facial features, and bone fragility. Previous cases of CCS are associated with genetic variations in P4HB, which encodes the protein disulfide isomerase (PDI), a key enzyme in protein folding. Patients with CCS caused by P4HB mutations often present with short stature, limb deformities, and abnormal epiphyseal plates. However, the underlying mechanisms are largely unknown. To investigate this, a mouse model expressing the P4hb^C402R mutation (corresponding to P4HB^C400R in humans) was generated. Although the mouse model did not exhibit craniofacial bone defects or brittle bone phenotypes, it did show significantly shortened long bones—a prominent characteristic of P4HB-induced CCS. This was due to impaired proliferation and delayed hypertrophy of growth plate chondrocytes. Mutant PDI was found to accumulate abnormally in the endoplasmic reticulum (ER), and in vitro experiments revealed defects in both the catalytic and chaperone activities of mutant PDI. In addition, we observed enhanced ER stress and activation of the PKR-like ER kinase (PERK) pathway in P4hb^C402R/+ chondrocytes. Inhibition of ER stress mitigated PERK activation, alleviated defective chondrocyte proliferation and differentiation, thereby rescuing bone length. Taken together, enhanced ER stress and the activation of the PERK, potentially initiated by the malfunctioning of PDI^C402R or its abnormal accumulation within the ER, or both, lead to compromised chondrocyte proliferation and differentiation in mice, and ultimately stunts mice growth. This provides new insights into the pathogenesis of P4HB-dominated CCS and offers potential therapeutic targets.

Cole-Carpenter综合征（CCS）是一种罕见的常染色体显性遗传病，其特征为颅缝紧闭、眼球突出、脑积水、独特的面部特征和骨骼脆弱。先前的CCS病例与P4HB的遗传变异有关，P4HB编码蛋白质二硫化物异构酶（PDI），这是蛋白质折叠的关键酶。由P4HB突变引起的CCS患者常表现为身材矮小、肢体畸形、骨骺板异常。然而，潜在的机制在很大程度上是未知的。为了研究这一点，我们构建了表达P4hbC402R突变的小鼠模型（对应于人类的P4HBC400R）。虽然小鼠模型没有表现出颅面骨缺损或脆性骨表型，但它确实表现出明显缩短的长骨，这是p4hb诱导的CCS的一个突出特征。这是由于生长板软骨细胞增殖受损和延迟肥大所致。发现突变型PDI在内质网（ER）中异常积聚，体外实验显示突变型PDI的催化和伴侣活性均存在缺陷。此外，我们在P4hbC402R/+软骨细胞中观察到内质网应激增强和磷酸化样内质网激酶（PERK）途径的激活。内质网应激抑制可减轻PERK激活，减轻缺陷软骨细胞增殖和分化，从而挽救骨长。综上所述，内质网应激的增强和PERK的激活，可能是由PDIC402R的功能失调或其在内质网内的异常积累引起的，或两者兼而有之，导致小鼠软骨细胞增殖和分化受损，并最终阻碍小鼠的生长。这为p4hb主导的CCS的发病机制提供了新的见解，并提供了潜在的治疗靶点。

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引用次数: 0

Renal tubular S100A7a impairs fatty acid oxidation and exacerbates renal fibrosis via both intracellular and extracellular pathway 肾小管S100A7a通过细胞内和细胞外途径损害脂肪酸氧化并加剧肾纤维化。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-06 DOI: 10.1016/j.bbadis.2025.167656

Pengxiao Sun , Qingzhou Chen , Xiaomei Chen , Jiaxin Zhou , Tantan Long , Yuanyuan Ma , Miaomiao Zhou , Zheng Hu , Jianwei Tian , Fengxin Zhu , Zhenhua Yang , Liling Xie , Qiaoyuan Wu , Jing Nie

A couple of S100 family proteins (S100s) have been reported to exert pro-inflammatory functions in the progression of renal fibrosis. Unlike some S100s which are expressed by both epithelial and stromal inflammatory cells, S100A7 is restricted expressed in epithelium. Persistent S100A7 expression occurs in some invasive carcinomas and is associated with poor prognostic factors. Whereas, whether it is implicated in renal tubular epithelial cell injury and kidney disease remains unexplored. In this study, we demonstrate that S100A7 is highly upregulated in tubular cells of both mouse renal fibrotic lesions and kidney biopsies from patients with chronic kidney disease (CKD). The level of renal S100A7 was associated with both the decline of renal function and the progression of renal fibrosis in CKD patients. Overexpressing S100A7a impaired fatty acid oxidation (FAO) and promoted lipid peroxidation in proximal tubular cells (PTCs). Mechanistically, S100A7a interacts with β-catenin, thereby preventing its ubiquitination and degradation by the β-TrCP-SCF complex, and in turn activated β-catenin signaling, downregulated the expression of PGC-1α. Additionally, S100A7a exacerbated lipid peroxidation via RAGE-p-ERK-NOX2 pathway. Specific deletion of S100a7a in tubular cells enhanced FAO and reduced lipid peroxidation, resulting in improved renal function and alleviation of renal fibrosis induced by unilateral ureteral obstruction and unilateral ischemia-reperfusion injury. Collectively, we delineate a previously unrecognized function of S100A7a in the progression of renal fibrosis.

据报道，一对S100家族蛋白（S100）在肾纤维化（RF）的进展中发挥促炎功能。S100A7不像某些在上皮细胞和间质炎症细胞中均表达的S100A7，在上皮细胞中表达受限。持续的S100A7表达发生在一些侵袭性癌中，并与不良预后因素相关。然而，它是否与肾小管上皮细胞损伤和肾脏疾病有关仍未研究。在这项研究中，我们证明S100A7在小鼠肾纤维化病变和慢性肾脏疾病（CKD）患者肾活检的小管细胞中高度上调。肾脏S100A7水平与CKD患者肾功能下降和肾纤维化进展相关。过表达S100A7a会损害近端小管细胞（ptc）的脂肪酸氧化（FAO）并促进脂质过氧化。机制上，S100A7a与β-catenin相互作用，从而阻止其被β-TrCP-SCF复合物泛素化和降解，进而激活β-catenin信号传导，下调PGC-1α的表达。此外，S100A7a通过RAGE-p-ERK-NOX2途径加剧脂质过氧化。小管细胞中S100a7a的特异性缺失增强了脂肪酸氧化（FAO），减少了脂质过氧化，从而改善肾功能，减轻单侧输尿管梗阻和单侧缺血再灌注损伤引起的肾纤维化。总的来说，我们描述了S100A7a在RF进展中以前未被认识的功能。

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引用次数: 0

Intravenous injection of PCSK9 gain-of-function mutation in C57BL/6J background mice on Angiotensin II-induced AAA

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-06 DOI: 10.1016/j.bbadis.2025.167657

Xingli Xu , Xiaohui Li , Chungang Zhai , Yuxin Yao , Xiang Li , Chunjie Ming , Juanjuan Sun , Hao Wang , Yang Mao , Lei Zhang

Objective

This study was performed to compare the incidence of Angiotensin II (Ang II)-induced abdominal aortic aneurysms (AAA) between intravenous and intraperitoneal injection of AAV8.mPCSK9^D377Y in wild-type (WT) mice with C57BL/6J background and the pathological differences of above model in WT and ApoE^−/− mice.

Design

Male WT mice were injected intraperitoneally or intravenously with either a AAV8.null or AAV8.mPCSK9^D377Y. Two weeks after injection, all WT mice were infused with Ang II, and simultaneously age-matched male ApoE^−/− mice were infused with saline or Ang II for 4 weeks.

Results

Compared with intraperitoneal injection of AAV8.mPCSK9^D377Y for AAA model in WT mice, a higher incidence of Ang II-induced AAA, increased blood pressure (BP) and lipid concentration, lower collagen deposition and up-regulated inflammation response were shown by intravenous injection, which was similar to ApoE^−/− mice infused with Ang II.

Conclusion

AAV8.mPCSK9^D377Y infected male WT mice intravenously facilitate a high incident and comparable severity of Ang II-induced AAA which could be greatly expedites AAA studies on a gene of interest.

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引用次数: 0